The Role of Hair Follicle Immune Privilege Collapse in Alopecia Areata: Status and Perspectives
2013; Elsevier BV; Volume: 16; Issue: 1 Linguagem: Inglês
10.1038/jidsymp.2013.7
ISSN1529-1774
Autores Tópico(s)Dermatology and Skin Diseases
ResumoAlopecia areata (AA) may represent a CD8+T cell–mediated, organ-specific autoimmune disease in which as yet elusive autoantigens are recognized, once they become exposed by ectopic major histocompatibility complex class I expression by anagen hair follicles (HFs) that have lost their relative immune privilege (IP). On this basis, AA research is chiefly challenged with identifying the autoreactive CD8+T cells and their cognate autoantigens as well as key inducers of HF-IP collapse and "HF-IP guardians" that prevent and/or can restore IP collapse. However, natural killer group 2D–positive (NKG2D+) cells (incl. NK, NKT, and CD8+T cells) and NKG2D–activating ligands from the MICA (MHC I–related chain A) family may also have a key role in AA pathogenesis, as a massive infiltrate of IFN-γ-secreting NKG2D+ cells alone suffices to induce the AA phenotype. Therefore, we speculate that AA may represent a stereotypic, but distinct HF response pattern to inflammatory insults associated with HF-IP collapse. Alopecia areata (AA) may represent a CD8+T cell–mediated, organ-specific autoimmune disease in which as yet elusive autoantigens are recognized, once they become exposed by ectopic major histocompatibility complex class I expression by anagen hair follicles (HFs) that have lost their relative immune privilege (IP). On this basis, AA research is chiefly challenged with identifying the autoreactive CD8+T cells and their cognate autoantigens as well as key inducers of HF-IP collapse and "HF-IP guardians" that prevent and/or can restore IP collapse. However, natural killer group 2D–positive (NKG2D+) cells (incl. NK, NKT, and CD8+T cells) and NKG2D–activating ligands from the MICA (MHC I–related chain A) family may also have a key role in AA pathogenesis, as a massive infiltrate of IFN-γ-secreting NKG2D+ cells alone suffices to induce the AA phenotype. Therefore, we speculate that AA may represent a stereotypic, but distinct HF response pattern to inflammatory insults associated with HF-IP collapse. alopecia areata hair follicle immune privilege natural killer natural killer group 2D immune privilege Over the past two decades, it has been elucidated that the hair follicle (HF) immune system in mice and man differs from the general skin immune system in many respects, and relies on a number of strategies to shield selected (epithelial) tissue compartments from autoaggressive immune attacks by generating anatomically circumscribed areas of relative immune privilege (IP) (Paus et al., 2005Paus R. Nickoloff B.J. Ito T. A "hairy" privilege.Trends Immunol. 2005; 26: 32-40Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). These strategies include the downregulation of major histocompatibility complex (MHC) class I and β2 microglobulin molecules in large parts of the central and proximal HF epithelium, incl. the bulge and bulb region, the local production of potent immunosuppressants (e.g., transforming growth factor-β1/2, α-melanocyte-stimulating hormone) and/or immunoinhibitory "no danger" signals (CD200), and the repression of intrafollicular antigen-presenting cell and perifollicular natural killer (NK) cell and mast cell functions (e.g., downregulation of MHC class II on HF Langerhans cells below the isthmus, downregulation of NKD2G ligands, upregulation of macrophage migration inhibitory factor) (Paus et al., 2005Paus R. Nickoloff B.J. Ito T. A "hairy" privilege.Trends Immunol. 2005; 26: 32-40Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar; Meyer et al., 2008Meyer K.C. Klatte J.E. Dinh H.V. et al.Evidence that the bulge region is a site of relative immune privilege in human hair follicles.Br J Dermatol. 2008; 159: 1077-1085PubMed Google Scholar; Ito et al., 2008bIto T. Meyer K.C. Ito N. et al.Immune privilege and the skin.Curr Dir Autoimmun. 