Class switch recombination in selective IgA‐deficient subjects

• Published in: Clinical and experimental immunology Vol. 144; no. 3; pp. 458 - 466
• Main Authors: Hummelshoj, L., Ryder, L. P., Nielsen, L. K., Nielsen, C. H., Poulsen, L. K.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2006; Blackwell; Oxford University Press; Blackwell Science Inc
• Subjects: Adult; Animals; B cells; B-Lymphocytes - immunology; Biological and medical sciences; CD40 Antigens - immunology; Cell Differentiation - immunology; class‐switch recombination; Clinical Studies; Cytidine Deaminase; Cytosine Deaminase - metabolism; Female; Flow Cytometry - methods; Fundamental and applied biological sciences. Psychology; Fundamental immunology; human; Humans; IgA deficiency; IgA Deficiency - immunology; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulin A - biosynthesis; Immunoglobulin D - blood; Immunopathology; Interferon-gamma - immunology; Interleukin-10 - immunology; Interleukin-4 - immunology; Lymphocyte Activation - immunology; Male; Medical sciences; Mice; Polymerase Chain Reaction - methods; Transcription, Genetic; Transforming Growth Factor beta - immunology; Human; Immunopathology; IgA; Recombination; IgA deficiency; Immunology; Deficiency; B-Lymphocyte; Isotype switching; B cells; Immune deficiency; class-switch recombination
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2006.03096.x

Summary Selective IgA deficiency is a common immunodeficiency in Caucasians, but the molecular basis of the disorder remains elusive. To address this issue we examined the molecular events leading to IgA production. Naive IgD positive B cells were purified from four donors with IgA deficiency and four control donors, all Caucasians. Stimulation of B cells from IgA‐deficient donors with the cytokines transforming growth factor (TGF)‐β, interferon (IFN)‐γ or interleukin (IL)‐10 in the presence of anti‐CD40 antibodies showed reduced expression of both activation‐induced cytidine deaminase (AID) and α germline transcripts (GLT) compared to controls. It was possible, however, to induce AID and α GLT when stimulating the cells with anti‐CD40 antibody and TGF‐β in the combination with IL‐10. Moreover, in anti‐CD40 antibody‐stimulated cultures, addition of IL‐10 or IL‐10 + TGF‐β in combination, induced IgA production, albeit lower than found in B cells from controls. The B cells from the IgA‐deficient subjects were less effective in differentiating into CD138+ X‐box binding protein 1 (XBP‐1)+ plasma cells when stimulated with TGF‐β, IFN‐γ or IL‐10. Interestingly, when adding IL‐4 to TGF‐β alone or in combination with IL‐10, the immunoglobulin production in B cells from IgA‐deficient donors was comparable with those of normal controls. These data show that in healthy subjects in vitro IgA production can be up‐regulated by addition of IL‐10 to CD40‐stimulated B cells, whereas a similar B cell differentiation does not occur in IgA‐deficient subjects. Addition of IL‐4, however, reverts this abnormality.