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Pathology_Robbins. activates innate immune cells expressing pattern recognition receptors. In the case of immunization with a protein antigen, as in a vaccine, a microbial mimic called an adjuvant that stimulates innate immune responses is given with the antigen. During the innate response, the microbe or adjuvant activates APCs to express molecules called costimulators and to secrete cytokines that stimulate the proliferation and differentiation of T lymphocytes. The principal costimulators for T cells are the B7 proteins (CD80 and CD86), which are expressed on APCs and are recognized by the CD28 receptor on naïve T cells. Antigen (“signal 1”) and costimulatory molecules produced during innate immune responses to microbes (“signal 2”) function cooperatively to activate antigen-specific lymphocytes. The requirement for microbe-triggered signal 2 ensures that the adaptive immune response is induced by microbes and not by harmless substances. In immune responses to tumors and transplants, “signal 2” may


Pathology_Robbins

Pathology_Robbins. for microbe-triggered signal 2 ensures that the adaptive immune response is induced by microbes and not by harmless substances. In immune responses to tumors and transplants, “signal 2” may be provided by substances released from necrotic cells (the damage-associated molecular patterns mentioned earlier).


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Pathology_Robbins. The reactions and functions of T lymphocytes and B lymphocytes differ in important ways and are best considered separately. Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of Intracellular Microbes Naïve T lymphocytes are activated by antigen and costimulators in peripheral lymphoid organs, and proliferate and differentiate into effector cells that migrate to any site where the antigen (microbe) is present (see Fig. 5.9 ). One of the earliest responses of CD4+ helper T cells is secretion of the cytokine IL-2 and expression of high-affinity receptors for IL-2. IL-2 is a growth factor that acts on these T lymphocytes and stimulates their proliferation, leading to an increase in the number of antigen-specific lymphocytes.


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Pathology_Robbins. The functions of helper T cells are mediated by the combined actions of CD40-ligand (CD40L) and cytokines. CD40 is a member of the TNF-receptor family, and CD40L is a membrane protein homologous to TNF. When CD4+ helper T cells recognize antigens being displayed by macrophages or B lymphocytes, the T cells express CD40L, which engages CD40 on the macrophages or B cells and activates these cells. Some of the activated CD4+ T cells differentiate into effector cells that secrete different sets of cytokines and perform different functions (


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Pathology_Robbins. Fig. 5.10 ). Cells of the TH1 subset secrete the cytokine IFN-γ, which is a potent macrophage activator. The combination of CD40-and IFN-γ– mediated activation results in “classical” macrophage activation (Chapter 3), leading to the induction of microbicidal substances in macrophages and the destruction of ingested microbes. TH2 cells produce IL-4, which stimulates B cells to differentiate into IgE-secreting plasma cells; IL-5, which activates eosinophils; and IL-13, which activates mucosal epithelial cells to secrete mucus, and induces the “alternative” pathway of macrophage activation, which is associated with tissue repair and fibrosis (Chapter 3). Eosinophils bind to and kill IgE-coated pathogens such as helminthic parasites. TH17 cells, so called because the signature cytokine of these cells is IL-17, recruit neutrophils and monocytes, which destroy some extracellular bacteria and fungi and are involved in certain inflammatory diseases.


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Pathology_Robbins. Activated CD8+ T lymphocytes differentiate into CTLs that kill cells harboring cytoplasmic microbes, thereby eliminating otherwise hidden reservoirs of infection. The principal mechanism of killing by CTLs depends on the perforin–granzyme system. Perforin and granzymes are stored in the granules of CTLs and are rapidly released when CTLs engage their targets (cells bearing the appropriate class I MHC–bound peptides). Perforin binds to the plasma membrane of the target cells and promotes the entry of granzymes, proteases that specifically cleave and thereby activate cellular caspases (Chapter 2), which induce the apoptosis of target cells.


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Pathology_Robbins. The responses of T cells are regulated by a balance between costimulatory and inhibitory receptors. The major costimulatory receptor is CD28, mentioned earlier as the molecule that recognizes B7 ligands on APCs and provides second signals that work together with antigen recognition. Other proteins of the CD28 family include two “coinhibitory” receptors, CTLA-4 and PD-1, which block signals from the TCR and from CD28 and thus terminate T cell responses. Blocking these coinhibitors has proved to be a powerful approach for enhancing anti-tumor immune responses (Chapter 6). Humoral Immunity: Activation of B Lymphocytes and Elimination of Extracellular Microbes Upon activation, B lymphocytes proliferate and then differentiate into plasma cells that secrete different classes of antibodies with distinct functions ( Fig. 5.11 ). There are two major pathways of B-cell activation.


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Pathology_Robbins. Fig. 5.11 ). There are two major pathways of B-cell activation. Fig. 5.10 Subsets of helper T (TH) cells. In response to stimuli (mainly cytokines) present at the time of antigen recognition, naive CD4+ T cells may differentiate into populations of effector cells that produce distinct sets of cytokines that act on different cells (indicated as target cells) and mediate different functions. The roles of these subsets in host defense and immunologic diseases are summarized. These populations may be capable of converting from one to another. Some activated T cells produce multiple cytokines and do not fall into a distinct subset. Functions of antibodies Neutralization of microbe and toxins Naive IgM+, and phago-IgG cytosis High-affinityT cells, IgGother stimuli Complement Lysis of activation microbes


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Pathology_Robbins. Functions of antibodies Neutralization of microbe and toxins Naive IgM+, and phago-IgG cytosis High-affinityT cells, IgGother stimuli Complement Lysis of activation microbes Fig. 5.11 Humoral immunity. Naive B lymphocytes recognize antigens, and under the influence of Th cells and other stimuli (not shown), the B cells are activated to proliferate and to differentiate into antibody-secreting plasma cells. Some of the activated B cells undergo heavy-chain class switching and affinity maturation, and some become long-lived memory cells. Antibodies of different heavy-chain classes (isotypes) perform different effector functions, shown on the right. Note that the antibodies shown are IgG; these and IgM activate complement; and the specialized functions of IgA (mucosal immunity) and IgE (mast cell and eosinophil activation) are not shown.


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Pathology_Robbins. T cell–independent. Many polysaccharide and lipid antigens have multiple identical antigenic determinants (epitopes) that are able to simultaneously engage and cross-link several antibody molecules on each B cell and initiate the process of B-cell activation. T cell–dependent. Typical globular protein antigens are not able to bind to multiple antigen receptors, and the full response of B cells to protein antigens requires help from CD4+ T cells. B cells also act as APCs—they ingest protein antigens, degrade them, and display peptides bound to class II MHC molecules for recognition by helper T cells. The helper T cells express CD40L and secrete cytokines, which work together to activate the B cells.


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Pathology_Robbins. Some of the progeny of the expanded B-cell clones differentiate into antibody-secreting plasma cells. Each plasma cell secretes antibodies with the same specificity as the cell surface antibodies (B-cell antigen receptors) that first recognized the antigen. Polysaccharides and lipids stimulate secretion mainly of IgM antibody. Protein antigens, by virtue of CD40L-and cytokine-mediated helper T-cell actions, induce the production of antibodies of different classes (IgG, IgA, IgE). Production of functionally different antibodies, all with the same specificity, relies on heavy-chain class (isotype) switching, which increases the range of functions that antibodies serve. Some of the isotype-specific functions of antibodies include opsonization and transplacental transfer of IgG, IgA secretion into mucosal lumens, and binding of IgE to mast cells. Helper T cells also stimulate the production of antibodies with higher affinity for the antigen. This process, called affinity maturation,


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Pathology_Robbins. into mucosal lumens, and binding of IgE to mast cells. Helper T cells also stimulate the production of antibodies with higher affinity for the antigen. This process, called affinity maturation, improves the quality of the humoral immune response. Some activated B cells migrate into follicles and form germinal centers, which are the major sites of isotype switching and affinity maturation. The helper T cells that stimulate these processes in B lymphocytes also migrate to and reside in the germinal centers and are called follicular helper T (Tfh) cells.


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Pathology_Robbins. The humoral immune response combats microbes in numerous ways (see Fig. 5.11 Antibodies bind to microbes and prevent them from infecting cells, thereby neutralizing the microbes. IgG antibodies coat (opsonize) microbes and target them for phagocytosis, since phagocytes (neutrophils and macrophages) express receptors for the Fc tails of IgG molecules. IgG and IgM activate the complement system by the classical pathway, and complement products promote phagocytosis and destruction of microbes. IgA is secreted in mucosal tissues and neutralizes microbes in the lumens of the respiratory and gastrointestinal tracts (and other mucosal tissues). IgG is actively transported across the placenta and protects the newborn until the immune system becomes mature. This is a form of passive immunity. IgE coats helminthic parasites and functions with mast cells and eosinophils to kill them.


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Pathology_Robbins. IgE coats helminthic parasites and functions with mast cells and eosinophils to kill them. Circulating IgG antibodies have half-lives of about 3 weeks, which is much longer than the half-lives of most blood proteins, as a consequence of special mechanisms for recycling IgG and reducing its catabolism. Some antibody-secreting plasma cells migrate to the bone marrow and live for years, continuing to produce low levels of antibodies.


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Pathology_Robbins. The majority of effector lymphocytes induced by an infectious pathogen die by apoptosis after the pathogen is eliminated, thus returning the immune system to its basal resting state. The initial activation of lymphocytes generates long-lived memory cells, which may survive for years after the infection. Memory cells are an expanded pool of antigen-specific lymphocytes (more numerous than the naïve cells specific for any antigen that are present before encounter with that antigen), and they respond faster and more effectively when reexposed to the antigen than do naïve cells. This is why the generation of memory cells is an important goal of vaccination. THENORMALIMMUNERESPONSE:OVERVIEWOFCELLS,TISSUES,RECEPTORS,ANDMEDIATORS Theinnateimmunesystemusesseveralfamiliesofreceptors,suchastheToll-likereceptors,torecognizemoleculespresentinvarioustypesofmicrobesandproducedbydamagedcells.


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Pathology_Robbins. CD8+ cytotoxicTlymphocyteskillcellsthatexpressantigensinthecytoplasmthatareseenasforeign(e.g.,virus-infectedandtumorcells)andcanalsoproducecytokines. Antibodiessecretedbyplasmacellsneutralizemicrobesandblocktheirinfectivity,andpromotethephagocytosisanddestructionofpathogens.Antibodiesalsoconferpassiveimmunitytoneonates. The brief outline of basic immunology presented here provides a foundation for considering the diseases of the immune system. We first discuss the immune reactions that cause injury, called hypersensitivity reactions, and then disorders caused by the failure of tolerance to self antigens, called autoimmune disorders, and the rejection of transplants. This is followed by diseases caused by a defective immune system, called immunodeficiency diseases. We close with a consideration of amyloidosis, a disorder that is often associated with immune and inflammatory diseases. HYPERSENSITIVITY:IMMUNOLOGICALLYMEDIATEDTISSUEINJURY


Pathology_Robbins

Pathology_Robbins. Immune responses that normally are protective also are capable of causing tissue injury. Injurious immune reactions are grouped under hypersensitivity, and the resulting diseases are called hypersensitivity diseases. This term originated from the idea that persons who mount immune responses against an antigen are sensitized to that antigen, so pathologic or excessive reactions represent manifestations of a hypersensitive state. Normally, an exquisite system of checks and balances optimizes the eradication of infecting organisms without serious injury to host tissues. However, immune responses may be inadequately controlled or directed against normally harmless antigens or inappropriately targeted to host tissues, and in such situations, the normally beneficial response is the cause of disease. In this section, we describe the causes and general mechanisms of hypersensitivity diseases and then discuss specific situations in which the immune response is responsible for the disease.


