Immunology_Janeway

Immunology_Janeway. easy to find isolated breakdowns of one or even more layers of protection, even in healthy individuals. Thus, activation of autoreactive lymphocytes does not necessarily equal autoimmune disease. In fact, a low level of autoreactivity is physiologic and crucial to normal immune function. Autoantigens help to form the repertoire of mature lymphocytes, and the survival of naive T cells and B cells in the periphery requires continuous exposure to autoantigens (see Chapter 8). Autoimmune disease develops only if enough safeguards are overcome to lead to a sustained reaction to self that includes the generation of effector cells and molecules that destroy tissues. Although the mechanisms by which this occurs are incompletely understood, autoimmunity is thought to result from a combination of genetic susceptibility, breakdown in natural tolerance mechanisms, and environmental triggers such as infections (Fig. 15.3).


Immunology_Janeway

Immunology_Janeway. 15-3 Central deletion or inactivation of newly formed lymphocytes is the first checkpoint of self-tolerance. Central tolerance mechanisms, which remove strongly autoreactive lymphocytes, are the first and most important checkpoints in self-tolerance (see Chapter 8). Without them, the immune system would be strongly self-reactive, and lethal autoimmunity would occur early in life. It is unlikely that peripheral tolerance mechanisms would be sufficient to compensate for the failure to remove self-reactive lymphocytes during primary development. Indeed, no known autoimmune diseases are attributable to complete failure of these mechanisms, although some are associated with a partial failure of central tolerance.


Immunology_Janeway

Immunology_Janeway. For a long time it was thought that many self antigens were not expressed in the thymus or bone marrow, and that peripheral mechanisms must be the only way of generating tolerance to them. It is now clear that many (but not all) tissue-specific antigens, such as insulin, are expressed in the thymus by either thymic epithelial cells in the medulla or a CD8α+ subset of dendritic cells, and thus self-tolerance against these antigens can be generated centrally. How these ‘peripheral’ genes are turned on ectopically in the thymus is not yet completely worked out, but an important clue has been found. A single transcription factor, AIRE (for autoimmune regulator), is thought to be responsible for turning on many peripheral genes in the thymus (see Section 8-23). The AIRE gene is defective in patients with a rare inherited form of autoimmunity—APECED (autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy), also known as autoimmune polyglandular syndrome type 1 (APS-1)—that leads to


Immunology_Janeway

Immunology_Janeway. with a rare inherited form of autoimmunity—APECED (autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy), also known as autoimmune polyglandular syndrome type 1 (APS-1)—that leads to destruction of multiple endocrine tissues, including insulin-producing pancreatic islets, and to fungal infections, particularly candidiasis. Mice engineered to lack the AIRE gene fail to express many peripheral genes in the thymus and develop a similar syndrome. This links AIRE to the expression of these genes, and the antigens they encode, indicating that an inability to express these antigens in the thymus leads to autoimmune disease (Fig. 15.4). The autoimmunity that accompanies AIRE deficiency takes time to develop and does not always affect all potential organ targets. So as well as emphasizing the importance of central tolerance, this disease shows that other layers of tolerance control have important roles.


Immunology_Janeway

Immunology_Janeway. In the absence of AIRE, T cells reactive to tissue-specifc antigens mature and leave the thymus In the thymus, T cells arise capable of recognizing tissue-speciÿc antigens Under control of the AIRE protein, thymic medullary cells express tissue-speciÿc proteins, leading to deletion of tissue-reactive T cells 15-4 Lymphocytes that bind self antigens with relatively low affinity activated.


Immunology_Janeway

Immunology_Janeway. Most circulating lymphocytes have a low affinity for self antigens but make no effector response to them, and may be considered ‘ignorant’ of self (see Section 8-6). Such ignorant but latently self-reactive cells can be recruited into autoimmune responses if their threshold for activation is exceeded by co-activating factors. One such stimulus is infection. Naive T cells with low affinity for a ubiquitous self-antigen can become activated if they encounter an activated dendritic cell presenting that antigen and expressing high levels of co-stimulatory signals or pro-inflammatory cytokines as a result of the presence of infection.


Immunology_Janeway

Immunology_Janeway. A situation in which normally ignorant lymphocytes may be activated is when their autoantigens are also ligands for Toll-like receptors (TLRs). These receptors are usually considered to be specific for microbe-associated molecular patterns (see Section 3-5), but some of these patterns can be found among self molecules. An example is unmethylated CpG sequences in DNA that are recognized by TLR-9. Unmethylated CpG is normally much more common in bacterial than mammalian DNA, but is enriched in apoptotic mammalian cells. In a scenario of extensive cell death coupled with inadequate clearance of apoptotic fragments, B cells specific for chromatin components can internalize CpG sequences via their B-cell receptors. These sequences can be recognized by TLR-9 intracellularly, leading to a co-stimulatory signal that activates the previously ignorant anti-chromatin B cell (Fig. 15.5). B cells activated in this way produce anti-chromatin autoantibodies and also can act as antigen-presenting


Immunology_Janeway

Immunology_Janeway. signal that activates the previously ignorant anti-chromatin B cell (Fig. 15.5). B cells activated in this way produce anti-chromatin autoantibodies and also can act as antigen-presenting cells for autoreactive T cells. Ribonucleoprotein complexes containing uridine-rich RNA have similarly been shown to activate


Immunology_Janeway

Immunology_Janeway. Fig. 15.4 The ‘autoimmune regulator’ gene AIRE promotes the expression of some tissue-specific antigens in thymic medullary cells, causing the deletion of immature thymocytes that can react to these antigens. Although the thymus expresses many genes, and thus self proteins, common to all cells, it is not obvious how antigens that are specific to specialized tissues, such as retina or ovary (first panel), gain access to the thymus to promote the negative selection of immature autoreactive thymocytes. It is now known that a gene called AIRE promotes the expression of many tissue‑specific proteins in thymic medullary cells. Some developing thymocytes will be able to recognize these tissue‑specific antigens (second panel). Peptides from these proteins are presented to the developing thymocytes as they undergo negative selection in the thymus (third panel), causing deletion of these cells. In the absence of AIRE, this deletion does not occur; instead, the autoreactive thymocytes mature and


Immunology_Janeway

Immunology_Janeway. as they undergo negative selection in the thymus (third panel), causing deletion of these cells. In the absence of AIRE, this deletion does not occur; instead, the autoreactive thymocytes mature and are exported to the periphery (fourth panel), where they could cause autoimmune disease. Indeed, people and mice that lack expression of AIRE develop an autoimmune syndrome called APECED, or autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy.


Immunology_Janeway

Immunology_Janeway. Fig. 15.5 Self antigens that are recognized by Toll-like receptors can activate autoreactive B cells by providing co-stimulation. The receptor TLR‑9 promotes the activation of B cells that produce antibodies specific for DNA, a common autoantibody in the autoimmune disease systemic lupus erythematosus (SLE) (see Fig. 15.1). Although B cells with strong affinity for DNA are eliminated in the bone marrow, some DNA‑specific B cells with lower affinity escape and persist in the periphery but are not normally activated. Under some conditions and in genetically susceptible individuals, the concentration of DNA may increase, leading to the ligation of enough B‑cell receptors to initiate activation of these B cells. B cells signal through their receptor (left panel) but also take up the DNA (center panel) and deliver it to an endosomal compartment (right panel). Here the DNA has access to TLR‑9, which recognizes DNA that is enriched in unmethylated CpG DNA sequences. Such CpG‑enriched


Immunology_Janeway

Immunology_Janeway. (center panel) and deliver it to an endosomal compartment (right panel). Here the DNA has access to TLR‑9, which recognizes DNA that is enriched in unmethylated CpG DNA sequences. Such CpG‑enriched sequences are much more common in microbial than eukaryotic DNA and normally this allows TLR‑9 to distinguish pathogens from self. DNA in apoptotic mammalian cells is enriched in unmethylated CpG, however, and the DNA‑specific B cell will also concentrate this self‑DNA in the endosomal compartment. This would provide sufficient ligands to activate TLR‑9, potentiating the activation of the DNA‑specific B cells and leading to the production of autoantibodies against DNA.


Immunology_Janeway

Immunology_Janeway. B cells with specifcity for DNA bind soluble fragments of DNA, sending a signal through the B-cell receptor The cross-linked B-cell receptor is internalized with the bound DNA molecule GC-rich fragments from the internalized DNA bind to TLR-9 in an endosomal compartment, sending a co-stimulatory signal TLR-9 naive B cells through binding by TLR-7 or TLR-8. Autoantibodies against DNA, chromatin, and ribonucleoproteins are produced in the autoimmune disease systemic lupus erythematosus (SLE), and this appears to be one mechanism by which self-reactive B cells are stimulated to produce them.


Immunology_Janeway

Immunology_Janeway. Another mechanism by which ignorant lymphocytes can be drawn into action is by the changing of the availability or form of self antigens. Some antigens are normally intracellular and not encountered by lymphocytes, but they may be released as a result of massive tissue injury or inflammation. These antigens can then activate ignorant T and B cells, leading to autoimmunity. This can occur after myocardial infarction, when an autoimmune response is detectable some days after the release of cardiac antigens. Such reactions are typically transient and cease when the autoantigens have been removed; however, when clearance mechanisms are inadequate, they can continue, causing clinical autoimmune disease.


Immunology_Janeway

Immunology_Janeway. Additionally, some autoantigens are present in great quantity but are usually in a nonimmunogenic form. IgG is a good example, as there are large quantities of it in blood and extracellular fluids. B cells specific for the IgG constant region are not usually activated, because IgG is monomeric and cannot cross-link the B-cell receptor. However, when immune complexes form following infection or immunization, enough IgG is in multivalent form to evoke a response from otherwise ignorant B cells. The anti-IgG autoantibody they produce is called rheumatoid factor because it is often present in rheumatoid arthritis. Again, this response is normally short-lived, as long as the immune complexes are cleared rapidly.


Immunology_Janeway

Immunology_Janeway. A unique situation can occur when activated B cells undergo somatic hypermutation in germinal centers (see Section 10-7), resulting in some activated B cells increasing their affinity for a self antigen or becoming newly self-reactive (Fig. 15.6). There seems, however, to be a mechanism to control germinal center B cells that have acquired affinity for self. In this case, if a hypermutated self-reactive B cell encounters strong cross-linking of its B-cell receptor in the germinal center, it undergoes apoptosis rather than further proliferation. 15-5 Antigens in immunologically privileged sites do not induce immune attack but can serve as targets.


