ACP medicine, 3rd Edition


Immunologic Tolerance and Autoimmunity

Paul Anderson MD, PHD1

1Associate Professor of Medicine, Harvard Medical School, Rheumatologist, Division of Rheumatology and Immunology, Brigham and Women's Hospital

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

August 2005

A central concept of immunology is that autoimmune reactions are injurious to the host. Around 1900, Paul Ehrlich postulated that the immune system acquires a state of tolerance to self-antigens; as a corollary to that, he proposed that the breakdown of tolerance would lead to self-destruction, a condition he described as ”horror autotoxicus.“1 Subsequent work by mid-20th-century researchers such as Ray Owen,2 Macfarlane Burnet,3 and Peter Medawar4 established the basic mechanism for the development of immunologic tolerance. In recent years, many important advances have been made in our understanding of tolerance at the molecular and cellular levels. These advances are beginning to transform the clinical management of autoimmune diseases and may lead to therapies that prevent rejection of transplanted organs.


Tolerance is defined as a state of immunologic unresponsiveness to antigens, whether self or foreign. Antigens are recognized by specific receptors expressed on the surface of T cells and B cells. Binding of an antigen to the receptor can either activate or inhibit these immune effector cells. The molecular and cellular factors that determine whether receptor ligation induces immunity or tolerance are beginning to be unraveled.


Tolerance results from one of three inhibitory influences on T and B cells: (1) clonal deletion, in which antigenic recognition leads to the activation-induced death of specific lymphocytes; (2) clonal anergy, in which lymphocytes are not killed but are rendered unresponsive to the recognized antigen; and (3) T cell-mediated suppression, in which regulatory T cells actively inhibit an immune response to an antigen. Several factors help determine which of those responses will occur.

Immature lymphocytes are more susceptible to induction of tolerance than are mature lymphocytes. Tolerance can be induced in immature lymphocytes either centrally or in the periphery. Central tolerance is acquired when immature lymphocytes encounter antigens in the organs that generate these cells: the thymus (T cells) and the bone marrow (B cells).

T cells recognize antigens that have been processed into peptides and presented in a complex with major histocompatibility complex (MHC) molecules (self-MHC-peptide complexes). Consequently, immature T cells must be screened for their ability to recognize self-MHC. This screening takes place in the thymus gland. T cells bearing receptors that recognize self-MHC are subjected to the processes of positive and negative selection [see Figure 1].5 Positive selection occurs when T cells bearing receptors with a moderate affinity for self-MHC-peptide complexes receive survival and maturation signals after receptor ligation. Once these cells mature, they are exported to the periphery. Negative selection occurs when T cells bearing receptors with a high affinity for self-MHC-peptide complexes undergo activation-induced death. The thymus gland is capable of presenting many self-antigens that are normally expressed outside of the thymus or during restricted developmental stages.6,7 This allows the elimination of most T cells bearing high-affinity receptors for self-MHC-peptide complexes and plays a major role in preventing autoimmunity in peripheral organs. The promiscuous expression of peripheral antigens in thymic epithelial cells is regulated by the autoimmune regulator (AIRE). This transcriptional modulator is mutated in persons with autoimmune polyglandular syndrome type 1 (APS-1), which is characterized by mucocutaneous candidiasis in association with autoimmune tissue damage that variably targets the parathyroid, adrenal glands, ovaries, and other tissues.6,7,8 The severity of this syndrome highlights the critical importance of central tolerance to immune homeostasis.


Figure 1. Selection of Immature T Cells in the Thymus

In the thymus, tolerance is induced through positive and negative selection of immature T cells. The fate of a particular T cell depends on the affinity of its receptor (TCR) for complexes of major histocompatibility complex (MHC) and self-peptides. After ligation, T cells whose receptors have low affinity for self-MCH-peptide complexes receive survival and maturation signals and are exported to the periphery (positive selection); T cells with high affinity undergo activation-induced death (negative selection).

CD4+ regulatory T cells (Tr) that express CD25 have intermediate affinity for self-MCH-peptide complexes. This subpopulation of T cells matures in the thymus gland; suppression of their activation takes place in the periphery.

Because positive selection allows the maturation of T cells bearing receptors capable of low-affinity interactions with self-MHC-peptide complexes, potentially self-reactive T cells are normally found in peripheral lymphoid organs. Peripheral tolerance prevents these cells from inducing autoimmune disease.

Peripheral tolerance is achieved in one of three ways.9 Perhaps the most common mechanism is the failure of T cells bearing low-affinity receptors to recognize self-antigen in the periphery. In this situation, the potentially self-reactive T cell is not activated and remains functionally naive. These cells are functional, however, as is shown by the fact that they can be activated by immunization with self-antigen delivered in the presence of immune adjuvants (e.g., complete Freund adjuvant, which contains microbial products that strongly activate the immune system at many levels). Failure to respond to self-antigen may simply reflect a receptor-binding affinity that is below the threshold for T cell activation.

