JIBTVA  Vol.2 No.3 , July 2013
Gender-Biased Regulation of Human IL-17-Producing Cells in Vitro by Peptides Corresponding to Distinct HLA-DRB1 Allele-Coded Sequences
ABSTRACT
Rheumatoid arthritis (RA) is associated with an HLA-DRB1-coded sequence motif called “shared epitope” (SE). To explore potential mechanisms of RA susceptibility, we analyze in vitro effect of peptides bearing different HLA-DR4 sequences on human peripheral blood-derived cells. Three 15-mer peptides were used: 65-79*0401 (HLA-DRB1*04:01- coded sequence SE motif, QKRAA); 65-79*0402 (HLA-DRB1*04:02-coded sequence SE-negative motif, DERAA); 65-79*0403 (HLA-DRB1*04:03-coded sequence SE-negative motif, QRRAE). We found that CD4 TH17 cells are regulated by peptide treatment with gender bias. In male-derived T cells, all peptide treatments significantly reduced TH17 cell differentiation in vitro when compared to no peptide treatment, and to female samples. TH17 differentiation in samples not treated with peptides, either in the presence or absence of TH17-polarizing cytokines, was higher in males than in females; however, in unfractionated PBMC after treatment with TH17 polarizing cytokines, IL-17A-positive cells were more abundant in females than in males. In addition, SE-positive females showed a significantly higher percentage of IL-17A-positive cells compared to SE-negative females. In conclusion, donor’s SE status and gender may both influence TH17 immune polarization.


Cite this paper
L. Blanco, M. Plegue, W. Fung-Leung and J. Holoshitz, "Gender-Biased Regulation of Human IL-17-Producing Cells in Vitro by Peptides Corresponding to Distinct HLA-DRB1 Allele-Coded Sequences," Journal of Immune Based Therapies, Vaccines and Antimicrobials, Vol. 2 No. 3, 2013, pp. 29-38. doi: 10.4236/jibtva.2013.23004.
References
[1]   M. Bax, J. Van Heemst, T. Huizinga and R. Toes, “Genetics of Rheumatoid Arthritis: What Have We Learned?” Immunogenetics, Vol. 63, No. 8, 2011, pp. 459-466. doi:10.1007/s00251-011-0528-6

[2]   D. E. De Almeida, S. Ling and J. Holoshitz, “New Insights into the Functional Role of the Rheumatoid Arthritis Shared Epitope,” FEBS Letters, Vol. 585, No. 23, 2011, pp. 3619-3626. doi:10.1016/j.febslet.2011.03.035

[3]   P. K. Gregersen, J. Silver and R. J. Winchester, “The Shared Epitope Hypothesis. An Approach to Understanding the Molecular Genetics of Susceptibility to Rheumatoid Arthritis,” Arthritis & Rheumatism, Vol. 30, No. 11, 1987, pp. 1205-1213. doi:10.1002/art.1780301102

[4]   N. Carrier, “The DERAA HLA-DR Alleles in Patients with Early Polyarthritis: Protection against Severe Disease and Lack of Association with Rheumatoid Arthritis Autoantibodies,” Arthritis and rheumatism, Vol. 60, No. 3, 2009, pp. 698-707. doi:10.1002/art.24353

[5]   S. L. Mackie, J. C. Taylor, S. G. Martin, P. Wordsworth, S. Steer, A. G. Wilson, J. Worthington, P. Emery, J. H. Barrett and A. W. Morgan, “A Spectrum of Susceptibility to Rheumatoid Arthritis within HLA-DRB1: Stratification by Autoantibody Status in a Large UK Population,” Genes Immun, Vol. 13, No. 2, 2012, pp. 120-128. doi:10.1038/gene.2011.60

[6]   I. B. McInnes and G. Schett, “The Pathogenesis of Rheumatoid Arthritis,” New England Journal of Medicine, Vol. 365, No. 23, 2011, pp. 2205-2219. doi:10.1056/NEJMra1004965

[7]   L. P. Blanco, S. Ling and J. Holoshitz, “Oxidative Stress in Rheumatoid Arthritis: New Insights.,” In: I. Dichi, A. Colado Simao, J. Wander Bregano and R. Cecchini, Eds., Role of Oxidative Stress in Chronic Diseases, Science Publishers, Hampshire, 2013.

