Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency

J Exp Med. 2010 Jul 5;207(7):1541-54. doi: 10.1084/jem.20091927. Epub 2010 Jun 14.

Abstract

The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro-B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP-keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4(+) T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell-activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation / immunology
  • Antibody-Producing Cells / immunology*
  • Antibody-Producing Cells / pathology*
  • Autoantibodies / blood
  • B-Cell Activating Factor / blood
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology*
  • Cell Proliferation
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology*
  • Humans
  • Immune Tolerance / immunology*
  • Immunity / immunology
  • Immunization
  • Immunologic Deficiency Syndromes / blood
  • Immunologic Deficiency Syndromes / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation / genetics
  • Spleen / immunology
  • Spleen / pathology

Substances

  • Autoantibodies
  • B-Cell Activating Factor
  • Homeodomain Proteins
  • Tnfsf13b protein, mouse
  • RAG-1 protein