The Underlying Insulin Receptor in Patients with Antireceptor Autoantibodies: Demonstration of Normal Binding and Immunological Properties

Abstract

Antibodies against self-antigens occur in a variety of autoimmune disorders. In most cases, it has been impossible to determine whether this is the result of some alteration in the endogenous antigen (perhaps induced by an infectious or toxic agent) or of a disorder in immunoregulation which allows selftolerance to be broken. In the present study, we have attempted to characterize the underlying insulin receptor in patients with insulin resistance due to autoantibodies against the receptor (Anti-R) by both its functional and immunological features. Freshly isolated peripheral monocytes obtained from patients with Anti-R characteristically show reduction in receptor affinity and loss of negative cooperativity. This defect appears to be the consequence of cell-bound Anti-R by several criteria. Thus, when the freshly isolated monocytes were exposed to an acidglycine buffer (pH 3.5), a procedure which removes cell-bound antibodies, there was an increase in receptor affinity toward normal and a return of negative cooperativity. Further, these defects can be produced in normal cells or in the acid-washed cells of the patient by exposure to antireceptor serum. More prolonged removal of Anti-R resulted in a complete normalization of insulin binding; cultured fibroblasts from two patients and cultured lymphocytes from one patient with Anti-R showed no differences in receptor affinity or number when compared to cells of normals. Even more striking was the finding that, in one patient with Anti-R whose disease went into spontaneous remission associated with a fall in antibody titer to undetectable levels, insulin receptors on her cells showed normal binding by equilibrium, kinetic, and specificity criteria. Moreover, exposure of her cells to graded concentrations of Anti-R produced the same inhibition of binding as observed with cells of a normalperson. In summary, these data suggest that the underlying insulin receptor in patients with Anti-R is normal and suggest that the disease may be the result of a disorder of the immune surveillance system or other mechanism of altered antigen recognition.