We fully agree with the statement of K.G.C. Smith et al. that “It is important that genetic data are analyzed critically before they are cited…” Therefore, we are surprised that they start their comment with the incorrect suggestion that our data confirm “FcγRIIB’s contribution to autoimmunity initially ascribed to it by observations in deficient mice made on the more problematic B6/129 background.…” Our data indicate that FcγRIIB deficiency in mice plays a minor role, if any, in the spontaneous development of autoantibodies characteristic for systemic lupus erythematosus (SLE). In the FcγRIIB knockout (KO) on 129/B6 background, not FcγRIIB deficiency, but epistatic interactions between the C57BL/6 genome and the 129-derived Fcγr2b flanking region (Sle16) cause loss of tolerance, resulting in the development of autoreactive B cells. In mice, FcγRIIB deficiency does not act as a disease initiator, as suggested initially, but as a downstream modifier by amplifying the pathogenic effects of the autoantibodies. The role of FcγRIIB as an amplifier was confirmed by the development of lupus in C57BL/6 FcγRIIB KO male mice in the presence of the Yaa autoimmune susceptibility locus.
Our observations in mice do not exclude FcγRIIB as a SLE susceptibility locus in humans. SLE is a multifactorial disease. From our mouse studies, we concluded that the main result of FcγRIIB deficiency is lowering the threshold for the pathogenic action of autoantibodies. Because it has been shown that the presence of autoantibodies is not sufficient for the development of disease, it might be that allelic variants associated with impaired FcγRIIB function contribute to SLE susceptibility in humans. In our introduction, we presented an overview of the status of the understanding of the role of FcγRIIB in autoimmune diseases based on genetic studies in mice and humans. Despite some inaccuracy in our citations, for which we apologize, in our opinion, the overall conclusion from the literature that the proposed role of FcγRIIB in autoimmunity both in mice and in humans needs further clarification is correct. The results of our studies presented in the manuscript of Boross et al. clearly demonstrate this notion with respect to the situation in mice. For humans, Smith et al. confirm this themselves by stating, “The association of variants in the promoter of human FCGR2B and SLE thus still needs clarification.” As confirmed by Smith et al., the FC receptor region is complex, and extensive gene homology and copy number variation hampers genetic analysis. Therefore, conclusions drawn from genetic studies of the human FC receptor region should be viewed with great caution.
