CHAPTER 14 Immunologic Tolerance and Autoimmunity
Immunologic tolerance is defined as unresponsiveness to an antigen that is induced by previous exposure to that antigen. When specific lymphocytes encounter antigens, the lymphocytes may be activated, leading to immune responses, or the cells may be inactivated or eliminated, leading to tolerance. Different forms of the same antigen may induce an immune response or tolerance. Antigens that induce tolerance are called tolerogens, or tolerogenic antigens, to distinguish them from immunogens, which generate immunity. A single antigen may be an immunogen or a tolerogen, depending on the conditions in which it is displayed to specific lymphocytes (e.g., in the presence or absence, respectively, of inflammation and innate immune responses). Tolerance to self antigens, also called self-tolerance, is a fundamental property of the normal immune system, and failure of self-tolerance results in immune reactions against self (autologous) antigens. Such reactions are called autoimmunity, and the diseases they cause are called autoimmune diseases. Elucidating the mechanisms of self-tolerance is the key to understanding the pathogenesis of autoimmunity.
In this chapter, we discuss immunologic tolerance mainly in the context of self-tolerance and how self-tolerance may fail, resulting in autoimmunity. We also mention the relevance of tolerance to unresponsiveness to foreign antigens and the potential of tolerance induction as a therapeutic strategy for immunologic diseases and to prevent the rejection of cell and organ transplants. Because of the importance of self-tolerance for the health of individuals and the therapeutic promise of tolerance, there has been great interest in understanding this phenomenon and learning how to apply it to humans.
General Features of Immunologic Tolerance
There are several characteristics of tolerance in T and B lymphocyte populations. It is important to appreciate the general principles before we discuss the specific mechanisms of tolerance in these lymphocytes.
The importance of self-tolerance for the health of individuals was appreciated from the early days of immunology. In Chapter 1, we introduced the concept of self-nonself discrimination, which is the ability of the immune system to recognize and respond to foreign antigens but not to self antigens. Macfarlane Burnet added to his clonal selection hypothesis the corollary that lymphocytes specific for self antigens are eliminated to prevent immune reactions against one’s own tissues. As we shall see later in this chapter, self-tolerance is maintained by several different mechanisms that prevent the maturation and activation of potentially harmful self-reactive lymphocytes.
FIGURE 14–1 Central and peripheral tolerance to self antigens.
Immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs and are deleted, change their specificity (B cells only), or (in the case of CD4+ T cells) develop into regulatory lymphocytes (central tolerance). Some self-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by encounter with self antigens in these tissues or are suppressed by the regulatory T cells (peripheral tolerance). (Note that T cells recognize antigens presented by antigen-presenting cells, which are not shown.)
We do not know which self antigens induce central or peripheral tolerance (or are ignored). It is technically difficult to identify rare cells that may be specific for natural self antigens because reagents for detecting antigen-specific lymphocytes are not widely used and few self antigens are defined for which such reagents could even be produced. Experimental approaches, especially the creation of genetically modified mice, have provided valuable models for analysis of self-tolerance, and many of our current concepts are based on studies with such models. Furthermore, by identifying genes that may be associated with autoimmunity in mice and humans, it has been possible to deduce some of the critical mechanisms of self-tolerance. In the sections that follow, we will discuss central and peripheral tolerance first in T cells and then in B lymphocytes, but many aspects of the processes are common to both lineages.
T Lymphocyte Tolerance
Tolerance in CD4+ helper T lymphocytes is an effective way of preventing immune responses to protein antigens because helper T cells are necessary inducers of both cell-mediated and humoral immune responses to proteins. This realization has been the impetus for a large amount of work on the mechanisms of tolerance in CD4+ T cells. Immunologists have also developed experimental models for studying tolerance in CD4+ T cells that have proved to be quite informative. Also, many of the therapeutic strategies that are being developed to induce tolerance to transplants and autoantigens are targeted to these T cells. Therefore, much of the following discussion, especially of peripheral tolerance, focuses on CD4+ T cells. Less is known about peripheral tolerance in CD8+ T cells, and this is summarized at the end of the section.
Central Tolerance in T Cells
During their maturation in the thymus, many immature T cells that recognize antigens with high avidity are deleted and some of the surviving cells in the CD4+ lineage develop into regulatory T cells (Fig. 14-2). The process of deletion, or negative selection, of T lymphocytes was described in Chapter 8, when the maturation of T cells in the thymus was discussed. This process affects both class I and class II MHC–restricted T cells and is therefore important for tolerance in both CD8+ and CD4+ lymphocyte populations. Negative selection of thymocytes is responsible for the fact that the repertoire of mature T cells that leave the thymus and populate peripheral lymphoid tissues is unresponsive to the self antigens that are present in the thymus. The two main factors that determine if a particular self antigen will induce negative selection of self-reactive thymocytes are the presence of that antigen in the thymus, either by local expression or delivery by the blood, and the affinity of the thymocyte T cell receptors (TCRs) that recognize the antigen. Thus, the important questions that are relevant to negative selection are what self antigens are present in the thymus and how are immature T cells that recognize these antigens killed.
FIGURE 14–2 Central T cell tolerance.
Recognition of self antigens by immature T cells in the thymus may lead to death of the cells (negative selection, or deletion) or the development of regulatory T cells that enter peripheral tissues.
