Abstract
The germline immunoglobulin (Ig) variable heavy chain 4-34 (VH4-34) 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, VH4-34-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 VH4-34-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.
© 2017 Schickel et al.
MeSH terms
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Adolescent
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Adult
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Amino Acid Sequence
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Antigens, Bacterial / immunology
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Autoantibodies / genetics
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Autoantibodies / immunology
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Bacteria / immunology*
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Child
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Child, Preschool
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Clonal Selection, Antigen-Mediated
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Female
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Gastrointestinal Microbiome / immunology
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Humans
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Immunoglobulin G / genetics
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Immunoglobulin G / immunology*
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Immunoglobulin Heavy Chains / genetics
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Immunoglobulin Heavy Chains / immunology*
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Immunoglobulin Variable Region / genetics
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Immunoglobulin Variable Region / immunology*
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Interleukin-1 Receptor-Associated Kinases / deficiency
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Interleukin-1 Receptor-Associated Kinases / genetics
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Interleukin-1 Receptor-Associated Kinases / immunology
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Male
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Mutation
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Myeloid Differentiation Factor 88 / deficiency
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / immunology
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Sequence Homology, Amino Acid
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism
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Young Adult
Substances
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Antigens, Bacterial
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Autoantibodies
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Immunoglobulin G
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Immunoglobulin Heavy Chains
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Immunoglobulin Variable Region
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MYD88 protein, human
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Myeloid Differentiation Factor 88
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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IRAK4 protein, human
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Interleukin-1 Receptor-Associated Kinases