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Pathology_Robbins. http://ebooksmedicine.net Pathologic immune responses may be directed against different types of antigens and may result from various underlying abnormalities. Autoimmunity: reactions against self antigens. Normally, the immune system does not react against one’s own antigens. This phenomenon is called self tolerance, implying that the body “tolerates” its own antigens. On occasion, self-tolerance fails, resulting in reactions against one’s own cells and tissues. Collectively, such reactions constitute autoimmunity, and diseases caused by autoimmunity are referred to as autoimmune diseases. We will return to the mechanisms of self-tolerance and autoimmunity later in this chapter.


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Pathology_Robbins. Reactions against microbes. There are many types of reactions against microbial antigens that may cause disease. In some cases, the reaction appears to be excessive or the microbial antigen is unusually persistent. If antibodies are produced against such antigens, the antibodies may bind to the microbial antigens to produce immune complexes, which deposit in tissues and trigger inflammation; this is the underlying mechanism of post-streptococcal glomerulonephritis (Chapter 14). T-cell responses against persistent microbes may give rise to severe inflammation, sometimes with the formation of granulomas (Chapter 3); this is the cause of tissue injury in tuberculosis and other infections. Rarely, antibodies or T cells reactive with a microbe cross-react with a host tissue; such cross-reactivity is believed to be the basis for rheumatic heart disease (Chapter 11). In some instances, the disease-causing immune response may be entirely normal, but in the process of eradicating the


Pathology_Robbins

Pathology_Robbins. is believed to be the basis for rheumatic heart disease (Chapter 11). In some instances, the disease-causing immune response may be entirely normal, but in the process of eradicating the infection, host tissues are injured. In viral hepatitis, the virus that infects liver cells is not cytopathic, but it is recognized as foreign by the immune system. Cytotoxic


Pathology_Robbins

Pathology_Robbins. Table 5.2 Mechanisms of Hypersensitivity Reactions T cells try to eliminate infected cells, and this normal immune response damages liver cells. • Reactions against environmental antigens. Almost 20% of the population is allergic to common environmental substances (e.g., pollens, animal danders, and dust mites), as well as some metal ions and therapeutic drugs. Such individuals are genetically predisposed to make unusual immune responses to noninfectious, typically harmless antigens to which all persons are exposed but against which only some react.


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Pathology_Robbins. In all of these conditions, tissue injury is mediated by the same mechanisms that normally function to eliminate infectious pathogens—namely, antibodies, effector T lymphocytes, and various other effector cells. The fundamental problem in these diseases is that the immune response is triggered and maintained inappropriately. Because the stimuli for these abnormal immune responses are difficult or impossible to eliminate (e.g., self antigens, persistent microbes, or environmental antigens), and the immune system has many intrinsic positive feedback loops (which normally promote protective immunity), once a hypersensitivity reaction starts, it is difficult to control or terminate it. Therefore, these diseases tend to be chronic and debilitating, and are therapeutic challenges. Since inflammation is a major component of the pathology of these disorders, they are sometimes grouped under the term immune-mediated inflammatory diseases.


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Pathology_Robbins. Hypersensitivity reactions can be subdivided into four types based on the principal immune mechanism responsible for injury; three are variations on antibody-mediated injury, and the fourth is T-cell mediated ( Table 5.2 ). The rationale for this classification is that the mechanism of http://ebooksmedicine.net immune injury is often a good predictor of the clinical manifestations and may help to guide the therapy. However, this classification of immune-mediated diseases is not perfect, because several immune reactions may coexist in any one disease. The main types of hypersensitivity reactions are as follows: In immediate (type I) hypersensitivity, often called allergy, the injury is caused by TH2 cells, IgE antibodies, and mast cells and other leukocytes. Mast cells release mediators that act on blood vessels and smooth muscle as well as cytokines that recruit and activate inflammatory cells.


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Pathology_Robbins. Antibody-mediated disorders (type II hypersensitivity) are caused by secreted IgG and IgM antibodies that bind to fixed tissue or cell surface antigens. Antibodies injure cells by promoting their phagocytosis or lysis and injure tissues by inducing inflammation. Antibodies also may interfere with cellular functions and cause disease without cell or tissue injury. In immune complex–mediated disorders (type III hypersensitivity), IgG and IgM antibodies bind antigens, usually in the circulation, and form antigen-antibody complexes that deposit in vascular beds and induce inflammation. The leukocytes that are recruited (neutrophils and monocytes) produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals.


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Pathology_Robbins. T cell–mediated (type IV) hypersensitivity disorders are caused mainly by immune responses in which T lymphocytes of the TH1 and TH17 subsets produce cytokines that induce inflammation and activate neutrophils and macrophages, which are responsible for tissue injury. CD8+ CTLs also may contribute to injury by directly killing host cells.


Pathology_Robbins

Pathology_Robbins. Immediate hypersensitivity is a tissue reaction that occurs rapidly (typically within minutes) after the interaction of antigen with IgE antibody bound to the surface of mast cells. The reaction is initiated by entry of an antigen, which is called an allergen because it triggers allergy. Many allergens are environmental substances that certain individuals are predisposed to developing allergic reactions against. TH2 cells and IgE are responsible for the clinical and pathologic manifestations of the reaction. Immediate hypersensitivity may occur as a local reaction that is merely annoying (e.g., seasonal rhinitis, hay fever), severely debilitating (asthma), or even fatal (anaphylaxis). Sequence of Events in Immediate Hypersensitivity Reactions Most hypersensitivity reactions follow a stereotypic sequence of cellular responses (


Pathology_Robbins

Pathology_Robbins. Sequence of Events in Immediate Hypersensitivity Reactions Most hypersensitivity reactions follow a stereotypic sequence of cellular responses ( Fig. 5.12 • Activation of TH2 cells and production of IgE antibody. Allergens may be introduced by inhalation, ingestion, or injection. Variables that probably contribute to the strong TH2 responses to allergens include the route of entry, dose, and chronicity of antigen exposure, and the genetic makeup of the host. It is not clear if allergenic substances also have unique structural or chemical properties that endow them with the ability to elicit TH2 Allergen (e.g., pollen) Mucosal lining Production of IgE IgE Binding of IgE to Repeat exposure to allergen Activation of mast cell; release of mediators Vasoactive amines, Cytokineslipid mediators Immediate hypersensitivity Late phase reaction reaction (minutes after (2–24 hours after repeat repeat exposure to allergen) exposure to allergen)


Pathology_Robbins

Pathology_Robbins. Vasoactive amines, Cytokineslipid mediators Immediate hypersensitivity Late phase reaction reaction (minutes after (2–24 hours after repeat repeat exposure to allergen) exposure to allergen) Fig. 5.12 Sequence of events in immediate (type I) hypersensitivity. Immediate hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates TH2 responses and IgE production in genetically susceptible individuals. IgE binds to Fc receptors (FcεRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic manifestations of immediate hypersensitivity. See text for abbreviations.


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Pathology_Robbins. responses. Immediate hypersensitivity is the prototypical TH2-mediated reaction. The TH2 cells that are induced secrete several cytokines, including IL-4, IL-5, and IL-13, which are responsible for essentially all the reactions of immediate hypersensitivity. IL-4 stimulates B cells specific for the allergen to undergo heavy-chain class switching to IgE and to secrete this immunoglobulin isotype. IL-5 activates eosinophils that are recruited to the reaction, and IL-13 acts on epithelial cells and stimulates mucus secretion. TH2 cells often are recruited to the site of allergic reactions in response to chemokines that are produced locally; one of these chemokines, eotaxin, also recruits eosinophils to the same site.


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Pathology_Robbins. Sensitization of mast cells by IgE antibody. Mast cells are derived from precursors in the bone marrow and widely distributed in tissues, often residing near blood vessels and nerves and in subepithelial locations. Mast cells express a high-affinity receptor for the Fc portion of the ε heavy chain of IgE, called FcεRI. Even though the serum concentration of IgE is very low (in the range of 1 to 100 µg/mL), the affinity of the mast cell FcεRI receptor is so high that the receptors are always occupied by IgE. These antibody-bearing mast cells are sensitized to react if the specific antigen (the allergen) binds to the antibody molecules. Basophils are circulating cells that resemble mast cells. They also express FcεRI, but their role in most immediate hypersensitivity reactions is not established (since these reactions occur in tissues and most basophils are in the circulation). The third cell type that expresses FcεRI is eosinophils, which often are present in these reactions.


Pathology_Robbins

Pathology_Robbins. Activation of mast cells and release of mediators. When a person who was sensitized by exposure to an allergen is reexposed to the allergen, the allergen binds to antigen-specific IgE molecules on mast cells, usually at or near the site of allergen entry. Cross-linking of these IgE molecules triggers a series of biochemical signals that culminate in the secretion of various mediators from the mast cells. Three groups of mediators are important in different immediate hypersensitivity reactions:


Pathology_Robbins

Pathology_Robbins. Three groups of mediators are important in different immediate hypersensitivity reactions: Vasoactive amines released from granule stores. The granules of mast cells contain histamine, which is released within seconds or minutes of activation. Histamine causes vasodilation, increased vascular permeability, smooth muscle contraction, and increased secretion of mucus. Other rapidly released mediators include chemotactic factors for neutrophils and eosinophils as well as neutral proteases (e.g., tryptase), which may damage tissues and also generate kinins and cleave complement components to produce additional chemotactic and inflammatory factors (e.g., C5a) (Chapter 3). The granules also contain acidic proteoglycans (heparin, chondroitin sulfate), the main function of which seems to be as a storage matrix for the amines.


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Pathology_Robbins. Newly synthesized lipid mediators. Mast cells synthesize and secrete prostaglandins and leukotrienes by the same pathways as do other leukocytes (Chapter 3). These lipid mediators have several actions that are important in immediate hypersensitivity reactions. Prostaglandin D2 (PGD2) is the most abundant mediator generated by the cyclooxygenase pathway in mast cells. It causes intense bronchospasm as well as increased mucus secretion. The leukotrienes LTC4 and LTD4 are the most potent vasoactive and spasmogenic agents known; on a molar basis, they are several thousand times more active than histamine in increasing vascular permeability and in causing bronchial smooth muscle contraction. LTB4 is highly chemotactic for neutrophils, eosinophils, and monocytes.


