Home | | Essential Clinical Immunology | Β-Cell Lesion: Nature of Effector Cells - Insulin Dependent Diabetes Mellitus

Chapter: Essential Clinical Immunology: Immunological Aspects of Endocrine Disease

Β-Cell Lesion: Nature of Effector Cells - Insulin Dependent Diabetes Mellitus

IDDM is characterized by the selective destruction of β cells (other islet cells, notably glucagon-producing cells remain intact).

THE Β-CELL LESION: NATURE OF EFFECTOR CELLS

 

IDDM is characterized by the selective destruction of β cells (other islet cells, notably glucagon-producing cells remain intact). The β-cell destruction is due to apoptosis. It is preceded by a long phase of prediabetes that has been well charac-terized in animal models. Initial insulitis is essentially of peripheral nature (perinsuli-tis) without β-cell aggression. It becomes progressively more active, resulting in “malignant” insulitis. Even at a late stage (diabetes onset), much of this aggression is reversible because of T-cell-mediated inflammation. One can thus explain that hyperglycemia in recently diagnosed dia-betic mice is corrected within twenty-four to forty-eight hours by treatment with an anti-T-cell antibody (anti-TCR or anti-CD3) and that islets derived from recently diagnosed diabetic NOD mice recover the capacity to produce insulin after in vitro culture in the absence of T cells or autoan-tibodies.

 

 

The nature of the cellular and molecular events at the origin of β-cell inflammation and destruction is still a matter of debate. The role of T cells is unquestionable. Dia-betes can be transferred to NOD-SCID mice (which do not spontaneously develop diabetes because they lack T cells) after infusion of purified T cells or T-cell clones. Both CD4 and CD8 T cells are necessary to obtain diabetes transfer when using poly-clonal T cells, even though transfer can be obtained with CD4+ or CD8+ T-cell clones injected alone. Emphasis has recently been put on the role of CD8+ T cells, but there has not yet been a clear demonstration of islet-specific cytotoxic T lymphocytes capable of destroying β cells in a FAS or a perforin-dependent manner (probably because of the difficulties met in using 51Cr release assay with β cells). Using major histocompatibility complex (MHC) class I tetramers with islet antigen mimetopes, it was shown that diabetes progression in the NOD mouse is associated with increasing numbers of high-avidity islet-specific CD8 T cells. CD4+ T cells are also important. They may have direct diabetogenic action through cytokine release. They may also intervene as helper T cells for CD8 T cells. A number of studies have attempted to dis-sect the molecular events leading to β-cell apoptosis. The role of free radicals and var-ious cytokines, notably IL-1, has been the matter of particular attention.

 

No role for islet-specific autoantibod-ies has been demonstrated so far. Transfer of sera from diabetic mice does not induce diabetes onset. Pure T-cell populations derived from diabetic mice injected into syngeneic recipients still induce diabetes when the recipients have previously been rendered agammaglobulinemic by post-natal anti-IgM antibody treatment. These observations do not preclude the possi-bility that B cells may play a role in the pathogenesis of IDDM since B-cell-less NOD mice (Ig    do not develop diabetes. One may assume that in this context, B cells act as antigen-presenting cells, rather than as producers of diabetogenic autoantibodies. The only evidence in favor of the pathogenic role of autoanti-bodies is the observation that newborns from diabetic autoantibody-positive NOD mouse mothers develop diabetes more rapidly than newborns from antibody-negative mothers. This intriguing obser-vation does not fit with clinical studies showing the higher IDDM incidence in descendants of diabetic fathers than of diabetic mothers and with the absence of difference in the incidence of diabe-tes in children from antibody-positive or antibody-negative mothers.

 

 

Study Material, Lecturing Notes, Assignment, Reference, Wiki description explanation, brief detail
Essential Clinical Immunology: Immunological Aspects of Endocrine Disease : Β-Cell Lesion: Nature of Effector Cells - Insulin Dependent Diabetes Mellitus |


Privacy Policy, Terms and Conditions, DMCA Policy and Compliant

Copyright © 2018-2023 BrainKart.com; All Rights Reserved. Developed by Therithal info, Chennai.