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The immune system has very powerful effector mechanisms that can eliminate a wide variety of pathogens. Early in the study of immunity, it was realized that these could, if turned against the host, cause severe tissue damage. Autoimmune responses resemble normal immune responses to pathogens as specifically activated by antigens, in this case self-antigens or auto-antigens, and give rise to auto-reactive effector cells and to antibodies, called autoantibodies, against the self-antigen. When reactions to self-tissues do occur and are then improperly regulated, they cause a variety of chronic syndromes called autoimmune diseases.

Immune Tolerance

Although individual autoimmune diseases are uncommon, collectively they affect approximately 5% of the populations in United States, and their incidence is on the rise. Nevertheless, their relative rarity indicates that the immune system has evolved multiple mechanisms to prevent damage to self-tissues. The most fundamental principle underlying these mechanisms is the discrimination of self from non self, but this discrimination is not easy to achieve.

The first mechanism proposed for distinguishing between self and non self was recognition of antigen by an immature lymphocyte leads to a negative signal that causes lymphocyte death or inactivation. The tolerance induced at this stage is known as central tolerance. Another antigenic quality that correlates with self is a sustained, high concentration of the antigen. Many self-proteins are expressed by multiple cell types in the body or are abundant in connective tissues. These can provide strong signals to lymphocytes, and even mature lymphocytes can be made tolerant to an antigen, or tolerized, by strong and constant signals through their antigen receptors. The third mechanism relies on the innate immune system, which provides signals that are crucial in enabling the activation of an adaptive immune response to infection. In the absence of infection, these signals are not generated. In these circumstances, the encounter of a naive lymphocyte with a self-antigen tends to lead to a negative inactivating signal, rather than no signal at all, or can promote the development of regulatory lymphocytes that suppress the development of effector responses that might injure tissues. Tolerance induced in the mature lymphocyte repertoire once cells have left the central lymphoid organs are known as peripheral tolerance.

1. T Cell Tolerance

Tolerance of CD4+ helper T lymphocytes is an effective way of preventing both cell-mediated and humoral immune responses to protein antigens because helper T cells are necessary inducers of all such responses.

a. Central T Cell Tolerance

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. This process is called T cell deletion, or negative selection. 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.

Immature T cells that express high-affinity receptors for self-antigens will die by apoptosis if encounter these antigens. 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 (Figure 1)

Central T cell tolerance

Figure 1. Central T cell tolerance. Recognition of self-antigens by immature T cells in the thymus leads to the death of the cells or to the development of regulatory T cells that enter peripheral tissues.

Antigens present in thymus include many circulating and cell-associated proteins that are widely distributed in tissues. The thymus also has a special mechanism for expressing many 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. These peripheral tissue antigens are expressed in thymic medullary epithelial cells under the control of the autoimmune regulator (AIRE) protein (Figure 2).

The function of AIRE in deletion of T cells in the thymus

Figure 2. The function of AIRE in deletion of T cells in the thymus. (TRAs: tissue restricted antigens)

b. Peripheral T Cell Tolerance

The mechanisms of peripheral tolerance are anergy, suppression by regulatory T cells, and deletion (cell death).

Exposure of mature T cells to an antigen in the absence of costimulation or innate immunity may make the cells incapable of responding to that antigen. Full activation of T cells requires the recognition of antigen by the TCR and recognition of costimulators, mainly B7-1 and B7-2, by CD28 (Figure 3a). Prolonged antigen recognition alone may lead to anergy (Figure 3b). Regulatory T lymphocytes are a subset of CD4+ T cells whose function is to suppress immune responses and maintain self-tolerance. It appears 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. (Figure 3c). T lymphocytes that recognize self-antigens with high affinity or are repeatedly stimulated by antigens may die by apoptosis. (Figure 3d)

Mechanisms of peripheral T cell tolerance

Figure 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).

2. B Cell 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.

a. Central B Cell Tolerance

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 as described in figure 4.

If immature B cells recognize self-antigens that are present at high concentration level in the bone marrow and especially if the antigen is displayed in multivalent form (e.g., on cell surfaces), many antigen receptors on each B cell are cross-linked, thus delivering strong signals to the cells. One consequence of such signaling is that the B cells reactivate their RAG1 and RAG2 genes and initiate a new round of VJ recombination. As a result, the self-reactive immature B cell is deleted, and a new Ig light chain is expressed, thus creating a B cell receptor with a new specificity. This process is called receptor editing and is an important mechanism for eliminating self-reactivity from the mature B cell repertoire. If editing fails, the immature B cells may die by apoptosis. The mechanisms of deletion are not well defined. (Figure 4a).

