Polymorphism of the human C3b/C4b receptor. Identification of a third allele and analysis of receptor phenotypes in families and patients with systemic lupus erythematosus.

Abstract

The human receptor for C3b and C4b (C3bR) t was initially isolated from pooled donor erythrocyte membranes (1). Although characterized as an integral membrane glycoprotein of ~200,000 daltons on SDS-polyacrylamide gels (1-4), recent studies have demonstrated that C3bR is polymorphic (5-7). In reports from our laboratory, autoradiographs of purified surface-labeled C3bR from erythrocytes (E) in 33 normal donors demonstrated three distinct patterns (5). ~70% of individuals had a single major band of -190,000 daltons (C3bR-AA), ~3% of individuals had a single major band of -220,000 daltons (C3bR-BB), and the remaining ~27% of individuals had both major bands (C3bR-AB). Family studies provided evidence that two codominant alleles regulated these major bands (5). Under this model, C3bR-AB individuals were heterozygous for the two alleles, A and B, and C3bR-AA or C3bR-BB individuals were homozygous for their respective alleles. Although the C3bR phenotype found on E was also present on other C3bR-bearing cells in the same individual, several cell-specific structural differences were also identified. First, on polymorphonuclear cells (PMN), the Mr of C3bR was ~5,000 daltons greater than that on E (6). Second, on E, less intense minor bands co-purified with C3bR and were found ~ 15,000 daltons above major bands on autoradiographs (5, 6). These minor bands, found only on E, accounted for <25% of the total C3bR. The percent represented by this minor band differed among individuals but was characteristic for a given individual. Third, among C3bR-AB individuals, vastly different (up to 30-fold) amounts of either the ~190,000-or ~220,000-dalton C3bR molecules were found on E and peripheral blood leukocytes (5, 6). The factors responsible for this variable expression among heterozygous individuals are unknown.In a study from another laboratory, this same polymorphism was described in a larger group of 111 unrelated individuals (7). However, as our laboratory has isolated C3bR from additional normal individuals we have found several novel

Altered expression of complement receptors as a pathogenetic factor in systemic lupus erythematosus

“…The frequency of the 2 major polymorphic forms of CR1 was the same among SLE patients and normal individuals (17), regardless of CR1 number on erythrocytes (16), except possibly for an increased occurrence of a rare variant of 160,000 M , in the patient population (17). In summary, most patients appeared to have low numbers of normal CRl on their erythrocytes, rather than nonfunctional, structurally altered forms of the protein that were antigenically intact.…”

“…Complement receptor type 1 (CRI), which had been termed the C3b/C4b receptor, is comprised of a single polypeptide chain (13,14) that exhibits genetically-determined differences in size ranging from 160,000 M , to 260,000 M , (15)(16)(17), which are not a result of differences in N-linked carbohydrate (16). These polymorphic forms do not appear to differ in their capacity for binding C3b (16) In addition to mediating the binding of complexes bearing these complement proteins, CR1 can serve as a co-factor for the cleavage of C3b to iC3b (13), of iC3b to C3dg (11,12), and of C4b to C4d (18), thereby generating ligands for CR2 and CR3.…”

Decreased expression of the C3b/C4b receptor (CR1) and the C3d receptor (CR2) on B lymphocytes and of CR1 on neutrophils of patients with systemic lupus erythematosus

“…The erythrocytes of many patients with systemic lupus erythematosus (SLE) have a relative deficiency of the C3b/C4b receptor (complement receptor type 1 [CRl]) (1-7), a polymorphic membrane protein of 160,000-260,000 M , (8)(9)(10). In normal individuals, the number of CRl on erythrocytes is genetically regulated (3,5,6).…”

The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera.

“…(5) and Dykman et al . (6)(7)(8) led to the discovery of an unusual size polymorphism of this receptor. Four codominantly inherited allelic size variants with M, of 190,000, 220,000, 250,000 and 280,000 were identified (9) .…”