Immunology_Janeway

Immunology_Janeway. 15-5 Antigens in immunologically privileged sites do not induce immune attack but can serve as targets. Foreign tissue grafts placed in some body sites do not elicit immune responses. For instance, grafts placed in the brain and anterior chamber of the eye do not induce rejection. Such locations are termed immunologically privileged sites (Fig. 15.7). It was originally believed that immunological privilege arose from the failure of antigens to leave privileged sites and induce immune responses. Subsequent studies have shown that antigens do leave these sites and interact with T cells. However, instead of eliciting an effector immune response, they induce a tolerogenic response that does not injure the tissue.


Immunology_Janeway

Immunology_Janeway. Immunologically privileged sites seem to be unusual in three ways. First, communication between the privileged site and the body is atypical in that extracellular fluid does not pass through conventional lymphatics, although proteins placed in these sites do leave and can have immunological effects. Privileged sites are generally surrounded by tissue barriers that exclude naive lymphocytes. The brain, for example, is guarded by the blood–brain barrier. Second, soluble factors that affect the course of an immune response are produced in privileged sites. The anti-inflammatory transforming growth factor (TGF)-β seems to be particularly important in this regard. Under homeostatic conditions, antigens recognized in concert with TGF-β tend to induce Treg responses, rather than pro-inflammatory TH17 responses, which are induced by TGF-β in the presence of IL-6 (see Section 9-21). Third, the expression of Fas ligand in immunologically privileged sites may provide a further level of


Immunology_Janeway

Immunology_Janeway. TH17 responses, which are induced by TGF-β in the presence of IL-6 (see Section 9-21). Third, the expression of Fas ligand in immunologically privileged sites may provide a further level of protection by inducing the apoptosis of Fas-bearing effector lymphocytes that enter these sites.


Immunology_Janeway

Immunology_Janeway. Paradoxically, antigens sequestered in immunologically privileged sites are often targets of autoimmune attack; for example, brain and spinal cord autoantigens such as myelin basic protein are targeted in the autoimmune disease multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system (see Fig. 15.1). Thus, the tolerance normally shown to these antigens cannot be due to previous deletion of the self-reactive T cells. In experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis, mice become diseased only when they are immunized with myelin antigens and adjuvants, which cause infiltration of the central nervous system with antigen-specific TH17 and TH1 cells that induce a local inflammatory response that damages nerve tissue.


Immunology_Janeway

Immunology_Janeway. Thus, some antigens expressed in immunologically privileged sites induce neither tolerance nor lymphocyte activation in normal circumstances, but if auto-reactive lymphocytes are activated elsewhere, these autoantigens can become targets for autoimmune attack. Likely, T cells specific for antigens sequestered in immunologically privileged sites are in a state of immunological ignorance. Further evidence comes from the eye disease sympathetic ophthalmia (Fig. 15.8). If one eye is ruptured by a blow or other trauma, an autoimmune response to eye proteins can occur, although this happens only rarely. Once the response is induced, it often attacks both eyes. Immunosuppression—and, rarely, removal of the damaged eye, the source of antigen—is required to preserve vision in the undamaged eye.


Immunology_Janeway

Immunology_Janeway. Unsurprisingly, effector T cells can enter immunologically privileged sites when such sites become infected. Effector T cells can enter most tissues after activation (see Chapter 11), but accumulation of cells is seen only when antigen is recognized in the site, triggering the production of cytokines that alter tissue barriers. 15-6 Autoreactive T cells that express particular cytokines may be nonpathogenic or may suppress pathogenic lymphocytes.


Immunology_Janeway

Immunology_Janeway. 15-6 Autoreactive T cells that express particular cytokines may be nonpathogenic or may suppress pathogenic lymphocytes. As described in Chapter 9, CD4 T cells can differentiate into various types of effector lineages, namely, TH1, TH2, and TH17 cells. These effector subsets evolved to control different types of infections and orchestrate distinct types of responses, as reflected in their different effects on antigen-presenting cells, B cells, and innate cells such as macrophages, eosinophils, and neutrophils (see Chapters 9–11). A similar paradigm holds true for autoimmunity: certain T-cell-mediated autoimmune diseases such as type 1 diabetes mellitus (see Fig. 15.1) depend on TH1 cells to cause disease, whereas others, such as psoriasis (an autoimmune disease of the skin), depend on TH17 cells.


Immunology_Janeway

Immunology_Janeway. Fig. 15.6 Elimination of autoreactive B cells in germinal centers. During somatic hypermutation in germinal centers (top panel), B cells with autoreactive B‑cell receptors can arise. Ligation of these receptors by soluble autoantigen (center panel) induces apoptosis of the autoreactive B cell by signaling through the B‑cell antigen receptor in the absence of helper T cells (bottom panel). Fig. 15.8 Damage to an immunologically privileged site can induce an autoimmune response. In the disease sympathetic ophthalmia, trauma to one eye releases the sequestered eye antigens into the surrounding tissues, making them accessible to T cells. The effector cells that are elicited attack the traumatized eye, and also infiltrate and attack the healthy eye. Thus, although the sequestered antigens do not induce a response by themselves, if a response is induced elsewhere they can serve as targets for attack.


Immunology_Janeway

Immunology_Janeway. In murine models of diabetes, when cytokines were infused to influence T-cell differentiation or when knockout mice predisposed to TH2 differentiation were studied, the development of diabetes was inhibited. In some cases, potentially pathogenic T cells specific for pancreatic islet-cell components, and expressing TH2 instead of TH1 cytokines, actually suppressed disease caused by TH1 cells of the same specificity. So far, attempts to control human autoimmune disease by switching cytokine profiles from one effector cell type to another (for example, TH1 to TH2), a procedure termed immune modulation, have not proved successful. Another subset of CD4 T cells, Treg cells, might prove to be more important in the prevention of autoimmune disease, and efforts to deviate effector to regulatory T-cell responses are being studied as a novel therapy for autoimmunity. 15-7 Autoimmune responses can be controlled at various stages by regulatory T cells.


Immunology_Janeway

Immunology_Janeway. 15-7 Autoimmune responses can be controlled at various stages by regulatory T cells. Autoreactive cells that escape the tolerance-inducing mechanisms described above can still be regulated so that they do not cause disease. This regulation takes two forms: the first is extrinsic, and is mediated by regulatory T cells that act on activated T cells and antigen-presenting cells; the second is intrinsic, and has its basis in limits on the size and duration of immune responses that are programmed into lymphocytes themselves. We shall first discuss the role of regulatory T cells (introduced in Chapter 9).


Immunology_Janeway

Immunology_Janeway. Tolerance due to regulatory lymphocytes is distinguished from other forms of self-tolerance by the fact that Treg cells have the potential to suppress self-reactive lymphocytes that recognize antigens different from those recognized by the Treg cell (Fig. 15.9). This type of tolerance is known as regulatory tolerance. The key feature of regulatory tolerance is that regulatory cells can suppress autoreactive lymphocytes that recognize a variety of different self antigens, as long as the antigens are from the same tissue or are presented by the same antigen-presenting cell. As discussed in Chapter 9, two general types of regulatory T cells have been defined experimentally. ‘Natural’ Treg (nTreg) cells are programmed in the thymus to express the transcription factor FoxP3 in response to self antigens. When activated by the same antigens in peripheral tissues, nTreg cells inhibit other self-reactive T cells that recognize antigens in the same tissue to prevent their differentiation into


Immunology_Janeway

Immunology_Janeway. antigens. When activated by the same antigens in peripheral tissues, nTreg cells inhibit other self-reactive T cells that recognize antigens in the same tissue to prevent their differentiation into effector T cells or prevent their effector function. ‘Induced’ T (iT ) cells also express FoxP3 but develop in peripheral immune tissues in response to antigens recognized in the presence of TGF-β but in the absence of pro-inflammatory cytokines. Giving animals large amounts of self antigen orally, which induces so-called oral tolerance (see Section 12-18), can sometimes lead to unresponsiveness to these antigens when given by other routes, and can prevent autoimmune disease. Oral tolerance is routinely generated to antigens such as food antigens and is accompanied by the generation of iTreg cells in the gut-draining mesenteric lymph nodes. These cells are known to suppress immune responses to the given antigen in the gut itself, but how the suppression in the rest of the peripheral immune


Immunology_Janeway

Immunology_Janeway. in the gut-draining mesenteric lymph nodes. These cells are known to suppress immune responses to the given antigen in the gut itself, but how the suppression in the rest of the peripheral immune system is achieved is unclear. Many investigators have hypothesized that iTreg cells could have therapeutic potential for the treatment of autoimmune disease if they could be isolated or induced to differentiate and then be infused into patients.


Immunology_Janeway

Immunology_Janeway. The importance of FoxP3—and the Treg cells whose development and function it controls—in the maintenance of immune tolerance is evident from the fact that humans and mice that carry mutations in the gene for FoxP3 rapidly develop severe, systemic autoimmunity (discussed in Section 15-21). A protective role for FoxP3-expressing Treg cells has been demonstrated in several autoimmune syndromes in mice, including diabetes, EAE, SLE, and inflammation of the large intestine, or colon (colitis). Experiments in mouse models of these diseases have established that FoxP3+ Treg cells actively suppress disease in the normal immune system, as depletion of these cells results in multi-organ autoimmune disease. Treg cells have also been shown to prevent or ameliorate other immunopathologic syndromes, such as graft-versus-host disease and graft rejection, which are described later in this chapter.


Immunology_Janeway

Immunology_Janeway. The importance of regulatory T cells has been demonstrated in several human autoimmune diseases. For example, in some patients with multiple sclerosis or with autoimmune polyglandular syndrome type 2 (a rare syndrome in which two or more autoimmune diseases occur simultaneously), the suppressive activity of FoxP3+ Treg cells is defective, although their numbers are normal. Thus, Treg cells have an important role in preventing autoimmunity, and a variety of functional defects in these cells may lead to autoimmunity. FoxP3-expressing Treg cells are not the only type of regulatory lymphocyte that has been identified. For example, FoxP3-negative regulatory T cells characterized by their production of IL-10 are enriched in the intestinal tissues, where they may suppress inflammatory bowel disease (IBD) through an IL-10dependent mechanism. The developmental origins of these cells are not currently understood.


Immunology_Janeway

Immunology_Janeway. Almost every type of lymphocyte has been shown to display regulatory activity in some circumstance. Even B cells can regulate experimentally induced autoimmune syndromes, including collagen-induced arthritis (CIA) and EAE. This activity is probably mediated in a similar way to that of regulatory CD4 T cells, with the secretion of cytokines that inhibit proliferation and differentiation of effector T cells.


