Maintenance of Hair Follicle Immune Privilege Is Linked to Prevention of NK Cell Attack

Abstract

Hair follicles (HFs) enjoy a relative immune privilege (IP) that is characterized by downregulation of major histocompatibility complex (MHC) class I and local expression of potent immunosuppressants. Normally, natural killer (NK) cells attack cells with absent/low MHC class I expression. However, because few perifollicular NK cells are found around healthy human anagen HFs, we asked how HFs escape from NK cell attack. This study suggests that this happens via an active NK cell suppression. Alopecia areata (AA), an organ-specific autoimmune disease thought to result from a collapse of HF-IP, in contrast, shows striking defects in NK cell inhibition/containment. We show that the NK cell inhibitor macrophage migration inhibitory factor is strongly expressed by the HF epithelium, and very few CD56(+)/NKG2D(+) NK cells are observed in and around normal anagen HFs compared to AA with prominent aggregations of CD56(+)/NKG2D(+) NK around AA-HFs. By flow cytometry, many fewer NK function-activating receptors (NKG2D, NKG2C) and significantly more killer cell Ig-like receptors-2D2/2D3 were found to be expressed on peripheral blood CD56(+) NK cells of healthy controls than on those of AA patients. In addition, only weak immunoreactivity for MHC class I chain-related A gene was observed in normal anagen HFs compared to AA. To our knowledge, this defect is previously unreported and must be taken into account in AA pathogenesis and its management.

Peripheral blood gene expression in alopecia areata reveals molecular pathways distinguishing heritability, disease and severity

“…Several of these genes and pathways have a previously described role in AA pathogenesis, validating that our experimental approach is sufficiently sensitive to capture disease-relevant processes. 10,33 Although it has been shown that NK cells aggregate perifollicularly in AA lesional skin 3,4,34 and peripheral blood, 35,36 there is limited data regarding the role of NK cells in AA pathogenesis. Our data show an upregulation of NK-cell cytotoxicity in AA peripheral blood that, as suggested by others, 11,12,37 may promote the failure of hair follicle immune privilege.…”

Bone marrow‐derived mesenchymal stem cells prevent alopecia areata development through the inhibition of NKG2D expression: A pilot study

“…NKG2D-expressing CD8 T cells infiltrate the surrounding HF in humans with AA. [3,4] We investigated whether MSCs inhibit CD8+NKG2D+ T-cell infiltration in AA skin lesions. The CD8+NKG2D+ T cells were less observed in MSCtreated skin lesions than in control skin ( Figure 2B, Table S2a).…”

“…[1] Th1 cytokines and chemokines, such as interferon (IFN)G, CXCL9 and CXCL10, are predominantly detected in AA lesions and might induce the collapse of the hair follicle immune privilege. [2,3] Recent studies have shown that a NK cell receptor, NKG2D-mediated signalling, has been strongly associated with the pathogenesis of AA. [4] The antibody-mediated blockade of IFNG prevented AA development in grafted mice and blocked the accumulation of CD8+NKG2D+ T cells in the skin.…”

Cicatricial alopecia: What’s new in etiology?

“…An unknown trigger may possibly be a signal to destroy eHFSCs which would eliminate hair follicle ability to regenerate and self-repair and at the same time to stimulate all other clinical and histopathological features of the disease. [19][20][21][22] The theory of the immune attack on eHFSCs is crucial for the etiology of cicatricial alopecia. MHC class I, β2-macroglobulin and MHC class II are subjected to different regulation within a hair bulb in the various cicatricial alopecia units compared to those in the not affected skin.…”