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Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency

Abstract

No genetic defect is known to cause common variable immunodeficiency (CVID), a heterogeneous human disorder leading to adult-onset panhypogammaglobulinemia. In a search for CVID candidate proteins, we found four of 32 patients to lack ICOS, the “inducible costimulator” on activated T cells, due to an inherited homozygous deletion in the ICOS gene. T cells from these individuals were normal with regard to subset distribution, activation, cytokine production and proliferation. In contrast, naive, switched and memory B cells were reduced. The phenotype of human ICOS deficiency, which differs in key aspects from that of the ICOS−/− mouse, suggests a critical involvement of ICOS in T cell help for late B cell differentiation, class-switching and memory B cell generation.

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Figure 1: Defective ICOS expression in CVID patients.
Figure 2: Deletion of 443 nucleotides within the ICOS mRNA and deletion of 1,815 base pairs from the genomic DNA in ICOS-deficient patients.
Figure 3: Reduced B cell numbers and lack of switched memory B cells in ICOS-deficient patients.

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Acknowledgements

We thank the patients and their families for continuous support; S. Schmidt, T. Meyer-ter-Vehn and E. Röther, the patients' physicians; F. Melchers, A. Radbruch, K. Resch, J.-L. Franco, P. Nielson, H. Pfister, K.-M. Toellner and M. Digweed for valuable advice; J. Puck and H.-P. Pircher for critical reading of the manuscript; and P. Jahn for technical assistance. The work was supported by the Deutsche Forschungsgemeinschaft (DFG) grant GR1617/3 (B.G.), Kr 827/13-2 (R.A.K.), the Landesforschungs-Förderprogramm Baden-Württemberg (H.H.P., M.S., K.W., H.E.), the European Community grant EU-IMPAD-contract Nr.QLCT-2001-01536 (H.H.P., H.E.), and the DFG-Sonderforschungsbereiche 506 (R.A.K.) and 620 (H.H.P.).

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Correspondence to Hans H. Peter.

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Grimbacher, B., Hutloff, A., Schlesier, M. et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4, 261–268 (2003). https://doi.org/10.1038/ni902

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