Self proteins are processed and presented in association with MHC molecules on thymic antigen-presenting cells (APCs). The antigens that are present in the thymus include many circulating and cell-associated proteins that are widely distributed in tissues. The thymus also has an unusual mechanism for expressing protein antigens that are typically present only in certain peripheral tissues, so that immature T cells specific for these antigens can be deleted from the developing T cell repertoire. Some of these peripheral tissue antigens are expressed in thymic medullary epithelial cells under the control of the autoimmune regulator (AIRE) protein. Mutations in the AIRE gene are the cause of a multiorgan autoimmune disease called the autoimmune polyendocrine syndrome (APS). This group of diseases is characterized by antibody- and lymphocyte-mediated injury to multiple endocrine organs, including the parathyroids, adrenals, and pancreatic islets. A mouse model of APS has been developed by knockout of the AIRE gene, and it recapitulates many of the features of the human disease. Studies with mice have shown that several proteins that are produced in peripheral organs (such as pancreatic insulin) are also normally expressed at low levels in thymic medullary epithelial cells, and immature T cells that recognize these antigens are deleted in the thymus. In the absence of functional AIRE (as in the patients and knockout mice) these antigens are not displayed in the thymus, and T cells specific for the antigens escape deletion, mature, and enter the periphery, where they attack the target tissues in which the antigens are expressed independent of AIRE. The AIRE protein may function as a transcription factor to promote the expression of selected tissue antigens in the thymus. It is a component of a multiprotein complex that is involved in transcriptional elongation and chromatin unwinding and remodeling. AIRE also contributes to pre-mRNA processing and induces the accumulation of processed spliced mRNAs (as opposed to unspliced mRNAs) of genes encoding peripheral tissue antigens. There is also evidence for AIRE-independent mechanisms of deletion in the thymus.
Many immature thymocytes with high-affinity receptors for self antigens that encounter these antigens in the thymus die by apoptosis. Negative selection occurs in double-positive T cells in the thymic cortex or newly generated single-positive cells in the medulla. In these locations, immature thymocytes with high-affinity receptors for self antigens encounter these antigens and die by apoptosis. T cell receptor (TCR) signaling in immature T cells leads to the activation of a protein called Bim, which triggers the mitochondrial pathway of apoptosis. The mechanisms of apoptosis are described later in the chapter, when we discuss deletion as a mechanism of peripheral T cell tolerance. Clearly, immature and mature lymphocytes interpret antigen receptor signals differently—the former die and the latter are activated. The biochemical basis of this difference is not known.
Some self-reactive CD4+ T cells that see self antigens in the thymus are not deleted but instead differentiate into regulatory T cells specific for these antigens (see Fig. 14-2). The regulatory cells leave the thymus and inhibit responses against self tissues in the periphery. Interestingly, deficiency of the AIRE protein, which interferes with deletion of T cells reactive with some antigens in the thymus, does not appear to prevent the development of thymic regulatory T cells specific for the same self antigens. This observation suggests that the requirements for T cell deletion and regulatory T cell development in the thymus are different, but what determines the choice between cell death and development of regulatory T cells is not known. The characteristics and functions of regulatory T cells are described later in the context of peripheral tolerance because these cells suppress immune responses in the periphery.
Although the importance of central T cell tolerance has been clearly established in animal models, and the autoimmune polyendocrine syndrome suggests that it has a fundamental role for tolerance to some peripheral tissue antigens, it is still not known if a failure of central tolerance contributes to common human autoimmune diseases.
Peripheral T Cell Tolerance
Peripheral tolerance is the mechanism by which mature T cells that recognize self antigens in peripheral tissues are rendered incapable of subsequently responding to these antigens. Peripheral tolerance mechanisms may be responsible for T cell tolerance to tissue-specific self antigens, especially those that are not abundant in the thymus. The same mechanisms may induce unresponsiveness to tolerogenic forms of foreign antigens. The mechanisms of peripheral tolerance are anergy (functional unresponsiveness), suppression, and deletion (cell death) (Fig. 14-3). We do not know if tolerance to different self antigens is maintained by one or another mechanism or if all these mechanisms function cooperatively to prevent dangerous autoimmunity.
FIGURE 14–3 Mechanisms of peripheral T cell tolerance.
The signals involved in a normal immune response (A) and the three major mechanisms of peripheral T cell tolerance (B) are illustrated.
Anergy (Functional Unresponsiveness)
Exposure of mature CD4+ T cells to an antigen in the absence of costimulation or innate immunity may make the cells incapable of responding to that antigen. In this process, the self-reactive cells do not die but become unresponsive to the antigen. We previously introduced the concept that full activation of T cells requires the recognition of antigen by the TCR (which provides signal 1) and recognition of costimulators, mainly B7-1 and B7-2, by CD28 (signal 2) (see Chapter 9). Prolonged signal 1 (i.e., antigen recognition) alone may lead to anergy. It is likely that self antigens are displayed to specific T cells in the absence of innate immunity and strong costimulation. Antigen-induced anergy has been demonstrated in a variety of experimental models, including studies with T cell clones exposed to antigens in vitro (which were the basis for the original definition of anergy), experiments in which antigens are administered to mice without adjuvants, and studies with transgenic mice in which particular protein antigens are expressed throughout life and are recognized by T cells in the absence of the inflammation and innate immune responses that normally accompany exposure to microbes. In many of these situations, the T cells that recognize the antigens become functionally unresponsive and survive for days or weeks in a quiescent state.
Anergy results from biochemical alterations that reduce the ability of lymphocytes to respond to signals from their antigen receptors (Fig. 14-4). It is believed that several biochemical pathways cooperate to maintain this unresponsive state.
FIGURE 14–4 Mechanisms of T cell anergy.
T cell responses are induced when the cells recognize an antigen presented by a professional antigen-presenting cell (APC) and activating receptors on the T cells (such as CD28) recognize costimulators on the APCs (such as B7). If the T cell recognizes a self antigen without costimulation, the T cell becomes unresponsive to the antigen because of a block in signaling from the TCR complex or engagement of inhibitory receptors (such as CTLA-4). The signaling block may be the result of recruitment of phosphatases to the TCR complex or the activation of ubiquitin ligases that degrade signaling proteins. The T cell remains viable but is unable to respond to the self antigen. DC, dendritic cell.
