Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Peripheral blood gene expression in alopecia areata reveals molecular pathways distinguishing heritability, disease and severity

Genes & Immunity volume 11, pages 531–541 (2010)Cite this article

Subjects

Abstract

Alopecia areata (AA) is an autoimmune hair loss disorder in which systemic disturbances have been described, but are poorly understood. To evaluate disease mechanisms, we examined gene expression in the blood of defined clinical subgroups (patchy AA persistent type, AAP, n=5; alopecia universalis, AU, n=4) and healthy controls (unaffected relatives, UaR, n=5; unaffected non-relatives, UaNR, n=4) using microarrays. Unsupervised hierarchical clustering separates all four patient and control groups, producing three distinct expression patterns reflective of ‘inheritance’, ‘disease’ and ‘severity’ signatures. Functional classification of differentially expressed genes (DEGs) comparing disease (AAP, AU) vs normal (UaR) groups reveals upregulation in immune response, cytokine signaling, signal transduction, cell cycle, proteolysis and cell adhesion-related genes. Pathway analysis further reveals the activation of several genes related to natural killer-cell cytotoxicity, apoptosis, mitogen activated protein kinase, Wnt signaling and B- and T-cell receptor signaling in AA patients. Finally, 35 genes differentially expressed in AA blood overlap with DEGs previously identified in AA skin lesions. Our results implicate innate and adaptive immune processes while also revealing novel pathways, such as Wnt signaling and apoptosis, relevant to AA pathogenesis. Our data suggest that peripheral blood expression profiles of AA patients likely carry new biomarkers associated with disease susceptibility and expression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Safavi K . Prevalence of alopecia areata in the first national health and nutrition examination survey. Arch Dermatol 1992; 128: 702.

    Article  CAS  Google Scholar 

  2. Madani S, Shapiro J . Alopecia areata update. J Am Acad Dermatol 2000; 42: 549–566; quiz 567-70.

    Article  CAS  Google Scholar 

  3. Perret C, Wiesner-Menzel L, Happle R . Immunohistochemical analysis of T-cell subsets in the peribulbar and intrabulbar infiltrates of alopecia areata. Acta Derm Venereol 1984; 64: 26–30.

    CAS  PubMed  Google Scholar 

  4. Ranki A, Kianto U, Kanerva L, Tolvanen E, Johansson E . Immunohistochemical and electron microscopic characterization of the cellular infiltrate in alopecia (areata, totalis, and universalis). J Invest Dermatol 1984; 83: 7–11.

    Article  CAS  Google Scholar 

  5. Brocker EB, Echternacht-Happle K, Hamm H, Happle R . Abnormal expression of class I and class II major histocompatibility antigens in alopecia areata: modulation by topical immunotherapy. J Invest Dermatol 1987; 88: 564–568.

    Article  CAS  Google Scholar 

  6. Gupta AK, Ellis CN, Cooper KD, Nickoloff BJ, Ho VC, Chan LS et al. Oral cyclosporine for the treatment of alopecia areata. A clinical and immunohistochemical analysis. J Am Acad Dermatol 1990; 22 (2 Part 1): 242–250.

    Article  CAS  Google Scholar 

  7. McDonagh AJ, Snowden JA, Stierle C, Elliott K, Messenger AG . HLA and ICAM-1 expression in alopecia areata in vivo and in vitro: the role of cytokines. Br J Dermatol 1993; 129: 250–256.

    Article  CAS  Google Scholar 

  8. McElwee KJ, Tobin DJ, Bystryn JC, King Jr LE, Sundberg JP . Alopecia areata: an autoimmune disease? Exp Dermatol 1999; 8: 371–379.

    Article  CAS  Google Scholar 

  9. Alexis AF, Dudda-Subramanya R, Sinha AA . Alopecia areata: autoimmune basis of hair loss. Eur J Dermatol 2004; 14: 364–370.

    CAS  PubMed  Google Scholar 

  10. Gilhar A, Kalish RS . Alopecia areata: a tissue specific autoimmune disease of the hair follicle. Autoimmun Rev 2006; 5: 64–69.

    Article  Google Scholar 

  11. Paus R, Ito N, Takigawa M, Ito T . The hair follicle and immune privilege. J Investig Dermatol Symp Proc 2003; 8: 188–194.

    Article  Google Scholar 

  12. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P . Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (3 Suppl): 483S–512S.

    Article  CAS  Google Scholar 

  13. Martinez-Mir A, Zlotogorski A, Gordon D, Petukhova L, Mo J, Gilliam TC et al. Genomewide scan for linkage reveals evidence of several susceptibility loci for alopecia areata. Am J Hum Genet 2007; 80: 316–328.

    Article  CAS  Google Scholar 

  14. Blaumeiser B, van der Goot I, Fimmers R, Hanneken S, Ritzmann S, Seymons K et al. Familial aggregation of alopecia areata. J Am Acad Dermatol 2006; 54: 627–632.

    Article  Google Scholar 

  15. van der Steen P, Traupe H, Happle R, Boezeman J, Strater R, Hamm H . The genetic risk for alopecia areata in first degree relatives of severely affected patients. An estimate. Acta Derm Venereol 1992; 72: 373–375.

    CAS  PubMed  Google Scholar 

  16. Scerri L, Pace JL . Identical twins with identical alopecia areata. J Am Acad Dermatol 1992; 27 (5 Part 1): 766–767.

    Article  CAS  Google Scholar 

  17. Jackow C, Puffer N, Hordinsky M, Nelson J, Tarrand J, Duvic M . Alopecia areata and cytomegalovirus infection in twins: genes versus environment? J Am Acad Dermatol 1998; 38: 418–425.

    Article  CAS  Google Scholar 

  18. Hendren OS . Identical alopecia areata in identical twins. Arch Derm Syphilol 1949; 60 (5, Part. 1): 793–795.

    Article  CAS  Google Scholar 

  19. Lenane P, Pope E, Krafchik B . Congenital alopecia areata. J Am Acad Dermatol 2005; 52 (2 Suppl 1): 8–11.

    Article  Google Scholar 

  20. de Viragh PA, Gianadda B, Levy ML . Congenital alopecia areata. Dermatology 1997; 195: 96–98.

    Article  CAS  Google Scholar 

  21. Puavilai S, Puavilai G, Charuwichitratana S, Sakuntabhai A, Sriprachya-Anunt S . Prevalence of thyroid diseases in patients with alopecia areata. Int J Dermatol 1994; 33: 632–633.

    Article  CAS  Google Scholar 

  22. Shellow WV, Edwards JE, Koo JY . Profile of alopecia areata: a questionnaire analysis of patient and family. Int J Dermatol 1992; 31: 186–189.

    Article  CAS  Google Scholar 

  23. Muller SA, Winkelmann RK . Alopecia areata. An evaluation of 736 patients. Arch Dermatol 1963; 88: 290–297.

    Article  CAS  Google Scholar 

  24. Kunz M . DNA microarray technology in dermatology. Semin Cutan Med Surg 2008; 27: 16–24.

    Article  CAS  Google Scholar 

  25. Oertelt S, Selmi C, Invernizzi P, Podda M, Gershwin ME . Genes and goals: an approach to microarray analysis in autoimmunity. Autoimmun Rev 2005; 4: 414–422.

    Article  CAS  Google Scholar 

  26. Orban T, Kis J, Szereday L, Engelmann P, Farkas K, Jalahej H et al. Reduced CD4+ T-cell-specific gene expression in human type 1 diabetes mellitus. J Autoimmun 2007; 28: 177–187.

    Article  CAS  Google Scholar 

  27. Fossey SC, Vnencak-Jones CL, Olsen NJ, Sriram S, Garrison G, Deng X et al. Identification of molecular biomarkers for multiple sclerosis. J Mol Diagn 2007; 9: 197–204.

    Article  CAS  Google Scholar 

  28. Dudda-Subramanya R, Coda AB, Sinha AA . Transcriptional profiling in alopecia areata defines immune and cell cycle control related genes within disease specific signatures. Genomics (in press).

  29. Carroll JM, McElwee KJ, L EK, Byrne MC, Sundberg JP . Gene array profiling and immunomodulation studies define a cell-mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans. J Invest Dermatol 2002; 119: 392–402.

    Article  CAS  Google Scholar 

  30. Muller-Rover S, Rossiter H, Lindner G, Peters EM, Kupper TS, Paus R . Hair follicle apoptosis and Bcl-2. J Investig Dermatol Symp Proc 1999; 4: 272–277.

