Endogenous Retinoids in the Pathogenesis of Alopecia Areata

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Presentation transcript:

Endogenous Retinoids in the Pathogenesis of Alopecia Areata F. Jason Duncan, Kathleen A. Silva, Charles J. Johnson, Benjamin L. King, Jin P. Szatkiewicz, Sonya P. Kamdar, David E. Ong, Joseph L. Napoli, Jinshan Wang, Lloyd E. King, David A. Whiting, Kevin J. McElwee, John P. Sundberg, Helen B. Everts Journal of Investigative Dermatology Volume 133, Issue 2, Pages 334-343 (February 2013) DOI: 10.1038/jid.2012.344 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Retinoid metabolism is altered in alopecia areata. Fold changes (FC) in (a) retinoic acid (RA) synthesis and (b) retinol degradation proteins determined by microarray analysis between C3H/HeJ mice grafted with alopecia areata skin and sham controls 5, 10, 15, and 20 weeks after surgery, or (c) between mice with spontaneous disease and unaffected mice. *P<0.05, q<0.05 all genes, **P<0.05, q<0.05 all genes except Lrat, Rara, and Cyp26b1, ***P<0.05, q<0.05 only Rbp4, Adh1, and Dgat1. (d) Diagram of retinoid metabolism with genes significantly altered highlighted. Red, FC>+3; pink, FC 0 to +3; dark green, FC<- 2; light green, FC 0 to -2. AA, alopecia areata. Journal of Investigative Dermatology 2013 133, 334-343DOI: (10.1038/jid.2012.344) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Retinoic acid synthesis enzymes and binding proteins are increased in alopecia areata. Immunohistochemistry (IHC) was performed on (a, e, i, m, q) C3H/HeJ mouse skin collected 10 weeks after grafting with sham controls, (b, f, j, n, r) alopecia areata, (c, g, k, o, s) biopsies from human patients with tinea capitis controls, (d, h, l, p, t) or alopecia areata with antibodies against (a–d) cellular retinol–binding protein (CRBP/RBP)1, (e–h) dehydrogenase reductase SDR family member 9 (DHRS9), (i–l) 2, 3, retinal dehydrogenase 1, 2, 3 (ALDH1A1), (m–p) ALDH1A3, (q–t) and cellular retinoic acid–binding protein II (CRABP2). Bar=50μm. Arrow, positive immune cells. Journal of Investigative Dermatology 2013 133, 334-343DOI: (10.1038/jid.2012.344) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Progression of alopecia areata (AA) was altered by dietary vitamin A. Mice were fed purified diets containing 0, 4, 12, or 28IU dietary vitamin A/g diet, or a control chow diet, starting 2 weeks before grafting and were killed (b, c) 5, 10, 15, or (d, e, f) 20 weeks post grafting. Ventral hair loss (a) was measured weekly, with 300 representing a full coat of hair. Data are shown as mean±SEM. Hematoxylin and eosin (H&E) slides were scored by JP Sundberg on a scale of 0–4. Data are shown as percentage of each score for (b) epidermal hyperplasia, (c) anagen, (d) lymphocytes, (e) outer root sheath hyperplasia, and (f) follicular dystrophy. n=8–11. *Significantly different from chow-fed mice, P<0.05, different letters are significantly different, P<0.05. ORS, outer root sheath. Journal of Investigative Dermatology 2013 133, 334-343DOI: (10.1038/jid.2012.344) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Granzyme B (GZMB) is significantly increased in mice with alopecia areata (AA) and altered by vitamin A. Immunohistochemistry (IHC) was performed and GZMB–positive cells enumerated in (a, b) the infundibulum, (c, d) isthmus, (e, f) suprabulbar, and (g, h) bulb. (a, c, e, g) Mann–Whitney tests were conducted to compare mice with AA lesions with mice without lesions (n=40–50). (b, d, f, h) Generalized linear model with the Poisson response function was then performed on mice that received the AA graft with hair follicles in mid-anagen through mid-catagen (n=1–10). Data are shown as mean±SE. *P<0.05 versus no lesion; different letters within a time point are significantly different, P<0.05; t5, t10, t15 significantly different from 5, 10, and 15 weeks, respectively, P<0.05. Journal of Investigative Dermatology 2013 133, 334-343DOI: (10.1038/jid.2012.344) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Alterations in protein levels of cytokines by high vitamin A during alopecia areata (AA) progression in C3H/HeJ mice. (a) Protein levels of cytokines IL13 and (b) IFNγ were determined by ELISA from dorsal lumbar skin. Data were natural log-(ln) transformed and analysis of variance performed using SPSS, v19. Data are shown as mean±SE. n=63–65 for a, and n=16–19 for b. Different letters are significantly different P<0.05. Journal of Investigative Dermatology 2013 133, 334-343DOI: (10.1038/jid.2012.344) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions