CXCL4, a chemokine upregulated in systemic sclerosis patients, abrogates TLR9 signaling and central tolerance in B cells

Abstract Background: Systemic sclerosis (SSc) is an autoimmune connective tissue disease, characterized by defective central B cell tolerance. Deficiency of MYD88, which mediates the function TLRs, results in a failure to silence autoreactive cells. CXCL4, chemokine found elevated sera SSc patients, potentiates IFN-α secretion from TLR9-induced plasmacytoid dendritic The objective investigate whether CXCL4 regulates TLR9 signaling and tolerance Methods: cells patients or healthy donors were cultured with ligand (TLR9-L) alone CXCL4. Cytokines gene expression analyzed. Delivery TLR9-L was analyzed Amnis confocal microscopy. NOD-scid-common gamma chain (γc) knockout immunodeficient mice engrafted CD34 +human fetal hematopoietic stem transduced lentivirus expressing human New emigrant/transitional sorted. Immunoglobulins chains these cloned transfected fibroblasts. Polyreactivity antibodies released fibroblasts assessed. Results: Defective observed patients. abrogated response when given alone, localized lysosomes LAMP-2 +compartments while prevented delivery vesicles. vivoexpression led responses increased number polyreactive Conclusions: Our data provide evidence for novel mechanism impairs altering intracellular trafficking ligands, hence inhibiting required removal developing