Advertisement

Molecular Medicine

, Volume 11, Issue 1–12, pp 21–29 | Cite as

Microarray Analyses of Peripheral Blood Cells Identifies Unique Gene Expression Signature in Psoriatic Arthritis

  • Franak M. Batliwalla
  • Wentian Li
  • Christopher T. Ritchlin
  • Xiangli Xiao
  • Max Brenner
  • Teresina Laragione
  • Tianmeng Shao
  • Robert Durham
  • Sunil Kemshetti
  • Edward Schwarz
  • Rodney Coe
  • Marlena Kern
  • Emily C. Baechler
  • Timothy W. Behrens
  • Peter K. Gregersen
  • Pércio S. Gulko
Articles

Abstract

Psoriatic arthritis (PsA) is a chronic and erosive form of arthritis of unknown cause. We aimed to characterize the PsA phenotype using gene expression profiling and comparing it with healthy control subjects and patients rheumatoid arthritis (RA). Peripheral blood cells (PBCs) of 19 patients with active PsA and 19 age- and sex-matched control subjects were used in the analyses of PsA, with blood samples collected in PaxGene tubes. A significant alteration in the pattern of expression of 313 genes was noted in the PBCs of PsA patients on Affymetrix U133A arrays: 257 genes were expressed at reduced levels in PsA, and 56 genes were expressed at increased levels, compared with controls. Downregulated genes tended to cluster to certain chromosomal regions, including those containing the psoriasis susceptibility loci PSORS1 and PSORS2. Among the genes with the most significantly reduced expression were those involved in downregulation or suppression of innate and acquired immune responses, such as SIGIRR, STAT3, SHP1, IKBKB, IL-11RA, and TCF7, suggesting inappropriate control that favors proinflammatory responses. Several members of the MAPK signaling pathway and tumor suppressor genes showed reduced expression. Three proinflammatory genes—S100A8, S100A12, and thioredoxin—showed increased expression. Logistic regression and recursive partitioning analysis determined that one gene, nucleoporin 62 kDa, could correctly classify all controls and 94.7% of the PsA patients. Using a dataset of 48 RA samples for comparison, the combination of two genes, MAP3K3 followed by CACNA1S, was enough to correctly classify all RA and PsA patients. Thus, PBC gene expression profiling identified a gene expression signature that differentiated PsA from RA, and PsA from controls. Several novel genes were differentially expressed in PsA and may prove to be diagnostic biomarkers or serve as new targets for the development of therapies.

Notes

Acknowledgements

This work was supported by the National Institutes of Health Autoimmune Biomarkers Collaborative Network contract NO1-AR-1-2256.

Supplementary material

10020_2005_1101021_MOESM1_ESM.pdf (2 mb)
Supplementary material, approximately 1.96 MB.
10020_2005_1101021_MOESM2_ESM.pdf (577 kb)
Supplementary material, approximately 576 KB.