    Article  CAS  Google Scholar 

  31. Deng YJ, Huang ZX, Zhou CJ, Wang JW, You Y, Song ZQ et al. Gene profiling involved in immature CD4+ T lymphocyte responsible for systemic lupus erythematosus. Mol Immunol 2006; 43: 1497–1507.

    Article  CAS  Google Scholar 

  32. Ishihara K, Hirano T . IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 2002; 13: 357–368.

    Article  CAS  Google Scholar 

  33. Benson M, Carlsson L, Guillot G, Jernas M, Langston MA, Rudemo M et al. A network-based analysis of allergen-challenged CD4+ T cells from patients with allergic rhinitis. Genes Immun 2006; 7: 514–521.

    Article  CAS  Google Scholar 

  34. Imai R, Takamori K, Ogawa H . Changes in populations of HLA-DR+CD3+ cells and CD57−CD16+ cells in alopecia areata after corticosteroid therapy. Dermatology 1994; 188: 103–107.

    Article  CAS  Google Scholar 

  35. Imai R, Miura J, Numata K, Takamori K . Increase in natural killer cells in the peripheral blood lymphocytes in patients with alopecia areata]. Nippon Hifuka Gakkai Zasshi 1988; 98: 1505–1507.

    CAS  PubMed  Google Scholar 

  36. Ito T, Ito N, Saatoff M, Hashizume H, Fukamizu H, Nickoloff BJ et al. Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack. J Invest Dermatol 2008; 128: 1196–1206.

    Article  CAS  Google Scholar 

  37. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P . Antithrombotic and thrombolytic therapy for ischemic stroke: american college of chest physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008; 133 (6 Suppl): 630S–669S.

    Article  CAS  Google Scholar 

  38. Polakowska RR, Haake AR . Apoptosis: the skin from a new perspective. Cell Death Differ 1994; 1: 19–31.

    CAS  PubMed  Google Scholar 

  39. Stenn KS, Paus R . Controls of hair follicle cycling. Physiol Rev 2001; 81: 449–494.

    Article  CAS  Google Scholar 

  40. Cantrell DA . GTPases and T cell activation. Immunol Rev 2003; 192: 122–130.

    Article  CAS  Google Scholar 

  41. Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W . beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 2001; 105: 533–545.

    Article  CAS  Google Scholar 

  42. Van Mater D, Kolligs FT, Dlugosz AA, Fearon ER . Transient activation of beta -catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice. Genes Dev 2003; 17: 1219–1224.

    Article  CAS  Google Scholar 

  43. Meyer KC, Klatte JE, Dinh HV, Harries MJ, Reithmayer K, Meyer W et al. Evidence that the bulge region is a site of relative immune privilege in human hair follicles. Br J Dermatol 2008; 159: 1077–1085.

    CAS  PubMed  Google Scholar 

  44. de Andrade M, Jackow CM, Dahm N, Hordinsky M, Reveille JD, Duvic M . Alopecia areata in families: association with the HLA locus. J Investig Dermatol Symp Proc 1999; 4: 220–223.

    Article  CAS  Google Scholar 

  45. Rincon M, Flavell RA, Davis RA . The JNK and P38 MAP kinase signaling pathways in T cell-mediated immune responses. Free Radic Biol Med 2000; 28: 1328–1337.

    Article  CAS  Google Scholar 

  46. Yu H, Leitenberg D, Li B, Flavell RA . Deficiency of small GTPase Rac2 affects T cell activation. J Exp Med 2001; 194: 915–926.

    Article  CAS  Google Scholar 

  47. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R . beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 1997; 16: 3797–3804.

    Article  CAS  Google Scholar 

  48. Reddy S, Andl T, Bagasra A, Lu MM, Epstein DJ, Morrisey EE et al. Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis. Mech Dev 2001; 107: 69–82.

    Article  CAS  Google Scholar 

  49. Plikus MV, Mayer JA, de la Cruz D, Baker RE, Maini PK, Maxson R et al. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature 2008; 451: 340–344.

    Article  CAS  Google Scholar 

  50. Wang LC, Liu ZY, Gambardella L, Delacour A, Shapiro R, Yang J et al. Regular articles: conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration. J Invest Dermatol 2000; 114: 901–908.

    Article  CAS  Google Scholar 

  51. Yamago G, Takata Y, Furuta I, Urase K, Momoi T, Huh N . Suppression of hair follicle development inhibits induction of sonic hedgehog, patched, and patched-2 in hair germs in mice. Arch Dermatol Res 2001; 293: 435–441.