[8]   M. Chabaud, J. M. Durand, N. Buchs, F. Fossiez, G. Page, L. Frappart and P. Miossec, “Human Interleukin-17: A T Cell—Derived Proinflammatory Cytokine Produced by the Rheumatoid Synovium,” Arthritis & Rheumatism, Vol. 42, No. 5, 1999, pp. 963-970. doi:10.1002/1529-0131(199905)42:5<963::AID-ANR15>3.0.CO;2-E

[9]   S. Kotake, N. Udagawa, N. Takahashi, K. Matsuzaki, K. Itoh, S. Ishiyama, S. Saito, K. Inoue, N. Kamatani, M. T. Gillespie, T. J. Martin and T. Suda, “IL-17 in Synovial Fluids from Patients with Rheumatoid Arthritis Is a Potent Stimulator of Osteoclastogenesis,” The Journal of Clinical Investigation, Vol. 103, No. 9, 1999, pp. 1345-1352. doi:10.1172/JCI5703

[10]   P. Miossec and W. B. Van Den Berg, “IL-17 as a Future Therapeutic Target for Rheumatoid Arthritis,” Nature Reviews Rheumatology, Vol. 5, No. 10, 2009, p. 549-553.

[11]   M. C. Genovese, F. Van Den Bosch, S. A. Roberson, S. Bojin, I. M. Biagini, P. Ryan and J. Sloan-Lancaster, “LY2439821, a Humanized Anti-Interleukin-17 Monoclonal Antibody, in the Treatment of Patients with Rheumatoid Arthritis: A Phase I Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study,” Arthritis & Rheumatism, Vol. 62, No. 4, 2010, pp. 929-939. doi:10.1002/art.27334

[12]   D. E. De Almeida, S. Ling, X. Pi, A. M. Hartmann-Scruggs, P. Pumpens and J. Holoshitz, “Immune Dysregulation by the Rheumatoid Arthritis Shared Epitope,” The Journal of Immunology, Vol. 185, No. 3, 2010, pp. 1927-1934. doi:10.4049/jimmunol.0904002

[13]   J. Holoshitz, D. E. De Almeida and S. Ling, “A Role for Calreticulin in the Pathogenesis of Rheumatoid Arthritis,” Annals of the New York Academy of Sciences, Vol. 1209, No. 1, 2010, pp. 91-98. doi:10.1111/j.1749-6632.2010.05745.x

[14]   J. Holoshitz, Y. Liu, J. Fu, J. Joseph, S. Ling, A. Colletta, P. Sharma, D. Begun, S. Goldstein and R. Taichman, “An HLA-DRB1—Coded Signal Transduction Ligand Facilitates Inflammatory Arthritis: A New Mechanism of Auto-immunity,” The Journal of Immunology, Vol. 190, No. 1, 2012, pp. 48-57. doi:10.4049/jimmunol.1202150

[15]   S. Ling, A. Lai, O. Borschukova, P. Pumpens and J. Holoshitz, “Activation of Nitric Oxide Signaling by the Rheumatoid Arthritis Shared Epitope,” Arthritis & Rheumatism, Vol. 54, No. 11, 2006, pp. 3423-3432. doi:10.1002/art.22178

[16]   S. Ling, A. Cheng, P. Pumpens, M. Michalak and J. Holoshitz, “Identification of the Rheumatoid Arthritis Shared Epitope Binding Site on Calreticulin,” PLoS One, Vol. 5, No. 7, 2010, p. e11703. doi:10.1371/journal.pone.0011703

[17]   S. Ling, X. Pi and J. Holoshitz, “The Rheumatoid Arthritis Shared Epitope Triggers Innate Immune Signaling via Cell Surface Calreticulin,” The Journal of Immunology, Vol. 179, No. 9, 2007, pp. 6359-6367.

