A Proinflammatory Cytokine Network Profile in Th1/Type 1 Effector B Cells Delineates a Common Group of Patients in Four Systemic Autoimmune Diseases

Abstract

Objective. The effector T cell and B cell cytokine networks have been implicated in the pathogenesis of systemic autoimmune diseases, but the association of these cytokine networks with the heterogeneity of clinical manifestations and immune profiles has not been carefully examined. This study was undertaken to examine whether cytokine profiles can delineate distinct groups of patients in 4 systemic autoimmune diseases (systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, and systemic sclerosis).Methods. A total of 179 patients and 48 healthy volunteers were enrolled in the multicenter cross-sectional PRECISE Systemic Autoimmune Diseases (PRECISESADS) study. Multi-low-dimensional omics data (cytokines, autoantibodies, circulating immune cells) were examined. Coculture experiments were performed to test the impact of the cytokine microenvironment on T cell/B cell cross-talk.Results. A proinflammatory cytokine profile defined by high levels of CXCL10, interleukin-6 (IL-6), IL-2, and tumor necrosis factor characterized a distinct group of patients in the 4 systemic autoimmune diseases. In each disease, this proinflammatory cluster was associated with a specific circulating immune cell signature, more severe disease, and higher levels of autoantibodies, suggesting an uncontrolled proinflammatory Th1 immune response. We observed in vitro that B cells reinforce Th1 differentiation and naive T cell proliferation, leading to the induction of type 1 effector B cells and IgG production. This process was associated with an increase in CXCL10, IL-6, IL-2, and interferon-γ production.Conclusion. This composite analysis brings new insights into human B cell functional heterogeneity based on T cell/B cell cross-talk, and proposes a better stratification of patients with systemic autoimmune diseases, suggesting that combined biomarkers would be of great value for the design of personalized treatments.

Ultra-Low Dose Cytokines in Rheumatoid Arthritis, Three Birds with One Stone as the Rationale of the 2LARTH® Micro-Immunotherapy Treatment

“…This study conducted in Poland would need to be generalized to more patients, but it reinforces the fact that a holistic approach to RA treatment, with multiple cytokine targets, could be highly beneficial for patients. These results are in line with the fact that both IL-2 and TNF-α were found to be parts of a specific pro-inflammatory cytokine profile also defined by high levels of CXCL10 and IL-6, characterizing severe outcomes in systemic autoimmune diseases [100].…”

Molecular Mechanisms Driving IL-10- Producing B Cells Functions: STAT3 and c-MAF as Underestimated Central Key Regulators?

“…The in-vitro -induced Be1 and Be2/Breg were obtained in coculture with naive and memory T cells, respectively, as previously described ( 126 ). After coculture, B cells were sorted with the “FACS MoFlo XDP cell sorter” (Beckman Coulter) with a purity greater than 98%.…”

“…We recently developed an in vitro model of B-cell polarization to induce pro-inflammatory B (Be1) cells and Bregs suppressing CD4 + T cell proliferation ( 126 ). In vitro- induced Breg cells included mostly activated B cells (IgM + CD38 + CD27 - ) and unswitched PB (CD19 + IgM + CD27 low CD38 + CD20 + ) able to simultaneously produce IL-10 and IgM.…”

Pathogenesis and Treatment of T-Large Granular Lymphocytic Leukemia (T-LGLL) in the Setting of Rheumatic Disease

“…Patients were found to primarily have increases in CXCL10, IL-2, IL-6, and tumor necrosis factor (TNF). The pro-inflammatory profile was also characterized by an abnormal B cell distribution, a CD8 cytotoxic T cell signature, and more severe clinical features ( 76 ). In vitro study suggested upregulation of this cytokine signature associated with B cell enhancement of Th1 differentiation and proliferation of activated naive T cells ( 76 ).…”