Class switch recombination in selective IgA-deficient subjects.
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)-beta, interferon (IFN)-gamma or interleukin (IL)-10 in the presence of anti-CD40 antibodies showed reduced expression of both activation-induced cytidine deaminase (AID) and alpha germline transcripts (GLT) compared to controls. It was possible, however, to induce AID and alpha GLT when stimulating the cells with anti-CD40 antibody and TGF-beta in the combination with IL-10. Moreover, in anti-CD40 antibody-stimulated cultures, addition of IL-10 or IL-10 + TGF-beta 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-beta, IFN-gamma or IL-10. Interestingly, when adding IL-4 to TGF-beta 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.
Hummelshoj
L
L
Laboratory of Medical Allergology, Allergy Clinic, National University Hospital, Copenhagen, Denmark. l.hummelshoj@rh.dk
Ryder
L P
LP
Nielsen
L K
LK
Nielsen
C H
CH
Poulsen
L K
LK
D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D017098:IgA Deficiency / Q000276:immunology*; D007070:Immunoglobulin A / Q000096:biosynthesis*; D007072:Immunoglobulin D / Q000097:blood; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction / Q000379:methods; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D019013:CD40 Antigens; D007070:Immunoglobulin A; D007072:Immunoglobulin D; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D043525:Cytosine Deaminase; D003564:Cytidine Deaminase