Mediation of Alopecia Areata by Cooperation Between CD4+ and CD8+ T Lymphocytes

Gilhar, Amos; Landau, Marina; Assy, Bedia; Shalaginov, Raya; Serafimovich, Siren; Kalish, Richard S.

doi:10.1001/archderm.138.7.916

Cited by 98 publications

(86 citation statements)

References 44 publications

(31 reference statements)

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“…Peptides derived from melanogenesis-associated autoantigens expressed only by melanin-producing anagen HFs are persuasive candidates as key autoantigens in AA [3]. Therefore, focusing on well-investigated MHC class I-restricted melanocyte-related antigens known to be recognized by CD8 + T cells is a sensible AA research strategy (supplementary text S1).…”

Section: Dear Editormentioning

confidence: 99%

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

Ito

Bertolini

Funakoshi

et al. 2013

Journal of Dermatological Science

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Section: Dear Editormentioning

confidence: 99%

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

Ito

Bertolini

Funakoshi

et al. 2013

Journal of Dermatological Science

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“…7,18 Under pro-inflammatory conditions, namely after IFN-␥ stimulation, many skin cell types (including keratinocytes) can become non-professional antigen presenting cells via up-regulation of MHC class II. 66,67 If this happens in an area of relative immune privilege, this must be expected to further accelerate and aggravate immune privilege collapse. 7,12,67 Therefore, it is interesting to note that control hair follicles, as expected, show MHC class-II-positive cells only on a few cells in connective tissue sheath in vitro ( Figure 4N).…”

Section: Igf-1 Also Down-regulates Ifn-␥-induced Ectopic Mhc Class IImentioning

confidence: 99%

“…66,67 If this happens in an area of relative immune privilege, this must be expected to further accelerate and aggravate immune privilege collapse. 7,12,67 Therefore, it is interesting to note that control hair follicles, as expected, show MHC class-II-positive cells only on a few cells in connective tissue sheath in vitro ( Figure 4N). Then, 75 U/ml IFN-␥, as expected, prominently induces MHC class II expression in the proximal ORS ( Figure 4O), which can be down-regulated again by 100 ng/ml IGF-1 in cultured hair follicles ( Figure 4P).…”

Section: Igf-1 Also Down-regulates Ifn-␥-induced Ectopic Mhc Class IImentioning

confidence: 99%

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

Ito

Bettermann

et al. 2004

The American Journal of Pathology

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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.

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“…3 Purified T cell injection experiments result suggested that both CD4-and CD8-positive T cells have a role in pathogenesis of alopecia areata, CD8-positive cells acting as the main effector cells with the regulatory control by CD4-positive T cells. 4 This study was undertaken to clarify whether Th1 CD4 lymphocytes or Th2 CD4 lymphocytes are dominant in the lesions of patients with alopecia areata and also to elucidate the effect of cytokine therapy applying recombinant interleukin-4 (Il4) and neutralizing anti-interferon-␥ (Ifng) antibody into the alopecia areata rodent model C3H/HeJ mice.…”

mentioning

confidence: 99%

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

Nakamura

Tabata

et al. 2008

The American Journal of Pathology

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Autoimmune alopecia (alopecia areata) is considered to be triggered by a collapse of immune privilege in hair follicles. Here we confirmed that infiltrating CD4 T lymphocytes around hair follicles of patients with alopecia areata were primarily CCR5-positive with few CCR4-positive cells, suggesting a dominant role of Th1 cells in the alopecic lesion. Given this finding, we sought to elucidate the effect of cytokine therapy in C3H/HeJ mice, a mouse model of alopecia areata, by applying recombinant interleukin-4 and neutralizing anti-interferon-␥ antibody. We found that local injections of both interleukin-4 and neutralizing anti-interferon-␥ antibody effectively treated alopecia in C3H/ HeJ mice. Results from immunohistochemistry and semiquantitative reverse transcription-polymerase chain reaction demonstrated that intralesional injection of interleukin-4 suppressed CD8 T cell infiltrates around the hair follicles and repressed enhanced interferon-␥ mRNA expression in the affected alopecic skin. Furthermore, Th1 transcription factor T-box21 small interfering RNAs conjugated to cationized gelatin showed mitigating effects on alopecia in C3H/HeJ mice, resulting in the restoration of hair shaft elongation. Taken together, the use of gelatin-small interfering RNA conjugates promises to be a novel, efficient, and safe tool as an alternative gene therapy for the treatment of various human diseases. To our knowledge, this is the first report of effective controlled delivery of small interfering RNA using biodegradable cationized gelatin microspheres in an animal model of disease.

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Mediation of Alopecia Areata by Cooperation Between CD4+ and CD8+ T Lymphocytes

Cited by 98 publications

References 44 publications

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

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

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

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

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