Skip to main content
SpringerLink
Log in

Evaluation of the Relationship between Alopecia Areata and Viral Antigen Exposure

  • short communication
  • Published:
American Journal of Clinical Dermatology Aims and scope Submit manuscript

Abstract

Background

Alopecia areata (AA) is an autoimmune disease characterized by non-scarring alopecia with T-cell infiltration at the affected hair follicle.

Objective

Our aim was to study the potential link between hepatitis B virus (HBV) antigen exposure and AA.

Methods

Two pediatric patients with AA following hepatitis B vaccination were identified in a general dermatology clinic. A bioinformatics analysis and an electronic medical record (EMR) database query were performed at the University of Rochester Medical Center to identify patients with AA, coexisting viral infections, vaccinations, or interferon (IFN) therapy in order to determine if the presence of AA and these conditions was higher than in AA patients without these associated conditions or therapy.

Results

An increased frequency of AA among those who received the HBV surface protein antigen [odds ratio (OR) 2.7, p < 0.0001] was identified, and an independent analysis revealed an increased frequency of AA in those receiving IFN-β treatment (OR 8.1, p < 0.05). One potential antigenic target identified was SLC45A2, a melanosomal transport protein important in skin and hair pigmentation. The longest potential vaccine peptide fragment match (8-mer) was to a segment of natural killer (NK) cell inhibitory receptors, KIR3DL2 and KIR3DL1. Predictive modeling of major histocompatibility complex (MHC)-peptide binding demonstrated potential binding of this peptide to MHC relevant to AA.

Limitations

The results will need to be verified in additional patient databases allowing analysis of temporal relationships, and with molecular experiments of the identified antigens.

Conclusions

Our data confirm associations between viral infection and IFN treatment with AA. It establishes that the hepatitis B surface protein antigen has shared epitopes with human killer immunoglobulin-like receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Gilhar A, Etzioni A, Paus R. Alopecia areata. N Engl J Med. 2012;366(16):1515–25.

    Article  CAS  PubMed  Google Scholar 

  2. Paus R, Nickoloff BJ, Ito T. A ‘hairy’ privilege. Trends Immunol. 2005;26(1):32–40.

    Article  CAS  PubMed  Google Scholar 

  3. Becker JC, Varki N, Brocker EB, Reisfeld RA. Lymphocyte-mediated alopecia in C57BL/6 mice following successful immunotherapy for melanoma. J Invest Dermatol. 1996;107(4):627–32.

    Article  CAS  PubMed  Google Scholar 

  4. Paus R, Slominski A, Czarnetzki BM. Is alopecia areata an autoimmune-response against melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagen hair bulb? Yale J Biol Med. 1993;66(6):541–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Gilhar A, Landau M, Assy B, Shalaginov R, Serafimovich S, Kalish RS. Melanocyte-associated T cell epitopes can function as autoantigens for transfer of alopecia areata to human scalp explants on Prkdc(scid) mice. J Invest Dermatol. 2001;117(6):1357–62.

    Article  CAS  PubMed  Google Scholar 

  6. Betz RC, Petukhova L, Ripke S, Huang H, Menelaou A, Redler S, et al. Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci. Nat Commun. 2015;6:5966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dudda-Subramanya R, Alexis AF, Siu K, Sinha AA. Alopecia areata: genetic complexity underlies clinical heterogeneity. Eur J Dermatol. 2007;17(5):367–74.

    CAS  PubMed  Google Scholar 

  8. Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol. 2012;42(1):102–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Freyschmidt-Paul P, McElwee KJ, Hoffmann R, Sundberg JP, Vitacolonna M, Kissling S, et al. Interferon-gamma-deficient mice are resistant to the development of alopecia areata. Br J Dermatol. 2006;155(3):515–21.

    Article  CAS  PubMed  Google Scholar 

  10. Gilhar A, Kam Y, Assy B, Kalish RS. Alopecia areata induced in C3H/HeJ mice by interferon-gamma: evidence for loss of immune privilege. J Invest Dermatol. 2005;124(1):288–9.

    Article  PubMed  Google Scholar 

  11. Jabbari A, Nguyen N, Cerise JE, Ulerio G, de Jong A, Clynes R, et al. Treatment of an alopecia areata patient with tofacitinib results in regrowth of hair and changes in serum and skin biomarkers. Exp Dermatol. 2016;25(8):642–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Suarez-Farinas M, Ungar B, Noda S, Shroff A, Mansouri Y, Fuentes-Duculan J, et al. Alopecia areata profiling shows TH1, TH2, and IL-23 cytokine activation without parallel TH17/TH22 skewing. J Allergy Clin Immunol. 2015;136(5):1277–87.