T cells bearing receptors with high affinity for a self-antigen can also remain in an unactivated state if that self-antigen is sequestered from immune effector cells. An example of an antigen that is sequestered from the immune system is myelin basic protein. Because T cells do not normally circulate through the central nervous system, potentially self-reactive cells can persist in an unactivated state in the periphery. Similarly, pancreatic islet cells are normally sequestered from the immune system. In transgenic mice, recombinant proteins expressed on pancreatic islet cells are ignored by high-affinity T cells specific for the recombinant protein. This appears to result from the failure of naive T cells to contact islet cells in the absence of inflammation. In contrast, T cells do become activated in an antigen-specific manner in transgenic mice that express the same recombinant protein in hepatocytes. It therefore appears that circulating lymphocytes contact different tissues in different ways.

A second mechanism of peripheral tolerance involves the elimination of self-reactive T cells by apoptosis. This process is analogous to clonal deletion in the thymus (i.e., negative selection). An example of peripheral deletion is the ability of superantigens (bacterial proteins that bridge selected T cell receptors and selected MHC molecules in an antigen-nonspecific manner) to induce the activation and subsequent death of T cells10 [see 7:XXX Sepsis]. Whether peripheral deletion plays an important role in tolerance to self-antigens is not known, however.

A third mechanism of peripheral tolerance involves the acquisition of anergy after ligation of the T cell receptor complex.11 This antigen-nonresponsive state can be induced in several distinct ways. The most extensively characterized mechanism of anergy induction occurs when the T cell receptor is ligated in the absence of costimulation. In the classic studies of Schwartz and colleagues, T cell clones that were activated by MHC-peptide complexes incorporated into artificial lipid bilayers were rendered nonresponsive to subsequent challenge with peptide-pulsed antigen-presenting cells (APCs).12 It was subsequently shown that once a T cell has bound with an antigen, the cell requires a so-called second signal delivered by one or more costimulatory molecules to be primed for an immune response. T cells express several surface molecules that can transmit this second signal. These costimulatory receptors are engaged by ligands expressed on the surface of APCs. T cells that are activated in the absence of costimulation acquire defects in the transcriptional control pathways for the production of interleukin-2 (IL-2), an important T cell autocrine growth factor.13 In vitro anergy can often be overcome by supplying exogenous IL-2 to anergic T cells.

Costimulatory signals can be delivered to T cells by soluble factors or cell surface molecules expressed on APCs. The most potent costimulatory signals are delivered when CD28,14 CD154,15 or both are ligated on the surface of T cells [see Figure 2]. Blockade of costimulatory signals by monoclonal antibodies or recombinant receptor antagonists confers potent immunosuppression and allows the acceptance of skin, cardiac, and pancreatic allografts in rodents.16 Simultaneous blockade of the CD28 and CD154 pathways is significantly more immunosuppressive than blockade of a single costimulatory pathway. The ligand for CD154 is CD40, a protein expressed on the surface of activated B cells, dendritic cells, and macrophages.15 The ligands for CD28 (B7-1, B7-2, and related proteins14) are expressed on the surface of APCs, such as dendritic cells, monocytes, and B cells. Their expression is induced when APCs are activated in the course of microbial infection. This property heightens the immune response in the setting of perceived danger (i.e., microbial infection). B7-1 and B7-2 have overlapping immunostimulatory roles: mice lacking either protein are only partially deficient in generating an immune response to foreign antigen.14 Additional costimulatory molecules that are involved in fine tuning the immune response include B7 homologues expressed on APCs (e.g., B7-H1, B7-H2, B7-H3, and B7-DC) that bind to ligands expressed on T cells (ICOS, PD-1, and possibly others).14


Figure 2. Activation of T Cells

Activation of T cells begins when the T cell receptor binds with a complex of an MHC molecule and a peptide expressed on the surface of an antigen-presenting cell (APC). Activation is completed by a second signal generated by the ligation of costimulatory molecules expressed on the cell surface of the APC. B7-1/B7-2 interacts with CD28 on the T cell, and CD40 interacts with CD154.

In unactivated T cells, CTLA-4 (a relative of CD28) is a component of intracellular vesicles. After CD28 ligation, CTLA-4 moves to the cell surface and binds with B7-1/B7-2, generating negative signals that turn off the immune response.