If developing B cells recognize self-antigens weakly (e.g., if the antigen is soluble and does not cross-link many antigen receptors or if the B cell receptors recognize the antigen with low affinity), the cells become functionally unresponsive (anergic) and exit the bone marrow in this unresponsive state (Figure 4b). Anergy is due to down regulation of antigen receptor expression as well as a block in antigen receptor signaling.

Central tolerance in B cells

Figure 4. Central tolerance in B cells.

b. 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. Signals from helper T cells may be absent if these T cells are deleted or anergic or if the self-antigens are non-protein antigens. Since self-antigens usually do not elicit innate immune responses, B cells will also not be activated via complement receptors or pattern recognition receptors. 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.

Some self-reactive B cells that are repeatedly stimulated by self-antigens become unresponsive to further activation.

B cells that recognize self-antigens with low affinity may be prevented from responding by the engagement of various inhibitory receptors. The function of these inhibitory receptors is to set a threshold for B cell activation, which allows responses to foreign antigens with T cell help but does not allow responses to self-antigens (Figure 5).

Peripheral tolerance in B cells

Figure 5. 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.

3. Foreign Protein Induced Tolerance

Foreign antigens may be administered in ways that preferentially induce tolerance rather than immune responses. In general, protein antigens administered cutaneously with adjuvants favor immunity, whereas high doses of antigens administered without adjuvants tend to induce tolerance.

Mechanisms of Autoimmunity

The factors that contribute to the development of autoimmunity are genetic susceptibility and environmental triggers, such as infections and local tissue injury. Susceptibility genes may disrupt self-tolerance mechanisms, and infection or necrosis in tissues promotes the influx of autoreactive lymphocytes and activation of these cells, resulting in tissue injury (Fig. 15-11). Infections and tissue injury may also alter the way in which self-antigens are displayed to the immune system, leading to failure of self-tolerance and activation of self-reactive lymphocytes.

1. Immunologic Abnormalities

Autoimmunity results from some combination of three main immunologic aberrations: Defective tolerance or regulation. Failure of the mechanisms of self-tolerance in T or B cells, leading to an imbalance between lymphocyte activation and control, is the underlying cause of all autoimmune diseases; Abnormal display of self-antigens. Abnormalities may include increased expression and persistence of self-antigens that are normally cleared, or structural changes in these antigens resulting from enzymatic modifications or from cellular stress or injury. If these changes lead to the display of antigenic epitopes that are not present normally, the immune system may not be tolerant to these epitopes, thus allowing anti-self responses to develop; Inflammation or an initial innate immune response. Infections or cell injury may elicit local innate immune reactions with inflammation. These may contribute to the development of autoimmune disease, perhaps by activating APCs, which overcomes regulatory mechanisms and results in excessive T cell activation.

2. Genetic Basis

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. Among the genes that are associated with autoimmunity, the strongest associations are with MHC genes.

3. Role of Infections

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. 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: Infections of particular tissues may induce local innate immune responses that recruit leukocytes into the tissues and result in the activation of tissue APCs. These APCs begin to express costimulators and secrete T cell activating cytokines, resulting in the breakdown of T cell tolerance. Thus, the infection results in the activation of T cells that are not specific for the infectious pathogen; this type of response is called bystander activation. Infectious microbes may contain antigens that cross react with self-antigens. So immune responses to the microbes may result in reactions against self-antigens. This phenomenon is called molecular mimicry because the antigens of the microbe cross react with, or mimic, self-antigens.

Role of infections in the development of autoimmunity

Figure 6. Role of infections in the development of autoimmunity. (a) 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. (b) 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.

4. Other Factors

Anatomic alterations in tissues, caused by inflammation (possibly secondary to infections), ischemic injury, or trauma, may lead to the exposure of self-antigens that are normally concealed from the immune system. Hormonal influences play a role in some autoimmune diseases.

5. Autoimmune Disease

From a clinical perspective it is often useful to distinguish between the following two major patterns of autoimmune disease: the diseases in which the expression of autoimmunity is restricted to specific organs of the body, known as 'organ-specific' autoimmune diseases; and those in which many tissues of the body are affected, the 'systemic' autoimmune diseases. In both types of autoimmunity, disease has a tendency to become chronic because, with a few notable exceptions (for example type 1 diabetes or Hashimoto's thyroiditis), the autoantigens are never cleared from the body (Figure 7).

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Organ specific and systemic autoimmune diseasee

Figure 7. Organ specific and systemic autoimmune disease.

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.

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1. Murphy K M. Janeway's immunobiology [M]. Garland Science, 2011.
2. Abbas A K, Lichtman A H H, Pillai S. Cellular and Molecular Immunology: with STUDENT CONSULT Online Access [M]. Elsevier Health Sciences, 2014.

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