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Pathology_Robbins. • Cytokines. Activation of mast cells results in the synthesis and secretion of several cytokines that are important for the late-phase reaction. These include TNF and chemokines, which recruit and activate leukocytes (Chapter 3), and IL-4 and IL-5, which amplify the TH2-initiated immune reaction. The reactions of immediate hypersensitivity clearly did not evolve to cause human discomfort and disease. The TH2 response plays an important protective role in combating parasitic infections. IgE antibodies target helminths for destruction by eosinophils and mast cells. Mast cells also are involved in defense against bacterial infections. And snake aficionados will be relieved to hear that their mast cells may protect them from some snake venoms by releasing granule proteases that degrade the toxins. Why these beneficial responses are inappropriately activated by harmless environmental antigens, giving rise to allergies, remains a puzzle. Development of Allergies


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Pathology_Robbins. Development of Allergies Susceptibility to immediate hypersensitivity reactions is genetically determined. An increased propensity to develop immediate hypersensitivity reactions is called atopy. Atopic individuals tend to have higher serum IgE levels and more IL-4–producing TH2 cells than does the general population. A positive family history of allergy is found in 50% of atopic individuals. The basis of familial predisposition is not clear, but genes that are implicated in susceptibility to asthma and other atopic disorders include those encoding HLA molecules (which may confer immune responsiveness to particular allergens), cytokines (which may control TH2 responses), a component of the FcεRI, and ADAM33, a metalloproteinase that may be involved in tissue remodeling in the airways.


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Pathology_Robbins. Environmental factors are also important in the development of allergic diseases. Exposure to environmental pollutants, all too common in industrialized societies, is an important predisposing factor for allergy. It is notable that dogs and cats living in the same environment as humans develop allergies, whereas chimps living in the wild do not despite their much closer genetic similarity to humans. This simple observation suggests that environmental factors may be more important in the development of allergic disease than genetics. Viral infections of the airways are important triggers for bronchial asthma, an allergic disease affecting the lungs (Chapter 13). Bacterial skin infections are strongly associated with atopic dermatitis.


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Pathology_Robbins. It is estimated that 20% to 30% of immediate hypersensitivity reactions are triggered by nonantigenic stimuli such as temperature extremes and exercise, and do not involve TH2 cells or IgE. It is believed that in these cases mast cells are abnormally sensitive to activation by various nonimmune stimuli. The incidence of many allergic diseases is increasing in developed countries and seems to be related to a decrease in infections during early life. These observations have http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. The incidence of many allergic diseases is increasing in developed countries and seems to be related to a decrease in infections during early life. These observations have http://ebooksmedicine.net Fig. 5.13 Phasesofimmediatehypersensitivityreactions.(A)Kineticsoftheimmediateandlate-phasereactions.Theimmediatevascularandsmoothmusclereactiontoallergendevelopswithinminutesafterchallenge(allergenexposureinapreviouslysensitizedindividual),andthelate-phasereactiondevelops2to24hourslater.Theimmediatereaction(B)ischaracterizedbyvasodilation,congestion,andedema,andthelate-phasereaction(C)ischaracterizedbyaninflammatoryinfiltraterichineosinophils,neutrophils,andTcells.(Courtesy of Dr. Daniel Friend, Department of Pathology, Brigham and Women’s Hospital, Boston,


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Pathology_Robbins. Massachusetts.) led to an idea, sometimes called the hygiene hypothesis, that early childhood and even prenatal exposure to microbial antigens educates the immune system in such a way that subsequent pathologic responses against common environmental allergens are prevented. Thus, too much hygiene in childhood may increase allergies later in life. The idea that early childhood exposure to antigens may reduce later allergies against those antigens has received support from clinical trials demonstrating that exposing infants to peanuts reduces the incidence of peanut allergy later in life. Often, the IgE-triggered reaction has two well-defined phases (


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Pathology_Robbins. Fig. 5.13 ): (1) the immediate response, which is stimulated by mast cell granule contents and lipid mediators and is characterized by vasodilation, vascular leakage, and smooth muscle spasm, usually evident within 5 to 30 minutes after exposure to an allergen and subsiding by 60 minutes; and (2) a second, late-phase reaction stimulated mainly by cytokines, which usually sets in 2 to 8 hours later, may last for several days, and is characterized by inflammation as well as tissue destruction, such as mucosal epithelial cell damage. The dominant inflammatory cells in the late-phase reaction are neutrophils, eosinophils, and lymphocytes, especially TH2 cells. Neutrophils are recruited by various chemokines; their roles in inflammation were described in Chapter 3. Eosinophils are recruited by eotaxin and other chemokines released from epithelium and are important effectors of tissue injury in the late-phase response. Eosinophils produce major basic protein and eosinophil cationic protein,


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Pathology_Robbins. eotaxin and other chemokines released from epithelium and are important effectors of tissue injury in the late-phase response. Eosinophils produce major basic protein and eosinophil cationic protein, which are toxic to epithelial cells, and LTC4 and platelet-activating factor, which promote inflammation. The TH2 cells produce cytokines that have multiple actions, as described earlier. These recruited leukocytes can amplify and sustain the inflammatory response, even in the absence of continuous allergen exposure. In addition, inflammatory leukocytes are responsible for much of the epithelial cell injury in immediate hypersensitivity. Because inflammation is a major component of many allergic diseases, notably asthma and atopic dermatitis, therapy includes anti-inflammatory drugs such as corticosteroids.


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Pathology_Robbins. An immediate hypersensitivity reaction may occur as a systemic disorder or as a local reaction ( Table 5.3 ). The route of antigen exposure often determines the nature of the reaction. Systemic exposure to protein antigens (e.g., in bee venom) or drugs (e.g., penicillin) may result in systemic anaphylaxis. Within minutes of the exposure in a sensitized host, itching, urticaria (hives), and skin erythema appear, followed in short order by profound respiratory difficulty caused by pulmonary bronchoconstriction and accentuated by hypersecretion of mucus. Laryngeal edema may exacerbate matters by causing upper airway obstruction. In addition, the musculature of the entire gastrointestinal tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea. Without immediate intervention, there may be systemic vasodilation with a fall Table 5.3 Examples of Disorders Caused by Immediate Hypersensitivity


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Pathology_Robbins. Table 5.3 Examples of Disorders Caused by Immediate Hypersensitivity Allergicrhinitis,Increasedmucussecretion;inflammationofsinusitis(hayfever)upperairwaysandsinuses FoodallergiesIncreasedperistalsisduetocontractionofintestinalmuscles,resultinginvomitinganddiarrhea http://ebooksmedicine.net in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes. Local reactions generally occur when the antigen is confined to a particular site, such as the skin (following contact), the gastrointestinal tract (following ingestion), or the lung (following inhalation). Atopic dermatitis, food allergies, hay fever, and certain forms of asthma are examples of localized allergic reactions. However, ingestion or inhalation of allergens also can trigger systemic reactions. Immediate(typeI)sensitivityisalsocalledanallergic reaction, orallergy.


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Pathology_Robbins. Theclinicalmanifestationsmaybelocalorsystemic,andrangefrommildlyannoyingrhinitistofatalanaphylaxis. Antibody-mediated (type II) hypersensitivity disorders are caused by antibodies directed against target antigens on the surface of cells or other tissue components. The antigens may be normal molecules intrinsic to cell membranes or in the extracellular matrix, or they may be adsorbed exogenous antigens (e.g., a drug metabolite). These reactions are the cause of several important diseases ( Table 5.4 Mechanisms of Antibody-Mediated Diseases Antibodies cause disease by targeting cells for phagocytosis, activating the complement system, or interfering with normal cellular functions ( Fig. 5.14 ). The antibodies that are responsible typically are high-affinity antibodies capable of activating complement and binding to the Fc receptors of phagocytes.


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Pathology_Robbins. Fig. 5.14 ). The antibodies that are responsible typically are high-affinity antibodies capable of activating complement and binding to the Fc receptors of phagocytes. • Opsonization and phagocytosis. When circulating cells, such as red blood cells or platelets, are coated (opsonized) with autoantibodies, with or without complement proteins, the cells become targets for phagocytosis by neutrophils and macrophages ( Fig. 5.14A ). These phagocytes express receptors for the Fc tails of IgG antibodies and for breakdown products of the C3 complement protein, and use these receptors to bind and ingest opsonized particles. Opsonized cells are usually eliminated in the spleen, and this is why splenectomy is of clinical benefit in some antibody-mediated diseases. Antibody-mediated cell destruction and phagocytosis occur in the following clinical situations: (1) transfusion reactions, in which cells from an incompatible


Pathology_Robbins

Pathology_Robbins. Antibody-mediated cell destruction and phagocytosis occur in the following clinical situations: (1) transfusion reactions, in which cells from an incompatible Table 5.4 Examples of Antibody-Mediated Diseases (Type II Hypersensitivity) Clinicopathologic Disease Target Antigen Mechanisms of Disease Manifestations AutoimmunehemolyticanemiaRedbloodcellmembraneproteinsOpsonizationandphagocytosisofredHemolysis,anemiabloodcells AutoimmunethrombocytopenicPlateletmembraneproteinsOpsonizationandphagocytosisofBleedingpurpura(Gpllb:Illaintegrin)platelets GoodpasturesyndromeProteininbasementmembranesofComplement-andFcreceptor–Nephritis,lunghemorrhagekidneyglomeruliandlungalveolimediatedinflammation AcuterheumaticfeverStreptococcalcellwallantigen;Inflammation,macrophageactivationMyocarditis,arthritisantibodycross-reactswithmyocardialantigen


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Pathology_Robbins. AcuterheumaticfeverStreptococcalcellwallantigen;Inflammation,macrophageactivationMyocarditis,arthritisantibodycross-reactswithmyocardialantigen MyastheniagravisAcetylcholinereceptorAntibodyinhibitsacetylcholinebinding,Muscleweakness,paralysisdown-modulatesreceptors http://ebooksmedicine.net enzymes, (C5a, C3a) TSH receptor Antibody to Thyroid Antibody inhibits binding of neurotransmitter to receptor Fig. 5.14 Mechanisms of antibody-mediated injury. (A) Opsonization of cells by antibodies and complement components and ingestion by phagocytes. (B) Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products. (C) Anti-receptor antibodies disturb the normal function of receptors. In these examples, antibodies to the acetylcholine (ACh) receptor impair neuromuscular transmission in myasthenia gravis, and antibodies against the thyroid-stimulating hormone (TSH) receptor activate thyroid cells in Graves disease.