References

  1. 1.
    Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. (2005) Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann. Rheum. Dis. 64 Suppl 2:ii14–7.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Veale DJ, Ritchlin C, FitzGerald O. (2005) Immunopathology of psoriasis and psoriatic arthritis. Ann. Rheum. Dis. 64 Suppl 2:ii26–9.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Kruithof E, Baeten D, De Rycke L, et al. (2005) Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res. Ther. 7:R569–80.CrossRefGoogle Scholar
  4. 4.
    Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. (2000) Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 356:385–90.CrossRefGoogle Scholar
  5. 5.
    Gladman DD, Hing EN, Schentag CT, Cook RJ. (2001) Remission in psoriatic arthritis. J. Rheumatol. 28:1045–8.PubMedGoogle Scholar
  6. 6.
    Staudt LM. (2002) Gene expression profiling of lymphoid malignancies. Annu. Rev. Med. 53:303–18.CrossRefGoogle Scholar
  7. 7.
    Baechler EC, Batliwalla FM, Karypis G, et al. (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl. Acad. Sci. U. S. A. 100:2610–5.CrossRefGoogle Scholar
  8. 8.
    Batliwalla FM, Baechler EC, Xiao X, et al. (2005) Peripheral blood gene expression profiling in rheumatoid arthritis. Genes Immunol. 6:388–97.CrossRefGoogle Scholar
  9. 9.
    Bomprezzi R, Ringner M, Kim S, et al. (2003) Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. Hum. Mol. Genet. 12:2191–9.CrossRefGoogle Scholar
  10. 10.
    Moll JM, Wright V. (1973) Psoriatic arthritis. Semin. Arthritis Rheum. 3:55–78.CrossRefGoogle Scholar
  11. 11.
    Arnett FC, Edworthy SM, Bloch DA, et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31:315–24.CrossRefGoogle Scholar
  12. 12.
    Eisen MB, Spellman PT, Brown PO, Botstein D. (1998) Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. U. S. A. 95:14863–8.CrossRefGoogle Scholar
  13. 13.
    Li W, Yang Y. (2002) Zipf’s law in importance of genes for cancer classification using microarray data. J. Theor. Biol. 219:539–51.CrossRefGoogle Scholar
  14. 14.
    Breiman L, Friedman J, Olshen R, Stone C. (1984) Classification and Regression Trees. CRC Press.Google Scholar
  15. 15.
    Zhang H, Yu CY, Singer B, Xiong M. (2001) Recursive partitioning for tumor classification with gene expression microarray data. Proc. Natl. Acad. Sci. U. S. A. 98: 6730–5.CrossRefGoogle Scholar
  16. 16.
    Therneau T, Atlinson E. (1997) An Introduction to Recursive Partitioning Using the RPART Routines. Mayo Foundation.Google Scholar
  17. 17.
    Jenisch S, Henseler T, Nair RP, et al. (1998) Linkage analysis of human leukocyte antigen (HLA) markers in familial psoriasis: strong disequilibrium effects provide evidence for a major determinant in the HLA-B/-C region. Am. J. Hum. Genet. 63:191–9.CrossRefGoogle Scholar
  18. 18.
    Tomfohrde J, Silverman A, Barnes R, et al. (1994) Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q. Science 264: 1141–5.CrossRefGoogle Scholar
  19. 19.
    Capon F, Novelli G, Semprini S, et al. (1999) Searching for psoriasis susceptibility genes in Italy: genome scan and evidence for a new locus on chromosome 1. J. Invest. Dermatol. 112:32–5.CrossRefGoogle Scholar
  20. 20.
    Baechler EC, Batliwalla FM, Karypis G, et al. (2004) Expression levels for many genes in human peripheral blood cells are highly sensitive to ex vivo incubation. Genes Immunol. 5:347–53.CrossRefGoogle Scholar
  21. 21.
    Bennett RM. (1997) Psoriatic arthritis. In: Koopman WJ (ed.) Arthritis and Allied Conditions: A Textbook of Rheumatology. Williams & Wilkins, Baltimore, pp. 1229–44.Google Scholar
  22. 22.
    Ventura M, Colizzi M, Ottolenghi A, et al. (1989) Cell-mediated immune response in psoriasis and psoriatic arthritis. Rec. Prog. Med. 80:449–54.Google Scholar
  23. 23.
    Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. (2002) B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 3:944–50.CrossRefGoogle Scholar
  24. 24.
    Riccobon A, Gunelli R, Ridolfi R, et al. (2004) Immunosuppression in renal cancer: differential expression of signal transduction molecules in tumor-infiltrating, near-tumor tissue, and peripheral blood lymphocytes. Cancer Invest. 22:871–7.CrossRefGoogle Scholar
  25. 25.
    Nervi S, Atlan-Gepner C, Kahn-Perles B, et al. (2000) Specific deficiency of p56lck expression in T lymphocytes from type 1 diabetic patients. J. Immunol. 165:5874–83.CrossRefGoogle Scholar
  26. 26.
    Criado G, Madrenas J. (2004) Superantigen stimulation reveals the contribution of Lck to negative regulation of T cell activation. J. Immunol. 172:222–30.CrossRefGoogle Scholar
  27. 27.
    Yamamoto T, Katayama I, Nishioka K. (1999) Peripheral blood mononuclear cell proliferative response against staphylococcal superantigens in patients with psoriasis arthropathy. Eur. J. Dermatol. 9:17–21.PubMedGoogle Scholar
  28. 28.
