Abstract

Autoimmune diseases affect 7.5% of the US population, and they are among the leading causes of death and disability. A notable feature of many autoimmune diseases is their greater prevalence in females than in males, but the underlying mechanisms of this have remained unclear. Through the use of high-resolution global transcriptome analyses, we demonstrated a female-biased molecular signature associated with susceptibility to autoimmune disease and linked this to extensive sex-dependent co-expression networks. This signature was independent of biological age and sex-hormone regulation and was regulated by the transcription factor VGLL3, which also had a strong female-biased expression. On a genome-wide level, VGLL3-regulated genes had a strong association with multiple autoimmune diseases, including lupus, scleroderma and Sjögren's syndrome, and had a prominent transcriptomic overlap with inflammatory processes in cutaneous lupus. These results identified a VGLL3-regulated network as a previously unknown inflammatory pathway that promotes female-biased autoimmunity. They demonstrate the importance of studying immunological processes in females and males separately and suggest new avenues for therapeutic development.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Gene Expression Omnibus

References

  1. 1.

    American Autoimmune Related Diseases Association. The cost burden of autoimmune disease: the latest front in the war on healthcare spending. (American Autoimmune Related Diseases Association, Eastpointe, Michigan, USA, 2011).

  2. 2.

    The X-files in immunity: sex-based differences predispose immune responses. Nat. Rev. Immunol. 8, 737–744 (2008).

  3. 3.

    Sex differences in autoimmune disease. Nat. Immunol. 2, 777–780 (2001).

  4. 4.

    The effects of hormones on sex differences in infection: from genes to behavior. Neurosci. Biobehav. Rev. 24, 627–638 (2000).

  5. 5.

    & The effects of hormone replacement therapy on autoimmune disease: rheumatoid arthritis and systemic lupus erythematosus. Climacteric 12, 378–386 (2009).

  6. 6.

    , , , & Demographic differences in the development of lupus nephritis: a retrospective analysis. Am. J. Med. 112, 726–729 (2002).

  7. 7.

    Science, medicine and the future: tolerance and autoimmunity. Br. Med. J. 321, 93–96 (2000).

  8. 8.

    et al. Menopause hormonal therapy in women with systemic lupus erythematosus. Arthritis Rheum. 56, 3070–3079 (2007).

  9. 9.

    et al. Safety of hormonal replacement therapy in postmenopausal patients with systemic lupus erythematosus. Scand. J. Rheumatol. 27, 342–346 (1998).

  10. 10.

    , , & Skin immune sentinels in health and disease. Nat. Rev. Immunol. 9, 679–691 (2009).

  11. 11.

    et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. Medicine (Baltimore) 72, 113–124 (1993).

  12. 12.

    & The epidemiology of autoimmune diseases. Autoimmun. Rev. 2, 119–125 (2003).

  13. 13.

    , , & The BAFF (APRIL) system in SLE pathogenesis. Nat. Rev. Rheumatol. 10, 365–373 (2014).

  14. 14.

    et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

  15. 15.

    et al. Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat. Genet. 44, 1084–1089 (2012).

  16. 16.

    , & Mammalian vestigial-like 2, a cofactor of TEF-1 and MEF2 transcription factors that promotes skeletal muscle differentiation. J. Biol. Chem. 277, 48889–48898 (2002).

  17. 17.

    et al. Sex-dependent dominance at a single locus maintains variation in age at maturity in salmon. Nature 528, 405–408 (2015).

  18. 18.

    , & Matrix metalloproteinase 9 and autoimmune diseases. J. Clin. Immunol. 26, 299–307 (2006).

  19. 19.

    et al. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 6, e1000841 (2010).

  20. 20.

    et al. IL-7 promotes TH1 development and serum IL-7 predicts clinical response to interferon-β in multiple sclerosis. Sci. Transl. Med. 3, 93ra68 (2011).

  21. 21.

    et al. Characterization of interleukin-7 and interleukin-7 receptor in the pathogenesis of rheumatoid arthritis. Arthritis Rheum. 63, 2884–2893 (2011).

