Collapse and Restoration of MHC Class-I-Dependent Immune Privilege

Abstract

The collapse of major histocompatiblity complex (MHC) class-I-dependent immune privilege can lead to autoimmune disease or fetal rejection. Pragmatic and instructive models are needed to clarify the as yet obscure controls of MHC class I down-regulation in situ, to dissect the principles of immune privilege generation, maintenance, and collapse as well as to develop more effective strategies for immune privilege restoration. Here, we propose that human scalp hair follicles, which are abundantly available and easily studied, are ideally suited for this purpose: interferon-␥ induces ectopic MHC class I expression in the constitutively MHC class-I-negative hair matrix epithelium of organ-cultured anagen hair bulbs, likely via interferon regulatory factor-1, along with up-regulation of the MHC class I pathway molecules ␤ 2 microglobulin and transporter associated with antigen processing (TAP-2). In the first report to identify natural immunomodulators capable of down-regulating MHC class I expression in situ in a normal, neuroectoderm-derived human tissue, we show that ectopic MHC class I expression in human anagen hair bulbs can be normalized by treatment with ␣-MSH, IGF-1, or TGF-␤1, all of which are locally generated, as well as by FK506. These agents are promising candidates for immune privilege restoration and for suppressing MHC class I expression where this is clinically desired (eg, in alopecia areata, multiple sclerosis, autoimmune uveitis, mumps orchitis, and fetal or allograft rejection). A select number of mammalian tissue sites, namely the brain, cornea, anterior chamber of the eye, testis, liver, fetotrophoblast, and the hamster cheek pouch, display a fascinating phenomenon called "immune privilege." [1][2][3][4][5] This name reflects that these tissue environments can award allotransplants relative protection from rejection by the host immune system.

Birth, life, and death of the MAGE3 hypothesis of alopecia areata pathobiology

“…Most currently available evidence suggests that, upon interferon (IFN)--induced collapse of the hair follicle's (HF's) physiological immune privilege (IP), as yet unidentified follicular autoantigens are exposed to preexisting autoreactive CD8 + T cells by ectopically expressed major histocompatibility (MHC) class I molecules within the epithelium of anagen hair bulbs [1,2]. Peptides derived from melanogenesis-associated autoantigens expressed only by melanin-producing anagen HFs are persuasive candidates as key autoantigens in AA [3].…”

Transcriptional regulation of major histocompatibility complex class I gene by insulin and IGF-I in FRTL-5 thyroid cells

“…Furthermore, treatment of mice with methimazole (MMI), a drug that decreases MHC class I gene expression in thyroid cells, reduces cell-surface expression of class I molecules and prevents the development of experimental SLE, blepharitis and experimental autoimmune uveitis (Singer et al 1994, Chan et al 1995, Wang et al 2003. Downregulation or absence of MHC class I expression is also considered the hallmark of tissue immune privilege (Ito et al 2004).…”

Controlled Delivery of T-box21 Small Interfering RNA Ameliorates Autoimmune Alopecia (Alopecia Areata) in a C3H/HeJ Mouse Model

“…Alopecia areata is a tissue-restricted autoimmune disease directed at the hair follicle resulting in hair loss. 1,2 It is a common disorder with an estimated prevalence of 1 in 1000 and sometimes extends to the whole scalp area (alopecia totalis). Total loss of scalp and body hair (alopecia universalis) may take place.…”