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Cd72(c) is a modifier gene that regulates Fas(lpr)-induced autoimmune disease

Miduo Xu1, Rong Hou, Aya Sato-Hayashizaki

  • 1Laboratory of Immunology, Graduate School of Biomedical Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.

Journal of Immunology (Baltimore, Md. : 1950)
|April 26, 2013
PubMed

Insights

The Cd72(c) gene acts as a crucial modifier, regulating Fas(lpr)-induced autoimmune diseases by impairing B cell signal inhibition. This finding highlights Cd72(c) as a key genetic factor in autoimmune disease development.

Area of Science:

  • Immunology
  • Genetics
  • Autoimmune Diseases

Background:

  • Modifier genes significantly influence autoimmune disease development, yet their roles in autoimmune diseases remain largely unexplored.
  • The Fas(lpr) mutation's impact on autoimmune disease severity varies across mouse genetic backgrounds, indicating the presence of critical modifier genes.
  • The Cd72 gene, encoding a B cell receptor (BCR) coreceptor, exists in different forms (haplotypes), with CD72(c) found in mouse strains prone to autoimmune disease.

Purpose of the Study:

  • To investigate the role of the Cd72(c) gene locus in regulating Fas(lpr)-induced autoimmune diseases.
  • To determine if the Cd72(c) haplotype contributes to lupus-like autoimmune disease development.
  • To elucidate the mechanism by which Cd72(c) influences B cell signaling and autoimmune disease pathogenesis.

Main Methods:

  • Generation of congenic mouse strains, B6.CD72(c)/lpr and MRL.CD72(b)/lpr, to isolate the effects of the Cd72 locus.
  • Phenotypic analysis of autoimmune disease severity in congenic mice compared to parental strains.
  • Functional assessment of CD72(c) allele activity in BCR signal inhibition and B cell regulation.

Main Results:

  • Introduction of the Cd72(c) locus into a non-autoimmune-prone B6 background induced lupus-like autoimmune disease only in the presence of the Fas(lpr) mutation.
  • Congenic mice with the Cd72(b) haplotype on the MRL background (MRL.CD72(b)/lpr) exhibited milder autoimmune disease compared to MRL/lpr mice.
  • The Cd72(c) allele demonstrated reduced inhibitory function in BCR signaling, and CD72 deficiency exacerbated autoimmune disease in Fas(lpr) mice.

Conclusions:

  • The Cd72(c) locus contains a critical modifier gene that regulates Fas(lpr)-induced autoimmune disease.
  • Reduced B cell signal regulation by the hypofunctional Cd72(c) allele is a key mechanism driving autoimmune disease.
  • Cd72(c) represents a significant genetic factor influencing the susceptibility and severity of lupus-like autoimmune conditions.

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