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Pathology_Robbins. donor react with preformed antibody in the host (Chapter 12); (2) hemolytic disease of the newborn (erythroblastosis fetalis), in which IgG anti–red blood cell antibodies from the mother cross the placenta and cause destruction of fetal red blood cells (Chapter 7); (3) autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia, in which individuals produce antibodies to their own blood cells (Chapter 12); and (4) certain drug reactions, in which a drug attaches to plasma membrane proteins of red blood cells and antibodies are produced against the drug-protein complex. • Inflammation. Antibodies bound to cellular or tissue antigens activate the complement system by the classical pathway (


Pathology_Robbins

Pathology_Robbins. • Inflammation. Antibodies bound to cellular or tissue antigens activate the complement system by the classical pathway ( Fig. 5.14B ). Products of complement activation serve several functions (see Fig. 3.11, Chapter 3), one of which is to recruit neutrophils and monocytes, triggering inflammation in tissues. Leukocytes also may be activated by engagement of Fc receptors, which recognize the bound antibodies. Antibody-mediated inflammation is responsible for tissue injury in some forms of glomerulonephritis, vascular rejection in organ grafts, and other disorders. • Antibody-mediated cellular dysfunction. In some cases, antibodies directed against a host protein impair or dysregulate important functions without directly causing cell injury or inflammation (


Pathology_Robbins

Pathology_Robbins. • Antibody-mediated cellular dysfunction. In some cases, antibodies directed against a host protein impair or dysregulate important functions without directly causing cell injury or inflammation ( Fig. 5.14C ). In myasthenia gravis, antibodies against acetylcholine receptors in the motor end plates of skeletal muscles inhibit neuromuscular transmission, with resultant muscle weakness. Antibodies also can stimulate cellular responses excessively. In Graves disease, antibodies against the thyroid-stimulating hormone receptor stimulate thyroid epithelial cells to secrete thyroid hormones, resulting in hyperthyroidism. Antibodies against hormones and other essential proteins can neutralize and block the actions of these molecules, causing functional derangements. Antigen–antibody (immune) complexes that are formed in the circulation may deposit in blood vessels, leading to complement activation and acute inflammation. Less Table 5.5 Examples of Immune Complex–Mediated Diseases


Pathology_Robbins

Pathology_Robbins. Table 5.5 Examples of Immune Complex–Mediated Diseases SystemiclupuserythematosusNuclearantigens(circulatingor“planted”inkidney)Nephritis,skinlesions,arthritis,others ReactivearthritisBacterialantigens(e.g.,Yersinia)Acutearthritis SerumsicknessVariousproteins(e.g.,foreignserumprotein)(horseArthritis,vasculitis,nephritisanti-thymocyteglobulin) frequently, the complexes may be formed at sites where antigen has been “planted” previously (called in situ immune complexes). The antigens that form immune complexes may be exogenous, such as a foreign protein that is injected or produced by an infectious microbe, or endogenous, if the individual produces antibody against self antigens (autoimmunity). Examples of immune complex disorders and the antigens involved are listed in


Pathology_Robbins

Pathology_Robbins. Table 5.5 . Immune complex–mediated diseases tend be systemic, but often preferentially involve the kidney (glomerulonephritis), joints (arthritis), and small blood vessels (vasculitis), all of which are common sites of immune complex deposition. Acute serum sickness is the prototype of a systemic immune complex disease; it was once a frequent sequela to the administration of large amounts of foreign serum (e.g., serum from immunized horses used for protection against diphtheria). In modern times, the disease is infrequent and usually seen in individuals who receive antibodies from other individuals or species, e.g. horse or rabbit antithymocyte globulin administered to deplete T cells in recipients of organ grafts. Nevertheless, it is an informative model that has taught us a great deal about immune complex disorders. The pathogenesis of systemic immune complex disease can be divided into three phases ( Fig. 5.15


Pathology_Robbins

Pathology_Robbins. The pathogenesis of systemic immune complex disease can be divided into three phases ( Fig. 5.15 Formation of Immune Complexes. The introduction of a protein antigen triggers an immune response that results in the formation of antibodies, typically about 1 week after the injection of the protein. These antibodies are secreted into the blood, where they react with the antigen still present in the circulation and form antigen-antibody complexes. Deposition of Immune Complexes. In the next phase, the circulating antigen-antibody complexes are deposited in various tissues. The factors that determine whether immune complex formation will lead to tissue deposition and disease are not fully understood, but the major influences seem to be the characteristics of the complexes and local vascular alterations. In general, complexes of medium size that are formed when antigen is in slight excess are the most pathogenic. Organs where blood is filtered at high


Pathology_Robbins

Pathology_Robbins. Fig. 5.15 Immunecomplexdisease.Thesequentialphasesintheinductionofsystemicimmunecomplex–mediateddiseases(typeIIIhypersensitivity). http://ebooksmedicine.net pressure to form other fluids, like urine and synovial fluid, are sites where immune complexes become concentrated and deposit; hence, immune complex disease often affects glomeruli and joints.


Pathology_Robbins

Pathology_Robbins. Inflammation and Tissue Injury. Once deposited in tissues, immune complexes initiate an acute inflammatory reaction via complement activation and engagement of leukocyte Fc receptors. Typically, the antibodies are IgG or IgM. Deposition of complement proteins can be detected at the site of injury. Consumption of complement during the active phase of the disease decreases serum levels of C3, which can be used as a marker for disease activity. During this phase (approximately 10 days after antigen administration), clinical features such as fever, urticaria, joint pain (arthralgia), lymph node enlargement, and proteinuria appear. Wherever complexes deposit, the tissue damage is similar. The resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomeruli, arthritis if it occurs in the joints, and so on.


Pathology_Robbins

Pathology_Robbins. Fig.5.24 In acute serum sickness induced by administration of a single large dose of antigen, the lesions tend to resolve as a result of phagocytosis and degradation of the immune complexes. A form of chronic serum sickness results from repeated or prolonged exposure to an antigen. This occurs in several diseases, such as systemic lupus erythematosus (SLE), which is associated with persistent antibody responses to autoantigens. In many diseases, the morphologic changes and other findings suggest immune complex deposition, but the inciting antigens are unknown. Included in this category are membranous glomerulonephritis and several vasculitides.


Pathology_Robbins

Pathology_Robbins. A model of local immune complex diseases is the Arthus reaction, in which an area of tissue necrosis appears as a result of acute immune complex vasculitis. The reaction is produced experimentally by injecting an antigen into the skin of a previously immunized animal with preformed antibody. Immune complexes form as the antigen diffuses into the vascular wall at the site of injection, triggering the same inflammatory reaction and histologic appearance as in systemic immune complex disease. Arthus lesions evolve over a few hours and reach a peak 4 to 10 hours after injection, when the injection site develops edema and hemorrhage, occasionally followed by ulceration. Antibodiescancoat(opsonize)cells,withorwithoutcomplementproteins,andtargetthesecellsforphagocytosisbyphagocytes(macrophages),whichexpressreceptorsfortheFctailsoflgGandforcomplementproteins.Theresultisdepletionoftheopsonizedcells.


Pathology_Robbins

Pathology_Robbins. Antibodiesandimmunecomplexesmaydepositintissuesorbloodvessels,andelicitanacuteinflammatoryreactionbyactivatingcomplement,withreleaseofbreakdownproducts,orbyengagingFcreceptorsofleukocytes.Theinflammatoryreactioncausestissueinjury. Antibodiescanbindtocellsurfacereceptorsorotheressentialmoleculesandcausefunctionalderangements(eitherinhibitionorunregulatedactivation)withoutcellinjury. Several autoimmune disorders, as well as pathologic reactions to environmental chemicals and persistent microbes, are now known to be caused by T cells ( 5.6 ). Two types of T cell reactions are capable of causing tissue injury and disease: (1) cytokine-mediated inflammation, in which the cytokines are produced mainly by CD4+ T cells, and (2) direct cell cytotoxicity, mediated by CD8+ T cells (


Pathology_Robbins

Pathology_Robbins. Fig. 5.16 ). This group of diseases is of great clinical interest because T cells are increasingly recognized as the basis of chronic inflammatory diseases, and many of the new rationally designed therapies for these diseases have been developed to target the abnormal T cell reactions. In CD4+ T cell–mediated hypersensitivity reactions, cytokines produced by the T cells induce inflammation that may be chronic and destructive. The prototype of T cell–mediated inflammation is delayed-type hypersensitivity (DTH), a tissue reaction to antigens given to immune individuals. In this reaction, an antigen administered into the skin of a previously immunized individual results in a detectable cutaneous reaction within 24 to 48 hours (hence the term delayed, in contrast to immediate hypersensitivity).


Pathology_Robbins

Pathology_Robbins. As described earlier, naïve T cells are activated in secondary lymphoid organs by recognition of peptide antigens displayed by dendritic cells. The T cells differentiate into effector cells under the influence of various cytokines (see Figs. 5.9 5.10 ). Classical T cell–mediated hypersensitivity is a reaction of TH1 effector cells, but TH17 cells also may contribute to the reaction, especially when neutrophils are prominent in the inflammatory infiltrate. TH1 cells secrete cytokines, mainly IFN-γ, which are responsible for many of the manifestations of delayed-type hypersensitivity. IFNγ-activated (classically activated) macrophages produce substances that destroy microbes and damage tissues, and mediators that promote inflammation (Chapter 3). http://ebooksmedicine.net Hypersensitivity: Immunologically Mediated Tissue Injury143 Table 5.6 T Cell–Mediated Diseases Specificity of Pathogenic T Cells Collagen?Citrullinated self proteins?


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Hypersensitivity: Immunologically Mediated Tissue Injury143 Table 5.6 T Cell–Mediated Diseases Specificity of Pathogenic T Cells Collagen?Citrullinated self proteins? Protein antigens in myelin (e.g., myelin basic protein) Antigens of pancreatic islet β cells (insulin, glutamic acid decarboxylase, others) Enteric bacteria; self antigens? Various environmental chemicals (e.g., urushiol from poison ivy or poison oak, therapeutic drugs) Principal Mechanisms of Tissue Injury Inflammation mediated by TH17 (and TH1?) cytokines; role of antibodies and immune complexes? Inflammation mediated by TH1 and TH17 cytokines, myelin destruction by activated macrophages T cell–mediated inflammation, destruction of islet cells by CTLs Inflammation mediated by TH1 (and TH17?) cytokines Chronic arthritis with inflammation, destruction of articular cartilage Insulitis (chronic inflammation in islets), destruction of β cells; diabetes


Pathology_Robbins

Pathology_Robbins. Chronic arthritis with inflammation, destruction of articular cartilage Insulitis (chronic inflammation in islets), destruction of β cells; diabetes Chronic intestinal inflammation, obstruction Epidermal necrosis, dermal inflammation, causing skin rash and blisters Examples of human T cell–mediated diseases are listed. In many cases, the specificity of the T cells and the mechanisms of tissue injury are inferred based on the similarity with experimental animal models of the diseases. Activated TH17 cells secrete cytokines that recruit neutrophils and monocytes.


