Humoral and genetic factors in thyrotoxic Graves disease and neonatal thyrotoxicosis

Abstract

Since the demise of the theory that postulated excessive pituitary thyroid-stimulating hormone [TSH] secretion, most hypotheses on the cause of thyroid gland hyperactivity in Graves disease have included some type of stimulation by immunoglobulins [Ig] or activated lymphocytes, with or without a role for an intrinsic abnormality of the thyroid gland. The presence of autoimmune phenomena in Graves disease is beyond dispute. Many patients have demonstrable antibodies to thyroid antigens, and Graves disease has a proved familial association with the archetypal autoimmune endocrine disease, Hashimoto thyroiditis. Graves disease is unique among autoimmune diseases in that an Ig that has biological effects similar to those of TSH tropin is frequently present. This long-acting thyroid stimulator, or LATS (an IgG), is present in IgG concentrates from most Graves sera, and can mimic the actions of TSH. LATS might be the proximate cause of thyroid hyperactivity in Graves disease. One cornerstone of the humoral theory of Graves disease has been the syndrome of neonatal thyrotoxicosis. A mother with Graves disease typically gives birth to an obviously thyrotoxic child, whose illness remits in a few weeks to months. In several such cases, LATS has been present at high titers in both mother and child, but later disappeared from the infant''s serum as the hyperthyroidism remitted. It was concluded that transplacental passage of maternal LATS had caused the neonatal hyperthyroidism. In seeking a more fundamental understanding of the cause of Graves disease, the emphasis on genetic factors seems appropriate; familial aggregations of cases have been found by many investigators. A growing list of diseases, many of which have autoimmune features, are associated with specific histocompatibility, or HL-A, antigens. Recently, an association has been found between HL-A8 antigen and Graves disease. To explain these associations, it has been postulated that the immune response genes that confer susceptibility to these diseases are closely linked to the genes that determine HL-A antigens. Graves disease might depend on the interaction between a specific immune-response gene and other unknown factors, such as other genes and environmental influences.