Glomerular microthrombosis (GMT) is a common vascular change in patients with lupus nephritis (LN). The mechanism underlying GMT is still unknown. In our previous study, we found that the level of IgG anti-beta2 glycoprotein I (beta2GPI) antibodies was higher in the LN-GMT group than in the LN-non-GMT group, which indicated that anti-beta2GPI antibodies may play a role in GMT formation. Many studies have demonstrated that the activation of the classical complement pathway may play a critical role in fetal loss and aPL-induced thrombosis formation. To investigate whether complement activation plays a role in GMT formation and to evaluate its relationship with aPL, we prospectively investigated deposition of C4d in 155 renal biopsy specimens of LN patients. The results revealed a strong relationship between the intensity of glomerular C4d staining and the presence of microthrombi (p < 0.001). The detection rate of IgG anti-beta2GPI antibodies was higher in the LN-GMT group than in the LN-non-GMT group (p < 0.05). Further, the intensity of glomerular C4d staining was significantly related with IgG anti-beta2GPI antibodies (p < 0.05). The results of our study suggest that anti-beta2GPI antibodies may play a role in GMT formation, and this process might involve complement activation.

CXCL12, also known as stromal cell-derived factor (SDF-1), is a CXC chemokine. Recent reports have shown that CXCL12 might play key roles in a murine model of lupus and in patients with systemic lupus erythematosus (SLE). A common variant at position 801 in 3'-untranslated region in CXCL12 gene (designated CXCL12-3'G801A) has been reported in association with autoimmune diseases, such as type 1 diabetes and systemic sclerosis. We investigated the influence of CXCL12-3'G801A polymorphism on susceptibility to SLE by genotyping this single nucleotide polymorphism in 422 SLE patients and 374 healthy controls. The frequency of G/G homozygote was observed in 60.0% of SLE patients and in 52.7% of healthy individuals (χ(2 )= 4.275, p = 0.039). Compared with patients with G/A and A/A genotype, SLE patients with G/G genotype were also more prone to developing photosensitivity (χ(2 )= 6.778, p = 0.034), renal damage (χ(2 )= 6.388, p = 0.041) and to producing antibodies against nucleosomes (χ(2 )= 8.341, p = 0.015). Moreover, the plasma level of CXCL12α was also significantly increased in patients with G/G homozygote than in healthy controls carrying the same genotype [(4067.0 ± 1092.3) pg/ml vs. (3278.5 ± 547.4) pg/ml, p = 0.002]. Our results suggest that polymorphism in CXCL12-3'G801A might be a genetic risk factor for developing SLE. The association of G/G homozygote with nephritis and skin damage developed in SLE patients might be due to its effects upon the production of auto-antibodies and CXCL12 protein.

It is generally accepted that the major autoantigen for antiphospholipid antibodies (aPL) is beta(2)glycoprotein I (beta(2)GPI). Interestingly, some aPL bind to beta(2)GPI and the homologous enzymatic domains of several proteases involved in hemostasis and fibrinolysis, and correspondingly hinder anticoagulant regulation and resolution of clots. These findings are consistent with several early findings of aPL and provide a new perspective about some aPL in terms of their binding specificities and related functional properties in promoting thrombosis. In addition, homologous enzymatic domains of the involved proteases share conformation epitope(s) with beta(2)GPI, thus providing a possible structural basis for some non-mutually exclusive mechanisms of aPL-mediated thrombosis.