Disease-associated autoimmunity and prevention of insulin-dependent diabetes mellitus

Insulin-dependent diabetes mellitus (IDDM) is a chronic autoimmune disease with a subclinical prodromal period characterized by selective destruction of insulin-producing beta cells in the pancreatic islets. This process is assumed to be T-cell mediated, but the emergence of disease-associated autoantibodies into the peripheral circulation is usually the first noticeable sign of beta-cell autoimmunity in human IDDM. Recent observations have suggested that beta-cell autoimmunity may be induced in any individual at any time. There are also data indicating that such autoimmunity may have been initiated prenatally in some individuals. Only a proportion of those with signs of islet cell autoimmunity progress to clinical disease, and harmless beta-cell autoimmunity reflected by positivity for a single autoantibody specificity seems to appear without any relation to genetic IDDM susceptibility. One can hypothesize that in most subjects HLA-conferred protection against IDDM prevents the beta-cell process from progressing to a stage of destructive insulitis that may lead to clinical disease. Environmental factors may trigger initial beta-cell damage and subsequently accelerate the destructive process. Non-HLA genes may also be involved in the regulation of the progression rate. Prospective observations of prediabetic individuals have revealed that IDDM-associated autoantibodies tend to appear sequentially, and that those who progress to clinical disease mount a strong humoral immune response to most known disease-associated antigens. This indicates that the immune response associated with beta-cell destruction is not purely T-helper 1 biased. Antigen-specific immunotherapy may in the future offer effective measures to intervene in preclinical IDDM to prevent end-stage insulitis. Substantially more data have to be generated, however, on the mechanisms, efficacy and safety of such therapy before it is possible to judge its clinical applicability.