Immunology_Janeway

Immunology_Janeway. In addition to the extrinsic regulation of autoreactive T and B cells by regulatory cells, lymphocytes have intrinsic proliferation and survival limits that can help restrict autoimmune as well as normal responses (see Section 11-16). This is illustrated by the development of spontaneous autoimmunity that is caused by mutations in pathways that control apoptosis, such as the Bcl-2 pathway or the Fas pathway (see Section 7-23); mutations in these pathways lead to spontaneous autoimmunity. This form of autoimmunity provides evidence that autoreactive cells are normally generated but are then eliminated by apoptosis. This seems to be an important mechanism for both Tand B-cell tolerance.


Immunology_Janeway

Immunology_Janeway. periphery thymus periphery Cytokines (IL-10 and TGF-˜) produced by Treg cells inhibit other self-reactive T cells TGF-˜Regulatory tolerance T cell specifc for self antigen recognized in thymus becomes a natural regulatory T cell (nTreg) T cell specifc for self or commensal microbiota antigen recognized in presence of TGF-˜becomes an induced regulatory T cell (iTreg) Fig. 15.9 Tolerance mediated by regulatory T cells can inhibit multiple autoreactive T cells that all recognize antigens from the same tissue.


Immunology_Janeway

Immunology_Janeway. Fig. 15.9 Tolerance mediated by regulatory T cells can inhibit multiple autoreactive T cells that all recognize antigens from the same tissue. Specialized autoreactive natural regulatory T (nTreg) cells develop in the thymus in response to stimulation by self antigens that is too weak to cause deletion but is greater than required for simple positive selection (upper left panel). Regulatory T cells can also be induced from naive self‑reactive T cells in the periphery if the naive T cell recognizes its antigen and is activated in the presence of the cytokine TGF‑β (upper right panel). The lower panel shows how regulatory T cells, both natural and induced, can inhibit other self‑reactive T cells. If regulatory T cells encounter their self antigen on an antigen‑presenting cell, they secrete inhibitory cytokines such as IL‑10 and TGF‑β that inhibit all surrounding autoreactive T cells, regardless of their precise autoantigen specificity. Summary.


Immunology_Janeway

Immunology_Janeway. Discrimination between self and nonself is imperfect, partly because a proper balance must be struck between preventing autoimmune disease and preserving immune competence. Self-reactive lymphocytes always exist in the natural immune repertoire but are not often activated. In autoimmune diseases, however, these cells become activated by autoantigens. If activation persists, autoreactive effector lymphocytes are generated and cause disease. The immune system has a remarkable set of mechanisms that work together to prevent autoimmune disease (see Fig. 15.2). This collective action means that each mechanism need not work perfectly nor apply to every possible self-reactive cell. Self-tolerance begins during lymphocyte development, when autoreactive T cells in the thymus and B cells in the bone marrow are deleted or, in the case of CD4 T cells, give rise to a subpopulation of self antigen-reactive FoxP3+ ‘natural’ or ‘thymic’ Treg cells that suppress autoimmune responses after exiting the


Immunology_Janeway

Immunology_Janeway. marrow are deleted or, in the case of CD4 T cells, give rise to a subpopulation of self antigen-reactive FoxP3+ ‘natural’ or ‘thymic’ Treg cells that suppress autoimmune responses after exiting the thymus. Mechanisms of peripheral tolerance, such as anergy and deletion, or the extrathymic production of ‘induced’ or ‘peripheral’ Treg cells, complement these central tolerance mechanisms for antigens that are not expressed in the thymus or bone marrow. Weakly self-reactive lymphocytes are not removed in the primary lymphoid tissues (thymus and bone marrow), as deletion of weakly autoreactive cells would impose too great a limitation on the immune repertoire, resulting in impaired immune responses to pathogens. Instead, weakly self-reactive cells are suppressed only if they are activated in the periphery, and the mechanisms that suppress them include inhibition by T cells, which are themselves autoreactive, although not pathogenic. T cells can inhibit self-reactive lymphocytes if the


Immunology_Janeway

Immunology_Janeway. in the periphery, and the mechanisms that suppress them include inhibition by T cells, which are themselves autoreactive, although not pathogenic. T cells can inhibit self-reactive lymphocytes if the regulatory cells are targeting autoantigens located in the same vicinity as the autoantigens to which the self-reactive lymphocytes respond. This allows regulatory cells to home to and suppress sites of autoimmune inflammation. A final mechanism that controls autoimmunity is the natural tendency of immune responses to be self-limited; intrinsic programs in activated lymphocytes make them prone to apoptosis. Activated lymphocytes also acquire sensitivity to external apoptosis-inducing signals, such as those mediated by Fas.


Immunology_Janeway

Immunology_Janeway. Autoimmune diseases and pathogenic mechanisms.


Immunology_Janeway

Immunology_Janeway. Here we describe some common clinical autoimmune syndromes, and ways in which loss of self-tolerance can generate self-reactive lymphocytes that cause tissue damage. The mechanisms of pathogenesis resemble in many ways those that target invading pathogens. Damage by autoantibodies, mediated through the complement and Fc receptor systems, has an important role in some diseases, such as SLE. Similarly, cytotoxic T cells directed at self tissues destroy them much as they would virus-infected cells; this is one way by which pancreatic β cells are destroyed in diabetes. However, unlike most pathogens, self proteins are not typically eliminated, so that, with rare exceptions—such as the islet cells in the pancreas—the response persists chronically. Some pathogenic mechanisms are unique to autoimmunity, such as antibodies against cell-surface receptors that affect their function, as in myasthenia gravis. In this part of the chapter we describe the pathogenic mechanisms of some major


Immunology_Janeway

Immunology_Janeway. to autoimmunity, such as antibodies against cell-surface receptors that affect their function, as in myasthenia gravis. In this part of the chapter we describe the pathogenic mechanisms of some major autoimmune diseases.


Immunology_Janeway

Immunology_Janeway. 15-8 Specific adaptive immune responses to self antigens can cause autoimmune disease.


Immunology_Janeway

Immunology_Janeway. In certain genetically susceptible strains of experimental animals, autoimmune disease can be induced by the injection of ‘self’ tissues that were taken from a genetically identical animal and mixed with strong adjuvants (see Appendix I, Section A-1). This shows directly that autoimmunity can be provoked by inducing a specific adaptive immune response to self antigens. Such experimental systems highlight the importance of the activation of other components of the immune system, primarily dendritic cells, by bacteria contained in the adjuvant. There are drawbacks to the use of such animal models for the study of autoimmunity, however. In humans and genetically autoimmune-prone animals, autoimmunity usually arises spontaneously: that is, we do not know what events initiate the immune response to self that leads to autoimmune disease. By studying the patterns of autoantibodies and particular tissues affected, it has been possible to identify some of the self antigens that are targets of


Immunology_Janeway

Immunology_Janeway. to self that leads to autoimmune disease. By studying the patterns of autoantibodies and particular tissues affected, it has been possible to identify some of the self antigens that are targets of autoimmune disease, although it has yet to be proven that the immune reaction was initiated in response to these same antigens.


Immunology_Janeway

Immunology_Janeway. Some autoimmune disorders may be triggered by infectious agents that express an epitope resembling a self antigen found in a tissue and that lead to sensitization of the patient against that tissue. There is, however, also evidence from animal models of autoimmunity that some autoimmune disorders are caused by internal dysregulation of the immune system without the apparent participation of infectious agents. 15-9 Autoimmunity can be classified into either organ-specific or systemic disease.


Immunology_Janeway

Immunology_Janeway. The classification of disease is an uncertain science, especially in the absence of a precise understanding of causative mechanisms. This is well illustrated by the difficulty in classifying autoimmune diseases. From a clinical perspective it is often useful to distinguish between the following two major patterns of autoimmunity: diseases restricted to specific organs of the body, known as ‘organ-specific’ autoimmune diseases; and those in which many tissues of the body are affected, the ‘systemic’ autoimmune diseases. In both types, disease has a tendency to become chronic because, with a few notable exceptions (for example, Hashimoto’s thyroiditis), autoantigens are rarely cleared from the body. Some autoimmune diseases seem to be dominated by the pathogenic effects of a particular immune effector pathway, either autoantibodies or effector T cells. However, both of these pathways often contribute to the overall pathogenesis.


Immunology_Janeway

Immunology_Janeway. In organ-specific diseases, autoantigens from one or a few organs are targeted, and disease is limited to those organs. Examples include Hashimoto’s thyroiditis and Graves’ disease, which both predominantly affect the thyroid gland; and type 1 diabetes, which is caused by immune attack on insulin-producing pancreatic β cells. Examples of systemic autoimmune disease are SLE and primary Sjögren’s syndrome, in which tissues as diverse as the skin, kidneys, and brain may all be affected (Fig. 15.10).


Immunology_Janeway

Immunology_Janeway. The autoantigens recognized in these two categories of disease are themselves organ-specific and systemic, respectively. Thus, Graves’ disease is characterized by the production of antibodies against the thyroid-stimulating hormone (TSH) receptor, Hashimoto’s thyroiditis by antibodies against thyroid peroxidase, and type 1 diabetes by anti-insulin antibodies. By contrast, SLE is characterized by the presence of antibodies against antigens that are ubiquitous and abundant in every cell of the body, such as chromatin and the proteins of the pre-mRNA splicing machinery—the spliceosome complex. A strict separation of diseases into organ-specific and systemic categories does, however, break down to some extent, because not all autoimmune diseases can be usefully classified in this manner. For example, autoimmune hemolytic anemia, in which red blood cells are destroyed, sometimes occurs


Immunology_Janeway

Immunology_Janeway. Diseases that tend to occur in clusters are grouped in single boxes. Clustering is defined as more than one disease affecting a single patient or different members of a family. Not all autoimmune diseases can be classified according to this scheme. For example, autoimmune hemolytic anemia can occur in isolation or in association with systemic lupus erythematosus. as a solitary entity and could be classified as an organ-specific disease. In other circumstances it can occur in conjunction with SLE as part of a systemic autoimmune disease.


Immunology_Janeway

Immunology_Janeway. A prevalent variant of chronic inflammatory disease is inflammatory bowel disease (IBD), which includes two main clinical entities—Crohn’s disease (discussed later in this chapter) and ulcerative colitis. We discuss IBD in this chapter because it has many features of an autoimmune disease, even though it is not primarily targeted against self-tissue antigens. Instead, the targets of the dysregulated immune response in IBD are antigens derived from the commensal microbiota resident in the intestines. Strictly speaking, therefore, IBD is an outlier among autoimmune diseases in that the immune response is not directed against ‘self’ antigens; rather, it is directed against microbial antigens of the resident, or ‘self,’ microbiota. Nevertheless, features of immune tolerance breakdown are also seen in IBD, and, as with the organ-specific autoimmune diseases, the tissue destruction wrought by the aberrant immune response is primarily localized to a single organ—the intestines.


