Ectopic expression of CXCL13, BAFF, APRIL and LT-β is associated with artery tertiary lymphoid organs in giant cell arteritis.
OBJECTIVE
To investigate whether artery tertiary lymphoid organs (ATLOs) are present in giant cell arteritis (GCA) and that their formation is associated with the ectopic expression of constitutive lymphoid tissue-homing chemokines.


METHODS
Reverse transcriptase PCR, immunohistochemical and immunofluorescence analysis were used to determine the presence of ectopic ATLOs in GCA and the expression of chemokines/chemokine receptors and cytokines involved in lymphoneogenesis in the temporal artery samples obtained from 50 patients with GCA and 30 controls. The presence of lymphatic conduits, of follicular dendritic cells (FDCs) precursors and lymphoid tissue inducer cells was also investigated. Finally, expression of CXCL13, B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL) and CCL21 by isolated myofibroblasts was evaluated before and after stimulation with Toll-like receptors (TLRs) agonists and cytokines.


RESULTS
ATLOs were observed in the media layer of 60% of patients with GCA in close proximity to high endothelial venules and independently by the age of patients and the presence of atherosclerosis. ATLO formation was also accompanied by the expression of CXCL13, BAFF, a proliferation-inducing ligand (APRIL), lymphotoxin (LT)-β, interleukin (IL)-17 and IL-7, the presence of FDC precursors and of lymphoid conduits. Stimulation of myofibroblasts with TLR agonists and cytokines resulted in the upregulation of BAFF and CXCL13.


CONCLUSIONS
ATLOs occur in the inflamed arteries of patients with GCA possibly representing the immune sites where immune responses towards unknown arterial wall-derived antigens may be organised.
Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università degli Studi di Palermo, Palermo, Italy.
Francesco
F
Ciccia
Dipartimento di Oncoematologia, Sezione di Anatomia Patologica, Azienda Ospedaliera Ospedali riuniti Villa Sofia Cervello, Palermo, Italy.
Aroldo
A
Rizzo
Dipartimento di Emergenze, Urgenze e Neuroscienze Cliniche, Università di Palermo, Palermo, Italy.
Rosario
R
Maugeri
Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università di Palermo, Palermo, Italy.
Riccardo
R
Alessandro
Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia, Italy.
Stefania
S
Croci
Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università degli Studi di Palermo, Palermo, Italy.
Giuliana
G
Guggino
Pathology Unit, Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia, Italy.
Alberto
A
Cavazza
Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università di Palermo, Palermo, Italy.
Stefania
S
Raimondo
Dipartimento di Oncoematologia, Sezione di Anatomia Patologica, Azienda Ospedaliera Ospedali riuniti Villa Sofia Cervello, Palermo, Italy.
Alessandra
A
Cannizzaro
Dipartimento di Emergenze, Urgenze e Neuroscienze Cliniche, Università di Palermo, Palermo, Italy.
Domenico Gerardo
DG
Iacopino
Unità operativa di Reumatologia, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy.
Carlo
C
Salvarani
Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università degli Studi di Palermo, Palermo, Italy.
Giovanni
G
Triolo
D000368:Aged; D000369:Aged, 80 and over; D053264:B-Cell Activating Factor / Q000378:metabolism; D001706:Biopsy; D002478:Cells, Cultured; D054382:Chemokine CXCL13 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D000066630:Ectopic Gene Expression / Q000276:immunology*; D005260:Female; D013700:Giant Cell Arteritis / Q000150:complications / Q000276:immunology* / Q000473:pathology; D006801:Humans; D053308:Lymphotoxin-beta / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D013699:Temporal Arteries / Q000473:pathology; D000072717:Tertiary Lymphoid Structures / Q000209:etiology / Q000276:immunology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism
D053264:B-Cell Activating Factor; C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; D018925:Chemokines; D016207:Cytokines; C505886:LTB protein, human; D053308:Lymphotoxin-beta; D019707:Receptors, Chemokine; C505719:TNFSF13B protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13
Chemokines; Cytokines; Giant Cell Arteritis