Pathology_Robbins

Pathology_Robbins. Activated TH17 cells secrete cytokines that recruit neutrophils and monocytes. The classic example of DTH is the tuberculin reaction (known in clinical medicine as the PPD skin test), which is produced by the intracutaneous injection of purified protein derivative (PPD, also called tuberculin), a protein-containing antigen of the Mycobacterium tuberculosis bacillus. In a previously exposed individual, reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter slowly subside. Morphologically, delayed-type hypersensitivity is characterized by the tion and inflammation. Drug reactions often manifest as skin rashes. CD4+ T cell–mediated inflammation is the basis of tissue injury in many organ-specific and systemic autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, as well as diseases probably caused by uncontrolled reactions to bacterial commensals, such as inflammatory bowel disease (see Table 5.6


Pathology_Robbins

Pathology_Robbins. Table 5.6 Fig. 5.17 Delayed hypersensitivity reaction in the skin. (A) Perivascular accumulation (“cuffing”) of mononuclear inflammatory cells (lymphocytes and macrophages), with associated dermal edema and fibrin deposition. (B) Immunoperoxidase staining reveals a predominantly perivascular cellular infiltrate that marks positively with anti-CD4 antibodies. (Courtesy of Dr. Louis Picker, Department of Pathology, Oregon Health Sciences University, Portland, Oregon.) accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules, producing perivascular “cuffing” ( Fig. 5.17


Pathology_Robbins

Pathology_Robbins. Fig. 5.17 Prolonged DTH reactions against persistent microbes or other stimuli may result in a special pattern of reaction called granulomatous inflammation. The initial perivascular CD4+ T cell infiltrate is progressively replaced by macrophages over a period of 2 to 3 weeks. These accumulated macrophages typically exhibit morphologic evidence of activation; that is, they become large, flat, and eosinophilic, and are called epithelioid cells. The epithelioid cells occasionally fuse under the influence of cytokines (e.g., IFN-γ) to form multinucleate giant cells. An aggregate of epithelioid cells, typically surrounded by a collar of lymphocytes, is called a granuloma ( Fig. 5.18A ). The process is essentially a chronic form of TH1-mediated inflammation and macrophage activation (see


Pathology_Robbins

Pathology_Robbins. Fig. 5.18A ). The process is essentially a chronic form of TH1-mediated inflammation and macrophage activation (see Fig. 5.18B ). Older granulomas develop an enclosing rim of fibroblasts and connective tissue. In certain situations, such as infection by helminths known as schistosomes, TH2 cells also are involved, and as a result eosinophils are prominent in the lesions. Recognition of granulomas is of diagnostic importance because they are seen only in a limited number of conditions (Chapter 3).


Pathology_Robbins

Pathology_Robbins. Contact dermatitis is a common example of tissue injury resulting from DTH reactions. It may be evoked by contact with urushiol, the antigenic component of poison ivy or poison oak, and presents as a vesicular dermatitis. It is thought that in these reactions, the environmental chemical binds to and structurally modifies self proteins, and peptides derived from these modified proteins are recognized by T cells and elicit the reaction. The same mechanism is responsible for many drug reactions, among the most common hypersensitivity reactions of humans. The responsible drug (often a reactive chemical) alters self proteins, including MHC molecules, and these neoantigens are recognized as foreign by T cells, leading to cytokine produc-


Pathology_Robbins

Pathology_Robbins. Fig. 5.18 Granulomatous inflammation. (A) A section of a lymph node shows several granulomas, each made up of an aggregate of epithelioid cells and surrounded by lymphocytes. The granuloma in the center shows several multinucleate giant cells. (B) The events that give rise to the formation of granulomas in type IV hypersensitivity reactions, illustrating the role of TH1 cytokines. In some granulomatous disorders (e.g., schistosomiasis), TH2 cells also contribute to the lesions. The role of TH17 cells in granuloma formation is not proven. (A, Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.)


Pathology_Robbins

Pathology_Robbins. In this type of T cell–mediated reaction, CD8+ CTLs kill antigen-expressing target cells. Tissue destruction by CTLs may be an important component of some T cell– mediated diseases, such as type 1 diabetes. CTLs directed against cell surface histocompatibility antigens play an important role in graft rejection, which is discussed later. They also play a role in reactions against viruses. In a virus-infected cell, viral peptides are displayed by class I MHC molecules and the complex is recognized by the TCR of CD8+ T lymphocytes. The killing of infected cells leads to elimination of the infection, but in some cases, it is responsible for cell damage that accompanies the infection (e.g., in viral hepatitis). CD8+ T cells also produce cytokines, notably IFN-γ, and are involved in inflammatory reactions resembling DTH, especially following virus infections and exposure to some contact sensitizing agents.


Pathology_Robbins

Pathology_Robbins. Cytokine-mediated inflammation: CD4+ TcellsareactivatedbyexposuretoaproteinantigenanddifferentiateintoTH1andTH17effectorcells.Subsequentexposuretotheantigenresultsinthesecretionofcytokines.IFN-γ activatesmacrophagestoproducesubstancesthatcausetissuedamageandpromotefibrosis,andIL-17andothercytokinesrecruitleukocytes,thuspromotinginflammation. TheclassicalTcell–mediatedinflammatoryreactionisdelayed-type hypersensitivity. ChronicTH1reactionsassociatedwithmacrophageactivationoftenleadtogranulomaformation. T cell–mediated cytotoxicity: CD8+ cytotoxicTlymphocytes(CTLs)specificforanantigenrecognizecellsexpressingthetargetantigenandkillthesecells.CD8+ TcellsalsosecreteIFN-γ. Now that we have described how the immune system can cause tissue damage, we turn to diseases in which normal control mechanisms fail. The prototypes of such diseases are autoimmune disorders, which are the result of failure of tolerance to self antigens.


Pathology_Robbins

Pathology_Robbins. Autoimmunity refers to immune reactions against self (“auto”) antigens. Autoimmune diseases are estimated to affect at least 1% to 2% of the U.S. population. The evidence that these diseases are indeed the result of autoimmune reactions is more persuasive for some than for others. For instance, in many of these disorders, high-affinity autoantibodies have been identified, and in some cases these antibodies are known to cause pathologic abnormalities. There is also growing evidence for the activation of pathogenic self-reactive T cells in some of these diseases. In addition, experimental models have proved very informative, providing circumstantial evidence supporting an autoimmune etiology. Nevertheless, it is fair to say that for many Table 5.7 Autoimmune Diseases Inflammatoryboweldiseases(Crohndisease,ulcerativecolitis) *AroleforTcellshasbeendemonstratedinthesedisorders,butantibodiesmayalsobeinvolvedintissueinjury.


Pathology_Robbins

Pathology_Robbins. Table 5.7 Autoimmune Diseases Inflammatoryboweldiseases(Crohndisease,ulcerativecolitis) *AroleforTcellshasbeendemonstratedinthesedisorders,butantibodiesmayalsobeinvolvedintissueinjury. †Anautoimmunebasisofthesedisordersissuspected,butthesupportingevidenceisnotstrong. ‡Thesedisordersmayresultfromexcessiveimmuneresponsestocommensalentericmicrobes,autoimmunity,oracombinationofthetwo. disorders traditionally classified as autoimmune, this etiology is suspected but not proved.


Pathology_Robbins

Pathology_Robbins. disorders traditionally classified as autoimmune, this etiology is suspected but not proved. Autoimmune diseases may be organ-specific, in which the immune responses are directed against one particular organ or cell type and result in localized tissue damage, or systemic, characterized by lesions in many organs ( 5.7 ). In systemic diseases that are caused by immune complexes and autoantibodies, the lesions principally affect the connective tissues and blood vessels of involved organs. Therefore, these diseases are often referred to as collagen vascular diseases or connective tissue diseases, even though the immunologic reactions are not specifically directed against constituents of connective tissue or blood vessels. Normal persons are unresponsive (tolerant) to their own (self) antigens, and autoimmunity results from a failure of self-tolerance. Therefore, understanding the pathogenesis of autoimmunity requires familiarity with the mechanisms of normal immunologic tolerance.


Pathology_Robbins

Pathology_Robbins. Immunologic tolerance is a state of unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that antigen. Self-tolerance refers to lack of immune responsiveness to one’s own tissue antigens. Billions of different antigen receptors are randomly generated in developing T lymphocytes and B lymphocytes, and it is not surprising that during this process, receptors are produced that can recognize self antigens. Since these antigens cannot all be concealed from the immune system, there must be a means of eliminating or controlling self-recognizing lymphocytes. Several mechanisms work in http://ebooksmedicine.net Thymus Development Treg of regulatory T cells Anergy (failure to Anergy respond) BB (failure to Fig. 5.19 Mechanisms of immunologic tolerance to self antigens. The principal mechanisms of central and peripheral self-tolerance in T cells and B cells are illustrated. APC, Antigen-presenting cell; Treg cells, regulatory T cells.


Pathology_Robbins

Pathology_Robbins. concert to select against self-reactivity and to thus prevent immune reactions against the body’s own antigens. Two broad mechanisms are recognized: central tolerance and peripheral tolerance ( Fig. 5.19


Pathology_Robbins

Pathology_Robbins. The principal mechanism of central tolerance is the antigen-induced deletion (death) of self-reactive T lymphocytes and B lymphocytes during their maturation in central (generative) lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). In the thymus, many autologous (self) protein antigens are processed and presented by thymic APCs. Any immature T cell that encounters such a self antigen undergoes apoptosis (a process called deletion, or negative selection), and the T cells that complete their maturation are thereby depleted of self-reactive cells. An exciting advance has been the identification of a protein called AIRE (autoimmune regulator), which stimulates expression of some peripheral tissue-restricted self antigens in the thymus and is thus critical for deletion of immature T cells specific for these antigens. Mutations in the AIRE gene are the cause of an autoimmune polyendocrinopathy (Chapter 20). Not all immature T cells that see self antigens


Pathology_Robbins

Pathology_Robbins. deletion of immature T cells specific for these antigens. Mutations in the AIRE gene are the cause of an autoimmune polyendocrinopathy (Chapter 20). Not all immature T cells that see self antigens in the thymus are deleted. Some CD4+ T cells survive and develop into regulatory T cells (described later).


Pathology_Robbins

Pathology_Robbins. Immature B cells that recognize self antigens with high affinity in the bone marrow also may die by apoptosis. Other self-reactive B cells are not deleted but instead undergo a second round of rearrangement of antigen receptor genes and then express new receptors that are no longer self-reactive (a process called receptor editing). Central tolerance, however, is imperfect. Not all self antigens are present in the thymus or bone marrow, and hence lymphocytes bearing receptors for such autoantigens escape into the periphery. Self-reactive lymphocytes that escape negative selection can inflict tissue injury unless they are eliminated or muzzled in the peripheral tissues.


