Role of Complement Receptors in the Pathogensis of Sle

Yount, William

Abstract

Erythrocytes (E) have a major role in the processing and clearance of circulating immune complexes (CIC). This function of E is mediated by a membrane receptor known as CR1 (the C3b-receptor), and so it is of interest that patients with SLE have reduced numbers of CR1/E, and that this may be an inherited trait that predisposes to SLE. The objective of this project is to characterize certain aspects of the pathogenesis of SLE and immune complex clearance that are mediated by E CR1, the complement (C) system, and the reticuloendothelial system. These objectives will be approached through the following specific aims: 1) To clarify the relationship of low numbers of CR1/E with ongoing C activation and evidence of tissue injury; 2) To determine whether inheritance of low numbers of CR1/E is a significant contributing factor that predisposes to SLE; 3) To investigate proteolysis as a possible mechanism for E CR1 loss SLE; 4) To determine if E CR1 are lost during CIC transfer to liver macrophages. CR1, fixed C3 fragments, and anti-E autoantibody will be quantitated on patients' E by a series of radioimmune assays with 125I-labeled monoclonal antibodies to CRI, C3c, C3g, C3d, IgG, and IgM. Serial studies of patients and in vitro studies with normal blood will examine the relationship of CIC concentration and the amount of fixed C3dg fragments detected on E. Analysis of E CR1 number in families of patients with SLE will be used to estimate the true CR1 number phenotype of patients with SLE. Identical twins sets, in which one twin has SLE, will also be used to establish CR1 number phenotypes. Statistical analyses will be performed to determine if there is a higher than normal incidence of low CR1 number inheritance among patients with SLE. Correlation of inheritance of low CR1 number and other predisposing factors such as HLA-DRw3 or C2 deficiency will also be investigated. E from patients with documented consumption of E CR1 will be examined for the presence of CR1 fragments isolated with a polyclonal anti-CR1. Finally, in vivo studies with rhesus (high CR1/E) and cynomolgus (los CR1/E) monkeys infused with soluble immune complexes, will examine E before and after they traverse the liver for number of CR1 per cell. Cytofluorographic techniques with double-labeling will be used to evaluate individual monkey E for fixed C3dg and loss of CR1. These studies will contribute to our knowledge of the role of CR1 in the pathogenesis of SLE and define more fully some of the basic mechanisms of immune complex clearance that may be abnormal in SLE as well as other different types of autoimmune disease.