CTLA-4, like the activating receptor CD28, binds to B7 molecules. CTLA-4 has a higher affinity than CD28 for B7 molecules and thus prevents B7 costimulators on APCs from engaging CD28; it may also remove B7 molecules from the surface of APCs (Fig. 14-5). In addition, CTLA-4 delivers inhibitory signals that negate the signals triggered by the TCR. In fact, the cytoplasmic tail of CTLA-4 has a potentially inhibitory motif that may counteract ITAM-dependent signals from the TCR and CD28. As we shall discuss later, CTLA-4 is also a mediator of the inhibitory function of regulatory T cells. The importance of CTLA-4 in tolerance induction is illustrated by the finding that knockout mice lacking CTLA-4 develop uncontrolled lymphocyte activation with massively enlarged lymph nodes and spleen and fatal multiorgan lymphocytic infiltrates suggestive of systemic autoimmunity. In other words, elimination of this one control mechanism results in a severe T cell–mediated disease, presumably because of defects in both T cell anergy and suppression by regulatory T cells. Blocking of CTLA-4 with antibodies also enhances autoimmune diseases in animal models, such as encephalomyelitis induced by immunization with myelin antigens and diabetes induced by T cells reactive with antigens in the β cells of pancreatic islets. In clinical trials of anti–CTLA-4 antibody to boost immune responses to cancers, some of the treated patients develop manifestations of autoimmunity with inflammation in various organs. Polymorphisms in the CTLA4 gene are associated with several autoimmune diseases in humans, including type 1 diabetes and Graves’ disease. All these findings indicate that CTLA-4 functions continuously to keep self-reactive T cells in check.
FIGURE 14–5 Mechanisms of action of CTLA-4.
A, The top panel shows the activation of T cells by antigen recognition and costimulation through CD28. B, The bottom panel shows the two postulated mechanisms of action of CTLA-4: delivery of inhibitory signals that block TCR- and CD28-mediated signals, and engagement of B7 molecules on APCs so they are inaccessible to CD28. Note that regulatory T cells (described later in the chapter) may also use CTLA-4 to block B7 and thus inhibit immune responses. There is some evidence that in addition to blocking B7, CTLA-4 may remove these molecules from the APC surface and internalize them (not shown).
Another inhibitory receptor of the CD28 family is PD-1 (programmed cell death 1, so called because it was originally thought to be involved in programmed cell death but now known to not have a role in T cell apoptosis). PD-1 recognizes two ligands, called PD-L1 and PD-L2; PD-L1 is expressed on APCs and many other tissue cells and PD-L2 mainly on APCs. Engagement of PD-1 by either ligand leads to inactivation of the T cells. Mice in which PD-1 is knocked out develop autoimmune diseases, including lupus-like kidney disease and arthritis in different inbred strains. The autoimmune disorders in PD-1 knockout mice are less severe than in CTLA-4 knockouts. It has been postulated that CTLA-4 functions mainly to control initial T cell activation in lymphoid organs whereas PD-1 is more important for limiting responses of differentiated effector cells in peripheral tissues.
How the balance of activating and inhibitory receptor signaling is normally regulated is not understood. As we mentioned in Chapter 9, one possible explanation for the engagement of CTLA-4 vs. CD28 by B7 molecules is that APCs that are presenting self antigens normally express low levels of B7-1 and B7-2, which is sufficient to engage the high-affinity inhibitory receptor CTLA-4. In contrast, microbes activate the APCs to increase the expression of B7 costimulators, and CD28, which has a lower affinity for B7 molecules than does CTLA-4, is engaged at these higher levels of B7 expression. This might explain why self antigen recognition tilts the balance toward CTLA-4, whereas microbial infections induce relatively more CD28 signals.
Dendritic cells that are resident in lymphoid organs and nonlymphoid tissues may present self antigens to T lymphocytes and maintain tolerance. Tissue dendritic cells are normally in a resting (immature) state and express few or no costimulators. Such APCs may be constantly presenting self antigens without activating signals, and T cells that recognize these antigens become anergic. There is also some evidence that resting dendritic cells tend to promote the development of regulatory T lymphocytes instead of effector and memory lymphocytes. By contrast, dendritic cells that are activated by microbes are the principal APCs for initiation of T cell responses (see Chapter 6). As we shall discuss later, local infections and inflammation may activate resident dendritic cells, leading to increased expression of costimulators, breakdown of tolerance, and autoimmune reactions against tissue antigens. The characteristics of dendritic cells that make them tolerogenic are not defined but presumably include low expression of costimulators. There is great interest in manipulating the properties of dendritic cells as a way of enhancing or inhibiting immune responses for therapeutic purposes.
Suppression of Self-Reactive Lymphocytes by Regulatory T Cells
The concept that some lymphocytes could control the responses of other lymphocytes was proposed many years ago and was soon followed by experimental demonstrations of populations of T lymphocytes that suppressed immune responses. These initial findings led to enormous interest in the topic, and “suppressor T cells” became one of the dominant themes of immunology in the 1970s. However, this field of research has had a somewhat checkered history, mainly because initial attempts to define populations of suppressor cells and their mechanisms of action were largely unsuccessful. More than 20 years later, the idea had an impressive rebirth, with the application of better approaches to define, purify, and analyze populations of T lymphocytes that inhibit immune responses. These cells are called regulatory T lymphocytes; their properties and functions are described next.
Regulatory T lymphocytes are a subset of CD4+ T cells whose function is to suppress immune responses and maintain self-tolerance (Fig. 14-6). The majority of these CD4+ regulatory T lymphocytes express high levels of the interleukin-2 (IL-2) receptor α chain (CD25) but not other markers of T cell activation. A transcription factor called FoxP3, a member of the forkhead family of transcription factors, is critical for the development and function of the majority of regulatory T cells. Mice with mutations in the foxp3 gene, and mice in which this gene has been knocked out, develop a multisystem autoimmune disease associated with an absence of CD25+ regulatory T cells. A rare autoimmune disease in humans called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) is also associated with deficiency of regulatory T cells and is now known to be caused by mutations in the FOXP3 gene. These results establish the importance of regulatory T cells for maintaining self-tolerance. The recent surge of interest in regulatory T cells is because of an increasing appreciation of their physiologic roles, as well as the possibility that defects in these cells may result in various autoimmune diseases and, conversely, that regulatory T cells can be used to treat inflammatory diseases.
FIGURE 14–6 Regulatory T cells.
