Background/Purpose: Giant cell arteritis (GCA) is a chronic immune-mediated vasculitis of large and medium vessels characterized by a chronic relapsing course with no good biomarkers that can predict activity and response to treatment. Fortunately, the accessibility of the temporal artery for tissue biopsy allows novel mechanistic studies that can characterize pathogenic macrophages which possess pro-inflammatory and pro-angiogenic properties which depend on their cross talk between the microenvironment of the compartments/layers of the vessel wall. The localization of particular activated macrophage subtypes (AMs) in a particular vessel compartment can provide insight on how AMs influence endothelial activation in the intima, and neoangiogenesis in the media and adventitia. In this pilot study, we evaluated the expression of 2 novel AM subtypes- folate receptor beta (FRB) and endothelin receptor beta (ETB) which are potential pathogenic populations and druggable targets for existing medications like methotrexate/new generation antifolates and endothelin receptor blockers We assessed their predominant distribution across the intima media and adventitial layers.

Methods:  Formalin-fixed paraffin embedded hematoxylin-eosin stained tissue sections were examined from 6 patients with GCA and 2 controls with no disease and normal temporal artery biopsies. Immunohistochemical stains were performed using FRB, CD68 and CD3 antibodies to enhance recognition of AMs, their distribution along the intima media and adventitial layers and composition of inflammatory infiltrates. We compared the expression of FRB and ETB in GCA versus controls and mild (no visual loss) versus severe disease (positive visual loss).

Results: In GCA patients, overall inflammation was moderate to severe with >90% destruction of the internal elastic lamina. AMs comprised 36.3 ± 4.1% of total leukocyte infiltrate while CD3(+) lymphocytes accounted for 61.7 ± 4.1%. FRBs were selectively expressed in AMs, which predominantly localized in the media/adventitia with a median of 9.8 cells/hpf (IQR = 7-12). ETBs were expressed predominantly in intimal macrophages- with a median of 20.5 cells/hpf (IQR = 15.2 – 21.5), smooth muscle and endothelial cells. There were no macrophages nor FRB expression demonstrated in the controls. A trend towards higher FRB and ETB expression was seen in GCA with complications of vision loss versus those without but did not reach statistical significance.

Conclusion:  FRBs macrophages are potential biomarkers that localize to the media/adventitia and may contribute to vasa vasorum angiogenesis. ETB is more ubiquitously expressed, and ETB macrophages localize to the intima where they may affect endothelial activation. FRB and ETB macrophages should be analyzed for pathogenicity, antifolate-binding properties and clinically correlated in larger samples in future and prospective studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/folate-receptor-beta-and-endothelin-receptor-beta-macrophage-subtypes-are-differentially-expressed-in-the-vascular-compartments-of-the-intima-and-mediaadventitia-in-giant-cell-arteritis-a-pilot-stud/