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International Immunology, Vol. 15, No. 11, pp. 1327-1340, November 2003
© 2003 Japanese Society for Immunology

Combined deficiency in CD44 and Fas leads to exacerbation of lymphoproliferative and autoimmune disease

Yoonkyung Do1, Asimah Q. Rafi-Janajreh, Robert J. Mckallip1, Prakash S. Nagarkatti2 and Mitzi Nagarkatti1

Departments of 1 Microbiology and Immunology and 2 Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA

Correspondence to: M. Nagarkatti; E-mail: mnagark{at}hsc.vcu.edu
Transmitting editor: P. S. Ohashi

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.

Keywords: activation-induced cell death, apoptosis, autoantibody, double-negative T cells, lupus


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