Regulatory T cells are generated by self antigen recognition in the thymus (sometimes called natural regulatory cells) and (probably to a lesser extent) by antigen recognition in peripheral lymphoid organs (called inducible or adaptive regulatory cells). The development and survival of these regulatory T cells require IL-2 and the transcription factor FoxP3. In peripheral tissues, regulatory T cells suppress the activation and effector functions of other, self-reactive and potentially pathogenic lymphocytes.
Phenotypic Markers and Heterogeneity of Regulatory T Cells
Regulatory T cells are phenotypically distinct from other lymphocyte populations (Table 14-1). Although numerous T cell populations have been described as possessing suppressive activity, the cell type whose regulatory role is best established is CD4+ FoxP3+ CD25high. Both FoxP3 and CD25 are essential for the generation, maintenance, and function of these cells. These cells typically express low levels of receptors for IL-7 (CD127), and as predicted from this pattern of receptor expression, they use IL-2 but not IL-7 as their growth and survival factor. Intriguingly, memory T cells have the opposite receptor expression and growth factor dependence; they are typically CD127high and CD25low and rely on IL-7 for their maintenance. FoxP3+ regulatory T cells also typically express high levels of CTLA-4, which is required for their function (discussed later).
Generation and Maintenance of Regulatory T Cells
Regulatory T cells are generated mainly by self antigen recognition in the thymus and by recognition of self and foreign antigens in peripheral lymphoid organs. In the thymus, development of regulatory T cells is one of the fates of T cells committed to the CD4 lineage that recognize self antigens; these thymus-derived cells are sometimes called natural regulatory T cells. In peripheral lymphoid organs, antigen recognition in the absence of strong innate immune responses favors the generation of regulatory cells from naive CD4+ T lymphocytes, although regulatory T cells can also develop after inflammatory reactions. These peripherally generated regulatory cells have been called adaptive or inducible because they may be induced to develop from naive CD4+ T cells as an adaptation of the immune system in response to certain types of antigen exposure. Predictably, thymically derived regulatory cells are specific for self antigens because these are the antigens mainly encountered in the thymus. Peripherally generated regulatory cells may be specific for self or foreign antigens. Also, it is not clear if both thymic-derived and peripheral regulatory T cells contribute to the maintenance of self-tolerance or if one of the populations is more important than the other for prevention of autoimmunity.
The generation and survival of regulatory T cells are dependent on the cytokines TGF-β and IL-2. Culture of naive T cells with activating anti-TCR antibodies together with TGF-β and IL-2 can induce the development of regulatory cells in vitro; these are sometimes also called induced regulatory T cells. In mice, elimination of TGF-β or blocking of TGF-β signals in T cells leads to a systemic inflammatory disease mainly because of a deficiency of functional regulatory T cells. TGF-β stimulates expression of FoxP3, the transcription factor that drives differentiation of T cells toward the regulatory lineage. Similarly, mice in which the gene for IL-2 or for the α or β chain of the IL-2 receptor is knocked out develop autoimmunity, manifested by inflammatory bowel disease, autoimmune hemolytic anemia, and multiple autoantibodies (including anti-erythrocyte and anti-DNA). These mice lack a full complement of CD25+ FoxP3+ regulatory T cells, and their disease can be corrected by restoring these cells (by providing bone marrow cells from normal animals that can generate FoxP3+ cells). IL-2 promotes differentiation of T cells into the regulatory subset and is also required for the survival and maintenance of this cell population. IL-2 activates the transcription factor STAT5, which may enhance expression of FoxP3 as well as other genes known to be involved in the function of regulatory T cells.
Particular populations or subsets of dendritic cells may be especially important for stimulating the development of regulatory T cells in peripheral tissues. There is some evidence that dendritic cells exposed to retinoic acid, the vitamin A analogue, are inducers of regulatory T cells, especially in mucosal lymphoid tissues (see Chapter 13).
Mechanisms of Action of Regulatory T Cells
Regulatory T cells appear to suppress immune responses at multiple steps—at the induction of T cell activation in lymphoid organs as well as the effector phase of these responses in tissues. Although several mechanisms of suppression have been described, the two that are supported by the most data involve inhibitory cytokines and a contact-mediated effect on APCs.
Other mechanisms of suppression by regulatory T cells that have been reported include consumption of IL-2, thus starving responding lymphocytes of this essential growth factor, and killing of responding T cells.
It is not established if all regulatory cells work by all these mechanisms or if there are subpopulations that use different mechanisms to control immune responses. In fact, there is some evidence in humans that two different populations of regulatory T cells can be distinguished by the expression of FoxP3 or production of IL-10 (see later), but this separation may not be absolute.
Inhibitory Cytokines Produced by Regulatory T Cells
TGF-β and IL-10 are involved in both the generation and the functions of regulatory T cells. These cytokines are produced by and act on many other cell types besides regulatory cells. Here we describe the properties and actions of these cytokines.
Transforming Growth Factor-β
TGF-β was discovered as a tumor product that promoted the survival of tumor cells in vitro. It is actually a family of closely related molecules encoded by distinct genes, commonly designated TGF-β1, TGF-β2, and TGF-β3. Cells of the immune system synthesize mainly TGF-β1. TGF-β1 is a homodimeric protein that is synthesized and secreted by CD4+ regulatory T cells, activated macrophages, and many other cell types. It is synthesized as an inactive precursor that is proteolytically cleaved in the Golgi complex and forms a homodimer. This mature TGF-β1 homodimer is secreted in a latent form in association with other polypeptides, which must be removed extracellularly by enzymatic digestion before the cytokine can bind to receptors and exert biologic effects. The TGF-β1 receptor consists of two different proteins, TGF-βRI and TGF-βRII, both of which phosphorylate transcription factors called SMADs. On cytokine binding, a serine/threonine kinase domain of TGF-βRI phosphorylates SMAD2 and SMAD3, which in complex with SMAD4 translocate to the nucleus, bind to promoters of target genes, and regulate their transcription.
TGF-β has many important and quite diverse roles in the immune system.