    Article  CAS  PubMed  Google Scholar 

  13. Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20(9):1043–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Agesta N, Zabala R, Diaz-Perez JL. Alopecia areata during interferon alpha-2b/ribavirin therapy. Dermatology. 2002;205(3):300–1.

    Article  CAS  PubMed  Google Scholar 

  15. 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(9):817–20.

    Article  PubMed  Google Scholar 

  16. Musch E, Andus T, Malek M. Induction and maintenance of clinical remission by interferon-beta in patients with steroid-refractory active ulcerative colitis-an open long-term pilot trial. Aliment Pharmacol Ther. 2002;16(7):1233–9.

    Article  CAS  PubMed  Google Scholar 

  17. 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(3):249–50.

    Article  CAS  PubMed  Google Scholar 

  18. Ghoreishi M, Martinka M, Dutz JP. Type 1 interferon signature in the scalp lesions of alopecia areata. Br J Dermatol. 2010;163(1):57–62.

    CAS  PubMed  Google Scholar 

  19. Craiglow BG, King BA. Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. J Invest Dermatol. 2014;134(12):2988–90.

    Article  CAS  PubMed  Google Scholar 

  20. Harris JE, Rashighi M, Nguyen N, Jabbari A, Ulerio G, Clynes R, et al. Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA). J Am Acad Dermatol. 2016;74(2):370–1.

    Article  PubMed  Google Scholar 

  21. Jabbari A, Dai Z, Xing L, Cerise JE, Ramot Y, Berkun Y, et al. Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib. EBioMedicine. 2015;2(4):351–5.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Pieri L, Guglielmelli P, Vannucchi AM. Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia. Am J Hematol. 2015;90(1):82–3.

    Article  PubMed  Google Scholar 

  23. Maticic M, Poljak M, Lunder T, Rener-Sitar K, Stojanovic L. Lichen planus and other cutaneous manifestations in chronic hepatitis C: pre- and post-interferon-based treatment prevalence vary in a cohort of patients from low hepatitis C virus endemic area. J Eur Acad Dermatol Venereol. 2008;22(7):779–88.

    Article  CAS  PubMed  Google Scholar 

  24. Podanyi B, Lengyel G, Harsing J, Becker K, Horvath A. Skin diseases associated with chronic hepatitis C [in Hungarian]. Orvosi Hetilap. 1998;139(44):2633–7.

    CAS  PubMed  Google Scholar 

  25. Rodriguez TA, Duvic M. National Alopecia Areata Registry. Onset of alopecia areata after Epstein-Barr virus infectious mononucleosis. J Am Acad Dermatol. 2008;59(1):137–9.

    Article  PubMed  Google Scholar 

  26. Skinner RB Jr, Light WH, Bale GF, Rosenberg EW, Leonardi C. Alopecia areata and presence of cytomegalovirus DNA. JAMA. 1995;273(18):1419–20.

    Article  PubMed  Google Scholar 

  27. Jadali Z, Mansouri P, Jadali F. These is no relationship between hepatitis C virus and alopecia areata. Eur J Dermatol. 2006;16(1):94–5.

    CAS  PubMed  Google Scholar 

  28. Offidani A, Amerio P, Bernardini ML, Feliciani C, Bossi G. Role of cytomegalovirus replication in alopecia areata pathogenesis. J Cutan Med Surg. 2000;4(2):63–5.

    Article  CAS  PubMed  Google Scholar 

  29. Wise RP, Kiminyo KP, Salive ME. Hair loss after routine immunizations. JAMA. 1997;278(14):1176–8.

    Article  CAS  PubMed  Google Scholar 

  30. 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(3):220–3.

    Article  PubMed  Google Scholar 

  31. Frentz G, Thomsen K, Jakobsen BK, Svejgaard A. HLA-DR4 in alopecia areata. J Am Acad Dermatol. 1986;14(1):129–30.

    Article  CAS  PubMed  Google Scholar 

  32. Haida Y, Ikeda S, Takagi A, Komiyama E, Mabuchi T, Ozawa A, et al. Association analysis of the HLA-C gene in Japanese alopecia areata. Immunogenetics. 2013;65(7):553–7.

    Article  CAS  PubMed  Google Scholar 

  33. Kavak A, Baykal C, Ozarmagan G, Akar U. HLA in alopecia areata. Int J Dermatol. 2000;39(8):589–92.

    Article  CAS  PubMed  Google Scholar 

  34. Kianto U, Reunala T, Karvonen J, Lassus A, Tiilikainen A. HLA-B12 in alopecia areata. Arch Dermatol. 1977;113(12):1716.

    Article  CAS  PubMed  Google Scholar 

  35. Morling N, Frentz G, Fugger L, Georgsen J, Jakobsen B, Odum N, et al. DNA polymorphism of HLA class II genes in alopecia areata. Dis Markers. 1991;9(1):35–42.