  22. 22.

    et al. Increased expression of interleukin-7 in labial salivary glands of patients with primary Sjögren's syndrome correlates with increased inflammation. Arthritis Rheum. 62, 969–977 (2010).

  23. 23.

    , , , & Intercellular adhesion molecule–1 (ICAM-1) expression is upregulated in autoimmune murine lupus nephritis. Am. J. Pathol. 136, 441–450 (1990).

  24. 24.

    et al. Distribution of immunoglobulin superfamily members ICAM-1, ICAM-2, ICAM-3 and the β2-integrin LFA-1 in multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 55, 1060–1072 (1996).

  25. 25.

    & Targeting ICAM-1–LFA-1 interaction for controlling autoimmune diseases: designing peptide and small-molecule inhibitors. Peptides 24, 487–501 (2003).

  26. 26.

    et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl. Acad. Sci. USA 100, 2610–2615 (2003).

  27. 27.

    & The interferon-α signature of systemic lupus erythematosus. Lupus 19, 1012–1019 (2010).

  28. 28.

    & Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25, 383–392 (2006).

  29. 29.

    & Inflammatory cytokines in systemic lupus erythematosus. J. Biomed. Biotechnol. 2011, 432595 (2011).

  30. 30.

    & Psoriasis: epidemiology. Clin. Dermatol. 25, 535–546 (2007).

  31. 31.

    et al. Distinct autoimmune syndromes in morphea: a review of 245 adult and pediatric cases. Arch. Dermatol. 145, 545–550 (2009).

  32. 32.

    et al. Prevalence, incidence, survival and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 48, 2246–2255 (2003).

  33. 33.

    et al. Molecular subsets in the gene expression signatures of scleroderma skin. PLoS One 3, e2696 (2008).

  34. 34.

    & The epidemiology of Sjögren's syndrome. Clin. Epidemiol. 6, 247–255 (2014).

  35. 35.

    et al. Systems analysis of primary Sjögren's syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model. Arthritis Res. Ther. 14, R238 (2012).

  36. 36.

    et al. High soluble-IL-7 receptor expression in Sjögren's syndrome identifies patients with increased immunopathology and dryness. Ann. Rheum. Dis. 75, 1735–1736 (2016).

  37. 37.

    et al. IL-7-activated T cells and monocytes drive B cell activation in patients with primary Sjogren's syndrome. Ann. Rheum. Dis. 70, A63 (2011).

  38. 38.

    , , & Interleukin-7 enhances the TH1 response to promote the development of Sjögren's-syndrome-like autoimmune exocrinopathy in mice. Arthritis Rheum. 65, 2132–2142 (2013).

  39. 39.

    , , , & Type I interferons in Sjögren's syndrome. Autoimmun. Rev. 12, 558–566 (2013).

  40. 40.

    , & Innate immune signaling induces interleukin-7 production from salivary gland cells and accelerates the development of primary Sjögren's syndrome in a mouse model. PLoS One 8, e77605 (2013).

  41. 41.

    , & Sex bias in trials and treatment must end. Nature 465, 688–689 (2010).

  42. 42.

    Sex, equity and science. Proc. Natl. Acad. Sci. USA 111, 5063–5064 (2014).

  43. 43.

    , & The dual roles of homeobox genes in vascularization and wound healing. Cell Adh. Migr. 6, 457–470 (2012).

  44. 44.

    , & Mechanism of the anti-inflammatory effect of colchicine in rheumatic diseases: a possible new outlook through microarray analysis. Rheumatology 45, 274–282 (2006).

  45. 45.

    et al. Lacrimal gland inflammation de-regulates extracellular matrix remodeling and alters molecular signature of epithelial stem/progenitor cells. Invest. Ophthalmol. Vis. Sci. 56, 8392–8402 (2015).

  46. 46.

    et al. Pulmonary mastocytosis and enhanced lung inflammation in mice heterozygous null for the Foxf1 gene. Am. J. Resp. Cell Mol. 39, 390–399 (2008).

  47. 47.

