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Cogan's syndrome as an autoimmune disease

2003; Volume: 361; Issue: 9356 Linguagem: Inglês

10.1016/s0140-6736(03)12478-6

0099-5355

Salvatore Benvenga, Francesco Trimarchi, Antonio Facchiano,

Adrenal Hormones and Disorders

With their finding that the isolated 12-residue Cogan's peptide is homologous to four autoantigens—laminin, connexin 26, the collagen disease-associated Ssa/Ro, and the receptor-like phosphatase DEP-1/CD148—and one viral protein, Claudio Lunardi and colleagues (Sept 21, p 915)1Lunardi C Bason C Leandri M et al.Autoantibodies to the inner ear and endothelial antigens in Cogan's syndrome.Lancet. 2002; 360: 915-921Summary Full Text Full Text PDF PubMed Scopus (192) Google Scholar have advanced greatly identification of the eye, inner ear, nervous system and endothelium autoantigens of Cogan's syndrome. Connexin 26 belongs to a family of gap-junction proteins, and thus it is important for cell-to-cell adhesion and for allowing aminoacids, electrolytes, and other small molecules to pass between adjacent cells. Laminins have a role in cell attachment through binding to various extracellular matrix components and cell-surface receptors, including integrins. Viral homology is relevant because infections of the upper respiratory tract typically precede onset of Cogan's syndrome. Hence, molecular mimicry between autoantigens and exogenous antigens could be one pathogenetic mechanism of this disorder.1Lunardi C Bason C Leandri M et al.Autoantibodies to the inner ear and endothelial antigens in Cogan's syndrome.Lancet. 2002; 360: 915-921Summary Full Text Full Text PDF PubMed Scopus (192) Google Scholar However, details on the computer-assisted search for homology were not provided by Lunardi and colleagues.1Lunardi C Bason C Leandri M et al.Autoantibodies to the inner ear and endothelial antigens in Cogan's syndrome.Lancet. 2002; 360: 915-921Summary Full Text Full Text PDF PubMed Scopus (192) Google Scholar Because of our interest in molecular mimicry,2Benvenga S Alesci F Trimarchi F Facchiano A Homologies of the thyroid sodium-iodide symporter with bacterial and viral proteins.J Endocrinol Invest. 1999; 22: 535-540Crossref PubMed Scopus (21) Google Scholar, 3Facchiano A Facchiano F van Renswoude J Divergent evolution may link human immunodeficiency virus GP41 to human CD4.J Mol Evol. 1993; 36: 448-457Crossref PubMed Scopus (4) Google Scholar we wished to expand the computer-assisted search done by Lunardi. We entered Cogan's peptide to search the SWISSPROT and SPTrEMBL databases with PATTINPROT.4Pôle bio-informatique Lyonnais. Network protein sequence analysis.http://npsa-pbil.ibcp.fr/cgi-bin/npsa_automat.pl?page=npsa_pattinprot.htmlGoogle Scholar We recorded no matches in the 100% to 68% range of aminoacid identity. We detected homologies (http://image.thelancet.com/extras/02cor11113webfigure.pdf) in the 58% (or seven of 12 identities) to 67% (or eight of 12) range, which is greater than the 33% (four of 12) to 58% (seven of 12) range reported by Lunardi and colleagues.1Lunardi C Bason C Leandri M et al.Autoantibodies to the inner ear and endothelial antigens in Cogan's syndrome.Lancet. 2002; 360: 915-921Summary Full Text Full Text PDF PubMed Scopus (192) Google Scholar The homologies we recorded included laminin and ladinin (another cell-adhesion molecule) and kinesin and calcineurin. Autoantibodies against these molecules are seen in autoimmune diseases of the skin or collagen. Microtubule-associated kinesins are contained in the cilia and flagella of eukaryotic and prokaryotic cells. Kinesin-2 is needed for transport pathways in motile and non-motile cilia and flagella; in these organisms it is essential for sensory functions in ciliated neurons such as the otic neuroepithelium. An immune response against ciliated or flagellated microorganisms can thus become an autoimmune response against ciliated human cells—eg, inner-ear hair cells— because of molecular mimicry between exogenous and endogenous kinesins. We also noted homology with integrins, calcineurin, receptor-like protein kinase, large tegument proteins, two bacterial proteins (selenocysteinespecific elongation factor and avirulence protein). Integrins and calcineurin are abundantly expressed in inner-ear cells, cochlear and vestibular nerve, cornea, retina, optic nerve, and endothelium. In the inner ear, integrins regulate hair-cell differentiation and cilia maturation, and transduce mechanosensation. Receptor-like protein kinase is homologous to a viral movement protein and several allergens. Large tegument proteins are expressed in viruses, and one model to explain herpes virus stromal keratitis is cross-reactivity of these and other viral proteins with corneal autoantigens.5Koelle DM Reymond SN Chen H et al.Tegument-specific, virus-reactive CD4 T cells localize to the cornea in herpes simplex virus interstitial keratitis in humans.J Virol. 2000; 74: 10930-10938Crossref PubMed Scopus (78) Google Scholar We noted homology with proteins expressed in bacteria and avirulence protein, which is implicated in bacterial pathogenesis. Finally, other homologous proteins we recorded are six small-molecule transporters in eukaryotes and pro-karyotes—eg, sodium proline symporter, lactose-proton symporter, and the galactoside transport ATP binding protein MGLA—and cecropins. MGLA is homologous to surface-presentation antigens of enteropathogens, including spirochaetes. Homology with cecropins, which are natural peptide effectors of innate immunity against pathogens, could result in formation of neutralising autoantibodies that would facilitate infections.