Interleukin-10
IL-10 is an inhibitor of activated macrophages and dendritic cells and is thus involved in the control of innate immune reactions and cell-mediated immunity. It is a member of a family of heterodimeric cytokines, each chain of which contains a six-helix bundle domain that intercalates with that of the other chain. Other members of the family include IL-19, IL-20, IL-22, IL-24, IL-26, and IL-27. The IL-10 receptor belongs to the type II cytokine receptor family (similar to the receptor for interferons) and consists of two chains, which associate with JAK1 and TYK2 Janus family kinases and activate STAT3. IL-10 is produced by many immune cell populations, including activated macrophages and dendritic cells, regulatory T cells, and TH1 and TH2 cells. Because it is both produced by and inhibits macrophage and dendritic cell functions, it is an excellent example of a negative feedback regulator. IL-10 is also produced by some nonimmune cell types (e.g., keratinocytes).
The biologic effects of IL-10 result from its ability to inhibit many of the functions of activated macrophages and dendritic cells.
A rare inherited autoimmune disease has been described in which mutations in the IL-10 receptor cause a severe colitis that develops early in life, before the age of 1 year. Knockout mice lacking IL-10 also develop colitis, probably as a result of uncontrolled activation of macrophages reacting to enteric microbes. It is believed that this cytokine is especially important for controlling inflammatory reactions in mucosal tissues, particularly in the gastrointestinal tract (see Chapter 13).
The Epstein-Barr virus contains a gene homologous to human IL-10, and viral IL-10 has the same activities as the natural cytokine. This raises the intriguing possibility that acquisition of the IL-10–like gene during the evolution of the virus has given it the ability to inhibit host immunity and thus a survival advantage in the infected host.
Roles of Regulatory T Cells in Self-Tolerance and Autoimmunity
The elucidation of the genetic basis of the disease IPEX and the similar disease in mice caused by mutations in the FoxP3 gene, described before, is convincing proof of the importance of regulatory T cells in maintaining self-tolerance and homeostasis in the immune system. Numerous attempts are being made to identify defects in the development or function of regulatory T cells in more common autoimmune diseases, such as inflammatory bowel disease, type 1 diabetes, and multiple sclerosis, in humans. It appears likely that defects in the generation or function of regulatory T cells or resistance of effector cells to suppression contribute significantly to the pathogenesis of many autoimmune diseases. There is also potential for generating regulatory cells and using them to control pathologic immune responses, and many attempts are ongoing to develop such therapies, particularly to treat transplant rejection (see Chapter 16).
Deletion of T Cells by Apoptotic Cell Death
T lymphocytes that recognize self antigens without inflammation or that are repeatedly stimulated by antigens die by apoptosis. There are two major pathways of apoptosis in various cell types (Fig. 14-7), both of which have been implicated in deletion of T cells by self antigens.
FIGURE 14–7 Pathways of apoptosis.
Apoptosis is induced by the mitochondrial and death receptor pathways, described in the text, which culminate in fragmentation of the dead cell and phagocytosis of apoptotic bodies.
Cells undergoing apoptosis develop membrane blebs, and fragments of the nucleus and cytoplasm break off in membrane-bound structures called apoptotic bodies. There are also biochemical changes in the plasma membrane, including the exposure of lipids such as phosphatidylserine, which is normally on the inner face of the plasma membrane. These alterations are recognized by receptors on phagocytes, and apoptotic cells are rapidly engulfed and eliminated, without ever having elicited a host inflammatory response.
The best evidence for the involvement of the two apoptotic pathways in the elimination of mature self-reactive lymphocytes is that genetic ablation of both in mice results in systemic autoimmunity. These two death pathways may function in different ways to maintain self-tolerance. Cell death that occurs as a consequence of exposure of mature T cells to antigen is sometimes called activation-induced cell death.
Peripheral Tolerance in CD8+ T Lymphocytes
Much of our knowledge of peripheral T cell tolerance is limited to CD4+ T cells, and much less is known about the mechanisms of tolerance in mature CD8+ T cells. It is likely that if CD8+ T cells recognize class I MHC–associated peptides without costimulation, innate immunity, or T cell help, the CD8+ cells become anergic. In this situation, the CD8+ T cells would encounter signal 1 (antigen) without second signals, and the mechanism of anergy would be essentially the same as for CD4+ T lymphocytes. The role of CTLA-4 and other inhibitory receptors in inducing anergy in CD8+ T cells is not established. CD25+ regulatory T cells can directly inhibit the activation of CD8+ T cells or suppress CD4+ helper cells that are required for full CD8+ responses (see Chapter 9). CD8+ T cells that are exposed to high concentrations of self antigens may also undergo apoptotic cell death.
Factors That Determine the Tolerogenicity of Self Antigens
Studies with a variety of experimental models have shown that many features of protein antigens determine whether these antigens will induce T cell activation or tolerance (Table 14-2). Self antigens have several properties that make them tolerogenic. Some self antigens are present in the thymus, and these antigens may induce negative selection or the development of regulatory T cells. In the periphery, self antigens, which are usually expressed for long times or throughout life, are capable of engaging antigen receptors for prolonged periods and are normally displayed to lymphocytes without inflammation or innate immunity. Under these conditions, APCs express few or no costimulators, and antigen recognition may either elicit no response (ignorance) or induce anergy, cell death, or regulatory T cells. A general concept that has emerged is that T cell receptor activation in the absence of innate immunity and inflammation tends to trigger one or more of the mechanisms of peripheral tolerance, whereas innate immunity, costimulation, and cytokines tilt the balance toward T cell proliferation and differentiation into effector and memory cells. Our understanding of the mechanisms that link the signals that a T cell receives at the time of antigen recognition with the fate of that T cell remains incomplete. These concepts are based largely on experimental models in which antigens are administered to mice or are produced by transgenes expressed in mice. One of the continuing challenges in this field is to define the mechanisms by which various normally expressed self antigens induce tolerance, especially in humans.
TABLE 14–2 Factors That Determine the Immunogenicity and Tolerogenicity of Protein Antigens
| Factor | Features That Favor Stimulation of Immune Responses | Features That Favor Tolerance |
|---|---|---|
| Persistence | Short-lived (eliminated by immune response) | Prolonged |
| Portal of entry; location | Subcutaneous, intradermal; absence from generative organs | Intravenous, mucosal; presence in generative organs |
| Presence of adjuvants | Antigens with adjuvants: stimulate helper T cells | Antigens without adjuvants: nonimmunogenic or tolerogenic |
| Properties of antigen-presenting cells | High levels of costimulators | Low levels of costimulators and cytokines |
B Lymphocyte Tolerance
Tolerance in B lymphocytes is necessary for maintaining unresponsiveness to thymus-independent self antigens, such as polysaccharides and lipids. B cell tolerance also plays a role in preventing antibody responses to protein antigens. Experimental studies have revealed multiple mechanisms by which encounter with self antigens may abort B cell maturation and activation.
Central Tolerance in B Cells
Immature B lymphocytes that recognize self antigens in the bone marrow with high affinity either change their specificity or are deleted. The mechanisms of central B cell tolerance have been best described in experimental models (Fig. 14-8).
FIGURE 14–8 Central tolerance in B cells.
Immature B cells that recognize self antigens in the bone marrow with high avidity (e.g., multivalent arrays of antigens on cells) die by apoptosis or change the specificity of their antigen receptors (receptor editing). Weak recognition of self antigens in the bone marrow may lead to anergy (functional inactivation) of the B cells.
Peripheral B Cell Tolerance
Mature B lymphocytes that recognize self antigens in peripheral tissues in the absence of specific helper T cells may be rendered functionally unresponsive or die by apoptosis (Fig. 14-9). Signals from helper T cells may be absent if these T cells are deleted or anergic or if the self antigens are nonprotein antigens. Since self antigens do not elicit innate immune responses, B cells will also not encounter any of the cytokines or other signals that are induced during such responses. Thus, as in T cells, antigen recognition without additional stimuli results in tolerance. Peripheral tolerance mechanisms also eliminate autoreactive B cell clones that may be generated as an unintended consequence of somatic mutation in germinal centers.
FIGURE 14–9 Peripheral tolerance in B cells.
B cells that encounter self antigens in peripheral tissues become anergic or die by apoptosis. In some situations, recognition of self antigens may trigger inhibitory receptors that prevent B cell activation.
The high rate of somatic mutation of Ig genes that occurs in germinal centers has the risk of generating self-reactive B cells (see Chapter 11). These B cells may be actively eliminated by the interaction of FasL on helper T cells with Fas on the activated B cells. The same interaction was described before as a mechanism for the death of self-reactive T cells. Failure of this pathway of peripheral B cell tolerance may contribute to the autoimmunity that is caused by mutations in the Fas and FasL genes in mice, and in patients with the autoimmune lymphoproliferative syndrome, referred to earlier.
Much has been learned about the mechanisms of tolerance in T and B lymphocytes, largely from the use of animal models such as genetically modified mice. Application of this knowledge to understanding the mechanisms of tolerance to different self antigens in normal individuals and to defining why tolerance fails, giving rise to autoimmune diseases, is an area of active investigation.
Tolerance induced by Foreign Protein Antigens
Foreign antigens may be administered in ways that preferentially induce tolerance rather than immune responses. Understanding how to induce tolerance by antigen administration is the key to developing antigen-specific tolerance as a treatment strategy for immunologic diseases. In general, protein antigens administered subcutaneously or intradermally with adjuvants favor immunity, whereas high doses of antigens administered systemically without adjuvants tend to induce tolerance. The likely reason for this is that adjuvants stimulate innate immune responses and the expression of costimulators on APCs, and in the absence of these second signals, T cells that recognize the antigen may become anergic or die or may differentiate into regulatory cells. Many other features of antigens, and how they are administered, may influence the balance between immunity and tolerance (see Table 14-2).
The oral administration of a protein antigen often leads to suppression of systemic humoral and cell-mediated immune responses to immunization with the same antigen. This phenomenon, called oral tolerance, was discussed in Chapter 13.
Some systemic infections (e.g., with viruses) may initiate an immune response, but the response is impaired before the virus is cleared, resulting in a state of persistent infection. In this situation, virus-specific T cell clones are present but do not respond normally and are unable to eradicate the infection. This phenomenon has been called clonal exhaustion, implying that the antigen-specific lymphocyte clones make an initial response but then become anergic, or “exhausted.” There is some evidence that clonal exhaustion is due to upregulation of inhibitory receptors such as PD-1 on virus-specific CD8+ T cells. This phenomenon has been seen in patients infected with the human immunodeficiency virus (HIV) and in animal models of chronic viral infection. How some microbes upregulate expression of inhibitory molecules in T cells is not known. Clonal exhaustion may favor viral persistence and is thus a mechanism of immune evasion used by some pathogens. Understanding of this process may open new avenues for therapeutic interventions in some chronic viral diseases, such as treatment with PD-1–blocking antibodies.
Pathogenesis of Autoimmunity
The possibility that an individual’s immune system may react against autologous antigens and cause tissue injury was appreciated by immunologists from the time that the specificity of the immune system for foreign antigens was recognized. In the early 1900s, Paul Ehrlich coined the rather melodramatic phrase “horror autotoxicus” for harmful (“toxic”) immune reactions against self. Autoimmunity is an important cause of disease in humans and is estimated to affect 2% to 5% of the U.S. population. The term autoimmunity is often erroneously used for any disease in which immune reactions accompany tissue injury, even though it may be difficult or impossible to establish a role for immune responses against self antigens in causing these disorders. Because inflammation is a prominent component of these disorders, they are sometimes grouped under immune-mediated inflammatory diseases, which does not imply that the pathologic response is directed against self antigens (see Chapter 18).
