Defective prevention of immune precipitation in autoimmune diseases is independent of C4A*Q0

Abstract

Increased prevalence of C4 null alleles is a common feature of autoimmune diseases. We have shown previously that complement-dependent prevention of immune precipitation (PIP) is defective in patients with systemic lupus erythematosus (SLE), and correlated this defect with C4A*Q0 and low levels of the C4A isotype. To further clarify the role of C4A in the aetiology of SLE, we now extend our studies to other diseases which have been associated with C4A*Q0. The frequency of C4A*Q0 was increased in Icelandic patients with coeliac disease (0.50; P < 0.001), Grave's disease (0.30; P = 0.002) and insulin-dependent diabetes mellitus (0.23; P = 0.04) and in British patients with dermatitis herpetiformis (0.42; P = 0.002) and this was reflected in low levels of C4A. In spite of this, PIP was normal in these patients, and in marked contrast to our previous observations on connective tissue diseases, PIP measurements in these patient groups correlated more strongly with levels of C4B (r = 0.51, P = 0.0000004) than C4A. Patients with increased levels of anti-C1q antibodies had significantly lower PIP than patients without such antibodies (P < 0.01) and a negative association of PIP with anti-C1q antibodies was also reflected in an increased prevalence (P = 0.006) and levels (P = 0.006) of anti-C1q antibodies in patients with subnormal PIP, as well as a negative correlation between PIP and anti-C1q antibodies (r = - 0.25, P = 0.02). These results show that the PIP defect cannot be explained by low levels of C4A alone and suggest that measurements of anti-C1q antibodies may be useful in future studies on the molecular cause of the PIP defect in autoimmune connective tissue disease.

Fig. 1

CH₅₀ and levels of C4, C3 and C3d in patients with gluten-sensitive diseases (GSD), insulin-dependent diabetes mellitus (IDDM) and autoimmune thyroid disease. Horizontal lines denote lower normal limits for CH₅₀, C4 and C3, and upper normal limits for C3d.

Fig. 2

Levels of C4 and C4A in patients with and without C4A*Q0.

Fig. 3

Prevention of immune precipitation in patients with gluten-sensitive diseases (GSD), autoimmune thyroid disease and insulin-dependent diabetes mellitus (IDDM). Open circles denote heterozygous and dotted circles homozygous C4A*Q0 carriers. Filled circles represent C4A*Q0 non-carriers. Patients with Hashimoto's disease are marked with arrows. Arbitary units: AU.

Fig. 4

Correlation of PIP to C4B*Q0 in insulin-dependent diabetes mellitus (IDDM), gluten-sensitive diseases (GSD) and autoimmune thyroid disease.

Fig. 5

Prevention of immune precipitation in patients with and without elevated IgG or IgA anti-C1q antibodies. AU: arbitrary units; • = outlier value.