Alopecia areata

Animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies

Amos Gilhar, Adam G. Schrum, Amos Etzioni, Herman Waldmann, Ralf Paus

Research output: Contribution to journalReview article

27 Citations (Scopus)

Abstract

One of the most common human autoimmune diseases, alopecia areata (AA), is characterized by sudden, often persisting and psychologically devastating hair loss. Animal models have helped greatly to elucidate critical cellular and molecular immune pathways in AA. The two most prominent ones are inbred C3H/HeJ mice which develop an AA-like hair phenotype spontaneously or after experimental induction, and healthy human scalp skin xenotransplanted onto SCID mice, in which a phenocopy of human AA is induced by injecting IL-2-stimulated PBMCs enriched for CD56. +/NKG2D. + cells intradermally. The current review critically examines the pros and cons of the available AA animal models and how they have shaped our understanding of AA pathobiology, and the development of new therapeutic strategies.AA is thought to arise when the hair follicle's (HF) natural immune privilege (IP) collapses, inducing ectopic MHC class I expression in the HF epithelium and autoantigen presentation to autoreactive CD8. + T cells. In common with other autoimmune diseases, upregulation of IFN-γ and IL-15 is critically implicated in AA pathogenesis, as are NKG2D and its ligands, MICA, and ULBP3.The C3H/HeJ mouse model was used to identify key immune cell and molecular principles in murine AA, and proof-of-principle that Janus kinase (JAK) inhibitors are suitable agents for AA management in vivo, since both IFN-γ and IL-15 signal via the JAK pathway. Instead, the humanized mouse model of AA has been used to demonstrate the previously hypothesized key role of CD8. + T cells and NKG2D. + cells in AA pathogenesis and to discover human-specific pharmacologic targets like the potassium channel Kv1.3, and to show that the PDE4 inhibitor, apremilast, inhibits AA development in human skin. As such, AA provides a model disease, in which to contemplate general challenges, opportunities, and limitations one faces when selecting appropriate animal models in preclinical research for human autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)726-735
Number of pages10
JournalAutoimmunity Reviews
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

Fingerprint

Alopecia Areata
Animal Models
Autoimmune Diseases
Janus Kinases
Interleukin-15
Hair Follicle
Inbred C3H Mouse
Kv1.3 Potassium Channel
Phosphodiesterase 4 Inhibitors
T-Lymphocytes
Skin
SCID Mice
Alopecia
Human Development
Scalp
Hair

Keywords

  • Alopecia areata
  • Alopecia areata humanized mouse model
  • Autoimmunity
  • C3H
  • Hair follicle
  • HeJ mouse model
  • Immune privilege
  • Jak3
  • Janus kinase(JAK)-1
  • NKG2D
  • T lymphocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Alopecia areata : Animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies. / Gilhar, Amos; Schrum, Adam G.; Etzioni, Amos; Waldmann, Herman; Paus, Ralf.

In: Autoimmunity Reviews, Vol. 15, No. 7, 01.07.2016, p. 726-735.

Research output: Contribution to journalReview article

Gilhar, Amos ; Schrum, Adam G. ; Etzioni, Amos ; Waldmann, Herman ; Paus, Ralf. / Alopecia areata : Animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies. In: Autoimmunity Reviews. 2016 ; Vol. 15, No. 7. pp. 726-735.
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abstract = "One of the most common human autoimmune diseases, alopecia areata (AA), is characterized by sudden, often persisting and psychologically devastating hair loss. Animal models have helped greatly to elucidate critical cellular and molecular immune pathways in AA. The two most prominent ones are inbred C3H/HeJ mice which develop an AA-like hair phenotype spontaneously or after experimental induction, and healthy human scalp skin xenotransplanted onto SCID mice, in which a phenocopy of human AA is induced by injecting IL-2-stimulated PBMCs enriched for CD56. +/NKG2D. + cells intradermally. The current review critically examines the pros and cons of the available AA animal models and how they have shaped our understanding of AA pathobiology, and the development of new therapeutic strategies.AA is thought to arise when the hair follicle's (HF) natural immune privilege (IP) collapses, inducing ectopic MHC class I expression in the HF epithelium and autoantigen presentation to autoreactive CD8. + T cells. In common with other autoimmune diseases, upregulation of IFN-γ and IL-15 is critically implicated in AA pathogenesis, as are NKG2D and its ligands, MICA, and ULBP3.The C3H/HeJ mouse model was used to identify key immune cell and molecular principles in murine AA, and proof-of-principle that Janus kinase (JAK) inhibitors are suitable agents for AA management in vivo, since both IFN-γ and IL-15 signal via the JAK pathway. Instead, the humanized mouse model of AA has been used to demonstrate the previously hypothesized key role of CD8. + T cells and NKG2D. + cells in AA pathogenesis and to discover human-specific pharmacologic targets like the potassium channel Kv1.3, and to show that the PDE4 inhibitor, apremilast, inhibits AA development in human skin. As such, AA provides a model disease, in which to contemplate general challenges, opportunities, and limitations one faces when selecting appropriate animal models in preclinical research for human autoimmune diseases.",
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