Thyroid-Stimulating Autoantibodies Usually Contain Only λ-Light Chains: Evidence for the “Forbidden Clone” Theory

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Abstract
Burnet's “forbidden clone” theory would predict that in patients with Graves' disease the pathogenic thyroidstimulating autoantibody (TSab)-secreting clones arise by somatic mutation. Because each lymphocyte and its progeny are permanently committed to producing antibodies of a single light chain type, a clone arising by somatic mutation occurring in a single cell would be expected to produce autoantibodies of exclusively κ or exclusively λ type in an individual patient. Using affinity chromatographic techniques and monoclonal antibodies, we investigated the light chain type of TSab in 11 patients with Graves' disease. In all patients tested, TSab activity was confined to a single light chain type, confirming the recent work of Zakarija who used affinity chromatography with polyclonal antisera, but contrasting with earlier studies which used immunoprecipitation methods. Furthermore, the light chain type was λ in 10 of the 11 patients. These observations provide support for the forbidden clone theory. In addition, the marked preponderance of patients producing TSab of the λ-light chain type ipdicates that TSab are more likely to arise from the λ repertoire of clones than from the κ repertoire and suggests that immunoglobulin light chain V genes may be genetic determinants for susceptibility to Graves' disease.