    Article  CAS  Google Scholar 

  52. Chiang C, Swan RZ, Grachtchouk M, Bolinger M, Litingtung Y, Robertson EK et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev Biol 1999; 205: 1–9.

    Article  CAS  Google Scholar 

  53. Fathke C, Wilson L, Shah K, Kim B, Hocking A, Moon R et al. Wnt signaling induces epithelial differentiation during cutaneous wound healing. BMC Cell Biol 2006; 7: 4.

    Article  Google Scholar 

  54. Holers VM, Boackle SA . Complement receptor 2 and autoimmunity. Curr Dir Autoimmun 2004; 7: 33–48.

    Article  CAS  Google Scholar 

  55. Boackle SA, Holers VM . Role of complement in the development of autoimmunity. Curr Dir Autoimmun 2003; 6: 154–168.

    Article  Google Scholar 

  56. Radny P, Bauer J, Caroli UM, Eigentler TK, Kamin A, Metzler G et al. Alopecia areata induced by adjuvant treatment with alpha-interferon in malignant melanoma? Dermatology 2004; 209: 249–250.

    Article  CAS  Google Scholar 

  57. Kernland KH, Hunziker T . Alopecia areata induced by interferon alpha? Dermatology 1999; 198: 418–419.

    CAS  PubMed  Google Scholar 

  58. Kartal ED, Alpat SN, Ozgunes I, Usluer G . Reversible alopecia universalis secondary to PEG-interferon alpha-2b and ribavirin combination therapy in a patient with chronic hepatitis C virus infection. Eur J Gastroenterol Hepatol 2007; 19: 817–820.

    Article  Google Scholar 

  59. Chakrabarti D, Hultgren B, Stewart TA . IFN-alpha induces autoimmune T cells through the induction of intracellular adhesion molecule-1 and B7.2. J Immunol 1996; 157: 522–528.

    CAS  PubMed  Google Scholar 

  60. Price VH, Willey A, Chen BK . Topical tacrolimus in alopecia areata. J Am Acad Dermatol 2005; 52: 138–139.

    Article  Google Scholar 

  61. Feldmann KA, Kunte C, Wollenberg A, Wolfe H . Is topical tacrolimus effective in alopecia areata universalis? Br J Dermatol 2002; 147: 1031–1032.

    Article  CAS  Google Scholar 

  62. Thiers BH . Topical tacrolimus: treatment failure in a patient with alopecia areata. Arch Dermatol 2000; 136: 124.

    Article  CAS  Google Scholar 

  63. Park SW, Kim JW, Wang HY . Topical tacrolimus (FK506): treatment failure in four cases of alopecia universalis. Acta Derm Venereol 2002; 82: 387–388.

    Article  Google Scholar 

  64. Duvic M, Norris D, Christiano A, Hordinsky M, Price V . Alopecia areata registry: an overview. J Investig Dermatol Symp Proc 2003; 8: 219–221.

    Article  Google Scholar 

  65. Olsen E, Hordinsky M, McDonald-Hull S, Price V, Roberts J, Shapiro J et al. Alopecia areata investigational assessment guidelines. National alopecia areata foundation. J Am Acad Dermatol 1999; 40 (2 Part 1): 242–246.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful for resources provided by The Research Technology Support Facility (RTSF) at Michigan State University and the Genomics Core. We also thank Jason R Smith for his technical assistance. We are grateful to the National Alopecia Areata Foundation for their help in patient recruitment. Finally, we thank the study participants without whom this study would not be possible.

Author information

Authors and Affiliations

  1. Division of Dermatology and Cutaneous Sciences, Center for Investigative Dermatology, College of Human Medicine, East Lansing, MI, USA

    A B Coda, V Qafalijaj Hysa, K Seiffert-Sinha & A A Sinha

Authors
  1. A B Coda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V Qafalijaj Hysa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Seiffert-Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A A Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A A Sinha.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coda, A., Qafalijaj Hysa, V., Seiffert-Sinha, K. et al. Peripheral blood gene expression in alopecia areata reveals molecular pathways distinguishing heritability, disease and severity. Genes Immun 11, 531–541 (2010). https://doi.org/10.1038/gene.2010.32

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2010.32

Keywords

This article is cited by

Search

Advanced search

Quick links