    , & Transcription repressor Hes1 is a selective regulator of TLR-induced CXCL1 expression and neutrophil responses. J. Immunol. 192, 62–69 (2014).

  48. 48.

    et al. Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and upregulates TGF-β1 secretion in vivo. J. Immunol. 166, 2041–2048 (2001).

  49. 49.

    et al. The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells. Blood 96, 4300–4306 (2000).

  50. 50.

    & The pathobiology of the septin gene family. J. Pathol. 204, 489–505 (2004).

  51. 51.

    et al. Analysis of long noncoding RNAs highlights tissue-specific expression patterns and epigenetic profiles in normal and psoriatic skin. Genome Biol. 16, 24 (2015).

  52. 52.

    et al. The NHGRI GWAS Catalog, a curated resource of SNP–trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).

  53. 53.

    Risk factors for developing atopic dermatitis. Dan. Med. J. 60, B4687 (2013).

  54. 54.

    , & Variations of basal cell carcinomas according to gender, age, location and histopathological subtype. Br. J. Dermatol. 147, 41–47 (2002).

  55. 55.

    et al. Retinoic acid receptor gene expression in human skin. J. Invest. Dermatol. 96, 425–433 (1991).

Download references

Acknowledgements

We thank A.A. Dlugosz for critical discussions and reading of the manuscript; S. Stoll, Y. Xu, T. Quan, Y. Li, L. Wolterink and L. Reingold for technical help; and A. Libs for help with biopsy samples and files. Supported by the US National Institutes of Health (K08-AR060802 and R01-AR069071to J.E.G.; and R03-AR066337 and K08-AR063668 to J.M.K.), an A. Alfred Taubman Medical Research Institute Kenneth and Frances Eisenberg Emerging Scholar Award (J.E.G.), the Doris Duke Charitable Foundation (2013106 to J.E.G.) and a Pfizer Aspire Award (J.E.G.).

Author information

Affiliations

  1. Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.

    • Yun Liang
    • , Lam C Tsoi
    • , Xianying Xing
    • , Maria A Beamer
    • , William R Swindell
    • , Mrinal K Sarkar
    • , Philip E Stuart
    • , Paul W Harms
    • , Rajan P Nair
    • , James T Elder
    • , John J Voorhees
    •  & Johann E Gudjonsson
  2. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.

    • Lam C Tsoi
  3. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

    • Lam C Tsoi
  4. Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.

    • Celine C Berthier
  5. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

    • Paul W Harms
  6. Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.

    • James T Elder
  7. Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA.

    • J Michelle Kahlenberg

Authors

  1. Search for Yun Liang in:

  2. Search for Lam C Tsoi in:

  3. Search for Xianying Xing in:

  4. Search for Maria A Beamer in:

  5. Search for William R Swindell in:

  6. Search for Mrinal K Sarkar in:

  7. Search for Celine C Berthier in:

  8. Search for Philip E Stuart in:

  9. Search for Paul W Harms in:

  10. Search for Rajan P Nair in:

  11. Search for James T Elder in:

  12. Search for John J Voorhees in:

  13. Search for J Michelle Kahlenberg in:

  14. Search for Johann E Gudjonsson in:

Contributions

Y.L., J.E.G., J.T.E., J.M.K. and J.J.V. designed the study and wrote the manuscript; Y.L., X.X., M.A.B., P.W.H., P.E.S., M.K.S., R.P.N. and C.C.B. collected and analyzed data; and L.C.T. and W.R.S. analyzed data. All authors reviewed and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Johann E Gudjonsson.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6

Excel files

  1. 1.

    Supplementary Table 1

    Lists of gender biased genes

  2. 2.

    Supplementary Table 2

    Details for TF screening for regulation of gender biased genes.

  3. 3.

    Supplementary Table 3

    VGLL3-regulated genes in keratinocytes

  4. 4.

    Supplementary Table 4

    Overlap between VGLL3-regulated genes and lupus-upregulated genes

  5. 5.

    Supplementary Table 5

    Lists of SCLE- and psoriasis-altered genes

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ni.3643

Further reading