Complement C4 and Autoimmune Diseases

Abstract

Abstract Complement activation on autologous cells causes tissue injuries but the process is not well studied. We seek to elucidate how C4 variants, their activation products and isotype deficiencies contribute to increased risks of children systemic lupus erythematous (cSLE) and juvenile dermatomyositis (JDM). We performed kinetic studies of C4A and C4B reactivities by measuring hemolysis of sensitized sheep erythrocytes (EA). EDTA-plasma diluted to 1% showed that C4B lysed EA immediately, as revealed by released hemoglobin at OD415 nm. Those of C4A exhibited hysteresis property. C4A probably mitigates damaging effects of activated C4B on host cells. We performed flow cytometry to evaluate cell-bound complement split products on blood cells using specific monoclonals for samples with cSLE (n=119), JDM (n=159), and controls (HC, n=109). Non-parametric analyses for median fluorescent intensities were compared with median and IQR presented. The three sets of data among cSLE, JDM and HC were 795 (523, 1161), 350 (181, 779) and 252 (163, 252), respectively, for E-C4d (cSLE/HC, p=3.8x10-22; JDM/HC, p=8.8x10-8); 201 (95, 328), 33 (4, 101), and 26 (6, 70), respectively, for E-C4Ad (p=5.3x10-10, cSLE/HC; p=0.02, JDM/HC); and 68 (30, 154), 11.9 (1.9, 23.8), and 13.5 (8, 19.2) for E-C3d (p=1.8x10-6, cSLE/HC; p=0.16, JDM/HC). In conclusion, complement activation on host cells is retarded after activation of C4. Moreover, activation of C4 is substantially higher in cSLE and JDM than HC.