Ligation of CD28 induces the expression of CTLA-4 (cytotoxic T lymphocyte-associated protein 4), a structurally related protein that turns off activated T cells.17,18 By this mechanism, the activated T cell initiates a program that will ensure its elimination at the conclusion of the immune response. Compared with CD28, CTLA-4 has a higher affinity for B7-1 and B7-2.14 The importance of the negative regulatory influence of CTLA-4 is dramatically observed in CTLA-4-null mice. These animals develop a fatal lymphoproliferative syndrome from the uncontrolled activation of self-reactive T cells.19

Given the central importance of CD28-B7 interactions in T cell activation and the ability of costimulatory blockade to prevent allograft rejection, it might seem paradoxical that NOD mice (a strain that develops spontaneous diabetes) lacking either CD28 alone or both B7-1 and B7-2 have more severe diabetes.20 The reason for this appears to be that CD28-B7 interactions are required for the maturation of self-reactive regulatory T cells (Tregs). Tregs, which are generated within the thymus gland, form a distinct class of regulatory T cells that play a major role in ensuring tolerance to self-antigens in the periphery. Just as APS-1 provides a clinical demonstration of the importance of central tolerance to normal immune function, the immune dysregulation, polyendrocrinopathy, enteropathy, and X-linked syndrome (IPEX) dramatically demonstrates the importance of Tregs in the maintenance of self-tolerance.21 IPEX patients have mutations in the FOXP3 transcription factor that is essential for the maturation and function of Tregs. These patients exhibit hyperactivation of T cells that are reactive with self-antigens, resulting in polyendocrinopathy, inflammatory bowel disease, and allergy.

In rodents, FOXP3-dependent Tregs comprise a subset of peripheral blood CD4+ T cells that express CD25, a subunit of the IL-2 receptor.22The selective removal of CD4+ and CD25+ T cells from BALB/c mice results in the development of T cell-mediated autoimmune thyroiditis, gastritis, and diabetes. The CD4+ and CD25+ Treg cells that mature in the thymus gland bear receptors that have an intermediate affinity for self-MHC-peptide complexes [see Figure 1]. In the periphery, antigen exposure confers the ability to suppress the activation of CD4+ and CD25+ T cells in an antigen-independent, cell contact-dependent manner. Although these cells secrete IL-10, a potent anti-inflammatory cytokine, their suppressive activity is cytokine independent. CD4+ and CD25+ T cells can suppress graft versus host disease in allotransplants, and they can prevent autoimmune disease in several different animal models. Consequently, these cells probably play an essential role in maintaining peripheral tolerance to self-antigens.

Although T cells play a dominant role in the maintenance of immune tolerance, non-T cells are also important in this process. Natural killer T (NKT) cells are specialized effectors of innate immunity that are activated by endogenous or microbe-derived lipids bound to CD1.23Activated NKT cells express large amounts of interferon gamma and IL-4, allowing them to have profound effects on the immune response. Results in animal models have implicated NKT cells in the suppression of autoimmune disease.24 Several autoimmune mouse strains (e.g., NOD, MRL-lpr/lpr, and SJL/J) have reduced the numbers of NKT cells as compared with nonautoimmune strains. In these models, adoptive transfer of NKT cells can ameliorate disease. Moreover, activation of NKT cells by the natural product α-galactosylceramide prevents autoimmune disease in several murine models. Although the role of NKT cells in human autoimmune disease remains to be determined, these results show that components of the innate immune response can have profound effects on discrimination of self from nonself [see6:II Innate Immunity].


Despite the multiple and redundant mechanisms that exist to ensure immunologic tolerance to self, autoimmune phenomena are relatively common. In some cases, autoimmune responses accompany a normal immune response to a microbial pathogen. Thus, the appearance of rheumatoid factor (anti-immunoglobulin antibodies) in the serum of patients with bacterial endocarditis is relatively common. In general, these autoantibodies are not pathogenic. Their appearance probably results from antigen-nonspecific activation of T cells and B cells bearing low-affinity receptors for self-antigens that are normally held in check by mechanisms of peripheral tolerance. The ability of bacterial products (e.g., lipopolysaccharide) to function as immune adjuvants appears to overcome these repressive influences.


