Mathematical analysis of antigen selection in somatically mutated immunoglobulin genes associated with autoimmunity

Lupus. 2010 Sep;19(10):1161-70. doi: 10.1177/0961203310367657. Epub 2010 May 25.

Abstract

Affinity maturation is a process by which low-affinity antibodies are transformed into highly specific antibodies in germinal centres. This process occurs by hypermutation of immunoglobulin heavy chain variable (IgH V) region genes followed by selection for high-affinity variants. It has been proposed that statistical tests can identify affinity maturation and antigen selection by analysing the frequency of replacement and silent mutations in the complementarity determining regions (CDRs) that contact antigen and the framework regions (FRs) that encode structural integrity. In this study three different methods that have been proposed for detecting selection: the binomial test, the multinomial test and the focused binomial test, have been assessed for their reliability and ability to detect selection in human IgH V genes. We observe first that no statistical test is able to identify selection in the CDR antigen-binding sites, second that tests can reliably detect selection in the FR and third that antibodies from nasal biopsies from patients with Wegener's granulomatosis and pathogenic antibodies from systemic lupus erythematosus do not appear to be as stringently selected for structural integrity as other groups of functional sequences.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibody Affinity / immunology
  • Autoimmunity / genetics
  • Autoimmunity / immunology
  • Binding Sites
  • Binomial Distribution
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology
  • Data Interpretation, Statistical*
  • Granulomatosis with Polyangiitis / genetics*
  • Granulomatosis with Polyangiitis / immunology
  • Humans
  • Immunoglobulin Heavy Chains / genetics*
  • Immunoglobulin Heavy Chains / immunology
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / immunology
  • Mutation
  • Reproducibility of Results

Substances

  • Complementarity Determining Regions
  • Immunoglobulin Heavy Chains