Immunology_Janeway

Immunology_Janeway. 15-10 Multiple components of the immune system are typically recruited in autoimmune disease. Immunologists have long been concerned with which parts of the immune system are important in different autoimmune syndromes, because this can be useful in understanding disease etiology and developing therapies. In myasthenia gravis, for example, autoantibodies produced against the acetylcholine receptor block receptor function at the neuromuscular junction, resulting in a syndrome of muscle weakness. In other autoimmune conditions, antibodies in the form of immune complexes are deposited in tissues and cause tissue damage as a consequence of the inflammation that results from complement activation and ligation of Fc receptors on inflammatory cells.


Immunology_Janeway

Immunology_Janeway. Relatively common autoimmune diseases in which effector T cells seem to be the main destructive agents include type 1 diabetes, psoriasis, IBD, and multiple sclerosis. In these diseases, T cells recognize self peptides or peptides derived from the commensal microbiota that are complexed with self MHC molecules. The damage in such diseases is caused by T cells recruiting and activating myeloid cells of the innate immune system to cause local inflammation, or by direct T-cell damage to tissue cells.


Immunology_Janeway

Immunology_Janeway. When disease can be transferred from a diseased individual to a healthy one by transferring autoantibodies and/or self-reactive T cells, this both confirms that the disease is autoimmune in nature and also proves the involvement of the transferred material in the pathological process. In myasthenia gravis, serum from affected patients can transfer symptoms to animal recipients, thus proving the pathogenic role of the anti-acetylcholine autoantibodies (Fig. 15.11). Similarly, in the animal model disease EAE, T cells from affected animals can transfer disease to normal animals (Fig. 15.12).


Immunology_Janeway

Immunology_Janeway. Fig. 15.11 Identification of autoantibodies that can transfer disease in patients with myasthenia gravis. Autoantibodies from the serum of patients with myasthenia gravis immunoprecipitate the acetylcholine receptor from lysates of skeletal muscle cells (right‑hand panels). Because the antibodies can bind to both the murine and the human acetylcholine receptor, they can transfer disease when injected into mice (bottom panel). This experiment demonstrates that the antibodies are pathogenic. However, to be able to produce antibodies, the same patients should also have CD4 T cells that respond to a peptide derived from the acetylcholine receptor. To detect them, T cells from patients with myasthenia gravis are isolated and grown in the presence of the acetylcholine receptor plus antigen‑presenting cells of the correct MHC type (left‑hand panels). T cells specific for epitopes of the acetylcholine receptor are stimulated to proliferate and can thus be detected.


Immunology_Janeway

Immunology_Janeway. Disease can be transmitted by transfer of T cells from affected animal Mice injected with myelin basic protein and complete Freund's adjuvant develop EAE and are paralyzed The disease is mediated by TH17 and TH1 cells specifc for myelin basic protein TNF-˜IFN-°paralysisparalysisMouse after induction of EAE (left), compared with normal healthy mouse IL-17TH17TH1


Immunology_Janeway

Immunology_Janeway. Fig. 15.12 T cells specific for myelin basic protein mediate can also cause these disease symptoms. Inflammation of the brain inflammation of the brain in experimental autoimmune and paralysis are mediated by TH1 and TH17 cells specific for MBP. encephalomyelitis (EAE). This disease is produced in experimental Cloned MBP‑specific TH1 cells can transfer symptoms of EAE to animals by injecting them with isolated spinal cord homogenized in naive recipients provided that the recipients carry the correct MHC complete Freund’s adjuvant. EAE is due to an inflammatory reaction allele. In this system it has therefore proved possible to identify the in the brain that causes a progressive paralysis affecting first the tail peptide:MHC complex recognized by the TH1 clones that transfer and hind limbs (as shown in the mouse on the left of the photograph, disease. Other purified components of the myelin sheath can also compared with a healthy mouse on the right) before progressing induce the


Immunology_Janeway

Immunology_Janeway. limbs (as shown in the mouse on the left of the photograph, disease. Other purified components of the myelin sheath can also compared with a healthy mouse on the right) before progressing induce the symptoms of EAE, so there is more than one autoantigen to forelimb paralysis and eventual death. One of the autoantigens in this disease. Photograph from Wraith, D., et al.: Cell 1989, identified in the spinal cord homogenate is myelin basic protein 59:247–255. With permission from Elsevier. (MBP). Immunization with MBP alone in complete Freund’s adjuvant


Immunology_Janeway

Immunology_Janeway. Pregnancy can demonstrate a role for antibodies in disease, as IgG antibodies, but not T cells, can cross the placenta (see Section 10-15). For some autoimmune diseases (Fig. 15.13), transmission of autoantibodies across the placenta leads to disease in the fetus or neonate (Fig. 15.14). This provides proof in humans that autoantibodies cause some of the symptoms of autoimmunity. The symptoms of disease in the newborn infant typically disappear rapidly as


Immunology_Janeway

Immunology_Janeway. Fig. 15.13 Some autoimmune diseases that can be transferred across the placenta by pathogenic IgG autoantibodies. These diseases are caused mostly by autoantibodies against cell‑surface or tissue‑matrix molecules. This suggests that an important factor determining whether an autoantibody that crosses the placenta causes disease in the fetus or newborn baby is the accessibility of the antigen to the autoantibody. Autoimmune congenital heart block is caused by fibrosis of the developing cardiac conducting tissue, which expresses abundant Ro antigen. Ro protein is a constituent of an intracellular small cytoplasmic ribonucleoprotein. It is not yet known whether it is expressed at the cell surface of cardiac conducting tissue to act as a target for autoimmune tissue injury. Nevertheless, autoantibody binding leads to tissue damage and results in slowing of the heart rate (bradycardia).


Immunology_Janeway

Immunology_Janeway. Fig. 15.14 Antibody-mediated autoimmune diseases can is little lasting damage because the symptoms disappear along with appear in the infants of affected mothers as a consequence the maternal antibody. In Graves’ disease, the symptoms are caused of transplacental antibody transfer. In pregnant women, IgG by antibodies against the thyroid‑stimulating hormone receptor antibodies cross the placenta and accumulate in the fetus before (TSHR). Children of mothers making thyroid‑stimulating antibody are birth (see Fig. 10.30). Babies born to mothers with IgG‑mediated born with hyperthyroidism, but this can be corrected by replacing autoimmune disease therefore frequently show symptoms similar to the plasma with normal plasma (plasmapheresis), thus removing the those of the mother in the first few weeks of life. Fortunately, there maternal antibody.


Immunology_Janeway

Immunology_Janeway. the maternal antibody is catabolized, but in some cases the antibodies cause organ injury before they are removed, such as damage to the conducting tissue of the heart in babies of mothers with SLE or Sjögren’s syndrome. Antibody clearance can be accelerated by exchange of the infant’s blood or plasma (plasmapheresis), although this is not useful after permanent injury has occurred. Figure 15.15 lists a selection of autoimmune diseases, along with the parts of the immune response that contribute to their pathogenesis. However, although the diseases noted above are clear examples that a particular effector function can drive disease, most autoimmune diseases are not caused solely by a single effector pathway. It is more useful to consider autoimmune responses, like immune responses to pathogens, as engaging the integrated immune system and typically involving T, B, and innate immune cells. Indeed,


Immunology_Janeway

Immunology_Janeway. Pathogenic Present, but role unclear Pathogenic Present, but role unclear T cells B cells AntibodyDisease Pathogenic Help for antibody Pathogenic Present antigen to T cells Present antigen to T cells Help for antibody Antibody secretion Pathogenic Present antigen to T cells Systemic lupus erythematosus Type 1 diabetes Myasthenia gravis Multiple sclerosis Autoimmune diseases involve all aspects of the immune response Fig. 15.15 Autoimmune diseases involve all aspects of the immune response.


Immunology_Janeway

Immunology_Janeway. Fig. 15.15 Autoimmune diseases involve all aspects of the immune response. Although some autoimmune diseases have traditionally been thought to be mediated by B cells or T cells, it is useful to consider that, typically, all aspects of the immune system have a role. For four important autoimmune diseases, the figure lists the roles of T cells, B cells, and antibody. In some diseases, such as SLE, T cells can have multiple roles such as helping B cells to make autoantibody and directly promoting tissue damage. B cells can have two roles as well—presenting autoantigens to stimulate T cells and secreting pathogenic autoantibodies.


Immunology_Janeway

Immunology_Janeway. although autoimmunity research has traditionally focused on identification of the antigen specificity and effector subclass of autoreactive T and B cells, experimental evidence shows that cells of the innate immune system—particularly phagocytic myeloid cells—are critical in mediating tissue damage in most autoimmune diseases. Innate lymphoid cells (ILCs) have also been found in autoimmune lesions, especially those at barrier surfaces. However, the exact role of ILCs, and whether they may be good therapeutic targets in autoimmune disorders, is currently unclear. feedback from inflammation, inability to clear the self antigen, and a broadening of the autoimmune response.


Immunology_Janeway

Immunology_Janeway. feedback from inflammation, inability to clear the self antigen, and a broadening of the autoimmune response. When normal immune responses are engaged to destroy a pathogen, the typical outcome is elimination of the foreign invader, after which the immune response ceases, accompanied by mass extinction of most effector cells and persistence of a small cohort of memory lymphocytes (see Chapter 11). In autoimmunity, however, the self antigen cannot be easily eliminated, because it is in vast excess or is ubiquitous (as is, for example, chromatin). Thus, a very important mechanism for limiting an immune response is abrogated in many autoimmune diseases.


Immunology_Janeway

Immunology_Janeway. In general, autoimmune diseases are characterized by an early activation phase with the involvement of only a few autoantigens, followed by a chronic stage. The constant presence of autoantigen leads to chronic inflammation. This leads to the release of more autoantigens as a result of tissue damage, and this breaks an important barrier to autoimmunity known as ‘sequestration,’ by which many self antigens are normally kept apart from the immune system. It also leads to the attraction of nonspecific effector cells such as macrophages and neutrophils that respond to the release of cytokines and chemokines from injured tissues (Fig. 15.16). The result is a continuing and evolving self-destructive process.


Immunology_Janeway

Immunology_Janeway. B cell is activated by a T cell specifc for self peptide B cells differentiate into plasma cells, secreting large amounts of self antigen-specifc antibody Circulating B cell binds self antigens released from injured cells At sites of injury, self antigen-specifc antibody initiates an infammatory response, causing more cell injury More B cells bind self antigens, amplifying the cycle of tissue damage Fig. 15.16 Autoantibody-mediated inflammation can lead to the release of autoantigens from damaged tissues, which in turn promotes further activation of autoreactive B cells. Autoantigens, particularly intracellular ones that are targets in SLE, stimulate B cells only when released from dying cells (first panel). The result is the activation of autoreactive T and B cells and the eventual secretion of autoantibodies (second and third panels).