Clinical observations have established a link between certain microbial infections and specific autoimmune syndromes. Examples include streptococcal infection and rheumatic fever, Borrelia burgdorferi infection and Lyme arthritis, Trypanosoma cruzi infection and Chagas disease, and B4 coxsackievirus infection and type 1 diabetes mellitus.25 These associations suggest that the immune response to a specific microbial peptide may be redirected toward a similar self-peptide, a phenomenon known as molecular mimicry. Although this is an appealing hypothesis, definitive evidence for molecular mimicry has yet to be demonstrated in any of these diseases. The strongest evidence, to date, for molecular mimicry comes from the molecular analysis of the immune response to the tick-borne spirochete B. burgdorferi. About 10% of infected patients develop persistent synovitis, despite the eradication of the spirochete by antibiotic therapy.26 Most patients with treatment-resistant Lyme arthritis have the HLA-DRB1*04041 or HLA-DRB1*0101 major histocompatibility alleles, implicating antigen presentation in disease pathogenesis. These same HLA alleles confer an increased relative risk for rheumatoid arthritis and, perhaps, for synovial disease in general. Treatment-resistant Lyme arthritis is associated with a cellular and humoral immune response to the B. burgdorferi outer-surface protein OspA, and a computer algorithm predicted that an immunodominant OspA epitope (OspA165-173) should bind to HLA-DRB1*0401. This prediction was confirmed experimentally, and indeed, most patients with treatment-resistant Lyme arthritis have T cells that recognize this immunodominant epitope. The computer algorithm also predicted that a peptide epitope encoded by leukocyte function-associated antigen-1α (LFA-1α) would bind to HLA-DRB1*0401. This binding was confirmed experimentally, and most patients with treatment-resistant Lyme arthritis have T cells that weakly respond to the LFA-1α peptide epitope. The LFA-1α peptide does not bind to HLA-DRB1*0101, however, indicating that this mechanism cannot explain all cases of treatment-resistant Lyme arthritis. Moreover, it remains to be proved that T cells reactive with LFA-1α are necessary and sufficient for the onset of treatment-resistant Lyme arthritis.27


A common feature of autoimmune diseases is the appearance of autoantibodies in the serum. In some cases, these autoantibodies are directly pathogenic: the clinical syndrome is produced when the antibody binds to its target antigen. The molecular pathogenesis of these autoimmune conditions can be determined with some precision. Unfortunately, the molecular defects that allow the bypass of tolerance to the disease-inducing autoantigen are less well understood.

Pathogenic Autoantibodies

Myasthenia gravis

Nearly all patients with myasthenia gravis have autoantibodies to acetylcholine receptors (ACRs) on skeletal muscle [see 11:III Diseases of Muscle and the Neuromuscular Junction]. However, the degree of neuromuscular blockade seen in this disease does not always parallel the serum levels of anti-ACR antibodies. The antibodies are polyclonal and bind to several distinct epitopes on the ACR. Although these antibodies can directly inhibit ACR function, they can also promote the endocytosis and accelerated degradation of the ACR or activate complement-mediated destruction of the postsynaptic surface.28 The supposition that these anti-ACR antibodies have direct pathogenic effects is supported by the fact that injection of ACR antibodies can induce myasthenic weakness in animals and that plasmapheresis is an effective treatment in some patients. Some patients with myasthenia gravis have a coincident thymoma, and thymectomy can be an effective treatment in such patients, suggesting that defects in thymic selection of maturing T cells may play a role in the autoimmune response to the ACR. This could involve impaired negative selection of CD4+ helper T cells reactive with ACR-derived peptides or impaired generation of Tregs specific for ACR-derived peptide epitopes.


Pemphigus vulgaris and bullous pemphigoid are autoimmune skin diseases characterized by the presence of serum autoantibodies that react with adhesion molecules found at the dermoepidermal basement membrane zone [see 2:IX Vesiculobullous Diseases]. In pemphigus vulgaris, a common target antigen is desmoglein 3, a desmosomal adhesion molecule. In bullous pemphigoid, common target antigens are two major hemidesmosomal proteins of 180 kd and 230 kd. Several lines of evidence have implicated autoantibodies targeting these proteins in the pathogenesis of pemphigus. First, autoantibodies are consistently present in patients with pemphigus, levels of those antibodies correlate with disease activity, and the removal of the antibodies by plasmapheresis results in improvement of symptoms. Second, serum from patients with pemphigus vulgaris causes pemphigus-like lesions in mice. Third, newborns of mothers with pemphigus have transient disease resulting from transplacental transmission of maternal antibody.

Autoimmune endocrinopathies

Autoantibodies reactive with hormone receptors can contribute to endocrine disorders. High levels of antibody reactive with the peripheral insulin receptor can result in insulin-dependent diabetes mellitus. Paradoxically, low levels of antibody may stimulate the insulin receptor by mimicking insulin, resulting in hypoglycemia.

