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Abstract
A distinct B cell population marked by elevated CD11c expression is found in patients with systemic lupus erythematosus (SLE). Cells with a similar phenotype have been described during chronic infection, but variable gating strategies and nomenclature have led to uncertainty of their relationship to each other. We isolated CD11chi cells from peripheral blood and characterized them using transcriptome and IgH repertoire analyses. Gene expression data revealed the CD11chi IgD+ and IgD− subsets were highly similar to each other, but distinct from naive, memory, and plasma cell subsets. Although CD11chi B cells were enriched in some germinal center (GC) transcripts and expressed numerous negative regulators of B cell receptor (BCR) activation, they were distinct from GC B cells. Gene expression patterns from SLE CD11chi B cells were shared with other human diseases, but not with mouse age-associated B cells. IgH V-gene sequencing analysis showed IgD+ and IgD− CD11chi B cells had somatic hypermutation and were clonally related to each other and to conventional memory and plasma cells. However, the IgH repertoires expressed by the different subsets suggested that defects in negative selection during GC transit could contribute to autoimmunity. The results portray a pervasive B cell population that accumulates during autoimmunity and chronic infection and is refractory to BCR signaling.
Highlights
A unique subset of B cells that express high levels of CD11c, an integrin, and T-bet (Tbx21), a transcription factor, is generated in humans during autoimmunity and chronic infection
Using deposited RNAseq data (Supplementary Data File 2) from systemic lupus erythematosus (SLE) patients (Supplementary Table 1) [1], principal component (PC) analysis revealed that CD11chi IgD+ and IgD− may be separate populations, but they are vastly different from naive (CD11c− CD27− IgD+) and memory (CD11c− CD27+ IgD−) B cells (Figure 1A)
Evidence that CD11chi B cells represent a distinct stage of B cell differentiation separate from naïve B cells or classical memory B cells comes from the thousands of Differentially expressed gene (DEG) compared to either of these populations, as well as the distinct separation of naïve, memory and CD11chi IgD+ and IgD− B cells by Principal Component Analysis (PCA)
Summary
A unique subset of B cells that express high levels of CD11c, an integrin, and T-bet (Tbx21), a transcription factor, is generated in humans during autoimmunity and chronic infection. In response to chronic infection, a similar B cell subset, termed atypical memory B cells, accumulates in individuals infected with malaria [11], HIV [12], Hepatitis C [13], tuberculosis [14], schistosomiasis [15], and Toxoplasma gondii [16] [reviewed in Karnell et al [17]]. These cells may accumulate during acute infection with SARS-CoV-2 infection [18, 19]. These B cells appear unresponsive to antigen stimulation through the B cell receptor (BCR) [7, 20, 21], it has been argued that they can be stimulated through antigen presented on membranes and differentiate into plasma cells [22]
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