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Mechanisms of Autoimmunity —Recent Concept— Ⅵ Autoimmune Diseases Mechanisms of Autoimmunity —Recent concept— JMAJ 47(9): 403–406, 2004 Kazuhiko YAMAMOTO Professor, Department of Allergy and Rheumatology, The University of Tokyo Abstract: Autoantibodies and autoreactive T cells, which exist even in healthy individuals, are usually regulated by a mechanism called immunological tolerance. For example, peripheral T cells are subject to various types of regulatory mechanisms, including clonal deletion, anergy, clonal ignorance, and T cells with regulatory functions. It is believed that autoimmune response may initiate when such regulated immune responses are pathologically activated by a certain trigger, probably a limited antigenic stimulation. Thereafter, other factors that promote autoimmune responses combine to develop an autoimmune disease. It is esti- mated that T cells are closely involved in these reactions. Key words: Immunological tolerance; Molecular mimicry; Epitope spreading Introduction assumes that the immune system definitely distinguishes between self and non-self, and Autoimmunity is generally defined as a phe- that autoreactive B and T cell clones are nomenon in which antibodies or T cells react eliminated before they mature. However, with autoantigens. Autoimmunity induces auto- recent studies have demonstrated that this immune diseases. Recent studies have revealed theory, although basically correct, does not that such autoantibodies or autoreactive T cells always hold true. B and T cells that react with exist even in healthy individuals. The immune autoantigens exist in the peripheral blood of system has various mechanisms to suppress the healthy individuals. immune response to the self, and the distur- For example, T cells that react with auto- bance of these mechanisms results in auto- antigens, such as myelin basic protein (MBP) immune diseases. of myelin sheath and type II collagen of car- tilage, can be separated from the peripheral Autoimmunity and blood of healthy individuals. Furthermore, auto- Autoimmune Diseases immune diseases such as thyroiditis can be induced in normal animals by immunizing them The conventional clonal deletion theory with organ-specific antigens such as thyro- This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 129, No. 7, 2003, pages 895–898). JMAJ, September 2004—Vol. 47, No. 9 403 K. YAMAMOTO globulin, indicating that lymphocytes that react Mechanisms of with the autoantigens exist in normal animals. Immunological Tolerance Therefore, it is believed that the existence of autoantibodies or autoreactive T cells is not Immunological tolerance is defined as a state enough to elicit autoimmune diseases. In in which the immune system does not posi- addition, it has been recently speculated that tively respond to autoantigens. The concept of auto-reactivity at a low level is physiological immunological tolerance for autoreactive T and necessary for a normal immune response. and B cells has been changing rapidly as new It has been reported that the weak reactivity experimental systems have been established. to autoantigens presented by major histo- T cells, which play a central role in acquired compatibility complexes (MHC; for humans, immunity, undergo clonal deletion by apo- HLA) might be necessary for the survival of ptosis when they are exposed to a sufficient peripheral mature T cells and maintenance of amount of autoantigens in the thymus where homeostasis. they differentiate. This is called central toler- Considering these factors, it is important to ance. It has been revealed recently that some distinguish specific autoimmune responses that molecules previously considered to be expressed cause various autoimmune diseases from the only in a specific organ are also expressed in existence of autoreactive lymphocytes or simple medullary epithelial cells of the thymus. This autoimmune response. For example, injection indicates that the thymus is intended to express of spermatozoa into an animal results only in as many autoantigens as possible in the body the production of autoantibodies against sper- to induce tolerance for them. However, this matozoa, but it does not cause any disease. mechanism is limited by the fact that not all However, the immunization of an animal with autoantigens are expressed in the thymus. spermatozoa mixed with an adjuvant that Furthermore, T cells that weakly react with strongly stimulates an immune response results autoantigens can migrate into peripheral tissue. in autoimmune testitis. Therefore, autoimmune Each antigen should have multiple amino acid diseases are distinguished from mere auto- sequences that can bind to antigen-presenting immune response not by the presence/absence MHC molecules. These sequences are called