Expression of receptor for advanced glycation end products in sarcoid granulomas.
BACKGROUND
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.


OBJECTIVE
We investigated a possible implication of RAGE in sarcoid granulomas.


METHODS
RAGE and major ligands (N-epsilon-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.


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.
Campo
Ilaria
I
Laboratorio di Biochimica & Genetica, Clinica Malattie Apparto Respiratorio, IRCSS Policlinico San Matteo, Università di Pavia, Via Taramelli 5, 27100 Pavia, Italy.
Morbini
Patrizia
P
Zorzetto
Michele
M
Tinelli
Carmine
C
Brunetta
Enrico
E
Villa
Chiara
C
Bombieri
Cristina
C
Cuccia
Mariaclara
M
Agostini
Carlo
C
Bozzi
Valeria
V
Facoetti
Angelica
A
Ferrarotti
Ilaria
I
Mazzola
Paola
P
Scabini
Roberta
R
Semenzato
Gianpietro
G
Pignatti
Pier Franco
PF
Pozzi
Ernesto
E
Luisetti
Maurizio
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D000071797:Butyrophilins; D004247:DNA / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D017127:Glycation End Products, Advanced; D006099:Granuloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics*; D012189:Retrospective Studies; D012507:Sarcoidosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
C408263:BTNL2 protein, human; D000071797:Butyrophilins; D017127:Glycation End Products, Advanced; D008562:Membrane Glycoproteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D004247:DNA