Immunology_Janeway

Immunology_Janeway. These autoantibodies can mediate tissue damage through a variety of effector functions (see Chapter 10), resulting in the further death of cells (fourth panel). A positive feedback loop is established because these additional autoantigens recruit and activate additional autoreactive B cells (fifth panel), which in turn can start the cycle over again, as shown in the first panel.


Immunology_Janeway

Immunology_Janeway. Progression of the autoimmune response is often accompanied by recruitment of new clones of lymphocytes reactive to new epitopes on the initiating autoantigen, as well as new autoantigens. This phenomenon is known as epitope spreading, and is important in perpetuating and amplifying disease. As seen in Chapter 10, activated B cells can internalize cognate antigens by receptor-mediated endocytosis via their antigen receptor, process them, and present the derived peptides to T cells. Epitope spreading can occur in several ways. Because antibody-bound antigens can be more efficiently presented, self antigens that are normally present in concentrations too low to activate naive cell processing of the internalized autoantigen can reveal novel, previously hidden, peptide epitopes called cryptic epitopes that the B cell can then present to T cells. Autoreactive T cells responding to these ‘new’ epitopes will provide help to any B cells presenting these peptides, recruiting additional B-cell


Immunology_Janeway

Immunology_Janeway. epitopes that the B cell can then present to T cells. Autoreactive T cells responding to these ‘new’ epitopes will provide help to any B cells presenting these peptides, recruiting additional B-cell clones to the autoimmune reaction, with the consequent production of a greater variety of autoantibodies. In addition, on binding and internalizing specific antigen via their B-cell receptor, B cells will also internalize any other molecules closely associated with that antigen. By these routes, B cells can act as antigen-presenting cells for peptides derived from antigens completely different from the original autoantigen that initiated the autoimmune reaction.


Immunology_Janeway

Immunology_Janeway. The autoantibody response in SLE initiates these mechanisms of epitope spreading. In this disease, autoantibodies against both the protein and DNA components of chromatin are found. Figure 15.17 shows how autoreactive B cells specific for DNA can recruit autoreactive T cells specific for histone proteins, another component of chromatin, into the autoimmune response. In turn, these T cells provide help not only to the original DNA-specific B cells but also to histone-specific B cells, resulting in the production of both anti-DNA and anti-histone antibodies. Another autoimmune disease in which epitope spreading is linked to the progression of disease is pemphigus vulgaris, which is characterized by severe blistering of the skin and mucosal membranes. It is caused by autoantibodies against desmogleins, a type of cadherin present in cell junctions (desmosomes) that hold cells of the epidermis together (Fig. 15.18). Binding of


Immunology_Janeway

Immunology_Janeway. Fig. 15.17 Epitope spreading occurs when B cells specific for various components of a complex antigen are stimulated by an autoreactive helper T cell of a single specificity. In patients with SLE, an ever‑broadening immune response is made against nucleoprotein antigens such as nucleosomes, which consist of histones and DNA and are released from dying and disintegrating cells. The upper panel shows how the emergence of a single clone of autoreactive CD4 T cells can lead to a diverse B‑cell response to nucleosome components. The T cell in the center is specific for a particular peptide (red) from the linker histone H1, which is present on the surface of the nucleosome. The B cells at the top are specific for epitopes on the surface of a nucleosome, on H1 and DNA, respectively, and thus bind and endocytose intact nucleosomes, process the constituents, and present the H1 peptide to the helper T cell. Such B cells will be activated to make antibodies, which in the case of the DNA‑specific


Immunology_Janeway

Immunology_Janeway. and endocytose intact nucleosomes, process the constituents, and present the H1 peptide to the helper T cell. Such B cells will be activated to make antibodies, which in the case of the DNA‑specific B cell will be anti‑DNA antibodies. The B cell at the bottom right is specific for an epitope on histone H2, which is hidden inside the intact nucleosome and is thus inaccessible to the B‑cell receptor. This B cell does not bind the nucleosome and does not become activated by the H1‑specific helper T cell. A B cell specific for another type of nucleoprotein particle, the ribosome (which is composed of RNA and specific ribosomal proteins), will not bind nucleosomes (bottom left) and will not be activated by the T cell. In reality a T cell interacts with one B cell at a time, but different members of the same T‑cell clone will interact with B cells of different specificity. The lower panel shows the broadening of the T‑cell response to the nucleosome. The H1‑specific B cell in the center has


Immunology_Janeway

Immunology_Janeway. of the same T‑cell clone will interact with B cells of different specificity. The lower panel shows the broadening of the T‑cell response to the nucleosome. The H1‑specific B cell in the center has processed an intact nucleosome and is presenting a variety of nucleosome‑derived peptide antigens on its MHC class II molecules. This B cell can activate a T cell specific for any of these peptide antigens, which will include those from the internal histones H2, H3, and H4 as well as those from H1. This H1‑specific B cell will not activate T cells specific for peptide antigens of ribosomes because ribosomes do not contain histones.


Immunology_Janeway

Immunology_Janeway. autoantibodies to the extracellular domains of these adhesion molecules causes dissociation of the junctions and dissolution of the affected tissue. Pemphigus vulgaris usually starts with lesions in the oral and genital mucosa; only later does the skin become involved. In the mucosal stage, only autoantibodies against certain epitopes on desmoglein Dsg-3 are found, and these antibodies seem unable to cause skin blistering. Progression to the skin disease is associated both with intramolecular epitope spreading within Dsg-3, which gives rise to autoantibodies that can cause deep skin blistering, and with intermolecular epitope spreading to another desmoglein, Dsg-1, which is more abundant in the epidermis. Dsg-1 is also the autoantigen in a less severe variant of the disease, pemphigus foliaceus. In that disease, the autoantibodies first produced against Dsg-1 cause no damage, and disease appears only after autoantibodies are made against epitopes on parts of the protein involved in


Immunology_Janeway

Immunology_Janeway. In that disease, the autoantibodies first produced against Dsg-1 cause no damage, and disease appears only after autoantibodies are made against epitopes on parts of the protein involved in the adhesion of epidermal cells.


Immunology_Janeway

Immunology_Janeway. 15-12 Both antibody and effector T cells can cause tissue damage in autoimmune disease. The manifestations of autoimmune disease are caused by effector mechanisms of the immune system being directed at the body’s own tissues. As discussed previously, the response can be amplified and maintained by the constant supply of new autoantigen. An exception to this rule is type 1 diabetes, in which the autoimmune response destroys most or all of the target cells. This leads to a failure to produce sufficient insulin to maintain glucose homeostasis, resulting in the symptoms of diabetes.


Immunology_Janeway

Immunology_Janeway. Historically, the mechanisms of tissue injury in autoimmunity have been classified according to a scheme adopted for ‘hypersensitivity’ reactions that were defined in the early 1960s, prior to a more modern understanding of immune mechanisms (Fig. 15.19; also see introduction to Chapter 14). We now recognize that the dominant types of immunity that are orchestrated for the clearance of different types of pathogens are the same ones that become dysregulated in autoimmunity, and that both B and T cells, as well as effector cells of the innate immune system, contribute—even in cases where a particular type of response (for example, autoantibody-mediated cellular injury) predominates in causing tissue damage. The antigen, or group of antigens, against which the autoimmune response is directed, and the mechanism by which the antigen-bearing tissue is damaged, together determine the pathology and clinical expression of the disease.


Immunology_Janeway

Immunology_Janeway. Type 2 immune responses mediated by IgE (previously referred to as type I hypersensitivity) typically cause allergic or atopic inflammatory disease (see Chapter 14) and play no major part in most forms of autoimmunity. By contrast, autoimmunity that damages tissues by autoantibodies—whether by binding of IgG or IgM to autoantigens located on cell surfaces or extracellular matrix (type II hypersensitivity) or by tissue localization of immune complexes composed of soluble autoantigens and their cognate autoantibodies (type III hypersensitivity)—often appears to be linked to dysregulated type 3 (TH17) or type 1 (TH1) immunity, or to T-cell-independent generation of IgM-producing B cells. Because antibody-mediated injury can target a specific cell or tissue type (for example, autoimmune thyroiditis), or it can result in immune complexes that are deposited in specific vascular beds (for example, rheumatoid arthritis), disease can be organ-specific or systemic. In some forms of


Immunology_Janeway

Immunology_Janeway. thyroiditis), or it can result in immune complexes that are deposited in specific vascular beds (for example, rheumatoid arthritis), disease can be organ-specific or systemic. In some forms of autoimmunity, such as SLE, autoantibodies cause damage by both of these mechanisms. Finally, several organ-specific autoimmune diseases are due to a type 1 response in which TH1 cells and/or cytotoxic T cells directly cause tissue damage (type IV hypersensitivity; for example, type 1 diabetes); alternatively, some such diseases are due to a type 3 response in which TH17 cells promote inflammation at barrier tissues (for example, psoriasis or Crohn’s disease).


Immunology_Janeway

Immunology_Janeway. Antibodies made against Dsg-1 and Dsg-3 unzip the adhesive interactions in desmosomes EC1EC2EC3EC4EC5Dsg-3 EC1EC2EC3EC4EC5Dsg-1 keratinocyte extracellular matrix early epitope targeted in mucosal stage of disease late epitope targeted in skin stage of disease Different B-cell epitopes on desmogleins are targeted by autoantibodies Fig. 15.18 Pemphigus vulgaris is a skin-blistering disease caused by autoantibodies specific for desmoglein.


Immunology_Janeway

Immunology_Janeway. Fig. 15.18 Pemphigus vulgaris is a skin-blistering disease caused by autoantibodies specific for desmoglein. An adhesion molecule in the cell junctions that hold keratinocytes together, desmoglein is a cell‑surface protein with five extracellular domains (EC1–EC5; upper panel). Early in the autoimmune response, antibodies are made against the EC5 domain of shed desmoglein‑3 (Dsg‑3), but do not cause disease. However, in time, intra‑and intermolecular epitope spreading occurs and IgG antibodies are made against the EC1 and EC2 domains of Dsg‑3 and Dsg‑1. These autoantibodies can inhibit adhesion of desmoglein in desmosomes (lower panel), and thereby interfere with the physiological adhesive interactions of desmoglein that are necessary for maintaining skin integrity. Consequently, the antibodies cause the outer layers of the skin to separate, producing blisters.


