Autoantibodies to the amino-terminal fragment of beta-fodrin expressed in glandular epithelial cells in patients with Sjögren's syndrome.
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.
Kuwana
M
M
Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. kuwanam@sc.itc.keio.ac.jp
Okano
T
T
Ogawa
Y
Y
Kaburaki
J
J
Kawakami
Y
Y
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
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