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Alopecia Areata: Autoimmune Disease or Hair Follicle Response Pattern to Immunological Damage?

Discussion of the immune privilege collapse model of alopecia areata pathogenesis, available evidence to support this hypothetical scenario, and promising avenues for future investigation.

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Alopecia Areata: Autoimmune Disease or Hair Follicle Response Pattern to Immunological Damage?

  1. 1. Alopecia areata: Autoimmune Disease or Hair Follicle Response Pattern to Immunological Damage ? Ralf Paus University of Miami Miller School of Medicine, Miami , FL & University of Manchester, Manchester, UK & Monasterium Laboratory, Münster, Germany Conflicts of interest: „Plenty“… Relevant: None
  2. 2. Paus et al. Yale J Biol Med 1993 AA is an autoimmune-response against melanogenesis-related autoantigens, exposed by abnormal MHC class I expression in an anagen hair bulb with collapsed hair follicle immune privilige (IP) Experimental confirmation: McElwee et al. Br J Dermatol 1996 (rat) Gilhar et al. J Clin Invest 1998 (human)
  3. 3. Gilhar / Etzioni /Paus N Engl J Med 2012 AA: IFNg collapse of bulb immune privilege  premature catagen, HF dystrophy, hair shaft shedding Bulb immune privilege AA portrayed as autoimmune disease
  4. 4. But… • How (auto-)antigen-specific is AA really? • Do we always face a CD8+ T cell- dependent autoimmune disease when we see an AA hair loss phenotype ? • Is a certain genetic predisposition required to develop AA ?
  5. 5. • How (auto-)antigen-specific is AA really? Can be triggered non-antigen-specifically • Is AA always CD8+ T cell-dependent ? No • Is a genetic predisposition required to develop AA lesions ? No 2 main lines of evidence 
  6. 6. NKG2D+ cells can induce AA in healthy human skin in vivo Gilhar/Paus,: J Invest Dermatol 2013a, 2013b, J Dermatol Sci 2014  Specific autoantigen & genetic predisposition DISPENSABLE for developing AA ? Perifollicular„IFNg storm“ NKG2D+ CD56+ NK cells involved in AA Ito et al. JID 2008 Petukhova et al Nature 2010
  7. 7. N=15-21 HFs/group from 6-7 AA patients or healthy donors. Vd1+T-cells infiltrate in /around AA hair bulbs A HS = healthy skin NL = non-lesional AA skin AA = lesional AA skin … also seen in experimentally induced AA in human skin xenotransplants in vivo (Gilhar‘s humanized AA mouse model) Youhei Uchida et al In prep. + increased NKG2D & IFNg expression !
  8. 8. Uchida et al., in prep. • Physiologically, dermal Vd1 T cells scout for stressed HFs • This becomes pathogenic when Vd1 T cells induce IP collapse & promote the AA response pattern AA response pattern Non-antigen- specific !
  9. 9. Paus in: McElwee et al., Exp Dermatol 2013 WCHR, Miami, Nov 2015 NAAF Summit 2016 Paus et al. JID Symp Proc 2018 • Several different pathobiology pathways lead to AA, • which all coalesce in a stereotypic HF damage response pattern, which creates the clinical AA phenotype. • This AA response pattern also occurs in healthy HFs
  10. 10. • AA is not a single disease entity, but just a stereotypic response pattern to inflammatory HF damage • that even the healtiest of HFs will show, • irrespective of genetic predisposition (but more easily so, if genetically predisposed, e.g. by contstitutively weak HF IP) if and only if • HF IP collapse coincides with anagen and attracts an inflammatory cell infiltrate (not necessarily only CD8+ T cells [Paus et al. Yale J Biol Med 1993] but also NK cells [Ito et al. JID 2008], gdTCs [Uchida et al., under prep.]) • that secretes so much IFNg that major HF dystrophy & premature catagen are induced
  11. 11. Gilhar / Etzioni /Paus N Engl J Med 2012 Bulb IP intact Bulb IP collapse