Immunology_Janeway

Immunology_Janeway. Autoimmune diseases can be grouped according to the predominant type of immune response and the mechanism by which it damages tissues. In many autoimmune diseases, several immunopathogenic mechanisms operate in parallel. This is illustrated here for rheumatoid arthritis, which appears in more than one category of immunopathogenic mechanism.


Immunology_Janeway

Immunology_Janeway. In most autoimmune diseases, however, several mechanisms of pathogenesis operate. Thus, helper T cells are almost always required for the production of pathogenic autoantibodies. Reciprocally, B cells often have an important role in the maximal activation of T cells that mediate tissue damage or help auto-antibody production. In type 1 diabetes and rheumatoid arthritis, for example, both T-celland antibody-mediated pathways cause tissue injury. SLE is an example of autoimmunity that was previously thought to be mediated solely by antibodies and immune complexes but is now known to have a component of T-cell-mediated pathogenesis. Moreover, in virtually all autoimmune diseases, innate immune cells contribute to inflammation and antibodyor T-cell-mediated tissue injury. We will first examine how autoantibodies cause tissue damage, then consider self-reactive T-cell responses and their role in autoimmunity. 15-13 Autoantibodies against blood cells promote their destruction.


Immunology_Janeway

Immunology_Janeway. 15-13 Autoantibodies against blood cells promote their destruction. IgG or IgM responses to antigens located on the surface of blood cells lead to the rapid destruction of these cells. An example of this is autoimmune hemolytic anemia, in which antibodies against self antigens on red blood cells trigger destruction of the cells, leading to anemia. This can occur in two ways (Fig. 15.20). Red cells with bound IgG or IgM antibody can be rapidly cleared from the circulation by interaction with Fc or complement receptors, respectively, on cells of the mononuclear–macrophage phagocytic system, particularly in the spleen. Alternatively, the autoantibody-sensitized red blood cells can be lysed by formation of the membrane-attack complex of complement. In autoimmune thrombocytopenic purpura, autoantibodies against the GpIIb:IIIa fibrinogen receptor or other platelet-specific surface antigens can cause thrombocytopenia (a depletion of platelets), which can in turn cause hemorrhage.


Immunology_Janeway

Immunology_Janeway. Lysis of nucleated cells by complement is less common because these cells are better defended by complement-regulatory proteins, which protect cells against immune attack by interfering with the activation of complement components (see Section 2-15). Nevertheless, circulating nucleated cells targeted by autoantibodies are still destroyed by cells of the mononuclear phagocytic system or NK cells via antibody-dependent cell-mediated cytotoxicity (ADCC). Autoantibodies against neutrophils, for example, cause neutropenia, which increases susceptibility to infection with pyogenic bacteria. In all these cases, accelerated clearance of autoantibody-sensitized cells is the cause of their depletion. One therapeutic approach to this type of autoimmunity is removal of the spleen, the organ in which the main clearance of red cells, platelets, and leukocytes occurs. Another is the administration of large quantities of nonspecific IgG (termed IVIG, for intravenous immunoglobulin), which among other


Immunology_Janeway

Immunology_Janeway. main clearance of red cells, platelets, and leukocytes occurs. Another is the administration of large quantities of nonspecific IgG (termed IVIG, for intravenous immunoglobulin), which among other mechanisms inhibits the Fc receptor-mediated uptake of antibody-coated cells and activates inhibitory Fc receptors to suppress production of inflammatory mediators by myeloid cells.


Immunology_Janeway

Immunology_Janeway. 15-14 The fixation of sublytic doses of complement to cells in tissues stimulates a powerful inflammatory response. The binding of IgG and IgM antibodies to cells in tissues causes inflammatory injury by a variety of mechanisms. One of these is the fixation of complement. Although nucleated cells are relatively resistant to lysis by complement, the assembly of sublytic amounts of the membrane-attack complex on their surface provides a powerful activating stimulus. Depending on the cell type, this interaction can cause cytokine release, a respiratory burst, or the mobilization of membrane phospholipids to generate arachidonic acid—the precursor of prostaglandins and leukotrienes, lipid mediators of inflammation.


Immunology_Janeway

Immunology_Janeway. Most cells in tissues are fixed in place, and innate and adaptive immune cells are attracted to them by chemoattractant molecules. One such molecule is the complement fragment C5a, which is released as a result of complement activation triggered by autoantibody binding. Other chemoattractants, such as leukotriene B4, can be released by the autoantibody-targeted cells. Inflammatory leukocytes are further activated by binding to autoantibody Fc regions and fixed complement C3 fragments on cells. Tissue injury can result from the products of the activated leukocytes and by antibody-dependent cellular cytotoxicity mediated by NK cells (see Section 10-23). A probable example of this type of autoimmunity is Hashimoto’s thyroiditis, in which autoantibodies against tissue-specific antigens are found at extremely high levels for prolonged periods. Direct T-cell-mediated cytotoxicity, which we discuss later, is probably also important in this disease.


Immunology_Janeway

Immunology_Janeway. Fig. 15.20 Antibodies specific for cell-surface antigens can destroy cells. In autoimmune hemolytic anemias, red blood cells (erythrocytes) coated with IgG autoantibodies against a cell‑surface antigen (upper panel) are rapidly cleared from the circulation by uptake by Fc receptor‑bearing macrophages located primarily in the spleen (lower left panel). Erythrocytes coated with IgM autoantibodies fix C3 and are cleared by CR1‑bearing macrophages. The binding of certain rare autoantibodies that fix complement extremely efficiently causes the formation of the membrane‑attack complex on the red cells, leading to intravascular hemolysis (lower right panel).


Immunology_Janeway

Immunology_Janeway. Fig. 15.21 Feedback regulation of thyroid hormone production is disrupted in Graves’ disease. Graves’ disease is caused by autoantibodies specific for the receptor for thyroid‑stimulating hormone (TSH). Normally, thyroid hormones are produced in response to TSH and limit their own production by inhibiting the production of TSH by the pituitary (left panels). In Graves’ disease, the autoantibodies are agonists for the TSH receptor and therefore stimulate the production of thyroid hormones (right panels). The thyroid hormones inhibit TSH production in the normal way but do not affect production of the autoantibody; the excessive thyroid hormone production induced in this way causes hyperthyroidism. 15-15 Autoantibodies against receptors cause disease by stimulating or blocking receptor function.


Immunology_Janeway

Immunology_Janeway. 15-15 Autoantibodies against receptors cause disease by stimulating or blocking receptor function. Autoimmune disease can occur when autoantibody binds a cell-surface receptor. Antibody binding to a receptor can either stimulate the receptor or block stimulation by the natural ligand. In Graves’ disease, autoantibodies against the thyroid-stimulating hormone (TSH) receptor on thyroid cells stimulate excessive production of thyroid hormone. The production of thyroid hormone is normally controlled by feedback regulation; high levels of thyroid hormone inhibit the release of TSH by the pituitary. In Graves’ disease, feedback inhibition fails because the autoantibody continues to stimulate the TSH receptor in the absence of TSH, and the patient produces chronically elevated levels of thyroid hormone (‘hyperthyroidism’; Fig. 15.21).


Immunology_Janeway

Immunology_Janeway. In myasthenia gravis, autoantibodies against the α chain of the nicotinic acetylcholine receptor present at neuromuscular junctions in skeletal muscle cells can block stimulation of muscle contraction. The antibodies are believed to drive internalization and degradation of the receptor (Fig. 15.22). Fig. 15.22 Autoantibodies inhibit receptor function in myasthenia gravis. In normal circumstances, acetylcholine released from stimulated motor neurons at the neuromuscular junction binds to acetylcholine receptors on skeletal muscle cells, triggering muscle contraction (upper panel). Myasthenia gravis is caused by autoantibodies against the α subunit of the receptor for acetylcholine. These autoantibodies bind to the receptor without activating it and also cause receptor internalization and degradation (lower panel). As the number of receptors on the muscle is decreased, the muscle becomes less responsive to acetylcholine.


Immunology_Janeway

Immunology_Janeway. Fig. 15.23 Autoimmune diseases caused by autoantibodies against cell-surface receptors. These antibodies produce different effects depending on whether they are agonists (which stimulate the receptor) or antagonists (which inhibit it). Note that different autoantibodies against the insulin receptor can either stimulate or inhibit signaling. Patients with myasthenia gravis develop potentially fatal progressive weakness as a result of their disease. Diseases caused by autoantibodies that act as agonists or antagonists on cell-surface receptors are listed in Fig. 15.23. 15-16 Autoantibodies against extracellular antigens cause inflammatory injury.


Immunology_Janeway

Immunology_Janeway. 15-16 Autoantibodies against extracellular antigens cause inflammatory injury. Antibody responses to extracellular matrix molecules are infrequent, but can be very damaging. In Goodpasture’s syndrome, antibodies are formed against the α3 chain of basement membrane collagen (type IV collagen). These antibodies bind to the basement membranes of renal glomeruli (Fig. 15.24) and, in some cases, to the basement membranes of pulmonary alveoli, causing a rapidly fatal disease if untreated. The autoantibodies bound to basement membrane ligate Fcγreceptors on innate effector cells, such as monocytes and neutrophils, leading to their activation. These cells, in turn, release chemokines that attract a further influx of monocytes and neutrophils into glomeruli, causing severe tissue injury. The autoantibodies also cause a local activation of complement, which amplifies tissue injury.


Immunology_Janeway

Immunology_Janeway. Immune complexes are produced when there is an antibody response to a soluble antigen. Normally, such complexes cause little tissue damage because they are cleared efficiently by red blood cells that bear complement receptors and by phagocytes of the mononuclear phagocytic system that have both complement and Fc receptors. This clearance system can, however, fail in circumstances where the production of immune complexes exceeds the capacity Fig. 15.24 Autoantibodies reacting with glomerular basement membrane cause the inflammatory glomerular disease known as Goodpasture’s syndrome.


Immunology_Janeway

Immunology_Janeway. Upper two panels: schematic of antibody‑mediated damage to a glomerulus of the kidney. The autoantibody binds to type IV collagen within the basement membrane of the glomerular capillaries, causing complement activation and recruitment and activation of neutrophils and monocytes. Third panel: section of renal glomerulus in biopsy taken from the kidney of a patient with Goodpasture’s syndrome. The glomerulus is stained for IgG deposition by immunofluorescence. Anti‑glomerular basement membrane antibody (stained green) is deposited in a linear fashion along the glomerular basement membrane. Bottom panel: silver staining of a section through a renal glomerulus shows that the glomerulus capillaries (G) are compressed by the formation of a crescent (C), composed of proliferating epithelial cells and an influx of neutrophils (N) and monocytes (M), that have filled the urinary (Bowman's) space surrounding the glomerular capillaries.


