Moreover, in patients with acquired thrombotic thrombocytopenic purpura (TTP) related to anti-ADAMTS13 autoantibodies, specific IgG subclasses have almost all been detected but with a clear predominance of IgG4 (12, 13). pathogenic IgG4-type anti-CFH antibodies in a patient suffering from IgG4-RD with major salivary gland enlargement, orbital disease, lymphadenopathy, and IgG4 nephritis. IgG4-RD physiopathology is still not well elucidated. Nevertheless, effectors mechanisms may include B and T NEK3 cell interactions, with a pathogenic role of CD4+ cytotoxic T lymphocytes (CTL) balanced by B-lymphocytes, as well as T helper lymphocytes (Th-2) and regulatory T cells (Treg) that also regulate B-cell differentiation and TGF–mediated tissue fibrosis. IgG4 overexpression and accumulation could be inflammatory leftovers of chronic inflammation that results from massive plasma cell production. IgG4 antibodies are supposed to be nonpathogenic in IgG4-RD (1). However, tissue IgG4 accumulation could modulate local inflammatory responses. Tissue fibrosis evolution may be the product of this accumulation in association with CD4+ CTL and Treg cytokines production (11). On the other hand, pathogenic autoreactive IgG4 antibodies have been observed in other autoimmune diseases such as myasthenia gravis, directed against muscle-specific tyrosine kinase (MuSK) receptor subtype, pemphigus vulgaris, directed against desmoglein 1, and idiopathic membranous glomerulonephritis, directed against M-type phospholipase A2 receptor (1). Moreover, in patients with acquired thrombotic thrombocytopenic purpura (TTP) related to anti-ADAMTS13 autoantibodies, specific IgG subclasses have all been detected but with a obvious predominance of IgG4 (12, 13). Interestingly, IgG4 pathogenic autoantibodies directed against ADAMTS13 were reported in PD0325901 a patient with IgG4-RD causing acquired TTP (14). Our observation illustrates the potential pathogenic role of IgG4 and adds complement-mediated TMA to the list of diseases possibly caused by autoreactive IgG4 antibodies. Finally, since IgG4 polyclonal proteins have been reported incorrectly as M-protein bands in electrophoretic analysis (15) and the patient had longstanding stable IgA lambda MGUS, it was important to clearly PD0325901 distinguish IgG4 from IgA in our analysis. To this end, the concurrent presence of IgA MGUS and elevated IgG4 levels was confirmed by specific nephelometry and ELISA assays. Complement-mediated TMA results from uncontrolled activation of the alternative pathway, and CFH autoantibodies are found in approximately 10% of reported cases. CFH is a major match regulatory factor that functions as a cofactor for match factor I (serine protease) transforming C3b to an inactive form, as a decay-accelerating factor competing with match factor B in binding to C3b, and dissociates the alternative C3 convertase with formation of C3b and Bb. CFH-related protein 1 (CFHR1) is likely to inhibit the formation of C5 convertase and may compete with CFH for binding to C3b. Deficiency of CFHR1 can arise from homozygote?and gene deletions. The later are considered as risk factors for complement-mediated TMA (10), since they may lead to structural changes that increase the antigenicity of CFH, or decrease the basal levels of effective CFHR (both in quantity and in function). CFHR alterations could therefore lead to a lower threshold for complement-mediated TMA in the presence of inhibitory anti-CFH IgG4 antibodies. Uncontrolled activation of the match cascade triggers endothelial dysregulation, inflammatory reactions with leucocyte recruitment, and platelet activation resulting in tissue damage and thrombus formation, especially in the kidney (16, 17). Therapeutic strategies for PD0325901 complement-mediated TMA are evolving with the recent introduction PD0325901 of match inhibitors in particular eculizumab, a monoclonal antibody that binds match component C5 and prevents.