The Role of Alpha-MSH as a Modulator of Ocular Immunobiology Exemplifies Mechanistic Differences between Melanocortins and Steroids

Clemson, Christine; Yost, John Kenneth; Taylor, Andrew W.

doi:10.3109/09273948.2015.1092560

Cited by 40 publications

(45 citation statements)

References 134 publications

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“…RPEconditioned medium can differentiate naive T cells to regulatory T (T reg ) cells (61,62). Cocultured RPE can suppress T-cell activation (11) by producing both soluble and membrane-associated immunomodulatory factors (63)(64)(65)(66). Results from our current study show that the ex vivo coculture of RPE with splenic gd T cells directed the differentiation toward regulatory gd T cells that produced suppressive cytokines, such as IL-4 and IL-10 (Fig.…”

Section: Discussionmentioning

confidence: 69%

Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury

et al. 2017

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γδ T cells located near the epithelial barrier are integral components of local inflammatory and innate immune responses. We have previously reported the presence of choroidal γδ T cells in a model of chronic degeneration of the retinal pigment epithelium (RPE). The goals of the current study were to further define the functions of choroidal γδ T cells and to explore the underlying mechanisms of their action. Our data demonstrate that choroidal γδ T cells are activated by RPE injury in response to NaIO treatment, and that they express genes that encode immunosuppressive cytokines, such as IL-4 and IL-10. γδ-T-cell-deficient mice developed profound RPE and retinal damage at doses that caused minimal effects in wild-type mice, and adoptive transfer of γδ T cells prevented sensitization. Intravitreal injection of IL-4 and IL-10 ameliorated RPE toxicity that was induced by NaIO coculture of γδ T cells with RPE explants activated the production of anti-inflammatory cytokines an aryl hydrocarbon receptor (AhR)-dependent mechanism. AhR deficiency abolished the protective effects of γδ T cells after adoptive transfer. Collectively, these findings define important roles for choroid γδ T cells in maintaining tissue homeostasis in the outer retina.-Zhao, Z., Liang, Y., Liu, Y., Xu, P., Flamme-Wiese, M. J., Sun, D., Sun, J., Mullins, R. F., Chen, Y., Cai, J. Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury.

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Section: Discussionmentioning

confidence: 69%

Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury

et al. 2017

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“…This is an important discovery because it indicates a potential to stimulate these receptors as a novel treatment for autoimmune uveitis. This sort of treatment is novel because it both suppresses the inflammatory response while simultaneously promoting a regulatory immune response223839, and is independent of corticosteroid-driven pathways40.…”

Section: Discussionmentioning

confidence: 99%

MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response

Lee

Preble

Lee

et al. 2016

Sci Rep

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Autoantigen-specific regulatory immunity emerges in the spleen of mice recovering from experimental autoimmune uveitis (EAU), a murine model for human autoimmune uveoretinitis. This regulatory immunity provides induced tolerance to ocular autoantigen, and requires melanocortin 5 receptor (MC5r) expression on antigen presenting cells with adenosine 2 A receptor (A2Ar) expression on T cells. During EAU it is not well understood what roles MC5r and A2Ar have on promoting regulatory immunity. Cytokine profile analysis during EAU revealed MC5r and A2Ar each mediate distinct T cell responses, and are responsible for a functional regulatory immune response in the spleen. A2Ar stimulation at EAU onset did not augment this regulatory response, nor bypass the MC5r requirement to induce regulatory immunity. The importance of this pathway in human autoimmune uveitis was assayed. PBMC from uveitis patients were assayed for MC5r expression on monocytes and A2Ar on T cells, and comparison between uveitis patients and healthy controls had no significant difference. The importance for MC5r and A2Ar expression in EAU to promote the induction of protective regulatory immunity, and the expression of MC5r and A2Ar on human immune cells, suggests that it may be possible to utilize the melanocortin-adenosinergic pathways to induce protective immunity in uveitic patients.

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“…αMSH, derived from the cleavage of pro‐opiomelanocortin polypeptide, 30,214,215 is strongly expressed in HFs 76,165,216,217 . Expression of αMSH can suppress the activities of IL‐1 and TNFα, and blocks endotoxin activation via toll like receptor‐4 218,219 …”

Section: Mechanisms Of Hf Ipmentioning

confidence: 99%

Hair follicle immune privilege and its collapse in alopecia areata

Bertolini

McElwee

Gilhar

et al. 2020

Experimental Dermatology

182

157

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Anagen stage hair follicles (HFs) exhibit “immune privilege (IP)” from the level of the bulge downwards to the bulb. Both passive and active IP mechanisms protect HFs from physiologically undesired immune responses and limit immune surveillance. IP is relative, not absolute, and is primarily based on absent, or greatly reduced, intra‐follicular antigen presentation via MHC class I and II molecules, along with prominent expression of “no danger” signals like CD200 and the creation of an immunoinhibitory signalling milieu generated by the secretory activities of HFs. Perifollicular mast cells, Tregs and other immunocytes may also contribute to HF IP maintenance in healthy human skin. Collapse of anagen hair bulb IP is an essential prerequisite for the development of alopecia areata (AA). In AA, lesional HFs are rapidly infiltrated by NKG2D + T cells and natural killer (NK) cells, while perifollicular mast cells acquire a profoundly pro‐inflammatory phenotype and interact with autoreactive CD8+ T cells. Using animal models, significant functional evidence has accumulated that demonstrates the dominance of the immune system in AA pathogenesis. Purified CD8+T‐cell and NK cell populations alone, which secrete fγ, suffice to induce the AA phenotype, while CD4+T‐cells aggravate it, and Tregs and iNKT cells may provide relative protection against AA development. While IP collapse may be induced by exogenous agents, inherent IP deficiencies might confer increased susceptibility to AA for some individuals. Thus, a key goal for effective AA management is the re‐establishment of a functional HF IP, which will also provide superior protection from disease relapse.

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The Role of Alpha-MSH as a Modulator of Ocular Immunobiology Exemplifies Mechanistic Differences between Melanocortins and Steroids

Cited by 40 publications

References 134 publications

Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury

Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury

MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response

Hair follicle immune privilege and its collapse in alopecia areata

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