Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1.

Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent. Instead, IVIg-dependent inhibition of osteoclastogenesis was abrogated in mice lacking receptors Dectin-1 or FcγRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcγRIIb membrane conformations that allowed productive IgG binding and enhanced interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcγRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation.

Solid phase-based cross-matching for solid organ transplantation: Currently out-of-stock but urgently required for improved allograft outcome.

Transplant recipients who have undergone sensitizing events, such as pregnancy, blood transfusion or previous transplants, frequently develop antibodies directed against the highly polymorphous human leukocyte antigen (HLA)-molecules. These pre-formed, donor-specific antibodies (DSA) present a high risk of causing organ failure or even complete loss of the grafted organ as a consequence of antibody-mediated, hyper-acute or acute allograft rejection. In order to detect DSA, the so-called functional complement-dependent lymphocytotoxicity assay (CDC-XM) was established about 50 years ago. Although effective in improving the outcome of solid organ allo-grafting, for the last ten years this assay has been controversially discussed due to its low sensitivity and especially because of its high susceptibility to various artificial factors, which generally do not yield reliable results. As a consequence, novel immunochemical test systems have been developed using ELISA- or bead-based solid phase assays as replacements for the traditional CDC-based assays. Because these assays are independent of single or vital cells, which are frequently not available, they have provided an additional and alternative diagnostic approach compared with the traditional CDC-based and flow-cytometric analyses. Unfortunately, however, the AMS-ELISA (Antibody Monitoring System), which was the first system to become commercially available, was recently discontinued by the manufacturer after seven years of successful use. Alternative procedures, such as the AbCross-ELISA, had to be either considerably modified, or did not yield reliable results, as in the case of the Luminex-based assay termed DSA. We draw the conclusion that due to the unique features and fields of application reviewed here, the implementation of solid phase cross-matching still represents an urgent requirement for any HLA-laboratory's routine tasks.