Autoimmune disease of the thyroid is associated with antibodies directed toward three antigens: microsomal thyroid peroxidase, thyroglobulin, and the thyroid receptor for thyroid-stimulating hormone (TSH). Antibodies to the TSH receptor may mimic the action of TSH, thereby resulting in Graves disease [see 3:I Thyroid]. Another apparent autoimmune disease of the thyroid, Hashimoto thyroiditis, is associated with antibodies to the TSH receptor, but the pathogenic role of the antibodies in this disease is unclear. Less commonly, antibodies to the TSH receptor may block the action of TSH and cause hypothyroidism. A pathogenic role for the other two classes of antithyroid autoantibodies has not been established.

Antiphospholipid syndrome

The antiphospholipid syndrome (APS) consists of recurrent thrombosis, fetal loss, and thrombocytopenia in association with antibodies to cardiolipin or other negatively charged phospholipids, along with abnormalities of certain clotting tests caused by an inhibitor referred to as the lupus anticoagulant [see 5:XIV Thrombotic Disorders]. APS can be primary or secondary; secondary APS is usually associated with systemic lupus erythematosus (SLE) or its variants. The antiphospholipid antibodies do not bind to phospholipids alone but to a complex of phospholipids and the plasma proteins β2-glycoprotein I and prothrombin. These antibodies induce the expression of adhesion molecules on endothelial cells that promote the binding of monocytes and platelets as the first step in a thrombotic cascade.

Nonpathogenic Autoantibodies

Autoantibodies reactive with intracellular targets can serve as markers of specific autoimmune diseases. For example, antibodies reactive with citrullinated peptides are specific markers of rheumatoid arthritis, antibodies reactive with the mitochondrial enzyme 2-oxo acid dehydrogenase are specific markers of primary biliary cirrhosis, and antibodies reactive with the Smith small nuclear ribonucleoprotein (snRNP) complex are specific markers of SLE. Although these autoantibodies are unlikely to be pathogenic, their presence is highly correlated with specific autoimmune diseases. An understanding of the process that promotes the disease-specific bypass of tolerance to a selected antigen is likely to shed light on the pathogenic mechanism underlying individual autoimmune syndromes. An important insight into the mechanism by which tolerance is abrogated in an antigen-specific manner came with the realization that the targets of many autoantibodies found in the serum of patients with autoimmune disease are proteins that are modified in cells undergoing apoptotic cell death.29 During apoptosis, myriad intracellular proteins, nucleic acids, and lipids are subjected to enzymatic and nonenzymatic modification. These modifications include protease cleavage, phosphorylation, transglutamination, ubiquitination, citrullination, and isoaspartylation.30 It has been proposed that these modifications create neo-epitopes to which the immune system has not been tolerized.

Although proteins that are modified during apoptosis are preferred targets of the autoantibodies found in the serum of patients with autoimmune disease, it is clear that apoptosis per se is not sufficient to break tolerance to these self proteins. Apoptosis is a ubiquitous process, yet most persons do not develop autoimmune disease. Apparently, the necessary additional element is delay in the execution of the apoptotic program or the clearance of the apoptotic cell. This phenomenon has been demonstrated in mice that lack the first component of complement. C1q functions as an opsonin that binds to apoptotic cells and promotes their clearance by professional phagocytes (neutrophils and macrophages). In the absence of C1q, the clearance of apoptotic corpses is delayed. Delayed clearance of apoptotic cells somehow increases their immunogenicity.31

A similar phenomenon occurs when the execution of the apoptotic program is delayed. For example, influenza virus-induced apoptosis in macrophages has been shown to increase the immunogenicity of viral proteins.32 This phenomenon requires the phagocytosis of infected macrophages by dendritic cells. By a process of cross-priming, the dendritic cell can then present antigens derived from the infected macrophage in a highly efficient manner. Because influenza virus encodes several genes that function to inhibit apoptosis (e.g., NS1), virus-induced apoptosis requires many hours to complete. During this delay, the virus replicates within the infected cell, and the virus-infected cell expresses stress-response proteins (heat shock proteins [HSPs]), including HSP70 and HSP90. These HSPs function as natural adjuvants that can deliver peptides to class I MHC molecules expressed by APCs.33 The generation of modified peptides and the induction of HSPs may account for the increased immunogenicity of apoptotic cells and the generation of autoantibodies reactive with proteins that are modified during apoptotic cell death.

In this model, the autoantibodies that serve as markers of specific autoimmune diseases are generated when the target cell undergoes delayed or aberrant apoptosis. This implies that the primary insult to the target tissue is produced by a stimulus that induces aberrant cell death and modification of the specific autoantigen. Such a process may be initiated by specific environmental factors (e.g., viruses, toxins, or ultraviolet radiation).