Pathology_Robbins

Pathology_Robbins. Several mechanisms silence potentially autoreactive T cells and B cells in peripheral tissues; these are best defined for T cells. These mechanisms include the following: • Anergy. This term refers to functional inactivation (rather than death) of lymphocytes that is induced by encounter with antigens under certain conditions. As described previously, activation of T cells requires two signals: recognition of peptide antigen in association with MHC molecules on APCs, and a set of second costimulatory signals (e.g., through B7 molecules) provided by the APCs. If the costimulatory signals are not delivered, or if an inhibitory receptor on the T cell (rather than the costimulatory receptor) is engaged when the cell encounters self antigen, the T cell becomes anergic and cannot respond to the antigen. Because costimulatory molecules are expressed at low levels or not at all on APCs presenting self antigens, the encounter between autoreactive T cells and self antigens in tissues may result


Pathology_Robbins

Pathology_Robbins. antigen. Because costimulatory molecules are expressed at low levels or not at all on APCs presenting self antigens, the encounter between autoreactive T cells and self antigens in tissues may result in anergy.


Pathology_Robbins

Pathology_Robbins. It is believed that if mature B cells encounter self antigen in peripheral tissues, especially in the absence of specific helper T cells, these B cells become unable to respond to the antigen. B lymphocytes also express inhibitory receptors that may play a role in limiting their activation and preventing responses to self antigens.


Pathology_Robbins

Pathology_Robbins. Suppression by regulatory T cells. A population of T cells called regulatory T cells functions to prevent immune reactions against self antigens. Regulatory T cells develop mainly in the thymus, but they also may be induced in peripheral lymphoid tissues. The best-defined regulatory T cells are CD4+ cells that express high levels of CD25, the α chain of the IL-2 receptor, and a transcription factor of the forkhead family, called FOXP3. Both IL-2 and FOXP3 are required for the development and maintenance of functional CD4+ regulatory T cells. Mutations in the FOXP3 gene result in severe autoimmunity in humans and mice; in humans, these mutations are the cause of a systemic autoimmune disease called IPEX (an acronym for immune dysregulation, polyendocrinopathy, enteropathy, X-linked).


Pathology_Robbins

Pathology_Robbins. The mechanisms by which regulatory T cells suppress immune responses are not fully defined, but their inhibitory activity may be mediated in part by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, which inhibit lymphocyte activation and effector functions. Regulatory T cells also express CTLA-4, which may bind to B7 molecules on APCs and reduce their ability to activate T cells via CD28.


Pathology_Robbins

Pathology_Robbins. Deletion by apoptosis. T cells that recognize self antigens may receive signals that promote their death by apoptosis. Two mechanisms of deletion of mature T cells have been proposed, based mainly on studies in mice. It is postulated that if T cells recognize self antigens, they upregulate a pro-apoptotic member of the Bcl-2 family called Bim, which triggers apoptosis by the mitochondrial pathway (Chapter 2). Another mechanism of apoptosis involves the death receptor Fas (a member of the TNF receptor family), which can be engaged by its ligand coexpressed on the same or neighboring cells. The importance of this pathway of self-tolerance is illustrated by the discovery that FAS mutations are responsible for an autoimmune disease called the autoimmune lymphoproliferative syndrome (ALPS), characterized by lymphadenopathy and production of autoantibodies.


Pathology_Robbins

Pathology_Robbins. Some self antigens are hidden (sequestered) from the immune system, because the tissues in which these antigens are located do not communicate with the blood and lymph. As a result, unless released into the circulation, these antigens fail to elicit immune responses and are essentially ignored by the immune system. This is believed to be the case for antigens that are only found in the testis, eye, and brain, all of which are called immune-privileged sites because antigens located in these sites tend to be shielded from the immune system. If the antigens are released from these tissues, for example, as a consequence of trauma or infection, the result may be an immune response that leads to prolonged tissue inflammation and injury. This is the postulated mechanism for post-traumatic orchitis and uveitis. Mechanisms of Autoimmunity: General Principles


Pathology_Robbins

Pathology_Robbins. Mechanisms of Autoimmunity: General Principles Now that we have summarized the principal mechanisms of self-tolerance, we can ask how these mechanisms might break down to give rise to pathologic autoimmunity. Infections, inflammation, tissue injury Failure of Activationself-tolerance of tissue APCs Influx of self-reactive lymphocytes into tissues Activation of self-reactive lymphocytes Tissue injury: autoimmune disease Fig. 5.20 Pathogenesis of autoimmunity. Autoimmunity results from multiple factors, including susceptibility genes that may interfere with self-tolerance and environmental triggers (such as infections, tissue injury, and inflammation) that promote lymphocyte entry into tissues, activation of self-reactive lymphocytes, and tissue damage.


Pathology_Robbins

Pathology_Robbins. Unfortunately, there are no simple answers to this question, and the underlying causes of most human autoimmune diseases remain to be determined. The best guess is that breakdown of self-tolerance and development of autoimmunity result from the combined effects of susceptibility genes, which influence lymphocyte tolerance, and environmental factors, such as infections or tissue injury, that alter the display of and responses to self antigens ( Fig. 5.20 Most autoimmune diseases are complex multigenic disorders. There is abundant evidence that inherited genes play a role in the development of autoimmune diseases. Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins.


Pathology_Robbins

Pathology_Robbins. Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins. Several autoimmune diseases are linked to the HLA locus, especially class II alleles (HLA-DR, HLA-DQ). The frequency of a disease in individuals with a particular HLA allele compared with those who do not inherit that allele, is called the odds ratio or relative risk ( Table 5.8 ). The relative risk ranges from 3 or 4 for Table 5.8 Association of HLA Alleles and Inflammatory Diseases SystemiclupusDRB1*03012erythematosusDRB1*15011.3 †TheoddsratioreflectsapproximatevaluesofincreasedriskforthediseaseassociatedwiththeinheritanceofparticularHLAalleles.ThedataarefromEuropean-derivedpopulations.


Pathology_Robbins

Pathology_Robbins. ‡Anti-CCP Ab referstoantibodiesdirectedagainstcycliccitrullinatedpeptides.Dataarefrompatientswhotestpositivefortheseantibodiesintheserum.¶SE referstoshared epitope, socalledbecausethesusceptibilityallelesmaptooneregionoftheDRB1protein(positions70–74).TheDRB1proteinistheproductoftheβ chainoftheHLADRmolecule.CourtesyofDr.MichelleFernando,ImperialCollegeLondon. rheumatoid arthritis (RA) and HLA-DR4 to 100 or more for ankylosing spondylitis and HLA-B27. However, how MHC genes influence the development of autoimmunity is still not clear. Notably, most individuals with a susceptibility-related MHC allele never develop disease, and, conversely, individuals without the relevant MHC gene may get it. Expression of a particular MHC gene is therefore but one variable that contributes to autoimmunity. • Genome-wide association (GWAS) studies and linkage studies in families are revealing many genetic polymorphisms that are associated with different autoimmune diseases (


Pathology_Robbins

Pathology_Robbins. • Genome-wide association (GWAS) studies and linkage studies in families are revealing many genetic polymorphisms that are associated with different autoimmune diseases ( Table 5.9 ). Some of these genetic variants are disease-specific, but many of the associations are seen in multiple disorders, suggesting that they affect general mechanisms of immune regulation and self-tolerance. However, the mechanism by which most of these genetic variants contribute to particular autoimmune diseases is not established. Role of Infections,Tissue Injury, and Other Environmental Factors A variety of microbes, including bacteria, mycoplasmas, and viruses, have been implicated as triggers for autoimmunity. Microbes may induce autoimmune reactions by several mechanisms ( Fig. 5.21


Pathology_Robbins

Pathology_Robbins. A variety of microbes, including bacteria, mycoplasmas, and viruses, have been implicated as triggers for autoimmunity. Microbes may induce autoimmune reactions by several mechanisms ( Fig. 5.21 Microbial infections with resultant tissue necrosis and inflammation can stimulate expression of costimulatory molecules on APCs in the tissue, thus favoring a breakdown of T cell tolerance and subsequent T cell activation. Viruses and other microbes may share cross-reacting epitopes with self antigens, and as a result responses induced by the microbe may extend to self tissues, a phenomenon called molecular mimicry. The best example of a pathogenic immunologic cross-reaction is rheumatic heart disease, in which an antibody response against streptococci cross-targets cardiac antigens. It is not known if mimicry has a role in more common autoimmune diseases.


Pathology_Robbins

Pathology_Robbins. Recently, there has been great interest in the idea that the development of autoimmunity is influenced by the normal gut and skin microbiome (the diverse collection of commensal microbes that live with us in a symbiotic relationship). It is possible that different commensal microbes Table 5.9 Selected Non–HLA Gene Variants Associated With Autoimmune Diseases PTPN22 RA,T1D,IBDProteintyrosinephosphatase;mayaffectsignalinginlymphocytesandmayalternegativeselectionoractivationofself-reactiveTcells IL23R IBD,PS,ASReceptorfortheTH17-inducingcytokineIL-23;mayalterdifferentiationofCD4+ TcellsintopathogenicTH17effectorcells CTLA4 T1D,RAInhibitsT-cellresponsesbyterminatingactivationandpromotingactivityofregulatoryTcells;mayinterferewithself-tolerance IL2RA MS,T1Dα chainofthereceptorforIL-2,whichisagrowthandsurvivalfactorforactivatedandregulatoryTcells;mayaffectdevelopmentofeffectorcellsand/orregulationofimmuneresponses


Pathology_Robbins

Pathology_Robbins. IL2RA MS,T1Dα chainofthereceptorforIL-2,whichisagrowthandsurvivalfactorforactivatedandregulatoryTcells;mayaffectdevelopmentofeffectorcellsand/orregulationofimmuneresponses IRF5, IFIH1 SLERoleintypeIinterferonproduction;typeIIFNisinvolvedinthepathogenesisofSLE(seetext) AS, Ankylosingspondylitis;IBD, inflammatoryboweldisease;IFN, interferon;MS, multiplesclerosis;PS, psoriasis;RA, rheumatoidarthritis;SLE, systemiclupuserythematosus;TID,typeIdiabetes.Theprobablelinkageofthesegeneswithvariousautoimmunediseaseshasbeendefinedbygenome-wideassociationstudies(GWAS)andothermethodsforstudyingdisease-associatedpolymorphisms.AdaptedfromZenewiczLA,AbrahamC,FlavellRA,etal:Unravelingthegeneticsofautoimmunity,Cell 140:791,2010. http://ebooksmedicine.net A Induction of costimulators on APCs Activation of APC Activation of T cells


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net A Induction of costimulators on APCs Activation of APC Activation of T cells Fig. 5.21 Postulated role of infections in autoimmunity. Infections may promote activation of self-reactive lymphocytes by inducing the expression of costimulators (A), or microbial antigens may mimic self antigens and activate self-reactive lymphocytes as a cross-reaction (B). affect the relative proportions of effector and regulatory T cells, and shape the host response toward or away from aberrant activation. However, it is still not clear which microbes contribute to specific diseases in humans, or if the microbiome can be manipulated to prevent or treat these disorders.


