Background/Purpose: The functional duality of B cells is central to balance immune homeostasis by regulating or promoting the immune response. However, the mechanisms by which the cytokine environment is involved in B-cell fate decisions leading to distinct B-cell functions are largely unknown.

Methods: We designed an in vitro approach to understand how extracellular components participate in human B-cell functional plasticity, and how this network might be involved in autoimmune diseases. Two activated T cell subsets (CD4⁺CD45RA⁺ (T_RA) and CD4⁺CD45RO⁺ (T_RO) T cells) were used to expose a common pool of B cells to distinct microenvironments. We showed that the same B-cell population could experience two possible opposite evolutions, to either helper or suppressor functions, in a flexible manner. These cells were thus referred to as effector B cells (Eff B) or suppressor B cells (Supp B). We analyzed the nature of those distinct bystander signals to assess the different functional cytokine clusters linked to phenotypic changes in B cells and explored the influence of those cytokine patterns in 179 Patients with systemic autoimmune diseases (SADs) and 48 healthy volonteers included in the PRECISESADS project [RA (n=44), SLE (n=45), systemic sclerosis (n=46), and Sjogren’s syndrome (SjS, n=44]).

Results: We showed that distinct cytokine modules were involved in the modulation of B-cell functions. The identification of functional cytokine modules showed that the suppressive function of B cells was associated with Th2-related cytokines (IL-13, IL-5, IL-9 and IL-10) while the effector module, headed by IL-6 and CXCL10, also included CXCL1 and IL-8. Finally, we observed a common last cluster of cytokines that we considered to be a master modulator group able to control each cytokine network. This module included TNF-α, IFN-γ, IL-2 and IL-21. The key players of the effector module consisting of IL-6 and CXCL10 were over-represented in the four SADs, underlining a common key pathogenic cytokine network. We then wanted to address whether the analysis of the two different clusters of patients could be linked to biological activities and/or clinical manifestations. The measure of anti-nuclear antigen autoAb in patients delimited a more autoreactive pattern in the disconnected SLE patients cluster, demonstrating a significant increase in anti-DNA Ab and anti-SSA-52KD Ab. We, next confirmed a selective increase in systemic autoreactivity in disconnected SjS patients cluster with the upregulation of anti-SSB Ab and the increase of rheumatoid factors in disconnected RA patients. Finally, we underlined a major increase of extra-glandular clinical manifestations in the disconnected SjS patients group depicting a strong systemic activity of the disease. We also observed in SLE patients that the appearance of clinical symptoms of nephritic disorders during the course of the disease was significantly higher in the disconnected cluster.

Conclusion: Our experimental and translational approach identified subgroups of SADs patients, particularly distinguished by an effector B-cell signature.

Support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS grant n° 115565

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/integration-of-cytokine-profiles-with-distinct-b-cell-functions-reveals-a-specific-micro-environmental-framework-in-autoimmune-diseases/