Molecular Heterogeneity of Second and Fourth Components of Complement and Their Genes in Systemic Sclerosis and Association of HLA Alleles A1, B8 and DR3 with Limited and DR5 with Diffuse Systemic Sclerosis

Abstract

Deficiency of the complement component C4 at the functional, protein and gene level and deficiency of complement component C2 at the functional level were investigated and HLA analysis was performed on patients with limited and diffuse systemic sclerosis (SSc). One of the patients with limited SSc (n = 15) had subnormal C4, 1 subnormal C2 and 1 subnormal C4 and C2 activities; the latter patient had HLA alleles A11;B35;Dw1 associated with type II C2 deficiency and therefore most likely had a defect at the C2 locus. One of the patients with diffuse SSC (n = 12) had subnormal C4 and 1 subnormal C4 and C2 activities. C2 deficiencies in patients other than the one with the haplotype associated with C2 deficiency appeared not to be determined by the gene at the C2 locus. The incidence of partial C2 deficiency in a normal Caucasian population is reported to be 16 in 10,000, and that of partial C4 deficiency also appears to be very low. The percentages of C4A*Q0 and C4B*Q0 alleles in normal controls (n = 45) were within the reported range. Seven patients with limited SSc (n = 14) had one or two C4A*Q0 alleles and 2 with diffuse SSc (n = 13) had one C4A*Q0 allele. Thus, the incidence of C4A*Q0 was higher than normal in limited SSc and within the normal range in diffuse SSc. The two-sided Fisher’s exact test applied on these data revealed that the association of C4A*Q0 with limited SSc did not reach a significant level (p = 0.10). Two of the 3 patients with limited SSc, who had two C4A*Q0 alleles, carried a heterozygous C4A-21-hydroxylase A (OHA) gene segment deletion as detected by Southern blotting. There was no correlation between the subnormal activity of C4 and the occurrence of one or two C4A*Q0 (and C4A-21-OHA segment deletion). HLA alleles A1, B8 and DR3 (p = 0.002) were associated with limited SSc (n = 23) and DR5(w11) (p = 0.018) with diffuse SSc (n = 17).

Human leukocyte antigen class II associations with systemic sclerosis in South Africans

“…The DRB1*0301 allele group and DQB1*02, which are in linkage disequilibrium, were significantly increased in the lcSSc subset compared to the dcSSc subset (OR = 9.0 and 6.6, respectively). The association with DRB1*03 has been previously reported in some Caucasian populations (17).…”

Reduced incidence of Crohn’s disease in systemic sclerosis: a nationwide population study

“…The frequency of the HLA-DR3 serotype was higher in patients of systemic sclerosis [ 10 , 11 ] but lower in Crohn’s disease [ 12 ]. On the other hand, the presence of the HLA-DR7 serotype was correlated with decreased risk of systemic sclerosis [ 13 ], but was associated with higher risk of Crohn’s disease [ 12 ].…”

HLA and Hypocomplementemia: The Disadvantage of Carrying the HLA-B35 and the Silent Alleles of the C4 Complement Component

“…The null C4A allele occurs in about 35% of all SLE patients compared with 10% of the general population (14). Recently Venneker et al (15), observed isolated partial and functional deficiencies of C4 in many family members of a proband with frontoparietal scleroderma. These authors hypothesized that hypocomplementemia can be determined also by a gene not linked to the HLA region.…”