The fundamental questions about autoimmunity are how self-tolerance fails and how self-reactive lymphocytes are activated. Answers to these questions are needed to understand the etiology and pathogenesis of autoimmune diseases, which is a major challenge in immunology. Our understanding of autoimmunity has improved greatly during the past two decades, mainly because of the development of informative animal models of these diseases, the identification of genes that may predispose to autoimmunity, and improved methods for analyzing immune responses in humans. Several important general concepts have emerged from studies of autoimmunity.
In our earlier discussion of the mechanisms of self-tolerance, we have referred to many of these abnormalities to illustrate how self-tolerance may fail, resulting in autoimmunity. We will return to these immunological aberrations as the basis of autoimmunity in the discussion that follows and in Chapter 18, when we consider selected diseases.
Much recent attention has focused on the role of T cells in autoimmunity, for two main reasons. First, helper T cells are the key regulators of all immune responses to proteins, and most self antigens implicated in autoimmune diseases are proteins. Second, several autoimmune diseases are genetically linked to the MHC (the HLA complex in humans), and the function of MHC molecules is to present peptide antigens to T cells. Failure of self-tolerance in T lymphocytes may result in autoimmune diseases in which tissue damage is caused by cell-mediated immune reactions. Helper T cell abnormalities may also lead to autoantibody production because helper T cells are necessary for the production of high-affinity antibodies against protein antigens.
FIGURE 14–10 Postulated mechanisms of autoimmunity.
In this proposed model of an organ-specific T cell–mediated autoimmune disease, various genetic loci may confer susceptibility to autoimmunity, in part by influencing the maintenance of self-tolerance. Environmental triggers, such as infections and other inflammatory stimuli, promote the influx of lymphocytes into tissues and the activation of self-reactive T cells, resulting in tissue injury.
FIGURE 14–11 Mechanisms of chronicity of autoimmune diseases.
Once an autoimmune reaction develops, amplification mechanisms (such as cytokines, shown as an illustrative example) promote activation of autoreactive lymphocytes, and release of self antigens from damaged cells and tissues leads to epitope spreading.
In the following section, we describe the general principles of the pathogenesis of autoimmune diseases, with an emphasis on susceptibility genes, infections, and other factors that contribute to the development of autoimmunity. The pathogenesis and features of some illustrative autoimmune diseases are described in Chapter 18.
Genetic Basis of Autoimmunity
From the earliest studies of autoimmune diseases in patients and experimental animals, it has been appreciated that these diseases have a strong genetic component. For instance, type 1 diabetes shows a concordance of 35% to 50% in monozygotic twins and 5% to 6% in dizygotic twins, and other autoimmune diseases show similar evidence of a genetic contribution. Linkage analyses in families, genome-wide association studies and large scale resequencing efforts are revealing new information about the genes that may play causal roles in the development of autoimmunity and chronic inflammatory disorders. From these studies, several general features of genetic susceptibility have become apparent.
Most autoimmune diseases are complex polygenic traits, in which affected individuals inherit multiple genetic polymorphisms that contribute to disease susceptibility and these genes act with environmental factors to cause the diseases. Some of these polymorphisms are associated with several autoimmune diseases, suggesting that the causative genes influence general mechanisms of immune regulation and self-tolerance. Other loci are associated with particular diseases, suggesting that they may affect organ damage or autoreactive lymphocytes of particular specificities. Each genetic polymorphism makes a small contribution to the development of particular autoimmune diseases and is also found in healthy individuals but at a lower frequency than in patients with the diseases. It is postulated that in individual patients, multiple such polymorphisms are coinherited and together account for development of the disease. Understanding the interplay of multiple genes with one another and with environmental factors is one of the continuing challenges in the field.
The best-characterized genes associated with autoimmune diseases and our current understanding of how they may contribute to loss of self-tolerance are described here.
Association of MHC Alleles with Autoimmunity
Among the genes that are associated with autoimmunity, the strongest associations are with MHC genes. In fact, in many autoimmune diseases, such as type 1 diabetes, 20 or 30 disease-associated genes have been identified; in most of these diseases, the HLA locus alone contributes half or more of the genetic susceptibility. HLA typing of large groups of patients with various autoimmune diseases has shown that some HLA alleles occur at higher frequency in these patients than in the general population. From such studies, one can calculate the odds ratio for development of a disease in individuals who inherit various HLA alleles (often referred to as the relative risk in the older literature) (Table 14-3). The strongest such association is between ankylosing spondylitis, an inflammatory, presumably autoimmune, disease of vertebral joints, and the class I HLA allele B27. Individuals who are HLA-B27 positive have an odds ratio of more than 100 for development of ankylosing spondylitis. Neither the mechanism of this disease nor the basis of its association with HLA-B27 is known. The association of class II HLA-DR and HLA-DQ alleles with autoimmune diseases has received great attention, mainly because class II MHC molecules are involved in the selection and activation of CD4+ T cells, and CD4+ T cells regulate both humoral and cell-mediated immune responses to protein antigens.
TABLE 14–3 Association of HLA Alleles with Autoimmune Disease
| Disease | HLA Allele | Odds Ratio1 |
|---|---|---|
| Rheumatoid arthritis (anti-CCP Ab positive)2 | DRB1, 1 SE allele3 | 4 |
| DRB1, 2 SE alleles | 12 | |
| Type 1 diabetes | DRB*0301-DQA1*0501-DQB1*0201 haplotype | 4 |
| DRB1*0401-DQA1*0301-DQB1*0302 haplotype | 8 | |
| DRB1*0301/0401 heterozygotes | 35 | |
| Multiple sclerosis | DRB1*1501 | 3 |
| Systemic lupus erythematosus | DRB1*0301 | 2 |
| DRB1*1501 | 1.3 | |
| Ankylosing spondylitis | B*27 (mainly B*2705 and *2702) | 100-200 |
| Celiac disease | DQA1*0501-DB1*0201 haplotype | 7 |
1 The odds ratio approximates values of increased risk of the disease associated with inheritance of particular HLA alleles. The data are from European-derived populations.
2 Anti-CCP Ab, antibodies directed against cyclic citrullinated peptides. Data are from patients who test positive for these antibodies in the serum.
