MOLECULAR HETEROGENEITY OF 2ND AND 4TH COMPONENTS OF COMPLEMENT AND THEIR GENES IN SYSTEMIC-SCLEROSIS AND ASSOCIATION OF HLA ALLELES A1, B8AND DR3 WITH LIMITED AND DR5 WITH DIFFUSE SYSTEMIC-SCLEROSIS

Deficiency of the complement component C4 at the functional, protein a nd gene level and deficiency of complement component C2 at the functio nal level were investigated and HLA analysis was performed on patients with limited and diffuse systemic sclerosis (SSc). One of the patient s with limited SSc (n = 15)had subnormal C4? 1 subnormal C2 and 1 subn ormal C4 and C2 activities: the latter patient had HLA alleles All;B35 ;Dw1 associated with type II C2 deficiency and therefore most Likely h ad a defect at the C2 locus. One of the patients with diffuse SC (n = 12) had subnormal C4 and I subnormal C4 and C2 activities. C2 deficien cies in patients other than the one with the haplotype associated with C2 deficiency appeared not to be determined by the gene at the C2 loc us. The incidence of partial C2 deficiency in a normal Caucasian popul ation is reported to be 16 in 10,000, and that of partial C4 deficienc y also appears to be very low. The percentages of C4AQ0 and C4B*Q0 al leles in normal controls (n = 45) were within the reported range. Seve n patients with limited SSc (n = 14) had one or two C4AQ0 alleles and 2 with diffuse SSc (n = 13) had one C4AQ0 allele. Thus. the incidenc e of C4AQ0 was higher than normal in limited SSc and within the norma l range in diffuse SSc. The two-sided Fisher's exact test applied on t hese data revealed that the association of C4AQ0 with limited SSc did not reach a significant level (p = 0.10). Two of the 3 patients with limited SSc? who had two C4AQ0 alleles, carried a heterozygous C4A-21 -hydroxylase A (OHA) gene segment deletion as detected by Southern blo tting. There was no correlation between the subnormal activity of C4 a nd the occurrence of one or two C4AQ0 land C4A21-OHA segment deletion ). HLA alleles Al, B8 and DR3 (p = 0.002) were associated with limited SSc (n = 23) and DRS(w11) (p = 0.018) with diffuse SSc (n = 17).