The autoantibodies that directly and indirectly contribute to the pathogenesis of autoimmune disease are produced by differentiated B cells. A reduced activation threshold for B cells has been implicated in the pathogenesis of SLE.34 Moreover, increased activation of B cells may contribute to the predisposition to lymphoma observed in some autoimmune diseases.34 Finally, preliminary results suggesting therapeutic efficacy of B cell-depleting monoclonal antibodies in patients with rheumatoid arthritis and SLE indicate that B cells play an important role in the pathogenesis of autoimmune disease.35,36


Systemic autoimmunity is a multigenic trait that is significantly influenced by environmental factors. For example, the concordance rate for SLE in monozygotic twins is only 30%, indicating that both genetic and environmental factors contribute to disease onset. The specific genes that promote autoimmunity can be identified in two ways. Most of the genes currently known to promote autoimmunity have been discovered using case-control association methodologies.37 These studies have linked the expression of specific HLA haplotypes to specific autoimmune diseases. In a similar fashion, case-control studies have linked defects in both classical pathway complement components (C1q, C2, and C4) and Fc receptor alleles to the development of SLE. In families in which two or more members have SLE, genetic linkage analysis has been applied in an attempt to identify disease-susceptibility loci. These studies have identified several chromosomal loci with significant linkage to human SLE.37 It is likely that future studies will identify a cohort of genes that, alone or in combination, contribute to the autoimmune diathesis.

Studies of transgenic mice that either lack or overexpress specific genes have identified three groups of genes that encode distinct classes of proteins that modify susceptibility to autoimmune disease. Absence of these genes results in autoimmunity. The first group of genes encode proteins involved in the initiation or execution of apoptotic cell death. These proteins include dedicated death receptors and their ligands. Specific members of this family (e.g., Fas and tumor necrosis factor type I [TNF RI]) are required for the clonal elimination of activated T cells after an immune response to microbial infection. Mice lacking either Fas or its ligand develop lymphadenopathy and splenomegaly from the accumulation of previously activated T cells. In some strains of transgenic mice (e.g., MRL), but not in others (e.g., BALB/c), failure to eliminate activated T cells results in an autoimmune disease that resembles SLE. Thus, the absence of Fas or Fas ligand (FasL) promotes the phenotypic expression of an autoimmune diathesis that is intrinsic to the MRL strain (a genetic phenomenon known as epistasis). Although defects in Fas or FasL are not linked to autoimmunity in patients with SLE, mutations in either Fas or FasL produce the autoimmune lymphoproliferative syndrome (ALPS), an autosomal dominant condition characterized by lymphadenopathy, splenomegaly, and autoantibody production.38 ALPS is also caused by mutations in caspase-10, a component of the effector arm of the apoptotic death program. Thus, ALPS is an autoimmune disease that results from defective execution of an apoptotic program in activated T cells. The importance of the apoptotic program in determining susceptibility to autoimmune disease is further demonstrated by the autoimmune syndromes observed in mice lacking BIM, a pro-apoptotic protein, or overexpressing BCL-2, an anti-apoptotic protein.

The second group of genes encode proteins involved in the recognition, clearance, or elimination of apoptotic cells. These include proteins that serve as opsonins to promote the phagocytosis of apoptotic cells (e.g., C1q, IgM, SAP/CRP), as well as phagocyte receptors that promote the recognition and ingestion of apoptotic cells (e.g., Mer).

The third group of genes encode proteins that set the threshold for lymphocyte activation. Increased activation of T cells or B cells is likely to disrupt normal mechanisms of tolerance, resulting in autoimmunity. Examples include costimulatory lymphocyte surface molecules (e.g., CD22, PD-1), kinases and phosphatases involved in lymphocyte activation (e.g., Lyn, Cbl-b), and transcription factors (e.g., Foxo3a) that promote lymphocyte activation. These animal studies reveal that genes involved in the regulation of apoptosis or lymphocyte activation are proven modifiers of autoimmune disease in mice and are candidates for the modulation of autoimmunity in humans.

Genome-wide linkage mapping has identified mutations in NOD2 as an etiologic factor in familial Crohn disease, an autoimmune inflammatory process that targets the intestinal mucosa.39 NOD2 is a cytosolic protein that recognizes muramyl dipeptide (MDP), a metabolite of bacterial peptidoglycan.40 Recognition of MDP promotes the oligomerization of NOD2, which results in activation of NF-κB and caspase-1—signaling events that lead to the secretion of inflammatory cytokines. Selected patients with Crohn disease possess mutant NOD2 that is unable to promote MDP-mediated activation of NF-κkB. The mechanism by which ineffective recognition of bacterial products leads to intestinal inflammation remains to be determined.


