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In total, this study provides insights into the multifaceted role of unswitched memory B cells during viral infection. Since many different types of B cells exist in homeostasis, arise in response to infection, or develop along with autoimmunity and strategies used in the field to identify subsets can be heterogeneous,Pernes et al.caution against using surface markers alone to profile B cell subsets. [...]this editor believes that development of technology that can link protein & gene expression with cellular function will ultimately provide the best advantage to shedding light on the complex nature of unswitched memory B cells in human health and disease. Conflict of interest The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

B cells play a crucial role in the immune response and contribute to various autoimmune diseases. Recent studies have revealed abnormalities in the B cell receptor (BCR) repertoire of patients with autoimmune diseases, with distinct features observed among different diseases and B cell subsets. Classically, BCR repertoire was used as an identifier of distinct antigen-specific clonotypes, but the recent advancement of analyzing large-scale repertoire has enabled us to use it as a tool for characterizing cellular biology. In this review, we provide an overview of the BCR repertoire in autoimmune diseases incorporating insights from our latest research findings. In systemic lupus erythematosus (SLE), we observed a significant skew in the usage of VDJ genes, particularly in CD27 + IgD + unswitched memory B cells and plasmablasts. Notably, autoreactive clones within unswitched memory B cells were found to be increased and strongly associated with disease activity, underscoring the clinical significance of this subset. Similarly, various abnormalities in the BCR repertoire have been reported in other autoimmune diseases such as rheumatoid arthritis. Thus, BCR repertoire analysis holds potential for enhancing our understanding of the underlying mechanisms involved in autoimmune diseases. Moreover, it has the potential to predict treatment effects and identify therapeutic targets in autoimmune diseases.

Background The interaction between immune cells and cancer has been extensively researched. However, little is known about the relationship between B Cells and lung squamous cell carcinoma (LUSC). Methods This study performed a comprehensive two-sample Mendelian randomization (MR) analysis of GWAS summary data to determine the causal relationship between the immune phenotypes of 199 subtypes of B cells and the risk of LUSC. Heterogeneity and horizontal pleiotropy were assessed using several methods, including MR-Egger regression and inverse variance weighting. Results MR analysis showed that an increase in the absolute count number of unswitched memory B cells (UMBC) was causally associated with the risk of LUSC at FDR < 0.05. Reverse MR analysis indicated that LUSC was causally associated with the increased expression of CD27 on IgD + CD38 − UMBCs and CD27 on UMBCs at p  < 0.05. Conclusion There is a strong association between the number of UMBCs and the risk of LUSC. These results provide a basis for developing new cancer immunotherapies.

Memory B cells are comprised of unswitched (CD27+IgD+) and switched (CD27+IgD-) subsets. The origin and function of unswitched human memory B cells are debated in the literature, whereas switched memory B cells are primed to respond to recurrent infection. Unswitched memory B cells have been described to be reduced in frequency with severe SARS-CoV2 infection and here we characterize their activation status, BCR functionality, and contribution to virally-induced cytokine production. Analyses of whole blood from healthy individuals, people immunized against SARS-CoV2, and those who have had mild and severe SARS-CoV2 infection, confirm a reduction in the frequency of unswitched memory B cells during severe SARS-CoV2 infection and demonstrate this reduction is associated with increased levels of systemic TNFα. We further document how severe viral infection is associated with an increased frequency of ‘IgD+’ only memory B cells that correlate with increased IgG autoantibody levels. Unswitched and switched memory B cells from severe SARS-CoV2 infection displayed evidence of heightened activation with a concomitant reduction in the expression of the inhibitory receptor CD72. Functionally, both populations of memory B cells from severe SARS-COV2 infection harbored a signaling-competent BCR that displayed enhanced BCR signaling activity in the unswitched population. Finally, we demonstrate that B cells from mild SARS-CoV2 infection are poised to secrete pro-inflammatory cytokines IL-6 and TNFα. Importantly, unswitched memory B cells were a major producer of IL-6 and switched memory B cells were a major producer of TNFα in response to viral TLR ligands. Together these data indicate that B cells contribute to the inflammatory milieu during viral infection.