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Expression of Receptor for Advanced Glycation End Products in Sarcoid Granulomas

¹ Laboratorio di Biochimica & Genetica, Clinica Malattie Apparto Respiratorio, ² Istituto di Anatomia ed Istologia Patologica, and ³ Unità di Biometria, IRCCS Policlinico San Matteo, Università di Pavia, Pavia, Italy; ⁴ Immunologia Clinica, Dipartimento di Medicina Clinica e Sperimentale, Università di Padova, Padova, Italy; ⁵ Dipartimento Materno-Infantile e di Biologia-Genetica, Università di Verona, Verona, Italy; and ⁶ Laboratorio di Immunogenetica, Dipartimento di Genetica e Microbiologia, and ⁷ Dipartimento di Biologia Animale, Università di Pavia, Pavia, Italy

Correspondence and requests for reprints should be addressed to Maurizio Luisetti, M.D., Clinica Malattie Apparto Respiratorio, IRCSS Policlinico San Matteo, Via Taramelli 5, 27100 Pavia, Italy. E-mail: m.luisetti{at}smatteo.pv.it

Rationale: The receptor for advanced glycation end products (RAGE) engages a number of ligands implicated in inflammatory processes. The RAGE coding gene maps to the 6p21.32 region, close to the genes DRB1 and BTNL2, which are associated with sarcoidosis.

Objectives: We investigated a possible implication of RAGE in sarcoid granulomas.

Methods: RAGE and major ligands (N--carboxy-methyl-lysine [CML], S100A12, and S100B) expression was investigated by immunostaining of 99 paraffin-embedded biopsies of sarcoid tissues, and expression patterns were determined. Among the three RAGE gene single-nucleotide polymorphisms investigated, –374 T/A was selected, characterized in terms of transcriptional effect (immunocytochemistry and real-time polymerase chain reaction), and its frequency was determined in DNA extracted from biopsies.

Measurements and Results: RAGE, CML, S100A12, and S100B immunoreactivity was observed in all sarcoid granulomas, although at different intensities. The degree of RAGE expression significantly correlated with the degree of S100A12 expression. The –374 TT/AT genotypes, associated with higher RAGE transcriptional activity, were more frequent in the sarcoidosis biopsy group than in control subjects, and the association was confirmed in a second, independent series of 101 patients with sarcoidosis.

Conclusions: We showed the association of RAGE and its ligands with sarcoidosis and suggest that an intrinsic genetic factor could be in part involved in its expression. In Italian patients, the –374 T/A polymorphism seems to be significantly associated with this disease.

Key Words: ligands • immunohistochemistry • genetics • real-time polymerase chain reaction

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The receptor for advanced glycation end products and its ligands represents a system for amplification of inflammatory processes. The RAGE gene maps close to DRB1 and BTNL2, two genes strongly associated with sarcoidosis. What This Study Adds to the Field RAGE and its ligands are expressed in sarcoid granulomas. The RAGE –374 T/A polymorphism is significantly associated with sarcoidosis.

 

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