For many years, organ-specific immunity was thought to result from the activation of lymphocytes bearing receptors specific for a tissue-restricted antigen. In rare cases of molecular mimicry, this may be the case. However, it now appears that the target of an autoimmune attack can shift from one tissue to another in response to defined or undefined genetic modifiers. For example, persons with APS-1 develop various combinations of autoimmune thyroiditis, parathyroid disease, and type 1 diabetes mellitus.41 Although the factors that determine which tissues become targets of autoimmune attack have not been identified, the fact that different tissues are affected in different persons suggests that unique, tissue-specific autoantigens may not be the primary triggers of disease.

The concept that organ-specific autoimmunity need not be driven by a tissue-specific autoantigen is supported by observations made in two different animal models of autoimmunity. In NOD mice whose MHC locus is replaced with that of another strain, autoimmune thyroiditis develops instead of diabetes.20 This result suggests that the NOD strain harbors an autoimmune diathesis that can manifest itself as different types of organ-specific autoimmunity. In support of this concept, NOD mice lacking the costimulatory molecule B7-2 develop autoimmune peripheral neuropathy, rather than diabetes.20 Although the mechanism by which individual tissues are selected for immune attack is not known, these results strongly suggest that factors other than tissue-restricted autoantigens can be the primary determinant of organ-specific autoimmune disease.

Another instructive example of organ-specific autoimmunity that arises in the absence of a defined, tissue-restricted autoantigenic trigger is the inflammatory arthritis that develops in the F1 progeny of K/B×NOD mice.42 The K/B strain expresses a transgenic T cell receptor that recognizes a self-peptide derived from glucose-6-phosphate isomerase (GPI) presented in the context of Ag7, a class II MHC molecule from the NOD strain. In K/B×NOD mice, T cells bearing the transgene provide help for B cells encoding immunoglobulins that bind to GPI. GPI is an enzyme expressed in all cells, yet anti-GPI antibodies somehow provoke a symmetrical, inflammatory arthritis involving diarthrodial joints in these mice. Although the mechanism by which anti-GPI antibodies provoke arthritis is not fully understood, this model illustrates the potential for an immune response that is directed at a ubiquitous antigen to trigger organ-specific autoimmunity.

One way in which organ-specific autoimmunity can be induced in the absence of a tissue-specific autoantigen is by the pathologic overexpression of inflammatory cytokines. Thus, overexpression of tumor necrosis factor-α (TNF-α) in transgenic mice is sufficient to induce a symmetrical polyarthritis that resembles rheumatoid arthritis.43 This appears to result from the ability of TNF-α to initiate an inflammatory cytokine cascade within the cells that make up the synovium. The importance of TNF-α in the pathogenesis of rheumatoid arthritis has been dramatically validated by the clinical efficacy of TNF blockers such as infliximab and etanercept44 [see 15:II Rheumatoid Arthritis]. In an analogous fashion, BAFF/Blys, a TNF-α-related protein that promotes the survival and differentiation of B cells, has been proposed to participate in the induction of SLE-like autoimmune syndromes.45,46 Transgenic mice engineered to overexpress BAFF/Blys develop hypergammaglobulinemia and autoimmune symptoms because of the survival of autoreactive B cells that would normally be deleted from the B cell repertoire. These observations suggest that neutralization of TNF family members may play an important role in the treatment of selected autoimmune diseases.


Figure 2 Seward Hung.