    Welte T, Zhang SS, Wang T, et al. (2003) STAT3 deletion during hematopoiesis causes Crohn’s disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc. Natl. Acad. Sci. U. S. A. 100:1879–84.CrossRefGoogle Scholar
  29. 29.
    Zhang J, Somani AK, Siminovitch KA. (2000) Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signaling. Semin. Immunol. 12:361–78.CrossRefGoogle Scholar
  30. 30.
    Smith SS, Patterson T, Pauza ME. (2005) Transgenic Ly-49A inhibits antigen-driven T cell activation and delays diabetes. J. Immunol. 174:3897–905.CrossRefGoogle Scholar
  31. 31.
    Garlanda C, Riva F, Polentarutti N, et al. (2004) Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc. Natl. Acad. Sci. U. S. A. 101:3522–6.CrossRefGoogle Scholar
  32. 32.
    McGovern DP, Hysi P, Ahmad T, et al. (2005) Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. Hum. Mol. Genet. 14:1245–50.CrossRefGoogle Scholar
  33. 33.
    Arbour N, Naniche D, Homann D, Davis RJ, Flavell RA, Oldstone MB. (2002) c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 signaling pathways have divergent roles in CD8(+) T cell-mediated antiviral immunity. J. Exp. Med. 195:801–10.CrossRefGoogle Scholar
  34. 34.
    Constant SL, Dong C, Yang DD, Wysk M, Davis RJ, Flavell RA. (2000) JNK1 is required for T cell-mediated immunity against Leishmania major infection. J. Immunol. 165:2671–6.CrossRefGoogle Scholar
  35. 35.
    Semprini S, Capon F, Tacconelli A, et al. (2002) Evidence for differential S100 gene over-expression in psoriatic patients from genetically heterogeneous pedigrees. Hum. Genet. 111:310–3.CrossRefGoogle Scholar
  36. 36.
    Schulze zur Wiesch A, Foell D, Frosch M, Vogl T, Sorg C, Roth J. (2004) Myeloid related proteins MRP8/MRP14 may predict disease flares in juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 22:368–73.Google Scholar
  37. 37.
    Bouma G, Lam-Tse WK, Wierenga-Wolf AF, Drexhage HA, Versnel MA. (2004) Increased serum levels of MRP-8/14 in type 1 diabetes induce an increased expression of CD11b and an enhanced adhesion of circulating monocytes to fibronectin. Diabetes 53:1979–86.CrossRefGoogle Scholar
  38. 38.
    Kane D, Roth J, Frosch M, Vogl T, Bresnihan B, FitzGerald O. (2003) Increased perivascular synovial membrane expression of myeloid-related proteins in psoriatic arthritis. Arthritis Rheum. 48:1676–85.CrossRefGoogle Scholar
  39. 39.
    Hofmann MA, Drury S, Fu C, et al. (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97:889–901.CrossRefGoogle Scholar
  40. 40.
    Foell D, Roth J. (2004) Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum. 50:3762–71.CrossRefGoogle Scholar
  41. 41.
    Hofmann MA, Drury S, Hudson Bl, et al. (2002) RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immunol. 3:123–35.CrossRefGoogle Scholar
  42. 42.
    Zenz R, Eferl R, Kenner L, et al. (2005) Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437:369–75.CrossRefGoogle Scholar
  43. 43.
    Burke-Gaffney A, Callister ME, Nakamura H. (2005) Thioredoxin: friend or foe in human disease? Trends Pharmacol. Sci. 26:398–404.CrossRefGoogle Scholar
  44. 44.
    Yoshida S, Katoh T, Tetsuka T, Uno K, Matsui N, Okamoto T. (1999) Involvement of thioredoxin in rheumatoid arthritis: its costimulatory roles in the TNF-alpha-induced production of IL-6 and IL-8 from cultured synovial fibroblasts. J. Immunol. 163:351–8.PubMedGoogle Scholar
  45. 45.
    Bowcock AM, Shannon W, Du F, et al. (2001) Insights into psoriasis and other inflammatory diseases from large-scale gene expression studies. Hum. Mol. Genet. 10:1793–805.CrossRefGoogle Scholar
  46. 46.
    Quekenborn-Trinquet V, Fogel P, Aldana-Jammayrac O, et al. (2005) Gene expression profiles in psoriasis: analysis of impact of body site location and clinical severity. Br. J. Dermatol. 152:489–504.CrossRefGoogle Scholar
  47. 47.
    Tsuji H, Okamoto K, Matsuzaka Y, Iizuka H, Tamiya G, Inoko H. (2003) SLURP-2, a novel member of the human Ly-6 superfamily that is up-regulated in psoriasis vulgaris. Genomics 81:26–33.CrossRefGoogle Scholar
  48. 48.
    Matsuzaka Y, Okamoto K, Tsuji H, et al. (2002) Identification of the hRDH-E2 gene, a novel member of the SDR family, and its increased expression in psoriatic lesion. Biochem. Biophys. Res. Commun. 297:1171–80.CrossRefGoogle Scholar
  49. 49.
    Koczan D, Guthke R, Thiesen HJ, et al. (2005) Gene expression profiling of peripheral blood mononuclear leukocytes from psoriasis patients identifies new immune regulatory molecules. Eur. J. Dermatol. 15:251–7.PubMedGoogle Scholar
  50. 50.
    Rappersberger K, Komar M, Ebelin ME, et al. (2002) Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated. J. Invest. Dermatol. 119:876–87.CrossRefGoogle Scholar
  51. 51.
    Gu J, Marker-Hermann E, Baeten D, et al. (2002) A 588-gene microarray analysis of the peripheral blood mononuclear cells of spondyloarthropathy patients. Rheumatology (Oxford) 41:759–66.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2005