Immunology_Janeway

Immunology_Janeway. monocyte or dendritic cell autoreactive B-cell survival Increased autoantibodies BAFF BAFF-R BCMA TACI dsDNA immune complex ssRNA apoptotic cellnecrotic cell IFN-˜IFN-˜plasmacytoid dendritic cell MyD88TLR-7 TLR-9 Nucleic acid-containing immune complexes generated from dying cells activate plasmacytoid DCs to produce IFN-˜IFN-˜stimulates myeloid cells to produce BAFF, which enhances the survival and autoantibody production of autoreactive B cells Fig. 15.25 Defective clearance of nucleic acid-containing immune complexes activates overproduction of BAFF and type I interferons that can cause SLE.


Immunology_Janeway

Immunology_Janeway. of the normal clearance mechanisms, or when there are deficiencies in normal clearance mechanisms. An example of the former is serum sickness (see Section 14-15), which is caused by the injection of large amounts of serum proteins or by small-molecule drugs binding to serum proteins and acting as haptens. Serum sickness is a transient disease, lasting until the immune complexes have been cleared. Similarly, normal clearance mechanisms can be overwhelmed in chronic infections, such as bacterial endocarditis, in which the immune response to bacteria lodged on a cardiac valve is incapable of clearing the infection. The persistent release of bacterial antigens from the valve infection in the presence of a strong antibacterial antibody response causes widespread immune-complex injury to small blood vessels in organs such as the kidney and the skin. Other chronic infections, such as hepatitis C infection, can lead to the production of cryoglobulins and the condition mixed essential


Immunology_Janeway

Immunology_Janeway. small blood vessels in organs such as the kidney and the skin. Other chronic infections, such as hepatitis C infection, can lead to the production of cryoglobulins and the condition mixed essential cryoglobulinemia, in which immune complexes are deposited in joints and tissues. Alternatively, there can be inherited impairment of mechanisms that contribute to normal clearance of immune complexes; such impairment may be caused by reduced expression of or functional defects in specific components of either complement or its receptors, or in Fc receptors, each of which occurs in subsets of patients with SLE.


Immunology_Janeway

Immunology_Janeway. Indeed, SLE can result from either the overproduction or the defective clearance of immune complexes, or both, at multiple levels (Fig. 15.25). In this disease, there is chronic IgG antibody production directed at ubiquitous self antigens present in nucleated cells, leading to a wide range of autoantibodies against common cellular constituents. The main antigens are three types of intracellular nucleoprotein particles—the nucleosome subunits of chromatin, the spliceosome, and a small cytoplasmic ribonucleoprotein complex containing two proteins known as Ro and La (named after the first two letters of the surnames of the two patients in whom autoantibodies against these proteins were discovered). For these autoantigens to participate in immune-complex formation, they must become extracellular. The autoantigens of SLE are exposed on dead and dying cells released from injured tissues.


Immunology_Janeway

Immunology_Janeway. In SLE, large quantities of antigen are available, so large amounts of small immune complexes are produced continuously and are deposited in the walls of small blood vessels in the renal glomerular basement membrane, joints, and other organs (Fig. 15.26). This leads to the activation of phagocytic cells through their Fc receptors. A hereditary deficiency of some complement proteins, specifically those for C1q, C2, and C4, is strongly associated with the development of SLE in humans. C1q, C2, and C4 are early components in the classical complement pathway, which is important in antibody-mediated clearance of apoptotic cells and immune complexes (see Chapter 2). If apoptotic cells and immune complexes are not cleared, the chance that their antigens will activate low-affinity self-reactive lymphocytes in the periphery is increased. The consequent tissue damage releases more nucleoprotein complexes, which in turn form more immune complexes. During this process, autoreactive T cells also


Immunology_Janeway

Immunology_Janeway. lymphocytes in the periphery is increased. The consequent tissue damage releases more nucleoprotein complexes, which in turn form more immune complexes. During this process, autoreactive T cells also become activated, although much less is known about their specificity. Animal models for SLE cannot be initiated without the help of T cells, and T cells can also be directly pathogenic, forming part of the cellular infiltrates in the skin and kidney. As discussed in the next section,


Immunology_Janeway

Immunology_Janeway. In SLE, it is believed that antibody:nucleic acid immune complexes containing, for example, ssRNA or dsDNA from dead cells, are bound by FcγRIIa (green rods) on plasmacytoid dendritic cells. The Fc receptor‑bound ssRNA and dsRNA are delivered to endosomes, where they activate TLR‑7 and TLR‑9, respectively, to induce IFN‑α production (upper panel). IFN‑α increases BAFF production by monocytes and dendritic cells, and BAFF interacts with receptors on B cells. Excess BAFF can increase autoreactive B‑cell survival, leading to increased autoantibody production (lower panel). T cells contribute to autoimmune disease in two ways: by helping B cells make antibodies, analogous to a normal T-dependent immune response; and by direct effector functions as they infiltrate and destroy target tissues. 15-17 T cells specific for self antigens can cause direct tissue injury and sustain autoantibody responses.


Immunology_Janeway

Immunology_Janeway. Traditionally, it has been more difficult for a number of reasons to demonstrate the existence of autoreactive T cells than the presence of autoantibodies. First, autoreactive human T cells cannot transfer disease to experimental animals because T-cell recognition is MHC-restricted. Second, autoantibodies can be used to stain self tissues to reveal distribution of the autoantigen, whereas T cells cannot be used in the same way. However, the use of fluorophore-labeled peptide–MHC tetramers (see Appendix 1, Section A-24) that can stain antigen-specific T cells for flow cytometry is now providing a means to both identify and track autoreactive T cells in vivo in autoimmune diseases. Furthermore, there is already strong evidence for the involvement of autoreactive T cells in many autoimmune diseases. In type 1 diabetes, for example, the insulin-producing βcells of the pancreatic islets are selectively destroyed by cytotoxic T cells. This is borne out by the finding that in the rare cases


Immunology_Janeway

Immunology_Janeway. In type 1 diabetes, for example, the insulin-producing βcells of the pancreatic islets are selectively destroyed by cytotoxic T cells. This is borne out by the finding that in the rare cases in which patients with diabetes were transplanted with half a pancreas from an identical twin donor, the βcells in the grafted tissue were rapidly and selectively destroyed by the recipient’s T cells. Recurrence of disease can be prevented by the immunosuppressive drug cyclosporin A (see Chapter 16), which inhibits T-cell activation.


Immunology_Janeway

Immunology_Janeway. Autoantigens recognized by CD4 T cells can be identified by adding cells or tissues containing autoantigens to cultures of blood mononuclear cells, and testing for recognition by CD4 cells derived from an autoimmune patient. If the autoantigen is present, it should be effectively recognized by autoreactive CD4 T cells. The identification of autoantigenic peptides is particularly difficult in autoimmune diseases in which CD8 T cells have a role, because autoantigens recognized by CD8 T cells are not effectively presented in such cultures. Peptides presented by MHC class I molecules must usually be made by the target cells themselves (see Chapter 6); intact cells of target tissue from the patient must therefore be used to study autoreactive CD8 T cells that cause tissue damage. Conversely, the pathogenesis of the disease can itself give clues to the identity of the antigen in some CD8 T-cell-mediated diseases. For example, in type 1 diabetes, the insulin-producing β cells seem to be


Immunology_Janeway

Immunology_Janeway. the pathogenesis of the disease can itself give clues to the identity of the antigen in some CD8 T-cell-mediated diseases. For example, in type 1 diabetes, the insulin-producing β cells seem to be specifically targeted and destroyed by CD8 T cells (Fig. 15.27). This suggests that a protein unique to β cells is the source of the peptide recognized by the pathogenic CD8 T cells. Studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes have shown that peptides from insulin itself are recognized by pathogenic CD8 T cells, confirming insulin as one of the principal autoantigens in this model of diabetes.


Immunology_Janeway

Immunology_Janeway. Multiple sclerosis (MS) is a T-cell-mediated neurologic disease caused by a destructive immune response against central nervous system myelin antigens, Fig. 15.26 Deposition of immune complexes in the renal glomeruli causes renal failure in systemic lupus erythematosus (SLE). Panel a: a section through a renal glomerulus from a patient with SLE, showing that the deposition of immune complexes has caused thickening of the glomerular basement membrane, seen as the clear ‘canals’ running through the glomerulus. Panel b: a similar section stained with fluorescent antiimmunoglobulin, revealing immunoglobulin deposits in the basement membrane. In panel c, the immune complexes are seen under the electron microscope as dense protein deposits between the glomerular basement membrane and the renal epithelial cells. Polymorphonuclear neutrophilic leukocytes are also present, attracted by the deposited immune complexes. Photographs courtesy of H.T. Cook and M. Kashgarian.


Immunology_Janeway

Immunology_Janeway. Fig. 15.27 Selective destruction of pancreatic β cells in type 1 diabetes indicates that the autoantigen is produced in β cells and recognized on their surface. In type 1 diabetes there is highly specific destruction of insulin‑producing β cells in the pancreatic islets of Langerhans, sparing other islet cell types (α and δ). This is shown schematically in the upper panels. In the lower panels, islets from normal (left) and diabetic (right) mice are stained for insulin (brown), which shows the β cells, and for glucagon (black), which shows the α cells. Note the lymphocytes infiltrating the islet in the diabetic mouse (right) and the selective loss of the β cells (brown), whereas the α cells (black) are spared. The characteristic morphology of the islet is also disrupted with the loss of the β cells. Photographs courtesy of I. Visintin.


