title: Autoantibodies to the amino-terminal fragment of beta-fodrin expressed in glandular epithelial cells in patients with Sjögren's syndrome.
abstract: Sjögrens's syndrome (SS) is an autoimmune disease characterized by destruction of lacrimal and salivary glands, but the mechanisms underlying the disease process are unclear. By immunoscreening a HepG2 cDNA library with serum from an SS patient we isolated a cDNA encoding amino-terminal 616 aa of beta-fodrin, a membrane skeleton protein associated with ion channels and pumps. Serum Ab to the amino-terminal fragment of beta-fodrin was frequently detected in SS patients compared with rheumatic disease patients without SS or healthy controls (70 vs 12 or 4%; p < 0.00001). All the anti-beta-fodrin-positive sera recognized the amino-terminal fragment with no homology to alpha-fodrin. Anti-beta-fodrin Abs in patients' sera as well as mouse polyclonal sera raised against the amino-terminal beta-fodrin fragment did not react with intact beta-fodrin, but recognized the 65-kDa amino-terminal fragment generated through cleavage by caspase-3 or granzyme B. When expression of intact and fragmented beta-fodrin in lacrimal glands was assessed by immunohistochemistry, the antigenic amino-terminal fragment was distributed diffusely in acinar epithelial cell cytoplasm, whereas the carboxyl-terminal fragment and/or intact beta-fodrin were localized in peripheral cytoplasm, especially at the basal membrane, in SS patients. In contrast, intact beta-fodrin was detected primarily at the apical membrane of epithelia, and the amino-terminal fragment was scarcely detected in control patients with chronic graft-vs-host disease. These findings suggest that cleavage and altered distribution of beta-fodrin in glandular epithelial cells may induce impaired secretory function and perpetuate an autoimmune response to beta-fodrin, leading to autoantibody production and glandular destruction in SS.
authors.affiliation: Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. kuwanam@sc.itc.keio.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Kuwana
authors.forename: T
authors.initials: T
authors.lastname: Okano
authors.forename: Y
authors.initials: Y
authors.lastname: Ogawa
authors.forename: J
authors.initials: J
authors.lastname: Kaburaki
authors.forename: Y
authors.initials: Y
authors.lastname: Kawakami
mesh_terms: D001323:Autoantibodies / Q000032:analysis*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D018076:DNA, Complementary / Q000302:isolation & purification; D004847:Epithelial Cells / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology; D053804:Granzymes; D006801:Humans; D007765:Lacrimal Apparatus / Q000276:immunology; D008840:Microfilament Proteins / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D012697:Serine Endopeptidases / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000276:immunology*; D013049:Spectrin
chemical_list: D001323:Autoantibodies; D002352:Carrier Proteins; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D018076:DNA, Complementary; D053804:Granzymes; D008840:Microfilament Proteins; D010446:Peptide Fragments; D012697:Serine Endopeptidases; D013049:Spectrin; C509213:GZMB protein, human; C509214:Gzmb protein, mouse; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse