Mechanisms of self-tolerance

To cany out its function of recognizing the universe of possible molecules, the immune system generates a great diversity of receptors. Inevitably, some of these receptors will react with antigens present in the body of the host itself. Recognition of autoantigens may result in harm to the host, referred to as autoimmune disease. It is important for survival that these self-directed reactions be avoided or limited so that harm does not follow, the phenomenon called self-tolerance. 

Even under the best circumstances, however, clonal deletion must be regarded as incomplete, because many self-reactive B cells and T cells escape to peripheral sites. Self-reactive B cells are evident from their low-affinity IgM products, which form a network of natural autoantibodies found in all normal sera. The presence of self-reactive T cells in the periphery can now be shown directly by the use of peptide tetramers. 

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Autoimmune Disease. Figure 1 Mechanisms of self tolerance. DC, dendritic (antigen presenting) cell T, T-lymphocyte Th, T helper lymphocyte Treg, T regulatory lymphocyte. For details see text. 

T- or B-lymphocytes which react with autoantigens. In healthy individuals kept under control by the mechanisms of self tolerance. 

Sakaguchi, S. et al., Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases, J. Immunol. 155, 1151-1164, 1995. 

Goodnow, C.C. et al., Cellular and genetic mechanisms of self tolerance and autoimmunity, Nature, 435, 590, 2005. 

In the last decade there has been increasing interest in the scientific community in T-cell-mediated immunosuppression or regulation as a mechanism of self-tolerance and immune regulation. To date. 

Anergy. Lack of immune responsiveness (usually defined as lack of response to common recall antigens). The failure of B or T cells to proliferate in response to defined autoantigens ( - clonal anergy) is a primary mechanism of self-tolerance. 

Sakaguchi, S., Sakaguchi. N..Asano.M., Itoh.M.. and Toda. M. (1995) Immunologic Self-Tolerance Maintained by Activated T Cells Expressing IL-2 Receptor Alpha-Chains (CD25). Breakdown of a Single Mechanism of Self-Tolerance Causes Various Autoimmune Diseases,/. Immunol. 155,1151 1164. 

During differentiation of T- or B-lymphocytes antigen recqrtors are generated which react to self or autoantigens. These are generally eliminated by the mechanisms of central tolerance or kept silent by the mechanisms of peripheral tolerance ( autoimmune disease). 

SLE is the prototype systemic autoimmune disease, with a hallmark of autoantibody production. The mechanism leading to loss of self-tolerance and production of autoantibodies is discussed in Section 2. 

In summary, impairment of all the foregoing mechanisms during a multistep process may be involved in the loss of self-tolerance in patients with SLE (Table 2). Self-reactive anergic lymphocytes may be reactivated when a genetically vulnerable person faces an environmental trigger from viral infection leading to sustained inflammation. The precise mechanism of anti-Ro/SSA, anti-La/SSB, and anti-dsDNA antibodies will be discussed in the following sections. 

Clonal anergy. State of specific functional unresponsiveness. Failure of B or T cells to proliferate in response to antigen by downregulation of the antigen receptor complex and/or cytokine receptors and costimulatory molecules. Primary mechanism involved in the induction and maintenance of - self-tolerance. 

Idiotypic network. Feedback inhibition of ongoing B or T cell responses by a network of (anti-idiotype-idiotype) interactions. Secondary mechanism involved in the induction and maintenance of self-tolerance. 

Immune deviation. A regulatory mechanism of the preferential activation of one arm (cellular versus humoral see also Thl and Th2 cells) of the adaptive immune system at the expense of the other. Although not a form of true tolerance, this regulatory mechanism may be involved in the induction and maintenance of + self-tolerance. 

The Th-1 /Th-2 paradigma forms a core mechanism regulating the nature of an immune response. More recently, this concept was further developed by identifying Th-subsets with predominantly suppressing properties, T-regulatory cells (Treg). These cells also play a major role in keeping those cells at rest, which have escaped central tolerance (peripheral self tolerance). 

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