Self-reactive VH4-34-expressing IgG B cells recognize commensal bacteria

• Published in: The Journal of experimental medicine 2017-07, Vol.214 (7), p.1991-2003
• Main Authors: Schickel, Jean-Nicolas, Glauzy, Salomé, Ng, Yen-Shing, Chamberlain, Nicolas, Massad, Christopher, Isnardi, Isabelle, Katz, Nathan, Uzel, Gulbu, Holland, Steven M, Picard, Capucine, Puel, Anne, Casanova, Jean-Laurent, Meffre, Eric
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Amino Acid Sequence; Antibodies; Antigens; Antigens, Bacterial - immunology; Autoantibodies - genetics; Autoantibodies - immunology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Bacteria; Bacteria - immunology; Carbohydrates; CD27 antigen; Child; Child, Preschool; Clonal Selection, Antigen-Mediated; Cloning; Containment; Erythrocytes; Female; Gastrointestinal Microbiome - immunology; Humans; Immune system; Immunoglobulin G; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Heavy Chains - immunology; Immunoglobulin Variable Region - genetics; Immunoglobulin Variable Region - immunology; Immunoglobulins; Immunological memory; Interleukin-1 Receptor-Associated Kinases - deficiency; Interleukin-1 Receptor-Associated Kinases - genetics; Interleukin-1 Receptor-Associated Kinases - immunology; Lymphocytes B; Male; Memory cells; Mutation; MyD88 protein; Myeloid Differentiation Factor 88 - deficiency; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Patients; Proteins; Receptor mechanisms; Receptors; Sequence Homology, Amino Acid; Somatic hypermutation; T cell receptors; TLR3 protein; Toll-like receptors; Tumor Necrosis Factor Receptor Superfamily, Member 7 - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 7 - metabolism; Young Adult
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20160201

The germline immunoglobulin (Ig) variable heavy chain 4-34 ( ) gene segment encodes in humans intrinsically self-reactive antibodies that recognize I/i carbohydrates expressed by erythrocytes with a specific motif in their framework region 1 (FWR1). VH4-34-expressing clones are common in the naive B cell repertoire but are rarely found in IgG memory B cells from healthy individuals. In contrast, CD27 IgG B cells from patients genetically deficient for IRAK4 or MYD88, which mediate the function of Toll-like receptors (TLRs) except TLR3, contained VH4-34-expressing clones and showed decreased somatic hypermutation frequencies. In addition, -encoded IgGs from IRAK4- and MYD88-deficient patients often displayed an unmutated FWR1 motif, revealing that these antibodies still recognize I/i antigens, whereas their healthy donor counterparts harbored FWR1 mutations abolishing self-reactivity. However, this paradoxical self-reactivity correlated with these -encoded IgG clones binding commensal bacteria antigens. Hence, B cells expressing germline-encoded self-reactive VH4-34 antibodies may represent an innate-like B cell population specialized in the containment of commensal bacteria when gut barriers are breached.