Role of aberrant hla-dr expression and antigen presentation in induction of endocrine autoimmunity

Organ-specific autoimmune diseases such as oophoritis, gastritis, thyroiditis, and orchitis were induced in female or male nude (nu/nu) mice by the transfer of nu/+spleen cells from which particular Lyt T cell subset(s) had been removed: nu/+spleen cells treated with anti-Lyt-1 plus complement (C) caused disease in recipient nude mice; anti-Lyt-2 plus C-treated spleen cells, in contrast, did not. The cells responsible for disease induction are believed to be Thy-1+, Lyt-1-, 2,3- (Thy-1, Lyt-1, 2,3), since spleen cells treated with mixed antisera, including anti-Lyt-1 and anti-Lyt-2, plus C, could induce the disease with almost the same incidence as anti-Lyt-1 plus C-treated cells (oophoritis 50%, gastritis 25%, thyroiditis 10-20%, and orchitis 40%). Cells treated with mixed antisera of anti-Thy-1, anti-Lyt-1, and anti-Lyt-2, plus C, could not induce autoimmune disease. Each induced autoimmune disease could be adoptively transferred to other nude mice via spleen cells, with resulting histological lesion of corresponding organs and development of specific circulating autoantibodies. Since anti-Thy-1 plus C treatment of donor spleen cells abrogated the capacity to transfer the disease, we conclude that T cells are required as effector cells, and that these may develop from Lyt-1-, 2,3- cells. Lyt-1+, 2,3- cells were demonstrated to have suppressive activity upon the development of the diseases; induction of autoimmunity was completely inhibited by the cotransfer of Lyt-1+, 2,3- cells with Lyt-1-, 2,3- cells. When anti-Lyt-2 plus C-treated cells (i.e., Lyt-1+, 2,3- and Lyt-1-, 2,3- cells) were mixed with anti-Lyt-1 and anti-Lyt-2 plus C-treated cells (i.e., Lyt-1-, 2,3- cells) in various ratios, then transferred to nude mice, the development of each autoimmune disease was clearly inhibited, even by small doses of Lyt-1+, 2,3- cells. The autoimmune disease we were able to induce was quite similar to human organ-specific autoimmune disease in terms of the spectrum of organs involved, histopathological features, and the development of autoantibodies to corresponding organ components (oocytes, parietal cells, thyroid colloid, including thyroglobulin, and sperm).(ABSTRACT TRUNCATED AT 400 WORDS)

https://rupress.org/jem/article-pdf/161/1/72/1095030/72.pdf

Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease

Autoimmunity has been considered to represent termination of the natural unresponsive state to self {Weigle 1977). It was originally thought that selftolerance is achieved by elimination of self-reactive lymphocyte clones early in ontogeny (Burnet 1959). However, we now know that such self-reactive clones are normally present in the intact immune system {Clagett & Weigle 1974, Cohen & Wekerle 1973, Bankhurst et al. 1973, Bankhurst & Williams 1975, Sawada et al. 1977, Wigzell 1977) and that self-recognition, based on the complementarity of interacting structures on T cells, B cells and macrophages, is the basis for immune responses {Katz 1977). The prevailing current concept is that self-recognition processes, essential to immune and possibly other physiologic systems, are normally controlled or suppressed by one or more mechanisms that counteract deleterious autoreactive consequences. A variety of events, either exogenous or endogenous, could tip the balance of such regulatory supervision, thereby upsetting its normal damping effect so that harmful autoreactivity is the outcome. Sometimes this imbalance is only transient, superceded by reestablishment of the normal damping mechanism and a return to control over the system. At other times, the defect is permanent, leading to a progressive increase in harmful autoreactivity. This sequence seems to account for the chronic autoimmune phenomena seen in some strains of mice and in certain human diseases, most notably systemic lupus erythematosus (SLE), the prototypic autoimmune disease.

Etiopathogenesis of Murine SLE1

Publisher Summary This chapter illustrates several ways in which radiation may be employed to dissect several individual cellular components of the immune response. The chapter considers the interrelationships between radiation and the various components of the immune response from three perspectives: (1) the effect of irradiation on normal lymphoid tissues and on isolated lymphocytes, (2) the effect of irradiation on antibody production, transplantation immunity, and other forms of cellular immunity, and (3) the effect of irradiation upon tolerance with specific references to putative autoimmune consequences after radiation-induced alterations in normal immunological homeostasis. A wide variety of approaches are available to characterize and define distinct populations of lymphocytes. These include biophysical and functional methods and characterization of antigenic and cell surface receptor components. The mechanisms of radiation effects in biological systems, particularly in humans, have been derived from experiments utilizing cells exposed in vitro and maintained in tissue culture. Such cells can be examined for: (1) loss of viability, (2) alterations in biophysical structure, (3) loss of functional capabilities, (4) biochemical changes, and (5) evidence of injury to subcellular components.