Pathology_Robbins

Pathology_Robbins. Adding to the complexity of the link between microbes and autoimmunity are recent observations suggesting that infections paradoxically protect individuals from some autoimmune diseases, notably type 1 diabetes, multiple sclerosis, and Crohn disease. The possible mechanisms underlying this effect are not understood. In addition to infections, the display of tissue antigens also may be altered by a variety of environmental insults. As discussed later, ultraviolet (UV) radiation causes cell death and may lead to the exposure of nuclear antigens, which elicit pathologic immune responses in lupus; this mechanism is the proposed explanation for the association of lupus flares with exposure to sunlight. Smoking is a risk factor for RA, perhaps because it leads to chemical modification of self antigens. Local tissue injury for any reason may lead to the release of self antigens and autoimmune responses.


Pathology_Robbins

Pathology_Robbins. Finally, there is a strong gender bias of autoimmunity, with many of these diseases being more common in women than in men. The underlying mechanisms are not well understood, but may involve the effects of hormones and other factors. An autoimmune response may itself promote further autoimmune attack. Tissue injury caused by an autoimmune response or any other cause may lead to exposure of self antigen epitopes that were previously concealed but are now presented to T cells in an immunogenic form. The activation of such autoreactive T cells is called epitope spreading, because the immune response spreads to epitopes that were not recognized initially. This is one of the mechanisms that may contribute to the chronicity of autoimmune diseases. Tolerance (unresponsiveness) to self antigens is a fundamentalproperty of the immune system, and breakdown of toleranceis the basis of autoimmune diseases.


Pathology_Robbins

Pathology_Robbins. Tolerance (unresponsiveness) to self antigens is a fundamentalproperty of the immune system, and breakdown of toleranceis the basis of autoimmune diseases. Central tolerance: immature T and B lymphocytes that recognize self antigens in the central (generative) lymphoid organsare killed by apoptosis; in the B-cell lineage, some of theself-reactive lymphocytes switch to new antigen receptorsthat are not self-reactive. Peripheral tolerance: mature lymphocytes that recognize selfantigens in peripheral tissues become functionally inactive (anergic),aresuppressedbyregulatoryTlymphocytes,ordiebyapoptosis. •Thefactorsthatleadtoafailureofself-toleranceandthedevelopmentofautoimmunityinclude(1)inheritanceofsusceptibilitygenesthatdisruptdifferenttolerancepathways,and (2)infectionsandtissueinjurythatexposeselfantigensandactivateAPCsandlymphocytesinthetissues.


Pathology_Robbins

Pathology_Robbins. Having discussed the general principles of tolerance and autoimmunity, we proceed to a discussion of some of the most common and important autoimmune diseases. Although each disease is discussed separately, considerable overlap is apparent in their clinical and morphologic features and underlying pathogenesis. Here we cover the systemic autoimmune diseases; autoimmune diseases that affect single organ systems are discussed in chapters that deal with the relevant organs.


Pathology_Robbins

Pathology_Robbins. SLE is an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues. Injury to the skin, joints, kidney, and serosal membranes is prominent, but virtually every organ in the body may be affected. The presentation of SLE is so variable that a complex set of criteria for this disorder have been proposed, to help clinicians and for the design and assessment of clinical trials (


Pathology_Robbins

Pathology_Robbins. Table 5.10 ). However, the disease is very heterogeneous, and any patient may present with any number of these features. SLE is a fairly common disease, with a prevalence that may be as high as 400 per 100,000 in certain populations. Although SLE often presents when a person is in the twenties or thirties, it may manifest at any age, even in early childhood. Similar to many autoimmune diseases, SLE predominantly affects women, with a female-to-male ratio of 9:1 for the reproductive age group of 17 to 55 years. By comparison, the female-to-male ratio is only 2:1 for disease developing during childhood or after 65 years of age. The prevalence of the disease is 2to 3-fold higher in blacks and Hispanics than in whites. Spectrum of Autoantibodies in SLE The hallmark of SLE is the production of autoantibodies. Some antibodies recognize nuclear and cytoplasmic components, while others are directed against cell surface antigens of blood cells. Apart from their value in the diagnosis


Pathology_Robbins

Pathology_Robbins. Some antibodies recognize nuclear and cytoplasmic components, while others are directed against cell surface antigens of blood cells. Apart from their value in the diagnosis Table 5.10 Revised Criteria for Classification of Systemic Lupus Erythematosus* AcutecutaneouslupusMalarrash(fixederythema,flatorraised,overthemalareminences),photosensitivity ChroniccutaneousDiscoidrash:erythematousraisedpatcheswithadherentkeratoticscalingandfollicularplugginglupus OralornasalulcersOralornasopharyngealulceration,usuallypainless JointdiseaseNonerosivesynovitisinvolvingtwoormoreperipheraljoints,characterizedbytenderness,swelling,oreffusion SerositisPleuritis(pleuriticpainorruborevidenceofpleuraleffusion),pericarditis RenaldisorderPersistentproteinuria>0.5g/24hours,orredcellcasts NeurologicdisorderSeizures,psychosis,myelitis,orneuropathy,intheabsenceofoffendingdrugsorotherknowncauses


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net “Generic”anti-nuclearantibodies(ANAs),whichmayreactagainstmanynuclearantigens,arepositiveinalargefractionofpatientswithSLEbutalsoarepositiveinotherautoimmunediseases.% positive referstotheapproximate%ofpatientswhotestpositiveforeachantibody.TablecompiledwiththeassistanceofDr.AntonyRosen,JohnsHopkinsUniversity,andDr.AndrewGross,UniversityofCaliforniaSanFrancisco. and management of patients with SLE, these autoantibodies are of major pathogenic significance, as, for example, in the immune complex–mediated glomerulonephritis so typical of this disease. Autoantibodies also are found in other autoimmune diseases, many of which tend to be associated with specific types of autoantibodies ( Table 5.11


Pathology_Robbins

Pathology_Robbins. Table 5.11 ANAs can be grouped into four categories: (1) antibodies to DNA, (2) antibodies to histones, (3) antibodies to nonhistone proteins bound to RNA, and (4) antibodies to nucleolar antigens. The most widely used method for detecting ANAs is indirect immunofluorescence, which can identify antibodies that bind to a variety of nuclear antigens, including DNA, RNA, and proteins (collectively called generic ANAs). The pattern of nuclear fluorescence suggests the type of antibody present in the patient’s serum. Several basic patterns are recognized ( Fig. 5.22 homogeneous or diffuse staining pattern usually reflects the presence of antibodies to chromatin, histones, and, occasionally, double-stranded DNA. rim or peripheral staining pattern is most often indicative of antibodies to double-stranded DNA and sometimes to nuclear envelope proteins.


Pathology_Robbins

Pathology_Robbins. rim or peripheral staining pattern is most often indicative of antibodies to double-stranded DNA and sometimes to nuclear envelope proteins. centromeric pattern is indicative of antibodies specific for centromeres. This pattern is often observed in patients with systemic sclerosis. speckled pattern refers to the presence of uniform or variable-sized speckles. This is one of the most commonly observed patterns of fluorescence and therefore the least specific. It reflects the presence of antibodies to non-DNA nuclear constituents such as Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens. •A nucleolar pattern refers to the presence of a few discrete spots of fluorescence within the nucleus and represents antibodies to RNA. This pattern is reported most often in patients with systemic sclerosis.


Pathology_Robbins

Pathology_Robbins. The fluorescence patterns are not absolutely specific for the type of antibody, and because many autoantibodies may be present, combinations of patterns are frequent. Attempts are ongoing to replace microscopic assays with quantitative assays for antibodies against specific nuclear and other antigens. Indeed, antibodies to double-stranded DNA and the so-called “Smith (Sm) antigen” can be detected by more quantitative assays and are virtually diagnostic of SLE. Nevertheless, the staining pattern has diagnostic value, and the test remains in use.


Pathology_Robbins

Pathology_Robbins. In addition to ANAs, lupus patients have a host of other autoantibodies. Some are directed against blood cells, such as red cells, platelets, and lymphocytes. Anti-phospholipid antibodies are present in 30% to 40% of lupus patients. They are actually directed against epitopes of various plasma proteins that are revealed when the proteins are in complex with phospholipids. Antibodies against the phospholipid– β2-glycoprotein complex also bind to cardiolipin antigen, used in syphilis serology, and therefore lupus patients may have a false-positive test result for syphilis. Because these antibodies bind to phospholipids, they may prolong the partial thromboplastin time, an in vitro clotting test that requires phospholipids. Therefore, these antibodies are sometimes referred to as lupus anti-coagulant. Despite the observed clotting delays in vitro, patients with antiphospholipid antibodies have complications related to excessive clotting (a hypercoagulable state), such as thrombosis


Pathology_Robbins

Pathology_Robbins. anti-coagulant. Despite the observed clotting delays in vitro, patients with antiphospholipid antibodies have complications related to excessive clotting (a hypercoagulable state), such as thrombosis (Chapter 4).


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 5.22 Stainingpatternsofanti-nuclearantibodies.(A)HomogeneousordiffusestainingofnucleiistypicalofantibodiesreactivewithdsDNA,nucleosomes,andhistones,andiscommoninSLE.(B)Aspeckledpatternisseenwithantibodiesagainstvariousnuclearantigens,includingSmandRNPs.(C)Thepatternofstainingofanti-centromereantibodiesisseeninsomecasesofsystemicsclerosis,Sjögrensyndrome,andotherdiseases.(D)Anucleolarpatternistypicalofantibodiesagainstnucleolarproteins.(From Wiik AS, Høier-Madsen M, Forslid J, et al: Antinuclear antibodies: a contemporary nomenclature using HEp-2 cells. J Autoimm35:276, 2010.) The fundamental defect in SLE is a failure of the mechanisms that maintain self-tolerance. Although what causes this failure of self-tolerance remains unknown, as is true of most autoimmune diseases, both genetic and environmental factors play a role. Many lines of evidence support a genetic predisposition to SLE.


Pathology_Robbins

Pathology_Robbins. Many lines of evidence support a genetic predisposition to SLE. Familial association. Family members have an increased risk for the development of SLE, and up to 20% of unaffected first-degree relatives have autoantibodies. There is a higher rate of concordance in monozygotic twins (25%) than in dizygotic twins (1%–3%). HLA association. The odds ratio (relative risk) for persons with HLA-DR2 or HLA-DR3 is 2 to 3, and if both haplotypes are present, the risk is about 5.


