The absence of CD44 ameliorates Fas(lpr/lpr) disease

The lpr mutation in the Fas gene leads to symptoms of autoimmune disease, including polyclonal B-lymphocyte activation and lymphoproliferation. The expanding T-lymphocyte populations in the disease are characterized by high expression levels of the memory marker CD44. It has not been known whether CD44 expression contributes to the pathophysiology of the condition or merely reflects a consequence of excessive lymphocyte activation. We therefore tested the role of CD44 gene products in Fas(lpr/lpr) disease in gene targeted mice. We bred CD44 knockout mice and C57Bl/6-lpr mice to generate the Fas(lpr/lpr) CD44+/+, and Fas(lpr/lpr) CD44-/- genotypes and analyzed the disease manifestations around 215 days of age. The absence of CD44 substantially reduced the immunoglobulin secretion and lymphocyte expansion that are characteristic of the Fas(lpr/lpr) syndrome. Surprisingly, the percentage of CD3+ CD4- CD8- (double negative) cells in peripheral lymphoid organs increased in Fas(lpr/lpr) CD44-/- mice almost to the same extent as in Fas(lpr/lpr) CD44+/+ mice. These results indicate that the expansion of the fraction of double negative cells in spleens and lymph nodes, believed to be generated by down-regulation of CD8, does not depend on increased lymphocyte numbers. Furthermore, they corroborate an essential role for CD44 gene products in the T-cell expansion and polyclonal B-cell activation that constitute the Fas(lpr/lpr) syndrome. The CD44 receptor may be a suitable therapeutic target for inhibition of lymphoproliferation in autoimmune diseases.