title: Combined deficiency in CD44 and Fas leads to exacerbation of lymphoproliferative and autoimmune disease.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Yoonkyung
authors.initials: Y
authors.lastname: Do
authors.forename: Asimah Q
authors.initials: AQ
authors.lastname: Rafi-Janajreh
authors.forename: Robert J
authors.initials: RJ
authors.lastname: McKallip
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology; D002843:Chromatin / Q000276:immunology; D004277:DNA, Single-Stranded / Q000276:immunology; D005260:Female; D018960:Hyaluronan Receptors / Q000235:genetics / Q000502:physiology*; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007376:Interleukin-2 / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008206:Lymphatic Diseases / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
chemical_list: D002843:Chromatin; D004277:DNA, Single-Stranded; D018960:Hyaluronan Receptors; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007376:Interleukin-2; D011994:Recombinant Proteins; D019014:fas Receptor; D017493:Leukocyte Common Antigens