    CAS  PubMed  Google Scholar 

  36. Odum N, Morling N, Georgsen J, Jakobsen BK, Frentz G, Jensen GF, et al. HLA-DP antigens in patients with alopecia areata. Tissue Antigens. 1990;35(3):114–7.

    Article  CAS  PubMed  Google Scholar 

  37. Orecchia G, Belvedere MC, Martinetti M, Capelli E, Rabbiosi G. Human leukocyte antigen region involvement in the genetic predisposition to alopecia areata. Dermatologica. 1987;175(1):10–4.

    Article  CAS  PubMed  Google Scholar 

  38. Xiao FL, Zhou FS, Liu JB, Yan KL, Cui Y, Gao M, et al. Association of HLA-DQA1 and DQB1 alleles with alolpecia areata in Chinese Hans. Arch Dermatol Res. 2005;297(5):201–9.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang J, Shao J, Wu X, Mao Q, Wang Y, Gao F, et al. Type I interferon related genes are common genes on the early stage after vaccination by meta-analysis of microarray data. Hum Vaccin Immunother. 2015;11(3):739–45.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Mihm S, Frese M, Meier V, Wietzke-Braun P, Scharf JG, Bartenschlager R, et al. Interferon type I gene expression in chronic hepatitis C. Lab Invest. 2004;84(9):1148–59.

    Article  CAS  PubMed  Google Scholar 

  41. Videira IF, Moura DF, Magina S. Mechanisms regulating melanogenesis. An Bras Dermatol. 2013;88(1):76–83.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Graf J, Hodgson R, van Daal A. Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation. Hum Mutat. 2005;25(3):278–84.

    Article  CAS  PubMed  Google Scholar 

  43. Jiang Y, Wu S, Zhou F, Bice T, Zhang Z, Liu J, et al. Alteration of inhibitory and activating natural killer cell receptor expression on T cells in human immunodeficiency virus-infected Chinese. Microbiol Immunol. 2011;55(10):715–25.

    Article  CAS  PubMed  Google Scholar 

  44. O’Connor GM, McVicar D. The yin-yang of KIR3DL1/S1: molecular mechanisms and cellular function. Crit Rev Immunol. 2013;33(3):203–18.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bjorkstrom NK, Beziat V, Cichocki F, Liu LL, Levine J, Larsson S, et al. CD8 T cells express randomly selected KIRs with distinct specificities compared with NK cells. Blood. 2012;120(17):3455–65.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wong W, Minchin RF. Binding and internalization of the melanocyte stimulating hormone receptor ligand [Nle4, D-Phe7] alpha-MSH in B16 melanoma cells. Int J Biochem Cell Biol. 1996;28(11):1223–32.

    Article  CAS  PubMed  Google Scholar 

  47. Doganay L, Fejzullahu A, Katrinli S, Yilmaz Enc F, Ozturk O, Colak Y, et al. Association of human leukocyte antigen DQB1 and DRB1 alleles with chronic hepatitis B. World J Gastroenterol. 2014;20(25):8179–86.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Al-Qahtani AA, Al-Anazi MR, Abdo AA, Sanai FM, Al-Hamoudi W, Alswat KA, et al. Association between HLA variations and chronic hepatitis B virus infection in Saudi Arabian patients. PLoS One. 2014;9(1):e80445.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Wang L, Zou ZQ, Wang K. Clinical relevance of HLA gene variants in HBV Infection. J Immunol Res. 2016;2016:9069375.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the Skin Cancer Research and Education Fund from the Rochester General Foundation.

Author information

Author notes

  1. Elaine S. Gilmore and Brian Poligone contributed equally to this work.

Authors and Affiliations

  1. Division of Allergy, Immunology and Rheumatology, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY, 14642, USA

    Christopher T. Richardson

  2. Rochester General Hospital Research Institute, 1425 Portland Avenue, Rochester, NY, 14621, USA

    Matthew S. Hayden & Brian Poligone

  3. Universal Dermatology, PLLC, 6800 Pittsford Palmyra Rd, Suite 150, Fairport, NY, 14450, USA

    Elaine S. Gilmore & Brian Poligone

Authors
  1. Christopher T. Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew S. Hayden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elaine S. Gilmore
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian Poligone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Elaine S. Gilmore or Brian Poligone.

Ethics declarations

Conflicts of interest

Christopher T. Richardson, Matthew S. Hayden, Elaine S. Gilmore, and Brian Poligone report no conflicts of interest relevant to this study.

The study was reviewed by the Institutional Review Board and was found to be exempt.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 568 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Richardson, C.T., Hayden, M.S., Gilmore, E.S. et al. Evaluation of the Relationship between Alopecia Areata and Viral Antigen Exposure. Am J Clin Dermatol 19, 119–126 (2018). https://doi.org/10.1007/s40257-017-0312-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40257-017-0312-y

Search

Navigation