Bruton's tyrosine kinase is essential for human B cell tolerance.
Most polyreactive and antinuclear antibodies are removed from the human antibody repertoire during B cell development. To elucidate how B cell receptor (BCR) signaling may regulate human B cell tolerance, we tested the specificity of recombinant antibodies from single peripheral B cells isolated from patients suffering from X-linked agammaglobulinemia (XLA). These patients carry mutations in the Bruton's tyrosine kinase (BTK) gene that encode an essential BCR signaling component. We find that in the absence of Btk, peripheral B cells show a distinct antibody repertoire consistent with extensive secondary V(D)J recombination. Nevertheless, XLA B cells are enriched in autoreactive clones. Our results demonstrate that Btk is essential in regulating thresholds for human B cell tolerance.
Laboratory of Biochemistry and Molecular Immunology, The Hospital for Special Surgery, New York, NY 10021, USA.
Yen-Shing
YS
Ng
Hedda
H
Wardemann
James
J
Chelnis
Charlotte
C
Cunningham-Rundles
Eric
E
Meffre
D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000276:immunology*; D000906:Antibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D002648:Child; D018076:DNA, Complementary / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D040181:Genetic Diseases, X-Linked / Q000276:immunology*; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*
D000906:Antibodies; D018076:DNA, Complementary; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human