Genetic evidence favouring cytotoxic T cell forbidden clones as the cause of insulin-dependent diabetes mellitus.
Recent evidence indicates that immunoglobulin light chain variable region genes are genetic determinants for Graves' disease, which is caused by autoantibodies which stimulate the thyroid gland. We have tested whether germline immunoglobulin kappa light chain variable region (V kappa) genes contribute to the genetic predisposition for IDDM. Status for the kappa light chain constant region (C kappa) allotype, Km(1), was determined in members of suitable multiplex IDDM families. Such families had two or more siblings with IDDM, together with one parent negative for Km(1) and the other heterozygous, so that each sibling had a 50% chance of receiving the kappa light chain marker. Twenty-one families of this type were found. Of the siblings, disregarding disease status, 31 were concordant with the diabetic proband for Km(1) and 29 were discordant, this close approximation to equality confirming the validity of the methodology. Of the diabetic siblings of the probands, 14 were concordant and 15 discordant. Of the non-diabetic siblings, 17 were concordant and 14 discordant. This similarity shows that V kappa genes, which are closely linked to C kappa genes, are not genetic determinants for IDDM. The contrast with Graves' disease favours the possibility that the islet beta cell destruction of IDDM is mediated by forbidden clones of cytotoxic T cells, rather than of B cells.
Knight
A
A
Autoimmunity Research Unit, Medical Research Council of New Zealand, Otago University Medical School, Dunedin.
Adams
D D
DD
Rich
S S
SS
Barbosa
J
J
D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D005260:Female; D005803:Genes, Immunoglobulin; D006580:Genetic Carrier Screening; D006720:Homozygote; D006801:Humans; D007126:Immunoglobulin Allotypes / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D008297:Male; D010375:Pedigree; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D007126:Immunoglobulin Allotypes; D007147:Immunoglobulin Light Chains; D007145:Immunoglobulin kappa-Chains