  12. 12. Bulb immune privilege Bulb IP continuously threatened: 1. HF „tissue stress“ e.g. trauma, hypoxia, excessive ROS production, metabolic st  Excessive MICA expr & chemokine release  Activates NK & gdTCs  IFNg release  further IP collapse 2. Psychoemotional stress  Perifollicular neurogenic inflammation SP, mast cells, NGF, CRH  SP induces IP collapse ! 3. HF dysbiosis  Excessive chemokine release  Attracts IFNg-secreting infiltrate (CD8+, gdTCs !) 4. Ectopic expression of HF autoantigens e.g. melanogenesis- & hair shaft-associated  Stimulation of pre-existing autoreactive CD8+TCs 5. Loss of peripheral tolerance / weak HF IP e.g. insufficient Treg activity & HF IP guardian production
  13. 13. Bulb IP intact Bulb IP collapse • Acquired & inherited interindividual differences in IP robustness, e.g. Constitutive levels of MHC I, HF guardian & VIP-R expression,; levels of Treg activity; atopy (proinflamm. MCs, eos), AIRE defective accelerate or slow down IP collapse 1. HF „tissue stress“ 2. Psychoemotional stress 3. HF dysbiosis 4. Ectopic HF autoantigen expression 5. Loss of peripheral tolerance
  14. 14. Alopecia areata is not one disease  Ikeda 1965 and some forms of AA may not even be a „disease“ at all ! Paus et al. JID Symp Proc 2018 NEW CONCEPT
  15. 15. Alopecia areata is a stereotypic response pattern that every healthy anagen HF will show whenever IFN-g-driven immunological damage triggers: 1 immune privilege (IP) collapse 2 HF damage (dystrophy) 3 premature catagen Paus et al. JID Symp Proc 2018
  16. 16. Only in some patients, this response pattern occurs because they have autoreactive, IFNg-secreting T cells that recognize an anagen HF-associated autoantigen = „AA disease“ Autoimmune alopecia areata (AAA ) Frequently relapsing episodes: AAA ? In these patients, causal & curative therapy only possible if autoantigen identified, peripheral tolerance restored and/or autoreactive T cells eliminated AA is not one disease, but a stereotypic HF response pattern HYPOTHESIS
  17. 17. In other AA patients, antigen-specific HF autoimmunity may be missing e.g. A: „IFNg storm“ : massive IFNg release by NK and/or gd T cells  AA after trauma/stress, infection, HF dysbiosis ?? B: stress-induced, substance P-dependent neurogenic inflammation Symptomatic therapy suffices here ! „You are treating a mere HF response pattern, not a disease“ AA is not one disease but a stereotypic HF response pattern HYPOTHESIS
  18. 18. • Both AA forms display the „ AA trio“: IP collapse, HF dystophy, premature catagen  Targeting the AA trio therapeutically always makes sense no matter how the AA response pattern was triggered!  restore IP  suppress catagen, restart anagen  repair HF damage We must get much more effective in this ! What else, besides JAK inhibitors…? Re-explore immune privilege guardians e.g. FK506, apremilast (PDE4 inh.), aprepitant (SP antag.), melanotan (aMSH)
  19. 19. Take home messages  CLINICALLY IMPORTANT HYPOTHESES • AA = „a stereotypic HF response pattern “ to IFNg-driven immunological HF damage, not necessarily a disease • Distinguish antigen-specific autoimmune AA (AAA) from non-antigen-specific AA  causal therapy only needed, possible & useful for AAA  symptomatic therapy suffices for all other AA variants • Personalized medicine approach to AA management needed ! • However: Protection from IP collapse & HF dystrophy works & is useful in all AA forms
  • MonaEltiar

    May. 24, 2020

Discussion of the immune privilege collapse model of alopecia areata pathogenesis, available evidence to support this hypothetical scenario, and promising avenues for future investigation.

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