of autoimmune response, but by the different epitopes or antigenic determinants. However, quality and quantity of the autoimmune some epitopes are not presented as antigens response. under usual conditions probably due to the Autoimmune diseases are divided into two relationship with other epitopes or proteolysis groups: the organ-specific autoimmune diseases, in the cells. Such epitopes are called “cryptic in which the target antigens and the tissue dis- epitopes,” which means hidden antigenic deter- orders are localized in one organ, and the minants. T cells cannot become tolerant to systemic autoimmune diseases, in which the them.1) response to a certain type of antigens that are T cells that migrate into peripheral tissues expressed widely in the body, such as an undergo clonal deletion by apoptosis in the intranuclear antigen and multiple organs are similar way as in the thymus when the stimulus involved. There are several autoimmune dis- of autoantigens is strong. When the stimulus is eases that stand between these two groups. It not strong enough, T cells undergo clonal remains unclear whether these two groups of anergy (clonal paralysis). When the amount of autoimmune diseases result from the same or autoantigens is further reduced, T cells become substantially different mechanisms. ignorant (non-tolerant and unresponsive). In this regard, it is important that naïve T cells circulate only in lymphoid organs without 404 JMAJ, September 2004—Vol. 47, No. 9 MECHANISMS OF AUTOIMMUNITY entering other organs to maintain the state of triggered by the development or activation of helper T cells that react with a specific םignorant. CD4 It has also been reported that tolerance may autoantigen. Based on various evidence, it is be actively suppressed by regulatory T cells. now proposed that a specific antigenic stimulus Recent studies have reported T cells with vari- is the first trigger of autoimmunity. This is ous regulatory functions, including those that called the “single initiating antigen hypoth- produce cytokines with suppressive effects, esis”.2) For example, molecular mimicry in such as interleukin (IL)-10 and transforming which immune response occurs to both an growth factor (TGF)-␤, and those that have external microbial antigen and an autoantigen surface markers and pro- because of their homology is considered one of םand CD25 םCD4 vide suppressive effect through cell-cell contact. the mechanisms of initiating autoimmunity. These various suppressive T cells may play Microbial infection may initiate autoimmune different roles, depending on the activation of response not only through molecular mimicry, autoreactive T cells. but also with polyclonal activation and release Thus, autoreactive T cells are under sub- of isolated autoantigen. Lipopolysaccharide stantially different conditions of tolerance, (LPS), a product of infectious microbes, bac- depending on the quality and quantity of auto- terial DNA, and viruses serve as an adjuvant antigens. For example, many autoantigens are to immune response. They bind to Toll-like too isolated from the immune system to activate receptors (TLRs) on the surface of macro- potential autoreactive T cells. Autoantigens phages or dendritic cells to stimulate natural expressed on non-hematopoietic cells may not immunity and inflammatory cytokine pro- stimulate T cells because they do not have co- duction, enhancing immune response by in- stimulatory molecules. Another mechanism creasing the expression of MHC antigen or has also been revealed in which the lymph co-stimulatory molecules, such as B7-2 and nodes around organs have dendritic cells that OX40L. These responses are usually helpful for take antigens to induce tolerance of auto- inducing acquired immunity, but may stimulate reactive T cells in the steady state condition. potential autoreactive T cells. Through these B cells have been reported to undergo anergy processes, it is also possible that cryptic epitopes in response to soluble autoantigens and clonal not expressed under usual conditions are deletion in response to stronger autoantigens, expressed to trigger an autoimmune response. such as those on cell surfaces in the bone Non-infectious factors are also considered marrow where they differentiate. B cells that as a trigger of autoimmunity. For example, strongly react with soluble antigens such as estrogen exacerbates systemic lupus erythema- self-molecules at the germinal center of periph- tosus (SLE) in a mouse model, while drugs, eral tissues are also deleted through apoptosis. such as procaine amide and hydralazine, induce B cells have been reported to cause a phenom- the production of antinuclear antibodies, caus- enon called receptor editing in which B cells ing an SLE-like pathologic state.
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