Authors and Affiliations

  • Franak M. Batliwalla
    • 1
    • 6
  • Wentian Li
    • 1
  • Christopher T. Ritchlin
    • 2
  • Xiangli Xiao
    • 1
  • Max Brenner
    • 1
    • 3
  • Teresina Laragione
    • 1
  • Tianmeng Shao
    • 2
  • Robert Durham
    • 2
  • Sunil Kemshetti
    • 2
  • Edward Schwarz
    • 2
  • Rodney Coe
    • 1
  • Marlena Kern
    • 1
  • Emily C. Baechler
    • 4
  • Timothy W. Behrens
    • 4
  • Peter K. Gregersen
    • 1
    • 5
    • 6
  • Pércio S. Gulko
    • 1
    • 5
    • 6
  1. 1.Robert S. Boas Center for Genomics and Human GeneticsFeinstein Institute for Medical ResearchManhassetUSA
  2. 2.Division of Rheumatology, Department of MedicineUniversity of RochesterRochesterUSA
  3. 3.North Shore-LIJ Graduate School of Molecular MedicineManhassetUSA
  4. 4.Division of Rheumatic and Autoimmune Diseases, Department of MedicineUniversity of MinnesotaMinneapolisUSA
  5. 5.Division of Rheumatology, Department of MedicineNorth Shore University HospitalManhassetUSA
  6. 6.Department of MedicineNew York University School of MedicineNew YorkUSA

Personalised recommendations