CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance.
Hyper-IgM (HIGM) syndromes are primary immunodeficiencies characterized by defects of class switch recombination and somatic hypermutation. HIGM patients who carry mutations in the CD40-ligand (CD40L) gene expressed by CD4(+) T cells suffer from recurrent infections and often develop autoimmune disorders. To investigate the impact of CD40L-CD40 interactions on human B cell tolerance, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from three CD40L-deficient patients. Antibody characteristics and reactivity from CD40L-deficient new emigrant B cells were similar to those from healthy donors, suggesting that CD40L-CD40 interactions do not regulate central B cell tolerance. In contrast, mature naive B cells from CD40L-deficient patients expressed a high proportion of autoreactive antibodies, including antinuclear antibodies. Thus, CD40L-CD40 interactions are essential for peripheral B cell tolerance. In addition, a patient with the bare lymphocyte syndrome who could not express MHC class II molecules failed to counterselect autoreactive mature naive B cells, suggesting that peripheral B cell tolerance also depends on major histocompatibility complex (MHC) class II-T cell receptor (TCR) interactions. The decreased frequency of MHC class II-restricted CD4(+) regulatory T cells in CD40L-deficient patients suggests that these T cells may mediate peripheral B cell tolerance through CD40L-CD40 and MHC class II-TCR interactions.
Hervé
Maxime
M
Laboratory of Biochemistry and Molecular Immunology, Hospital for Special Surgery, New York, NY 10021, USA.
Isnardi
Isabelle
I
Ng
Yen-shing
YS
Bussel
James B
JB
Ochs
Hans D
HD
Cunningham-Rundles
Charlotte
C
Meffre
Eric
E
D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000172:deficiency* / Q000235:genetics*; D005434:Flow Cytometry; D006681:HLA-D Antigens / Q000235:genetics*; D006801:Humans; D053306:Hyper-IgM Immunodeficiency Syndrome / Q000235:genetics*; D007108:Immune Tolerance; D007075:Immunoglobulin M / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D006681:HLA-D Antigens; D007075:Immunoglobulin M; D023201:CD40 Ligand