3 SE refers to shared epitope, so called because the susceptibility alleles map to one region of the DRB1 protein (positions 70-74).
(Courtesy Dr. Michelle Fernando, Imperial College, London.)
Several features of the association of HLA alleles with autoimmune diseases are noteworthy.
The mechanisms underlying the association of particular HLA alleles with various autoimmune diseases are still not clear. When positive associations of MHC alleles with disease are noted, the disease-associated MHC molecule may present a particular self peptide and activate pathogenic T cells, and this has been established in a few cases. When a particular allele is shown to be protective (a negative association with disease), it is surmised that this allele might induce negative selection of some developing and potentially pathogenic T cells, thus creating a “hole in the repertoire,” or it might promote the development of regulatory T cells.
Polymorphisms in Non-HLA Genes Associated with Autoimmunity
Linkage analyses of autoimmune diseases identified a few disease-associated genes and many chromosomal regions in which the identity of the associated genes was suspected but not established. The technique of genome-wide association studies has greatly extended analysis of the genetic basis of complex diseases, and we now know several genes that are associated with autoimmune diseases (Table 14-4). Before the genes that are most clearly validated are discussed, it is important to summarize some of the general features of these genes.
Some of the genes associated with human autoimmune diseases, which have been defined by linkage analyses and genome-wide association studies, are described briefly next.
There has been a tremendous increase in the number of polymorphisms identified in inflammatory diseases, largely because of genome-wide association studies. However, these studies do not necessarily identify a causal gene but may point to a region where a putative causal gene is located. Genome-wide association studies are not suitable for the identification of rare variants that may be highly penetrant and may actually be the cause of the disease. The advent of whole genome sequencing is likely to reveal even more single nucleotide polymorphisms (SNPs) in various diseases, so the list is certain to grow. One of the great challenges in the field of genetics of complex diseases, including autoimmune and inflammatory diseases, is to correlate the genetic polymorphisms with phenotypic changes. Until this is done, it will be difficult to elucidate the roles of these genes in the pathogenesis of the diseases.
Single-Gene Abnormalities That Cause Autoimmunity
Studies with mouse models and patients have identified several genes that strongly influence the maintenance of tolerance to self antigens (Table 14-5). Unlike the polymorphisms in complex diseases described before, these single-gene defects are examples of mendelian disorders in which the mutation is rare but has a high penetrance, so that most individuals carrying the mutation are affected. Many of these genes were mentioned earlier in the chapter, when we discussed the mechanisms of self-tolerance. Although these genes are associated with rare autoimmune diseases, their identification has provided valuable information about the importance of various molecular pathways in the maintenance of self-tolerance. The known genes contribute to the established mechanisms of central tolerance (AIRE), generation of regulatory T cells (FoxP3, IL-2, IL-2R), anergy and the function of regulatory T cells (CTLA-4), and peripheral deletion of T and B lymphocytes (Fas, FasL). Here we describe two other genes that are associated with autoimmune diseases in humans.
Role of Infections in Autoimmunity
Viral and bacterial infections may contribute to the development and exacerbation of autoimmunity. In patients and in some animal models, the onset of autoimmune diseases is often associated with or preceded by infections. (One notable and unexplained exception is the NOD [non-obese diabetic] mouse strain, a model of type 1 diabetes, in which infections tend to ameliorate insulitis and diabetes.) In most of these cases, the infectious microorganism is not present in lesions and is not even detectable in the individual when autoimmunity develops. Therefore, the lesions of autoimmunity are not due to the infectious agent itself but result from host immune responses that may be triggered or dysregulated by the microbe.
Infections may promote the development of autoimmunity by two principal mechanisms (Fig. 14-12).
FIGURE 14–12 Role of infections in the development of autoimmunity.
A, Normally, encounter of a mature self-reactive T cell with a self antigen presented by a costimulator-deficient resting tissue antigen-presenting cell (APC) results in peripheral tolerance by anergy. (Other possible mechanisms of self-tolerance are not shown.) B, Microbes may activate the APCs to express costimulators, and when these APCs present self antigens, the self-reactive T cells are activated rather than rendered tolerant. C, Some microbial antigens may cross-react with self antigens (molecular mimicry). Therefore, immune responses initiated by the microbes may activate T cells specific for self antigens.
Microbes may also engage Toll-like receptors (TLRs) on dendritic cells, leading to the production of lymphocyte-activating cytokines, and on autoreactive B cells, leading to autoantibody production. A role of TLR signaling in autoimmunity has been demonstrated in mouse modes of SLE.
The significance of limited homologies between microbial and self antigens in common autoimmune diseases remains to be established, and it has been difficult to prove that a microbial protein can actually cause a disease that resembles a spontaneous autoimmune disease. On the basis of transgenic mouse models, it has been suggested that molecular mimicry is involved in triggering autoimmunity when the frequency of autoreactive lymphocytes is low; in this situation, the microbial mimic of the self antigen serves to expand the number of self-reactive lymphocytes above some pathogenic threshold. When the frequency of self-reactive lymphocytes is high, the role of microbes may be to induce tissue inflammation, to recruit self-reactive lymphocytes into the tissue, and to provide second signals for the activation of these bystander lymphocytes.
Some infections may protect against the development of autoimmunity. Epidemiologic studies suggest that reducing infections increases the incidence of type 1 diabetes and multiple sclerosis, and experimental studies show that diabetes in NOD mice is greatly retarded if the mice are infected. It seems paradoxical that infections can be triggers of autoimmunity and also inhibit autoimmune diseases. How they may reduce the incidence of autoimmune diseases is unknown.
Other Factors in Autoimmunity
The development of autoimmunity is related to several factors in addition to susceptibility genes and infections.
Autoimmune diseases are among the most challenging scientific and clinical problems in immunology. The current knowledge of pathogenic mechanisms remains incomplete, so theories and hypotheses continue to outnumber facts. The application of new technical advances and the rapidly improving understanding of self-tolerance will, it is hoped, lead to clearer and more definitive answers to the enigmas of autoimmunity.
Summary
Immunological Tolerance, General Mechanisms
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