efficient-tonsillar-t-follicular-helper-cell-processing-functional

Efficient Tonsillar T Follicular Helper Cell Processing and Functional Analysis through High-dimensional Flow Cytometry

T follicular helper cells (Tfh) are a subset of CD4+ T helper cells that aid in B cell isotype switching, germinal center (GC) formation, somatic ...

National Institutes of Health

B-1 B cells derive from a developmental program distinct from that of conventional B cells, through B cell receptor (BCR)-dependent positive selection of fetally derived precursors. Here, we used direct labeling of B cells reactive with the N-acetyl-D-glucosamine (GlcNAc)-containing Lancefield group A carbohydrate of Streptococcus pyogenes to study the effects of bacterial antigens on the emergent B-1 B cell clonal repertoire. The number, phenotype, and BCR clonotypes of GlcNAc-reactive B-1 B cells were modulated by neonatal exposure to heat-killed S. pyogenes bacteria. GlcNAc-reactive B-1 clonotypes and serum antibodies were reduced in germ-free mice compared with conventionally raised mice. Colonization of germ-free mice with a conventional microbiota promoted GlcNAc-reactive B-1 B cell development and concomitantly elicited clonally related IgA plasma cells in the small intestine. Thus, exposure to microbial antigens in early life determines the clonality of the mature B-1 B cell repertoire and ensuing antibody responses, with implications for vaccination approaches and schedules.

Neonatal Exposure to Commensal-Bacteria-Derived Antigens Directs Polysaccharide-Specific B-1 B Cell Repertoire Development.

We report on patients with STAT3 loss-of-function (LOF) mutations who developed lupus-like autoimmunity. Immune dysregulation seen in STAT3 LOF patients suggests a susceptibility to systemic autoimmunity with important implications in monitoring and management of these patients.

Lupus-like autoimmunity and increased interferon response in patients with STAT3-deficient hyper-IgE syndrome.

Monogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown.

Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features.

Two seminal observations suggest that the African genome contains genes selected by malaria that protect against systemic lupus erythematosus (SLE) in individuals chronically exposed to malaria, but which in the absence of malaria, are risk factors for SLE. First, Brian Greenwood observed that SLE was rare in Africa and that malaria prevented SLE-like disease in susceptible mice. Second, African-Americans, as compared with individuals of European descent, are at higher risk of SLE. Understanding that antibodies play central roles in malaria immunity and SLE, we discuss how autoreactive B cells contribute to malaria immunity but promote SLE pathology in the absence of malaria. Testing this model may provide insights into the regulation of autoreactivity and identify new therapeutic targets for SLE.

The tangled web of autoreactive B cells in malaria immunity and autoimmune disease.

In an era of predicted emerging pandemics, the production of effective vaccines may require an in-depth understanding of the biology of human naive B (B) cells. Here we provide evidence that the majority of B cells expressed CD73, an ecto-5'-nucleotidase often associated with immune cell suppression, and demonstrated features of anergy, including an IgMIgD surface phenotype, reduced calcium flux in response to IgM crosslinking, and increased PTEN expression. Analysis of antibody sequences encoded by the inherently autoreactive V4-34 heavy chain produced by plasmablasts seven days following influenza vaccination showed that in younger but not in older individuals, anergic B cells provided a reservoir of B cells capable of responding to vaccination by somatic mutation, resulting in diversification and loss of autoreactivity. These results suggest that effective human vaccines may require the ability to awaken or 'redeem' anergic B cells that can be repurposed to participate in pathogen-specific responses.

Article	Year
Neonatal Exposure to Commensal-Bacteria-Derived Antigens Directs Polysaccharide-Specific B-1 B Cell Repertoire Development. Immunity\| PubMed ID: 32610078	2020
Lupus-like autoimmunity and increased interferon response in patients with STAT3-deficient hyper-IgE syndrome. The Journal of allergy and clinical immunology\| PubMed ID: 32768442	2021
Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features. Annals of the rheumatic diseases\| PubMed ID: 33619160	2021
The tangled web of autoreactive B cells in malaria immunity and autoimmune disease. Trends in parasitology\| PubMed ID: 35120815	2022
Human naïve B cells show evidence of anergy and clonal redemption following vaccination. NPJ vaccines\| PubMed ID: 40368926	2025

Brian L. P. Dizon

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