Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells
- Author(s)
- Ma, CS; Hare, NJ; Nichols, KE; Dupre, L; Andolfi, G; Roncarolo, MG; Adelstein, S; Hodgkin, PD; Tangye, SG;
- Details
- Publication Year 2005-04,Volume 115,Issue #4,Page 1049-1059
- Journal Title
- JOURNAL OF CLINICAL INVESTIGATION
- Publication Type
- Journal Article
- Abstract
- X-linked lymphoproliferative disease (XLP) is an often-fatal immunodeficiency characterized by hypogammaglobuhnemia, fulminant infectious mononucleosis, and/or lymphoma. The genetic lesion in XLP, SH2D1A, encodes the adaptor protein SAP (signaling lymphocytic activation molecule-associated [SLAM-associated] protein); however, the mechanism(s) by which mutations in SH2D1A causes hypogammaglobulinemia is unknown. Our analysis of 14 XLP patients revealed normal B cell development but a marked reduction in the number of memory B cells. The few memory cells detected were IgM(+), revealing deficient isotype switching in vivo. However, XLP B cells underwent proliferation and differentiation in vitro as efficiently as control B cells, which indicates that the block in differentiation in vivo is B cell extrinsic. This possibility is supported by the finding that XLP CD4(+) T cells did not efficiently differentiate into IL-10(+) effector cells or provide optimal B cell help in vitro. Importantly, the B cell help provided by SAP-deficient CD4(+) T cells was improved by provision of exogenous IL-10 or ectopic expression of SAP, which resulted in increased IL-10 production by T cells. XLP CD4(+) T cells also failed to efficiently upregulate expression of inducible costimulator (ICOS), a potent inducer of IL-10 production by CD4(+) T cells. Thus, insufficient IL-10 production may contribute to hypogammaglobulinemia in XLP. This finding suggests new strategies for treating this immunodeficiency.
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Keywords
- MEMORY B-CELLS; COMMON VARIABLE IMMUNODEFICIENCY; PROTEIN-TYROSINE-PHOSPHATASE; DOMAIN-CONTAINING PROTEINS; NATURAL-KILLER-CELLS; BARR-VIRUS INFECTION; CUTTING EDGE; GENE-PRODUCT; IMMUNOGLOBULIN PRODUCTION; INDUCIBLE COSTIMULATOR
- Publisher's Version
- https://doi.org/10.1172/JCI23139
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2005-04-01 12:00:00