Impaired Ig class switch in mice deficient for the X-linked lymphoproliferative disease gene Sap

Blood. 2005 Sep 15;106(6):2069-75. doi: 10.1182/blood-2004-07-2731. Epub 2005 Jun 7.

Abstract

X-linked lymphoproliferative disease (XLP) is characterized by abnormal immune responses to Epstein-Barr virus attributed to inactivating mutations of the SAP gene. Previous studies showed immunoglobulin E (IgE) deficiency and low serum IgG levels in Sap-deficient mice before and after viral infections, which are associated with impaired CD4+ T-helper function. In the present work, we find that signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is expressed in B cells and this expression is down-regulated after stimulation with lipopolysaccharide (LPS) and interleukin 4 (IL-4). We demonstrate that B cells from Sap-deficient mice exhibit reduced IgG and IgA production in vitro. This impairment correlates with decreased circular transcript levels of Ialpha, Igamma2a, Igamma2b, and Igamma3 after stimulation, which indicate a defective Ig switch recombination in Sap-deficient B cells. While XLP is believed to cause defects in T, natural killer T (NKT), and natural killer (NK) cells, our results indicate that B cells are also affected.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology*
  • Down-Regulation / drug effects
  • Immunoglobulin A / biosynthesis
  • Immunoglobulin Class Switching*
  • Immunoglobulin G / biosynthesis
  • Interleukin-4 / pharmacology
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Lipopolysaccharides / pharmacology
  • Lymphoproliferative Disorders / genetics
  • Lymphoproliferative Disorders / immunology*
  • Mice
  • RNA, Messenger / analysis
  • Signaling Lymphocytic Activation Molecule Associated Protein

Substances

  • Immunoglobulin A
  • Immunoglobulin G
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • RNA, Messenger
  • Sh2d1a protein, mouse
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Interleukin-4