2008; 10: 27-52Crossref PubMed Scopus (49) Google Scholar; Sugawara et al., 2012Sugawara K. Biro T. Tsuruta D. et al.Endocannabinoids limit excessive mast cell maturation and activation in human skin.J Allergy Clin Immunol. 2012; 129: e728Abstract Full Text Full Text PDF Scopus (91) Google Scholar). Taken together, this has resurrected the concept pioneered by R Billingham, who had observed that growing (anagen) HFs allow melanocyte allotransplants to escape immune rejection, that HFs enjoy IP (Billingham and Silvers, 1971Billingham R.E. Silvers W.K. A biologist's reflections on dermatology.J Invest Dermatol. 1971; 57: 227-240Crossref PubMed Scopus (58) Google Scholar). Subsequently, it was proposed that a collapse of the physiological IP of anagen HFs is a crucial element of alopecia areata (AA) pathogenesis (Paus et al., 1993Paus R. Slominski A. Czarnetzki B.M. Is alopecia areata an autoimmune-response against melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagen hair bulb?.Yale J Biol Med. 1993; 66: 541-554PubMed Google Scholar). Today, this concept is well-supported by experimental and clinical evidence (e.g., Gilhar et al., 1998Gilhar A. Ullmann Y. Berkutzki T. et al.Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice.J Clin Invest. 1998; 101: 62-67Crossref PubMed Scopus (225) Google Scholar; Kang et al., 2010Kang H. Wu W.Y. Lo B.K. et al.Hair follicles from alopecia areata patients exhibit alterations in immune privilege-associated gene expression in advance of hair loss.J Invest Dermatol. 2010; 130: 2677-2680Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar; Yoshida et al., 2011Yoshida R. Tanaka K. Amagai M. et al.Involvement of the bulge region with decreased expression of hair follicle stem cell markers in senile female cases of alopecia areata.J Eur Acad Dermatol Venereol. 2011; 25: 1346-1350Crossref PubMed Scopus (12) Google Scholar; Bertolini et al., 2012Bertolini M. Gilhar A. Paus R. Alopecia areata as a model for T cell-dependent autoimmune diseases.Exp Dermatol. 2012; 21: 477-479Crossref PubMed Scopus (24) Google Scholar; Gilhar et al., 2012Gilhar A. Etzioni A. Paus R. Alopecia areata.N Engl J Med. 2012; 366: 1515-1525Crossref PubMed Scopus (306) Google Scholar). Namely, although the disease cannot be transferred by HF autoantibodies, the transfer of CD8+T cells alone, which recognize MHC class I–presented autoantigens, suffices to induce AA lesions in two distinct AA mouse models (Gilhar et al., 1998Gilhar A. Ullmann Y. Berkutzki T. et al.Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice.J Clin Invest. 1998; 101: 62-67Crossref PubMed Scopus (225) Google Scholar; McElwee et al., 2005McElwee K.J. Freyschmidt-Paul P. Hoffmann R. et al.Transfer of CD8(+) cells induces localized hair loss whereas CD4(+)/CD25(-) cells promote systemic alopecia areata and CD4(+)/CD25(+) cells blockade disease onset in the C3H/HeJ mouse model.J Invest Dermatol. 2005; 124: 947-957Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). Thus, current evidence favors the pathobiology concept that AA is a CD8+T cell–mediated, organ-specific autoimmune disease in which elusive (e.g., melanogenesis-associated) autoantigens are recognized, once they become exposed by ectopic MHC class I expression by an anagen HF epithelium that has lost its relative IP (Paus et al., 1993Paus R. Slominski A. Czarnetzki B.M. Is alopecia areata an autoimmune-response against melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagen hair bulb?.Yale J Biol Med. 1993; 66: 541-554PubMed Google Scholar, Paus et al., 2005Paus R. Nickoloff B.J. Ito T. A "hairy" privilege.Trends Immunol. 2005; 26: 32-40Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar; Gilhar et al., 2012Gilhar A. Etzioni A. Paus R. Alopecia areata.N Engl J Med. 2012; 366: 1515-1525Crossref PubMed Scopus (306) Google Scholar). Consequently, AA research must strive to identify the autoreactive CD8+T cells and their cognate autoantigens. Also, the most important inducers of HF-IP collapse (e.g., IFN-γ and substance P) and the constitutive "HF-IP guardians" (e.g., α-melanocyte-stimulating hormone, transforming growth factor-β2, calcitonin gene–related peptide, and vasoactive intestinal peptide) that normally prevent IP collapse have to be identified (Ito et al., 2004Ito T. Ito N. Bettermann A. et al.Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model.Am J Pathol. 2004; 164: 623-634Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar; Peters et al., 2007Peters E.M. Liotiri S. Bodo E. et al.Probing the effects of stress mediators on the human hair follicle: substance P holds central position.Am J Pathol. 2007; 171: 1872-1886Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar; Siebenhaar et al., 2007Siebenhaar F. Sharov A.A. Peters E.M. et al.Substance P as an immunomodulatory neuropeptide in a mouse model for autoimmune hair loss (alopecia areata).J Invest Dermatol. 2007; 127: 1489-1497Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar; Meyer et al., 2009Meyer K.C. Brzoska T. Abels C. et al.The alpha-melanocyte stimulating hormone-related tripeptide K(D)PT stimulates human hair follicle pigmentation in situ under proinflammatory conditions.Br J Dermatol. 2009; 160: 433-437Crossref PubMed Scopus (18) Google Scholar; Bertolini et al., 2012Bertolini M. Gilhar A. Paus R. Alopecia areata as a model for T cell-dependent autoimmune diseases.Exp Dermatol. 2012; 21: 477-479Crossref PubMed Scopus (24) Google Scholar; Kinori et al., 2012Kinori M. Bertolini M. Funk W. et al.Calcitonin gene-related peptide (CGRP) may award relative protection from interferon-gamma-induced collapse of human hair follicle immune privilege.Exp Dermatol. 2012; 21: 223-226Crossref PubMed Scopus (28) Google Scholar). Therapeutically, we need to explore how IP guardians and IP–protective drugs (e.g., FK506, α-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+T cell responses. In future AA management, HF-IP restoration may be sensibly complemented by modulating CTLA4 (cytotoxic T lymphocyte antigen 4)–mediated signaling (Petukhova et al., 2010Petukhova L. Duvic M. Hordinsky M. et al.Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010; 466: 113-117Crossref PubMed Scopus (468) Google Scholar; John et al., 2011John K.K. Brockschmidt F.F. Redler S. et al.Genetic variants in CTLA4 are strongly associated with alopecia areata.J Invest Dermatol. 2011; 131: 1169-1172Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar; Sundberg et al., 2011Sundberg J.P. McElwee K.J. Carroll J.M. et al.Hypothesis testing: CTLA4 co-stimulatory pathways critical in the pathogenesis of human and mouse alopecia areata.J Invest Dermatol. 2011; 131: 2323-2324Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar) and by restoring defective functions of regulatory CD4+/CD25+T cells. This scenario has been complicated by evidence that natural killer group 2D–positive (NKG2D+) cells (incl. NK, NKT, and some CD8+T cells) as well as NKG2D–activating ligands from the MICA (MHC I–related chain A) family may also have a key role in AA pathogenesis (Ito et al., 2008aIto T. Ito N. Saatoff M. et al.Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack.J Invest Dermatol. 2008; 128: 1196-1206Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, Ito et al., 2008bIto T. Meyer K.C. Ito N. et al.Immune privilege and the skin.Curr Dir Autoimmun. 2008; 10: 27-52Crossref PubMed Scopus (49) Google Scholar; Petukhova et al., 2010Petukhova L. Duvic M. Hordinsky M. et al.Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010; 466: 113-117Crossref PubMed Scopus (468) Google Scholar). This is supported by genotyping (Barahmani et al., 2006Barahmani N. de Andrade M. Slusser J.P. et al.Major histocompatibility complex class I chain-related gene A polymorphisms and extended haplotypes are associated with familial alopecia areata.J Invest Dermatol. 2006; 126: 74-78Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar) and genome-wide association study evidence (Petukhova et al., 2010Petukhova L. Duvic M. Hordinsky M. et al.Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010; 466: 113-117Crossref PubMed Scopus (468) Google Scholar; Jagielska et al., 2012Jagielska D. Redler S. Brockschmidt F.F. et al.Follow-up study of the first genome-wide association scan in alopecia areata: IL13 and KIAA0350 as susceptibility loci supported with genome-wide significance.J Invest Dermatol. 2012; 132: 2192-2197Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Interestingly, the injection of peripheral blood mononuclear cells from healthy individuals that were enriched for NKG2D+ or CD56+ cells and activated by IL-2 into healthy human scalp skin transplanted onto severe-combined immunodeficient mice can induce a hair loss pattern that copies the human AA phenotype (Gilhar et al., 2013Gilhar A. Keren A. Shemer A. et al.Autoimmune disease induction in a healthy human organ: a humanized mouse model of alopecia areata.J Invest Dermatol. 2013; 133: 844-847Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). This not only provides the first functional evidence for the importance of NKG2D+ cells and/or NKG2D–activating ligands in AA pathogenesis and HF-IP collapse but also suggests that a massive infiltrate of IFN-γ-secreting NKG2D+ cells alone can suffice to induce HF-IP collapse and subsequently the characteristic AA phenotype, seemingly independent of genetic susceptibility factors and a pre-existing HF-IP collapse. This intriguing new humanized mouse of AA (Gilhar et al., 2013Gilhar A. Keren A. Shemer A. et al.Autoimmune disease induction in a healthy human organ: a humanized mouse model of alopecia areata.J Invest Dermatol. 2013; 133: 844-847Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar) invites the speculation that AA is not a single disease entity, but rather a stereotypic, clinically and histologically distinct HF response pattern to various inflammatory insults associated with (e.g., IFN-γ-induced) HF-IP collapse. Such a pathogenesis concept is in line with the underappreciated heterogeneity of AA (see Ikeda, 1965Ikeda T. A new classification of alopecia areata.Dermatologica. 1965; 131: 421-445Crossref PubMed Scopus (154) Google Scholar), and integrates the fact that human HF-IP collapse can be induced by very distinct stimuli (e.g., IFN-γ (Ito et al., 2004Ito T. Ito N. Bettermann A. et al.Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model.Am J Pathol. 2004; 164: 623-634Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar), substance P (Peters et al., 2007Peters E.M. Liotiri S. Bodo E. et al.Probing the effects of stress mediators on the human hair follicle: substance P holds central position.Am J Pathol. 2007; 171: 1872-1886Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar), NKG2D/CD56–enriched, IL-2-stimulated peripheral blood mononuclear cell (Gilhar et al., 2013Gilhar A. Keren A. Shemer A. et al.Autoimmune disease induction in a healthy human organ: a humanized mouse model of alopecia areata.J Invest Dermatol. 2013; 133: 844-847Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar)) and that the innate immune system, namely mast cells, may also impact on AA pathogenesis (Bertolini et al., 2012Bertolini M. Gilhar A. Paus R. Alopecia areata as a model for T cell-dependent autoimmune diseases.Exp Dermatol. 2012; 21: 477-479Crossref PubMed Scopus (24) Google Scholar). If confirmed, this novel hypothesis of AA pathobiology has important clinical implications: autoantigen- and T cell specificity as well as selective gene targeting in future AA would then be much less important for effective AA management than suppressing this general, stereotypic HF response pattern to IP collapse–inducing inflammatory stimuli that we currently know under the name of "AA". For example, disease progression may best be halted by nonspecific, but effective "response pattern suppression", whereas disease remission and hair regrowth may mainly call for "HF-IP restoration" therapy. Funding for the Summit and publication of this article was provided by the National Alopecia Areata Foundation.
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