Analysis of in vivo role of alpha-fodrin autoantigen in primary Sjogren's syndrome.
The alpha-fodrin N-terminal portion (AFN) autoantigen mediates in vivo immunoregulation of autoimmune responses in primary Sjögren's syndrome (SS). We further examined this process and found that cleavage products of AFN were frequently detected in the salivary gland duct cells of SS patients. In in vitro studies using human salivary gland HSY cells, anti-Fas-induced apoptosis resulted in specific cleavage of alpha-fodrin into the 120-kd fragment, in association of alpha-fodrin with mu-calpain, and activation of caspase 3. Significant proliferative responses against AlphaFN autoantigen were observed in the peripheral blood mononuclear cells (PBMCs) from SS patients with higher pathological score (grade 4) and with short duration from onset (within 5 years). In vivo roles of AFN peptides were investigated using PBMCs from patients with SS, systemic lupus erythematosus, and rheumatoid arthritis. Significant proliferative T-cell responses of PBMCs to AFN peptide were detected in SS but not in systemic lupus erythematosus or rheumatoid arthritis. AFN peptide induced Th1-immune responses and accelerated down-regulation of Fas-mediated T-cell apoptosis in SS. Our data further elucidate the in vivo role of AFN autoantigen on the development of SS and suggest that the AFN autoantigen is a novel participant in peripheral tolerance.
Miyazaki
Katsushi
K
Department of Pathology, Tokushima University School of Dentistry, 3 Kuramotocho, Tokushima 770, Japan.
Takeda
Noriaki
N
Ishimaru
Naozumi
N
Omotehara
Fumie
F
Arakaki
Rieko
R
Hayashi
Yoshio
Y
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002154:Calpain / Q000378:metabolism; D002352:Carrier Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004789:Enzyme Activation; D005260:Female; D005663:Furans / Q000494:pharmacology; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007564:Japan / Q000453:epidemiology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000528:radiation effects; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008840:Microfilament Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010306:Parotid Gland / Q000166:cytology; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000473:pathology*; D013936:Thymidine / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism; D013049:Spectrin
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D002154:Calpain; D002352:Carrier Proteins; D053148:Caspase 3; D020169:Caspases; D005663:Furans; D005982:Glutathione Transferase; D008840:Microfilament Proteins; D011993:Recombinant Fusion Proteins; D013936:Thymidine; D019014:fas Receptor; D013049:Spectrin; C072665:2-propyl-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran; C505407:CASP3 protein, human; C484806:CAPN1 protein, human