B-cell tolerance checkpoint violations in systematic lupus erythematosus

Kirthi Raman Kumar, Chandra Mohan

Research output: Contribution to journalReview articlepeer-review

Abstract

B cells play a crucial role in the pathogenesis of the prototypic autoimmune disease systemic lupus erythematosus. The presence of autoantibodies in lupus is indicative of a breach in B-cell tolerance to self. Studies conducted over the past 15 years indicate that tolerance checkpoints exist at various stages of B-cell development to ensure that self-reactive B cells are censored and do not produce autoantibodies. These include an early checkpoint operative at the immature B-cell stage in the bone marrow, with receptor editing and deletion as the two main mechanism. Additional checkpoints exist in the periphery and include receptor revision and anergy at the mature naive stage, with further checkpoints being operative at the germinal center and memory B-cell stages. In a recent study, It has been shown that mice harboring the lupus susceptibility gene Sle lb2/Ly 1082 display defective tolerance both at the immature as well as the mature B-cel stage in the periphery. This, along with other studies conducted both in murine and human lupus, indicates that several key tolerance checkpoints may be violated in lupus B cells. Put together, these have provided a possible explanation for the presence of autoantibodies in lupus. B cells are key components of the adaptive immune system and generate responses to potentially pathogenic foreign antigens. It is also important that the B cells do not respond to self-antigens as this would lead to autoimmune diseases. Numerous mechanism, mostly developmentally encoded, exist to ensure that this does not happen. Recent literature reports point to the existence of at least two key developmental checkpoints that seem to be operative in preventing the survival of self-reactive B cells. Checkpoint I - operative at the immature B-cell stage, with deletion and receptor editing of self-reactive immature B cells as the two main mechanisms of tolerance induction, and checkpoint II - operative at several successive mature B-cell stages, with numerous contributing mechanisms, such as anergy, cell death and receptor revision, In this review, we will focus on these tolerance checkpoints and mechanisms, highlighting some of the recent advances in the field.

Original languageEnglish (US)
Pages (from-to)415-422
Number of pages8
JournalFuture Rheumatology
Volume2
Issue number4
DOIs
StatePublished - Aug 1 2007

Keywords

  • Anergy
  • Autoantibodies
  • Autoimmunity
  • B cells
  • Germinal center
  • Lupus
  • Receptor editing
  • Tolerance
  • Transgenic

ASJC Scopus subject areas

  • Rheumatology

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