Ionizing radiation and the immune response.

Publisher Summary This chapter describes membrane immunoglobulins and antigen receptors on B and T lymphocytes. There are several qualitative and quantitative distinctions between T-cell and B-cell M-Ig that may explain many of the apparent differences in reactivity of these cells without requiring the existence of a different set of V genes or non-Ig receptors in T cells. Both T and B cells derive from hematopoietic, precursor, stem cells by antigen-independent differentiation. This involves the activation of L-chain and p-type H-chain genes in both cell types. The T-cell and B-cell M-Ig differ primarily in density per cell and possibly in relative exposure on the cell surface with much of the H-chain Fc region inaccessible on T cells. Moreover, the antigen-recognition receptor of both T and B cells involves their M-Ig. On B cells, the receptor is solely the M-Ig, whereas on T cells it is suggested that the specificity of recognition controlled primarily by the M-Ig and binding of antigen to the cell can solely be by the M-Ig receptor. Finally, the activation of the T cell requires an additional interaction of the antigen with another ceIl surface structure that is coded for by a polymorphic H-2 linked gene.

Membrane immunoglobulins and antigen receptors on B and T lymphocytes.

Lymphocytes binding human thyroglobulin in healthy people and its relevance to tolerance for autoantigens

The tissue damage caused by virus infection has been traditionally explained by the ability of viruses to multiply in cells and thereby injure or destroy them. Recent evidence suggests, however, that lesions may also be caused by the host's immune response to viral antigens and that the immune system itself may be perturbed by some viruses. This memorandum reviews recent developments in viral immunopathology, with special reference to animal model systems, and indicates the possible relevance of the new concepts and techniques for certain diseases of man. Certain viruses, notably the leukaemia viruses and some of those causing persistent infections, depress the host's ability to mount an antibody response to antigens, while other viruses may enhance the antibody response. Cell-mediated immunity may also be depressed. Another immunopathological manifestation of virus infection is immune-complex disease. When viruses or their antigens persist in the circulation they combine with specific antibody, and the resulting complexes lodge in various sites, especially the kidney. Further combination with complement leads to the release of tissue-damaging substances. A third condition associated with virus infection is antibody-mediated immunologic injury. Both oncogenic and non-oncogenic viruses frequently induce new antigens on the surface of the cells they invade. When antibody attaches to these antigens in the presence of complement, the cells are destroyed.

Virus-associated immunopathology: animal models and implications for human disease. 1. Effects of viruses on the immune system, immune-complex diseases, and antibody-mediated immunologic injury.

Part 2 of this memorandum describes further mechanisms whereby the interaction of a virus with the host's immune system may lead to tissue damage. Cell-mediated immunity plays a vital role in promoting recovery from virus infections, but under some circumstances tissue damage may be caused by the reaction of immune cells with viral antigens. When mice are infected with lymphocytic choriomeningitis virus neonatally or as adults while receiving immunosuppressive drugs, widespread invasion of cells is seen but there is little overt disease. If, however, normal adults are infected or if immune cells are transfused into tolerant mice, cell injury and death follow. Viruses have long been suspected of contributing to the pathogenesis of autoimmune diseases. Antibodies directed against normal cell constituents have been reported in several virus infections. Viruses may conceivably unmask or release host antigens, alter host antigens and act as "helper determinants", or perhaps in other ways provoke immune responses against normal body constituents. The immunopathological manifestations caused by viruses may also be influenced by the host's genetic makeup. Certain observations indicate that, in addition to controlling susceptibility to virus infection, genetic factors partly determine the effectiveness of the immune response. The memorandum calls attention to the possible implications of these concepts and findings for clinical research. Some of the diseases of animals and man that serve as models for studies of virus-associated immunopathology are briefly described.

Virus-associated immunopathology: animal models and implications for human disease. 2. Cell-mediated immunity, autoimmune diseases, genetics, and implications for clinical research.

Allison Ac

Papers

Lymphocytes binding human thyroglobulin in healthy people and its relevance to tolerance for autoantigens

Virus-associated immunopathology: animal models and implications for human disease. 1. Effects of viruses on the immune system, immune-complex diseases, and antibody-mediated immunologic injury.

Virus-associated immunopathology: animal models and implications for human disease. 2. Cell-mediated immunity, autoimmune diseases, genetics, and implications for clinical research.