  1. Ehrlich P, Morgenroth J: On haemolysis: third communication. Berlin Klin Wochenschr 37:453, 1900
  2. Owen R: Immunogenetic consequences of vascular anastomosis between bovine twins. Science 102:400, 1945
  3. Burnet F: Clonal selection theory: a modification of Jerne's theory of antibody production using the concept of clonal selection. Aust J Sci 20:67, 1957
  4. Billingham R, Brent L, Medawar P: Actively acquired tolerance of foreign cells. Nature 172:603, 1953
  5. Nossal GJ: Negative selection of lymphocytes. Cell 76:229, 1994
  6. Kyewski B, Derbinski J: Self-representation in the thymus: an extended view. Nat Rev Immunol 4:688, 2004
  7. Mathis D, Benoist C: Back to central tolerance. Immunity 20:509, 2004
  8. Peterson P, Pitkanen J, Sillanpaa N, et al: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a model disease to study molecular aspects of endocrine autoimmunity. Clin Exp Immunol 135:348, 2004
  9. Fazekas de St. Groth B: DCs and peripheral T cell tolerance. Semin Immunol 13:311, 2001
  10. Sundberg E, Li Y, Mariuzza R: So many ways of getting in the way: diversity in the molecular architecture of superantigen-dependent T-cell signaling complexes. Curr Opin Immunol 14:36, 2002
  11. Macian F, Im S, Garcia-Cozar F, et al: T-cell anergy. Curr Opin Immunol 16:209, 2004
  12. Quill H, Schwartz R: Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes. J Immunol 138:3704, 1987
  13. Nelson BH: IL-2, regulatory T cells, and tolerance. J Immunol 172:3983, 2004
  14. Sharpe AH, Freeman GJ: The B7-CD28 superfamily. Nat Rev Immunol 2:116, 2002
  15. Quezada SA, Jarvinen LZ, Lind EF, et al: CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 22:307, 2004
  16. Sun Y, Subudhi SK, Fu YX: Co-stimulation agonists as a new immunotherapy for autoimmune diseases. Trends Mol Med 9:483, 2003
  17. Chikuma S, Bluestone JA: CTLA-4 and tolerance: the biochemical point of view. Immunol Res 28:241, 2003
  18. Greenwald RJ, Latchman YE, Sharpe AH: Negative co-receptors on lymphocytes. Curr Opin Immunol 14:391, 2002
  19. Tivol E, Borriello F, Schweitzer A, et al: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541, 1995
  20. Lesage S, Goodnow C: Organ-specific autoimmune disease: a deficiency of tolerogenic stimulation. J Exp Med 194:F31, 2001
  21. Torgerson T, Ochs H: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and immune dysregulation. Curr Opin Immunol 2:481, 2002
  22. Sakaguchi S: Naturally arising CD4+regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531, 2004
  23. Brigl M, Brenner MB: CD1: antigen presentation and T cell function. Annu Rev Immunol 22:817, 2004
  24. Van Kaer L: α-Galactosylceramide therapy for autoimmune diseases: prospects and obstacles. Nat Rev Immunol 5:31, 2004
  25. Rose N, Mackay I: Molecular mimicry: a critical look at exemplary instances in human diseases. Cell Mol Life Sci 57:542, 2000
  26. Steere AC, Glickstein L: Elucidation of Lyme arthritis. Nat Rev Immunol 4:143, 2004
  27. Benoist C, Mathis D: Autoimmunity provoked by infection: How good is the case for T cell epitope mimicry? Nature Immunol 2:797, 2001
  28. Hughes BW, Moro De Casillas ML, Kaminski HJ: Pathophysiology of myasthenia gravis. Semin Neurol 24:21, 2004
  29. Hall JC, Casciola-Rosen L, Rosen A: Altered structure of autoantigens during apoptosis. Rheum Dis Clin North Am 30:455, 2004
  30. Utz P, Gensler T, Anderson P: Death, autoantigen modifications, and tolerance. Arthritis Res 2:101, 2000
  31. Manderson A, Botto M, Walport M: The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 22:431, 2004
  32. Albert M, Sauter B, Bhardwaj N: Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392:86, 1998
  33. Albert ML: Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nat Rev Immunol 4:223, 2004
  34. Criscione LG, Pisetsky DS: B lymphocytes and systemic lupus erythematosus. Curr Rheumatol Rep 5:264, 2003
  35. Looney RJ, Anolik JH, Campbell D, et al: B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituzimab. Arthritis Rheum 50:2580, 2004
  36. Kotzin BL: The role of B cells in the pathogenesis of rheumatoid arthritis. J Rheumatol Suppl 73:14, 2005
  37. Raman K, Mohan C: Genetic underpinnings of autoimmunity—lessons from studies in arthritis, diabetes, lupus and multiple sclerosis. Curr Opin Immunol 15:651, 2003
  38. Rieux-Laucat F, Fischer A, Deist FL: Cell-death signaling and human disease. Curr Opin Immunol 15:325, 2003
  39. Beutler B: Autoimmunity and apoptosis: the Crohn's connection. Immunity 15:5, 2001
  40. Inohara N, Nunez G: NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3:371, 2003
  41. Ruan Q, She J: Autoimmune polyglandular syndrome type 1 and the autoimmune regulator. Clin Lab Med 24:305, 2004
  42. Monach PA, Benoist C, Mathis D: The role of antibodies in mouse models of rheumatoid arthritis, and relevance to human disease. Adv Immunol 82:217, 2004
  43. Sfikakis P, Kollias G: Tumor necrosis factor biology in experimental and clinical arthritis. Curr Opin Rheumatol 15:380, 2003
  44. Vilcek J, Feldmann M: Historical review: cytokines as therapeutics and targets of therapeutics. Trends Pharmacol Sci 25:201, 2004
  45. Ramanujam M, Davidson A: The current status of targeting BAFF/BLyS for autoimmune diseases. Arthritis Res Ther 6:197, 2004
  46. Cancro M: The BLyS family of ligands and receptors: an archetype for niche-specific regulation. Immunol Rev 202:237, 2004

Editors: Dale, David C.; Federman, Daniel D.