The August issue of JDD and this October issue are
both dedicated to psoriasis, a cutaneous disorder teaching us the human immune system and the molecular biology of the epidermis.
Steve Feldman wrote the August editorial pointing out how vitamin D is under utilized in the treatment of psoriasis especially
in conjunction with high potency steroids. Keratinocyte hyper proliferation, aberrant keratinocyte differentiation,
angiogenisis, inflammation, and infiltrating immune cells are hallmarks of psoriasis. While the precise mechanism underlying
the therapeutic effect of vitamin D analogs in psoriasis is not completely understood, vitamin D is known to have a
normalizing effect on skin cells, promoting keratinocyte differentiation and inhibiting hyper proliferation, reestablishing
epidermal barrier function. In addition, vitamin D has an immunomodulatory effect, inhibiting activation of T cells and
inducing the generation of CD25/CD4 positive regulatory T cells, inhibiting IFNγ, IL-8, IL-17, and IL-22 expression, and
stimulating IL-4, IL-5, IL-10, and IL-13. Several large clinical trials have demonstrated improved efficacy and safety of the
combination of vitamin D and corticosteroid over mono treatments and there is a clear scientific rationale for synergy
combining the two very complementary therapies.1,2 Feldman also identified two new oral agents that affect the T cell and
while not yet FDA approved for psoriasis both Apremalist and Xeljanz are showing promise. Vitamin D is in the class of
nuclear receptors that include RORgT known to be critical for the induction of the TH17 class of lymphocytes identified in
the immunopathogenesis of psoriasis,3 leprosy,4 and another T-cell disorder similar to multiple sclerosis, EAE.5 Th17 was
reduced in the central nervous system of EAE with the single dose of calcitriol/Vitamin D in addition to the increase in
Helios/FoxP3/Tregs.5 The Th17 lymphocytes represent an unstable phenotype that is in Ying/Yang with Tregs and the FoxP3
nuclear receptor.6 In the leprosy model, Liu et al.7 have found that microRNA-21 down regulates IFNγ induced IL12a, which
allows M. leprae to escape TLR 1 and 2 induced anti-microbial peptides.7 MicroRNA-21 is high in most cancers and in
psoriasis and low in the tuberculoid form of leprosy associated with an epidermal proliferation similar to psoriasis.8 Tregs
in psoriasis show a reduced number, function, and migration.9 This functional analysis of Tregs in psoriasis coupled with
advances in our understanding of microRNA regulation of Treg plasticity10 and microRNA profiling of psoriasis where both
microRNA-31 that down regulate FoxP3 and microRNA-21 that up regulate FoxP3 are abundant.11 The leprosy and psoriasis models
favor the hypothesis of complete plasticity of Tregs. Tregs are capable of differentiating into any class of lymphocyte
including Th1, Th2, Th17, Th22, Th9 and still undiscovered T cell subsets, although this model is controversial and needs
further study.12 In a future issue, we plan to further explore the epigenetics of Th1 psoriasis and microRNA regulation of
T-cell subsets in skin diseases including leprosy and Th2 atopic dermatitis.
William R. Levis MD and Frank Martiniuk PhD
Department of Dermatology, New York University School of Medicine, New York, NY
The authors have no conflicts to disclose.
- Segaert S, Røpke M. The biological rationale for use of vitamin D analogs in combination with corticosteroids for the topical treatment of plaque psoriasis. J Drugs Derm 2013;12: E129-E137.
- Silver S, Tuppal R, Gupta AK, Clonier F, Olesen M, Leeder R, Taraska V. Effect of calcipotriene plus betamethasone dipropionate topical suspension on the hypothalamic-pituitary-adrenal axis and calcium homeostasis in subjects with extensive psoriasis vulgaris: An open, non-controlled, 8-week trial. J Drugs Derm 2013;12:882-887.
- Chiricozzi A, Krueger JG. IL-17 targeted therapies for psoriasis. Expert Opin Investig Drugs 2013;22:993-1005.
- Martiniuk F, Giovinazzo J, Tan AU, Shahidullah R, Haslett P, Kaplan G and Levis WR. Lessons of leprosy: The emergence of TH17 cytokines during type II reactions (ENL) is teaching us about T-cell plasticity. J Drugs Derm 11:507-511, 2012.
- Nashold FE, Nelson CD, Brown LM, Hayes CE. One calcitriol dose transiently increases Helios+FoxP3+ T cells and ameliorates autoimmune demyelinating disease. J Neuroimmunol2013: S0165-5728(13)00205-1. [Epub ahead of print].
- O'Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol 2011;11:239-50.
- Liu PT, Wheelwright M, Teles R, Komisopoulou E, Edfeldt K, Ferguson B, Mehta MD, Vazirnia A, Rea TH, Sarno EN, Graeber TG, Modlin RL. MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy. Nat Med 2012;18:267-73.
- Fischer MK, Myer KA, Que SKS, Harris JA, Martiniuk FT, Meehan SA and Levis WR. Pseudoepitheliomatous hyperplasia and transepidermal elimination in lepromatous leprosy: Does T-cell Plasticity Play a Role? J Drugs Derm 11:1232-5, 2012.
- Soler DC, Sugiyama H, Young AB, Massari JV, McCormick TS, Cooper KD. Psoriasis patients exhibit impairment of the high potency CCR5+ T regulatory cell subset. Clin Immunol 2013;149:111-118.
- Baumjohann D, Ansel KM. MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol 2013;13:666-78.
- Xu N, Meisgen F, Butler LM, Han G, Wang XJ, Söderberg-Nauclér C, Ståhle M, Pivarcsi A, Sonkoly E. MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40. J Immunol 2013;190:678-88.
- Pierson W, Cauwe B, Policheni A, Schlenner SM, Franckaert D, Berges J, Humblet-Baron S, Schönefeldt S, Herold MJ, Hildeman D, Strasser A, Bouillet P, Lu LF, Matthys P, Freitas AA, Luther RJ, Weaver CT, Dooley J, Gray DH, Liston A. Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3(+) regulatory T cells. Nat Immunol 2013;14:959-65.