C4AQ0 superimposed on a primary defect increases the susceptibility to systemic lupus erythematosus (SLE) in a family with association between C4AQ0 and SLE

OBJECTIVE: To investigate the association of C4AQ0 with increased incidence of systemic lupus erythematosus (SLE) or positive serology (28%) in an extended Icelandic family, and whether this can be explained by impaired complement function in handling immune complexes (IC). METHODS: The ability of the classical pathway to opsonize nascent IC [alkaline phosphatase (AP)-anti-AP] and bind them to human erythrocytes was evaluated by the new ICRB assay. The capacity of erythrocytes from family members to bind nascent IC was also measured by a modification of the ICRB assay. IC levels were measured by complement consumption assay, C3d by a sandwich ELISA, factor B by immunoelectrophoresis, and the alternative pathway function by a hemolytic assay. RESULTS: Family members with homozygous or heterozygous C4AQ0 (47%) showed no impaired complement dependent opsonization of IC and binding to erythrocytes. Their factor B and alternative pathway function was normal. Fifty-six percent of the family members (n=18) had abnormally high IC levels, seemingly independent of C4AQ0. However, 6 of the 7 individuals with high IC levels and SLE symptoms had C4AQ0 compared to 2 of 11 symptom-free individuals with high IC levels. CONCLUSION: Our results suggest that the susceptibility for SLE in this family may result from 2 different defects, one leading to elevated IC levels, and another associated with C4AQ0 without detectable impairment in the complement dependent IC transport mechanism. Individuals with both abnormalities have increased susceptibility to SLE.