Apoptosis with FasL+ cell infiltration in the periphery and thymus of corrected autoimmune mice.
Fas (CD95) ligand (L) is a death factor that binds to its receptor, Fas, and induces apoptotic cell death, a crucial process in immunological tolerance. gld (generalized lymphoproliferative disorder) mice, which have a point mutation in the FasL gene, develop spontaneous systemic autoimmune syndromes characterized by hypergammaglobulinaemia and lymphoid hyperplasia owing to accumulation of abnormal B220+ CD3+ cells. Transplantation of wild-type (wt) bone marrow cells into old gld mice on the same strain background results in normalization of autoimmune syndromes. We characterized the cellular mechanisms (functionally and histologically) of the above phenomena in gld mice after bone marrow transplantation (BMT) to determine the role of apoptosis via Fas/FasL interactions in inducing and maintaining self-tolerance in vivo. Activated splenocytes from wt and BMT (wt to gld) mice showed significant cytotoxic activity against Fas transfectant cells while those from BMT (gld to gld) mice did not. Cells in the thymus, spleen and lymph nodes of gld mice uniformly upregulated Fas expression and were sensitive to Fas-mediated apoptosis compared with those in wt mice. Cells sensitive to Fas-mediated apoptosis in gld mice resided not only among abnormal B220+ CD3+ cells but also among conventional lymphocytes. More importantly, histological analysis revealed that cells in the spleen, lymph nodes and thymus frequently underwent apoptosis with infiltration of FasL+ cells in BMT (wt to gld) mice compared with BMT (gld to gld) mice. Our results indicated that apoptosis via Fas/FasL interactions can directly eliminate pathogenic cells responsible for autoimmunity in the periphery and possibly in the thymus in vivo.
Kobata
T
T
Rheumatology Program, St Marianna University School of Medicine, Kawasaki, Japan.
Takasaki
K
K
Asahara
H
H
Hong
N M
NM
Masuko-Hongo
K
K
Kato
T
T
Hirose
S
S
Shirai
T
T
Kayagaki
N
N
Yagita
H
H
Okumura
K
K
Nishioka
K
K
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000628:therapy; D015551:Autoimmunity; D016026:Bone Marrow Transplantation; D008198:Lymph Nodes / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
D019014:fas Receptor