CSL Limited is an Australian multinational specialty biotechnology company that researches, develops, manufactures, and markets products to treat and prevent serious human medical conditions. CSL's product areas include blood plasma derivatives, vaccines, antivenom, and cell culture reagents used in various medical and genetic research and manufacturing applications.
The eukaryotic COMMD family of proteins are core subunits of the Commander protein complex, with a central role in endosomal membrane trafficking and signalling. Previous crystal and cryoEM structures show that COMMD and COMMD-like proteins form homo-oligomeric and hetero-decameric assemblies with a central ring structure formed by their small C terminal COMM domains. Their α-helical N-terminal (HN) domains decorate each side of these rings, and in the eukaryotic Commander complex engage the coiled-coil proteins CCDC22 and CCDC93. Here, we have determined new crystal structures of the isolated HN domains of human Commd4, Commd9 and Commd10, and find that all three proteins form domain swapped structures with a remarkably consistent topology. This occurs via a conformational change in a hinge-loop between helices α2 and α3, leading to exchange of helices α3 to α6 between protomers. The hinge-loops of Commd9 and Commd10 possess several serine and threonine residues that can be phosphorylated, and we find that specific phospho-mimicking mutations in Commd10 can promote or inhibit domain swapping. Whether the unique COMMD HN domains play any roles beyond assembly with CCDC proteins is unclear, but this work suggests a common conformational switch exists with a potential to regulate their function. ### Competing Interest Statement The authors have declared no competing interest. National Health and Medical Research Council, https://ror.org/011kf5r70, APP2016410, APP2009732, APP2042760 Australian Research Council, DP240101315 Dementia Australia, N/A
High-dose intravenous immunoglobulin (IVIG) is used to treat autoimmune and inflammatory diseases, and several studies demonstrate that the therapeutic effects of IVIG can be recapitulated with the fragment crystallizable (Fc) portion. Further, recent data indicate that recombinant multimeric Fc molecules exhibit potent anti-inflammatory properties. In this study, we investigated the biochemical and biological properties of different recombinant human IgG1 Fc molecules with increasing valency and avidity, combined with mutations to increase binding affinity to complement protein C1q. These molecules were investigated for their potential dual antagonism: to antagonize Fcγ receptor (FcγR) effector functions (Ab-dependent cellular phagocytosis) in vitro, and to inhibit the activation of the classical complement pathway. C1q-binding mutants demonstrated an exponential increase in potency to inhibit the classical pathway in correlation with increasing multimerization. Importantly, in contrast to other multimeric Fc constructs such as Fc hexamers, no generation of complement C4a was observed. Reducing the binding affinity to FcγRIIB resulted in a half-life extension of the trivalent hIgG1-Fc molecules in human neonatal Fc receptor transgenic (hFcRn Tg) mice. Our data demonstrate a potent anti-inflammatory effect of recombinant human IgG1-Fc C1q-binding mutants in vitro and in vivo, mediated by blockade of FcγRs and inhibition of complement activation.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and progressive joint destruction, driven by complex pathogenic mechanisms. Aberrant activation of various cellular components and their dynamic interactions contribute significantly to the onset and progression of RA. Key cell types involved include non-immune cells, such as fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes (MLS), innate immune cells (neutrophils, dendritic cells, and macrophages) and adaptive immune cells (B cells and T cells). These cells collectively release high levels of proinflammatory cytokines (e.g., TNF, IL-1β, IL-6, IL-17, GM-CSF, and lymphotoxins), chemokines (e.g., CCL17, CCL22, CXCL8 and CXCL10), growth factors (e.g., PDGF, and TGF-β), pro-angiogenic factors (e.g., VEGF and FGF), matrix metalloproteinases (e.g., MMP2 and MMP9), and autoantibodies (e.g., RF and ACPA) that collectively contribute to maintaining an inflammatory microenvironment in RA joints. These molecular mediators recruit and activate distinct cellular subsets that perpetuate inflammation. This review provides an overview of the major cellular subpopulations and their intricate interactions within the RA synovium that ultimately lead to sustained synovial inflammation, bone erosion and cartilage damage. In addition, some insights into the potential disruption of such cellular activations and interactions as therapeutic strategies to achieve better treatment outcomes are also provided.
