Combined deficiency in CD44 and Fas leads to exacerbation of lymphoproliferative and autoimmune disease
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- Combined deficiency in CD44 and Fas leads to exacerbation of lymphoproliferative and autoimmune disease
- Do, Yoonkyung; Rafi-Janajreh, AQ; Mckallip, RJ; Nagarkatti, PS; Nagarkatti, M
- Activation-induced cell death; Apoptosis; Autoantibody; Double-negative T cells; Lupus
- Issue Date
- OXFORD UNIV PRESS
- INTERNATIONAL IMMUNOLOGY, v.15, no.11, pp.1327 - 1340
- Patients with mutations in Fas develop autoimmune lymphoproliferative disease (ALPS), While their family members with similar mutations are often normal, thereby suggesting that additional factors may play a role in the development of ALPS. In the current study, we tested the role of CD44 in the development of lymphoproliferative disease by generating CD44 -/-/Fas -/-mice, which failed to express CD44 and Fas, and compared them to CD44 +/+/Fas -/- mice that expressed CD44, but not Fas. The results showed that CD44 -/-/Fas -/- mice developed a more severe lymphoproliferative and autoimmune disease when compared to CD44 +/+/Fas -/- mice. This was indicated by increased numbers of cells in their lymph nodes, and a greater proportion of B220 +CD4 -CD8 - (double-negative) T cells as well as antibodies against single-stranded DNA and chromatin. The heightened severity of lymphoproliferative disease seen in CD44 -/-/Fas -/- mice correlated with increased resistance of T cells, but not B cells, to undergo activation-induced cell death (AICD). The current study suggests that deficiency in CD44 in combination with a defect in one of the molecules involved in the death receptor family such as Fas can further down-regulate AICD, and exacerbate the lymphoproliferative and autoimmune disease.
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