Pathology_Robbins

Pathology_Robbins. HLA association. The odds ratio (relative risk) for persons with HLA-DR2 or HLA-DR3 is 2 to 3, and if both haplotypes are present, the risk is about 5. • Other genes. Genetic deficiencies of classical pathway complement proteins, especially C1q, C2, or C4, are seen in about 10% of patients with SLE. The complement deficiencies may result in defective clearance of immune complexes and apoptotic cells, and failure of B-cell tolerance. A polymorphism in the inhibitory Fc receptor, FcγRIIb, has been described in some patients; this may contribute to inadequate control of B-cell activation. Additional genes have been implicated by genome-wide association studies, but their contribution to the development of the disease remains unclear. There are many indications that environmental factors also are involved in the pathogenesis of SLE.


Pathology_Robbins

Pathology_Robbins. There are many indications that environmental factors also are involved in the pathogenesis of SLE. • Exposure to UV light exacerbates the disease in many individuals. UV irradiation may induce apoptosis and also may alter DNA and make it immunogenic, perhaps http://ebooksmedicine.net by enhancing its recognition by TLRs. In addition, UV light may modulate the immune response, for example, by stimulating keratinocytes to produce IL-1, a cytokine that promotes inflammation. The gender bias of SLE is partly attributable to actions of sex hormones and partly related to genes on the X chromosome, independent of hormone effects. Drugs such as hydralazine, procainamide, and D-penicillamine can induce an SLE-like disorder. Recent studies in animal models and patients have revealed several immunologic aberrations that collectively may result in the persistent and uncontrolled activation of self-reactive lymphocytes.


Pathology_Robbins

Pathology_Robbins. Recent studies in animal models and patients have revealed several immunologic aberrations that collectively may result in the persistent and uncontrolled activation of self-reactive lymphocytes. Failure of self-tolerance in B cells results from defective elimination of self-reactive B cells in the bone marrow or defects in peripheral tolerance mechanisms. CD4+ helper T cells specific for nucleosomal antigens also escape tolerance and contribute to the production of high-affinity pathogenic autoantibodies. The autoantibodies in SLE show characteristics of T cell–dependent antibodies produced in germinal centers, and increased numbers of follicular helper T cells have been detected in the blood of SLE patients.


Pathology_Robbins

Pathology_Robbins. Type I interferons. Blood cells show a striking molecular signature that indicates exposure to interferon-α (IFNα), a type I interferon that is produced mainly by plasmacytoid DCs. Some studies have shown that such cells from SLE patients produce abnormally large amounts of IFN-α. TLR signals. Studies in animal models have shown that TLRs that recognize DNA and RNA, notably the DNA-recognizing TLR9 and the RNA-recognizing TLR7, produce signals that activate B cells specific for self nuclear antigens. Other cytokines that may play a role in unregulated B-cell activation include the TNF family member BAFF, which promotes survival of B cells. In some patients and animal models, increased production of BAFF has been reported, and this has led to modest success of an antibody that blocks BAFF as a therapy for SLE.


Pathology_Robbins

Pathology_Robbins. It is clear from this discussion that the immunologic abnormalities in SLE—both documented and postulated—are varied and complex. Nevertheless, an attempt can be made to synthesize results from human studies and animal models into a hypothetical model of the pathogenesis of SLE (


Pathology_Robbins

Pathology_Robbins. Fig. 5.23 ). UV irradiation and other environmental insults lead to the apoptosis of cells. Inadequate clearance of the nuclei of these cells results in a large burden of nuclear antigens. Underlying abnormalities in B lymphocytes and T lymphocytes are responsible for defective tolerance, because of which self-reactive lymphocytes survive and remain functional. These lymphocytes are stimulated by nuclear self antigens, and antibodies are produced against the antigens. Complexes of the antigens and antibodies bind to Fc receptors on B cells and dendritic cells, and may be internalized. The nucleic acid components engage TLRs and stimulate B cells to produce more auto-antibodies. TLR stimuli also activate dendritic cells to SUSCEPTIBILITY EXTERNAL TRIGGERS GENES (e.g., UV radiation) Defective clearance of apoptotic bodies B and T cells specific for Increased burden of self nuclear antigens nuclear antigens


Pathology_Robbins

Pathology_Robbins. SUSCEPTIBILITY EXTERNAL TRIGGERS GENES (e.g., UV radiation) Defective clearance of apoptotic bodies B and T cells specific for Increased burden of self nuclear antigens nuclear antigens Fig. 5.23 Modelforthepathogenesisofsystemiclupuserythematosus.Inthishypotheticalmodel,susceptibilitygenesinterferewiththemaintenanceofself-tolerance,andexternaltriggersleadtopersistenceofnuclearantigens.Theresultisanantibodyresponseagainstselfnuclearantigens,whichisamplifiedbytheactionofnucleicacidsondendriticcells(DCs)andBcells,andtheproductionoftypeIinterferons.TLRs, Toll-likereceptors. produce interferons and other cytokines, which further enhance the immune response and cause more apoptosis. The net result is a cycle of antigen release and immune activation resulting in the production of high-affinity autoantibodies. Different autoantibodies are the cause of most of the lesions of SLE.


Pathology_Robbins

Pathology_Robbins. Different autoantibodies are the cause of most of the lesions of SLE. • Most of the systemic lesions are caused by immune complexes (type III hypersensitivity). DNA-anti-DNA complexes can be detected in the glomeruli and small blood vessels. Low levels of serum complement (secondary to consumption of complement proteins) and granular deposits of complement and immunoglobulins in the glomeruli further support the immune complex nature of the disease. T cell infiltrates are also frequently seen in the kidneys, but the role of these cells in tissue damage is not established.


Pathology_Robbins

Pathology_Robbins. Autoantibodies of different specificities contribute to the pathology and clinical manifestations of SLE (type II hypersensitivity). Autoantibodies specific for red blood cells, white blood cells, and platelets opsonize these cells and promote their phagocytosis, resulting in cytopenias. There is no evidence that ANAs, which are involved in immune complex formation, can penetrate intact cells. If cell nuclei are exposed, however, the ANAs can bind to them. In tissues, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and become homogeneous, producing so-called “LE bodies” or hematoxylin bodies. Related to this phenomenon are LE cells, which are readily seen when blood is agitated in vitro. An LE cell is a phagocyte (neutrophil or macrophage) that has engulfed the denatured nucleus of an injured cell. The demonstration of LE cells in vitro was used in the past as a test for SLE. With new techniques for detection of ANAs, however, this test is now only of historic


Pathology_Robbins

Pathology_Robbins. nucleus of an injured cell. The demonstration of LE cells in vitro was used in the past as a test for SLE. With new techniques for detection of ANAs, however, this test is now only of historic interest. Sometimes, LE cells are found in pericardial or pleural effusions in patients.


Pathology_Robbins

Pathology_Robbins. Anti-phospholipid antibody syndrome. Patients with antiphospholipid antibodies may develop venous and arterial thromboses, which may be associated with recurrent spontaneous miscarriages and focal cerebral or ocular ischemia. This constellation of clinical features, in association with lupus, is referred to as the secondary antiphospholipid antibody syndrome. The mechanisms of thrombosis are not defined, and antibodies against clotting factors, platelets, and endothelial cells have all been proposed as being responsible for thrombosis (Chapter 4). Some patients develop these autoantibodies and the clinical syndrome without associated SLE. They are said to have the primary anti-phospholipid antibody syndrome (Chapter 4).


Pathology_Robbins

Pathology_Robbins. The neuropsychiatric manifestations of SLE have been attributed to antibodies that cross the blood-brain barrier and react with neurons or receptors for various neurotransmitters. However, this is not established in all cases, and mechanisms involving other immune factors, such as cytokines, also may underlie the cognitive dysfunction and other CNS abnormalities that are associated with SLE. MORPHOLOGYThemorphologicchangesinSLEareextremelyvariable.Thefrequencyofindividualorganinvolvementisshownin Table5.12 .Themostcharacteristiclesionsresultfromimmunecomplexdepositioninbloodvessels,kidneys,connectivetissue,andskin. Blood Vessels. Anacutenecrotizingvasculitisinvolvingcapillaries,smallarteries,andarteriolesmaybepresentinanytissue.Thearteritisleadstofibrinoidnecrosisofthevesselwalls.Inchronicstages,vesselsundergofibrousthickeningwithluminalnarrowing.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig. 5.24 Lupusnephritis.(A)Focalproliferativeglomerulonephritis,withtwofocalnecrotizinglesionsatthe11o’clockand2o’clockpositions(H&Estain).Extracapillaryproliferationisnotprominentinthiscase.(B)Diffuseproliferativeglomerulonephritis.Notethemarkedincreaseincellularitythroughouttheglomerulus(H&Estain).(C)Lupusnephritisshowingaglomeruluswithseveral“wire-loop”lesionsrepresentingextensivesubendothelialdepositsofimmunecomplexes(periodicacid-Schiffstain).(D)ElectronmicrographofarenalglomerularcapillaryloopfromapatientwithSLEnephritis.Subendothelialdensedeposits(arrowheads) onbasementmembrane(arrow)correspondto“wireloops”seenbylightmicroscopy.(E)DepositionofIgGantibodyinagranularpattern,detectedbyimmunofluorescence.(AtoC,Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts. D,Courtesy of Dr. Edwin Eigenbrodt, Department of Pathology, University of Texas, Southwestern Medical School, Dallas,Texas. E,Courtesy of Dr. Jean Olson, Department


Pathology_Robbins

Pathology_Robbins. Hospital, Boston, Massachusetts. D,Courtesy of Dr. Edwin Eigenbrodt, Department of Pathology, University of Texas, Southwestern Medical School, Dallas,Texas. E,Courtesy of Dr. Jean Olson, Department of Pathology, University of California, San Francisco, California.) http://ebooksmedicine.net nephritis,halformoreoftheglomeruliareaffected.Involvedglomerulishowproliferationofendothelial,mesangial,andepithelialcells(see


Pathology_Robbins

Pathology_Robbins. Fig.5.25A ).Inthedermis,thereisvariableedemaandperivascularinflammation.Vasculitiswithfibrinoidnecrosismaybeprominent.Immunofluorescencemicroscopyshowsdepositsofimmunoglobulinandcomplementalongthedermoepidermaljunction( Fig.5.25B );thesealsomaybepresentinuninvolvedskin.ThisfindingisnotdiagnosticofSLEandissometimesseeninsclerodermaanddermatomyositis. Joints. Jointinvolvementistypicallyanonerosivesynovitiswithlittledeformity,whichcontrastswithrheumatoidarthritis. Central Nervous System. AlthoughitwassuggestedinthepastthattheneuropsychiatricmanifestationsofSLEmaybeduetoacutevasculitis,inhistologicstudiesofthenervoussysteminsuchpatients,significantvasculitisisrarelypresent.Instead,noninflammatoryocclusionofsmallvesselsbyintimalproliferationissometimesnoted,whichmaybeduetoendothelialdamagecausedbyautoantibodiesorimmunecomplexes. Pericarditis and Other Serosal Cavity Involvement.