Shared transcriptional profiles of atypical B cells suggest common drivers of expansion and function in malaria, HIV, and autoimmunity

Abstract

Chronic infectious diseases have a substantial impact on the human B cell compartment including a notable expansion of B cells here termed atypical B cells (ABCs). Using unbiased single-cell RNA sequencing (scRNA-seq), we uncovered and characterized heterogeneities in naïve B cell, classical memory B cells, and ABC subsets. We showed remarkably similar transcriptional profiles for ABC clusters in malaria, HIV, and autoimmune diseases and demonstrated that interferon-γ drove the expansion of ABCs in malaria. These observations suggest that ABCs represent a separate B cell lineage with a common inducer that further diversifies and acquires disease-specific characteristics and functions. In malaria, we identified ABC subsets based on isotype expression that differed in expansion in African children and in B cell receptor repertoire characteristics. Of particular interest, IgD+IgMlo and IgD−IgG+ ABCs acquired a high antigen affinity threshold for activation, suggesting that ABCs may limit autoimmune responses to low-affinity self-antigens in chronic malaria.

CD21– CD27– Atypical B Cells in a Pediatric Cohort Study: An Extensive Single Center Flow Cytometric Analysis

“…In studies focusing on different infections, atBCs have shown the ability to produce isotype switched antibodies, contributing to the protective response against the infectious agent, therefore whether atBCs are dysfunctional cells still remains controversial (53)(54)(55). More recently, CD21 − CD27 − atBCs in 14 malariaexposed children were described as switched B cells (21). The herein presented malaria cases were too few to confirm previous reports on the subject.…”

“…As a result, the simultaneous presence of CD19, CD27, and CD21 in our panel has been essential for the identification of atBCs, whereas CD24 and CD38 have been useful to exclude transitional B cells (CD24 + , CD38 ++ , CD21 ± ) and plasmablasts (CD24 − , CD38 ++ , CD27 ++ , CD21 − ). The staining and the gating strategies proved to be optimal to compare relative percentages of atBCs in different pathologies, as previously reported (21,30,(32)(33)(34)(35). More recently, a study based on single-cell RNA sequencing showed that CD21 − CD27 − B cells represent "true" atBCs, defined as an alternative lineage of B cells implicated in conventional immune responses to vaccination and infections in humans (8).…”

“…Previous immunoglobulins expression analysis on atBCs of healthy and non-healthy adults demonstrated the presence of switched and unswitched B cells (2,21), whereas very little is known about immunoglobulins expression distribution in children. With this aim, we selected samples with relative atBCs percentages > 5% (246/1,571), we analyzed the expressions of IgM and IgD in this B-cell subset and compared them with MBC population.…”

Age-associated B cells in viral infection

“…One major topic that requires further research is heterogeneity of the ABC population between contexts. Recently, substantial overlap in the transcriptional profiles of ABCs between individuals with malaria, HIV, and SLE was shown [ 47 ], though some differences were identified. Additional side-by-side comparisons of the ABC population between the contexts of aging, autoimmunity, and infection would be valuable.…”

Atypical B cells up-regulate costimulatory molecules during malaria and secrete antibodies with T follicular helper cell support

“…Previous studies found that total atBCs up-regulate proteins involved in antigen presentation to T cells, including ICOSL, CD86, and HLA-DR (9,12,35). To determine whether Pf-specific atBCs up-regulate these proteins, we performed flow cytometry analysis of paired PBMC samples collected from 2 to 17 year olds (see data file S1 for additional information) at baseline before the malaria season and 1 week after treatment of their first malaria episode of the ensuing malaria season.…”