Calcitonin gene‐related peptide (CGRP) may award relative protection from interferon‐γ‐induced collapse of human hair follicle immune privilege

Abstract

In the GWAS group, age at onset was 36 years and in the non-GWAS group 28 years. The difference is mainly owing to the inclusion of a subset of individuals from a paediatric cohort (disease onset before 15 years of age) into the non-GWAS samples whereas the GWAS samples included only individuals with adult onset of disease.Strong association to HLA genes is a hallmark of common immune-mediated diseases. HLA genes are extremely polymorphic with minor sequence variation between genotypes. In view of increasing demand for dissection of genetic and clinical heterogeneity of many common immunologically based diseases, precise determination of HLA genotypes will become critical. In this respect, we propose that the method presented herein represents a real contribution in the psoriasis field. AcknowledgementsThe authors thank Anna-Lena Kastman, Anna Ehrensvärd, Kerstin Bergh, Leonid Padyukov and Maria Seddighzadeh for the excellent assistance, technical support and advice. This work was supported by grants from the Swedish Medical Research Council, the Swedish Psoriasis Association, the Welander and Finsen Foundations, Stockholm County and Karolinska Institutet. Conflict of interestsThe authors have declared no conflicting interests. Supporting InformationAdditional Supporting Information may be found in the online version of this article: Table S1. HLA-Cw*06:02 readings from four SNPs genotypes.Please note: Wiley-Blackwell is not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. Abstract: Interferon-c (IFNc)-induced collapse of hair follicle (HF) immune privilege (IP) is a key element in the pathogenesis of alopecia areata. In this pilot study, we investigated whether the immunosuppressive neuropeptide, calcitonin gene-related peptide (CGRP), can protect from and ⁄ or restore IFNc-induced HF-IP collapse. After showing that human scalp HFs express CGRP receptor-like receptor (CRLR) immunoreactivity, anagen HFs were cultured in the presence of IFNc, with CGRP added before or after. Adding CGRP after IFNc administration ('restoration assay') failed to downregulate IFNc-induced ectopic MHC class I expression, while MHC class II expression was reduced. However, administering CGRP before IFNc application ('protection assay') significantly reduced the IFNc-induced overexpression and ectopic expression of MHC class I and II and reduced the increased degranulation of perifollicular mast cells induced by IFNc. This suggests that CGRP may not restore HF-IP once it has collapsed, but may protect it from collapsing. Therefore, CRLR stimulation might help to retard AA progression.

Adrenomedullin 2 Improves Early Obesity-Induced Adipose Insulin Resistance by Inhibiting the Class II MHC in Adipocytes

“…Here, ADM2 was demonstrated to inhibit MHCII expression in adipocytes primarily through CRLR/RAMP1, which is the classical pharmacological CGRP 1 receptor (45). In agreement with our present findings, some reports have shown that CGRP reduced MHCII expression in dendritic cells and hair follicle dermal papilla (46,47), although the exact mechanism remains unclear.…”

Efficacy of tofacitinib in treatment of alopecia universalis in two patients

“…Multiple strategies are employed by follicular cells to actively maintain immune privilege. Some of the most studied anti‐inflammatory mechanisms include the suppression of major histocompatibility complex (MHC) class 1, accumulation of immunosuppressant ‘IP guardians,’ and use of ‘no danger’ signals . Equally, pro‐inflammatory mechanisms, including the actions of antigen‐presenting cells (APC), natural killer (NK) and mast cells, are shut down …”

“…a). Suppression is accomplished via the upregulation of ‘IP guardians’ such as transforming growth factor β (TGFβ)‐1/2, α‐melanocyte stimulating hormone (α‐MSH), insulin growth factor (IGF)‐1 and calcitonin gene‐related peptide (CGRP) . CGRP, e.g.…”

“…CGRP, e.g. is believed to downregulate interferon (IFN)‐γ which is the stimulus for MHC class I expression via IRF‐1 …”

The Role of Hair Follicle Immune Privilege Collapse in Alopecia Areata: Status and Perspectives

“…Also, the most important inducers of HF-IP collapse (e.g., IFN-g and substance P) and the constitutive ''HF-IP guardians'' (e.g., a-melanocyte-stimulating hormone, transforming growth factor-b2, calcitonin gene-related peptide, and vasoactive intestinal peptide) that normally prevent IP collapse have to be identified (Ito et al, 2004;Peters et al, 2007;Siebenhaar et al, 2007;Meyer et al, 2009;Bertolini et al, 2012;Kinori et al, 2012). Therapeutically, we need to explore how IP guardians and IP-protective drugs (e.g., FK506, a-melanocyte-stimulating hormone) and/ or antagonists of HF-IP collapse inducers (e.g., NK1 antagonists) can best be used to restore a collapsed IP in AA patients, until it has become possible to tolerize specifically AA patients against relevant key autoantigens and related undesired CD8 þ T cell responses.…”