Surface BCR “cap” formation induced by soluble stimulation was enhanced in cIIAKO B-cells. NMII inhibition by cIIAKO did not affect B-cell spreading on PLB but delayed B-cell contraction and altered BCR clustering. NMII recruitment depended on phosphatidylinositol 5-phosphatase (SHIP1), an inhibitory signaling molecule. Upon BCR binding to antibody-coated planar lipid bilayers (PLB), NMIIA was recruited to the B-cell contact membrane and formed a ring-like structure during B-cell contraction. Utilizing a B-cell-specific, partial NMIIA knockout (cIIAKO) mouse model and NMII inhibitors, this study examined the role of NMII in BCR signaling. However, whether and how NMII regulates humoral responses through BCR signaling remains elusive. Non-muscle myosin II (NMII), an actin motor, is involved in B-cell development and antibody responses by mediating B-cell migration, cytokinesis, and Ag extraction from Ag-presenting cells. We previously showed that actin-mediated B-cell contraction on Ag-presenting surfaces negatively regulates BCR signaling. However, prolonged or uncontrolled BCR signaling is associated with the development of self-reactive B-cells and autoimmune diseases. Collectively, our findings suggest that active immunoregulation prevents clinical autoimmunity in ANA+ NS and that this becomes impaired in patients who progress to SARD, resulting in an imbalance favoring inflammation.Īntigen (Ag)-triggered B-cell receptor (BCR) signaling initiates antibody responses. When comparing ANA+ individuals without SARD who progressed clinically over the subsequent 2 years with those who did not, we found that progressors had significantly increased T and B cell activation, as well as increased levels of LAG3+ T regulatory cells and TGF-ß1. Patients with SARD also had increases in the proportion of pro-inflammatory innate immune cell populations, such as CD14+ myeloid dendritic cells, and intermediate and non-classical monocytes, as compared to ANA+ NS individuals. In ANA+ NS individuals, there were significant increases in T regulatory subsets and TGF-ß1 that normalized in SARD patients, whereas in SARD patients there were increases in Th2 and Th17 helper cell levels as compared with ANA+ NS individuals, resulting in a shift in the balance between inflammatory and regulatory T cell subsets. Several immune populations were expanded in ANA+ individuals with and without SARD, as compared with ANA- healthy controls, particularly follicular and peripheral T helper, and antibody-producing B cell subsets. To address this question, we used flow cytometry to examine peripheral blood immune populations in ANA+ individuals, with and without SARD, including 20 individuals who subsequently demonstrated symptom progression. Both the immunological changes that promote development of clinical symptoms in SARD and those that prevent autoimmunity in asymptomatic ANA+ individuals (ANA+ NS) remain largely unexplored. ANAs are also seen in healthy individuals and can be detected years before disease onset in SARD. Systemic Autoimmune Rheumatic Diseases (SARDs) are characterized by the production of anti-nuclear antibodies (ANAs).
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