Immunology_Janeway

Immunology_Janeway. ˜ cell˛ cell˝ cellThe islets of Langerhans contain several cell types secreting distinct hormones. Each cell expresses different tissue-speciÿc proteins glucagoninsulinsomatostatinGlucagon and somatostatin are still produced by the ˜and °cells, but no insulin can be made In type 1 diabetes an effector T cell recognizes peptides from a ˛-cell speciÿc protein and kills the ˛cell CTL including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG) (Fig. 15.28). MS takes its name from the hard (sclerotic) lesions, or plaques, that develop in the white matter of the central nervous system. These lesions show dissolution of the myelin sheath that normally surrounds nerve cell axons, along with inflammatory infiltrates of lymphocytes and macrophages, particularly surrounding blood vessels. Patients with MS may develop a variety of neurological symptoms, including muscle weakness, ataxia, blindness, and paralysis. Normally, few lymphocytes cross


Immunology_Janeway

Immunology_Janeway. particularly surrounding blood vessels. Patients with MS may develop a variety of neurological symptoms, including muscle weakness, ataxia, blindness, and paralysis. Normally, few lymphocytes cross the blood–brain barrier, but if this barrier breaks down, activated CD4 T cells specific for myelin antigens and expressing α4:β1 integrin can bind vascular cell adhesion molecules (VCAMs) on activated endothelium (see Section 11-3), enabling the T cells to migrate out of the blood vessel. There they reencounter their specific autoantigen presented by MHC class II molecules on infiltrating macrophages or microglial cells (phagocytic macrophage-like cells resident in the central nervous system). Inflammation causes increased vascular permeability, and the site becomes heavily infiltrated by TH17 and TH1 effector CD4 T cells, which produce IL-17, IFN-γ, and GM-CSF. Cytokines and chemokines produced by these effector T cells in turn recruit and activate myeloid cells that exacerbate


Immunology_Janeway

Immunology_Janeway. by TH17 and TH1 effector CD4 T cells, which produce IL-17, IFN-γ, and GM-CSF. Cytokines and chemokines produced by these effector T cells in turn recruit and activate myeloid cells that exacerbate inflammation, resulting in further recruitment of T cells, B cells, and innate immune cells to the lesion. Autoreactive B cells produce autoantibodies against myelin antigens with help from T cells. These combined activities lead to demyelination and interference with neuronal function.


Immunology_Janeway

Immunology_Janeway. The clinical course of MS both mirrors what is seen in other autoimmune diseases and also displays how the tissue specificity of such conditions affects their progression. Most MS patients experience a disease course characterized by acute attacks (relapse) followed by a reduction in disease activity (remission) that may last for months or years. This relapsing–remitting course is characteristic of many autoimmune diseases (besides MS, Crohn’s disease and rheumatoid arthritis, among others), in terms of both the symptoms patients experience and the degree of immune-cell infiltration into the affected organ. Not only are the triggers of relapses not always clear, but the events leading to spontaneous disease remission—even when the autoantigen is still present


Immunology_Janeway

Immunology_Janeway. Infammatory reaction occurs in the brain due to mast-cell activation, complement activation, antibodies, and cytokines in the organ—remain to be discovered. Furthermore, the relapsing–remitting nature of diseases such as MS makes conducting clinical trials around these disorders especially difficult, as they must be performed over relatively long periods of time to ensure a therapy is effective in preventing relapses and disability.


Immunology_Janeway

Immunology_Janeway. Ultimately, often after decades, most MS patients change from a relapsing– remitting disease course to ‘secondary progressive’ MS. In this phase patients begin to undergo a steady neurologic decline without overt periods of remission, and for many patients their disease becomes less responsive to the therapies that effectively target the adaptive immune system in relapsing–remitting MS. The reasons for this are unclear, though it has been suggested that the long-term relapsing–remitting course ultimately exhausts the central nervous system’s regenerative capacity, leading to chronic neurodegeneration. Further, prolonged disease may allow immune cells and activated microglia to remain behind the blood–brain barrier, continuing to promote neuronal damage without the need for continuous recruitment of large numbers of inflammatory cells from the periphery.


Immunology_Janeway

Immunology_Janeway. Rheumatoid arthritis (RA) is a chronic disease characterized by inflammation of the synovium (the thin lining of a joint). As disease progresses, the inflamed synovium invades and damages the cartilage; this is followed by bone erosion (Fig. 15.29), leading to chronic pain, loss of function, and disability. RA was first considered an autoimmune disease driven by B cells producing anti-IgG autoantibodies called rheumatoid factor (see Section 15-4). However, the identification of rheumatoid factor in some healthy individuals, and its absence in some patients with rheumatoid arthritis, suggested that more complex mechanisms orchestrate this pathology. The discovery that RA has an association with particular class II HLA-DR genes of the MHC suggested that T cells are also involved in the pathogenesis of this disease. In RA, as in MS, most data from humans and mouse models indicate that, at least early in disease development, autoreactive TH17 cells become activated. Autoreactive T cells


Immunology_Janeway

Immunology_Janeway. of this disease. In RA, as in MS, most data from humans and mouse models indicate that, at least early in disease development, autoreactive TH17 cells become activated. Autoreactive T cells provide help to B cells to produce arthritogenic antibodies. The activated TH17 cells also produce cytokines that recruit neutrophils and monocytes/macrophages, which, along with endothelial cells and synovial fibroblasts, are stimulated to produce more pro-inflammatory cytokines such as TNF-α, IL-1, or chemokines (CXCL8, CCL2), and finally matrix metalloproteinases, which are responsible for tissue destruction. IL-17A, which has been found in high concentrations in the synovium and synovial fluid of RA patients, can induce expression of the ligand for receptor activator of NFκB (RANKL), which stimulates the differentiation of osteoclast precursors into mature osteoclasts that resorb bone in affected joints. Although we do not yet know how RA starts, mouse models have shown that both T cells and B


Immunology_Janeway

Immunology_Janeway. the differentiation of osteoclast precursors into mature osteoclasts that resorb bone in affected joints. Although we do not yet know how RA starts, mouse models have shown that both T cells and B cells are needed to initiate disease. Interestingly, interrupting


Immunology_Janeway

Immunology_Janeway. Fig. 15.28 The pathogenesis of multiple sclerosis. At sites of inflammation, activated T cells autoreactive for brain antigens can cross the blood–brain barrier and enter the brain, where they reencounter their antigens on microglial cells and secrete cytokines such as IFN‑γ. The production of T‑cell and macrophage cytokines exacerbates the inflammation and induces a further influx of blood cells (including macrophages, dendritic cells, and B cells) and blood proteins (such as complement) into the affected site. Mast cells also become activated. The individual roles of these components in demyelination and loss of neuronal function are still not well understood. CNS, central nervous system.


Immunology_Janeway

Immunology_Janeway. osteoclast joint cartilage MMPs attack tissues. Activation of bone-destroying osteoclasts by RANK ligand results in joint destruction cytokines fbroblasts IL-6 RANK ligandMMP TNF-˜Cytokines induce production of MMP and RANK ligand by fbroblasts Unknown trigger sets up initial focus of infammation in synovial membrane, attracting leukocytes into the tissue Autoreactive CD4 T cells activate macrophages, resulting in production of pro-infammatory cytokines and sustained infammation


Immunology_Janeway

Immunology_Janeway. Fig. 15.29 The pathogenesis of rheumatoid arthritis. Inflammation of the synovial membrane, initiated by some unknown trigger, attracts autoreactive lymphocytes and macrophages to the inflamed tissue. Autoreactive effector CD4 T cells activate macrophages, and pro‑inflammatory cytokines such as IL‑1, IL‑6, IL‑17, and TNF‑α are produced. Fibroblasts activated by cytokines produce matrix metalloproteinases (MMPs), which contribute to tissue destruction. The TNF family cytokine RANK ligand, expressed by T cells and fibroblasts in the inflamed joint, is the primary activator of bone‑destroying osteoclasts. Antibodies against several joint proteins are also produced (not shown), but their role in pathogenesis is uncertain. this complex cascade at multiple levels—including therapeutic antibodies against cytokines (TNF-α), B cells, and T-cell activation—have all been successful in treating the symptoms of the disease (discussed in Section 16-8).


Immunology_Janeway

Immunology_Janeway. Studies of the targets of autoantibodies in RA have yielded insights into how this disease develops, and have also identified a more global mechanism by which self proteins may be seen as foreign in other autoimmune conditions. During inflammation, the amino acid arginine can be converted into citrulline, and this change may result in structural alterations of the self protein that cause the immune system to now view it as nonself (Fig. 15.30). Experimental models have shown that antibodies against these altered proteins can be pathogenic, and diagnostic tests for anti-citrullinated protein antibodies (ACPAs) are highly specific for RA. Interestingly, smoking—long known as the most important environmental risk factor for RA development—has been associated with APCAs in patients with HLA risk alleles, suggesting that this tolerance-breaking mechanism may be an important node in the gene–environment interactions that lead to autoimmunity. Finally, other post-translational modifications


Immunology_Janeway

Immunology_Janeway. alleles, suggesting that this tolerance-breaking mechanism may be an important node in the gene–environment interactions that lead to autoimmunity. Finally, other post-translational modifications (oxidation, glycosylation) of self proteins in the periphery have now been shown to stimulate Tand B-cell responses in other autoimmune diseases.


Immunology_Janeway

Summary.

Immunology_Janeway. Summary.


Immunology_Janeway

Immunology_Janeway. Autoimmune diseases can be broadly classified into those that affect a specific organ and those that affect tissues throughout the body. Organ-specific autoimmune diseases include type 1 diabetes, multiple sclerosis, Graves’ disease, and Crohn’s disease. In each case the effector functions target autoantigens that are restricted to particular organs—insulin-producing β cells of the pancreas (type 1 diabetes), the myelin sheathing on axons in the central nervous system (multiple sclerosis), and the thyroid-stimulating hormone receptor (Graves’ disease)—or, in the case of Crohn’s disease, components of the intestinal microbiota. In contrast, systemic diseases such as systemic lupus erythematosus (SLE) cause inflammation in multiple tissues because their autoantigens, which include chromatin and ribonucleoproteins, are found in most cells of the body. In some organ-specific diseases, immune destruction of the target tissue and the unique self antigens it expresses leads to cessation of


Immunology_Janeway

Immunology_Janeway. and ribonucleoproteins, are found in most cells of the body. In some organ-specific diseases, immune destruction of the target tissue and the unique self antigens it expresses leads to cessation of autoimmune activity, but systemic diseases tend to be chronically active if untreated, because their autoantigens cannot be cleared. Another way of classifying autoimmune diseases is according to the effector functions that are most important in pathogenesis. It is becoming clear, however, that many diseases once thought to be mediated solely by one effector function actually involve several. In this way, autoimmune diseases resemble pathogen-directed immune responses, which typically elicit the activities of multiple effectors—adaptive and innate.


Immunology_Janeway

Immunology_Janeway. For a disease to be classified as autoimmune, the tissue damage must be shown to be caused by the adaptive immune response to self antigens. Autoinflammatory reactions directed against the commensal microbiota of the intestines, such as those seen in inflammatory bowel diseases (IBDs), are a special case in that the target antigens are not strictly ‘self,’ but are derived from the ‘extended self’ of the intestinal microbiota. IBD, nevertheless, shares immunopathogenic features with other autoimmune diseases. The most convincing proof that the immune response is causal in autoimmunity is the transfer of disease by transferring the active component of the immune response to an appropriate recipient. Autoimmune diseases are mediated by autoreactive lymphocytes and their soluble products, pro-inflammatory cytokines, and autoantibodies responsible for inflammation and tissue injury. A few autoimmune diseases are caused by antibodies that bind to cell-surface receptors, causing either