[18]   S. Ling, E. N. Cline, T. S. Haug, D. A. Fox and J. Holoshitz, “Citrullinated Calreticulin Potentiates Rheumatoid Arthritis Shared Epitope Signaling,” Arthritis & Rheumatism, Vol. 65, No. 3, 2012, pp. 618-626.

[19]   F. A. Arosa, O. De Jesus, G. Porto, A. M. Carmo and M. de Sousa, “Calreticulin Is Expressed on the Cell Surface of Activated Human Peripheral Blood T Lymphocytes in Association with Major Histocompatibility Complex Class I Molecules,” Journal of Biological Chemistry, Vol. 274, No. 24, 1999, pp. 16917-16922. doi:10.1074/jbc.274.24.16917

[20]   P. P. Banerjee, D. S. Vinay, A. Mathew, M. Raje, V. Parekh, D. V. R. Prasad, A. Kumar, D. Mitra and G. C. Mishra, “Evidence That Glycoprotein 96 (B2), a Stress Protein, Functions as a Th2-Specific Costimulatory Molecule,” The Journal of Immunology, Vol. 169, No. 7, 2002, pp. 3507-3518. doi:10.1371/journal.pone.0007207

[21]   A. K. Mangalam, G. Rajagopalan, V. Taneja and C. S. David, “HLA Class II Transgenic Mice Mimic Human Inflammatory Diseases,” In: W. A. Frederick, Ed., Advances in Immunology, Vol. 97, Academic Press, Waltham, 2008, pp. 65-147. doi:10.1111/j.1399-0039.2012.01881.x

[22]   L. A. Baxter-Lowe and J. A. Gorsky, “Method for HLA Typing,” 1995. http://www.google.com/patents/US5468611

[23]   M. Horlitz, A. Lucas and M. Sprenger-Haussels, “Optimized Quantification of Fragmented, Free Circulating DNA in Human Blood Plasma Using a Calibrated Duplex Real-Time PCR,” PLoS One, Vol. 4, No. 9, 2009, p. e7207.

[24]   H. Erlich, “HLA DNA Typing: Past, Present, and Future,” Tissue Antigens, Vol. 80, No. 1, 2012, pp. 1-11.

[25]   J. Holoshitz, “The Rheumatoid Arthritis HLA-DRB1 Shared Epitope,” Current Opinion in Rheumatology, Vol. 22, No. 3, 2010, pp. 293-298. doi:10.1097/BOR.0b013e328336ba63

[26]   U. Nussinovitch and Y. Shoenfeld, “The Role of Gender and Organ Specific Autoimmunity,” Autoimmunity Reviews, Vol. 11, No. 6-7, 2012, pp. A377-A385. doi:10.1016/j.autrev.2011.11.001

[27]   M. Behrens, M. Smart, D. Luckey, H. Luthra and V. Taneja, “To B or Not to B: Role of B Cells in Pathogenesis of Arthritis in HLA Transgenic Mice,” Journal of Autoimmunity, Vol. 37, No. 2, 2011, pp. 95-103. doi:10.1016/j.jaut.2011.05.002

[28]   V. Taneja, M. Behrens, E. Basal, J. Sparks, M. M. Griffiths, H. Luthra and C. S. David, “Delineating the Role of the HLA-DR4 ‘Shared Epitope’ in Susceptibility versus Resistance to Develop Arthritis,” The Journal of Immunology, Vol. 181, No. 4, 2008, pp. 2869-2877.

[29]   V. Taneja, M. Behrens, A. Mangalam, M. M. Griffiths, H. S. Luthra and C. S. David, “New Humanized HLA-DR4-Transgenic Mice That Mimic the Sex Bias of Rheumatoid Arthritis,” Arthritis & Rheumatism, Vol. 56, No. 1, 2007, pp. 69-78. doi:10.1002/art.22213

[30]   S. Ling, Z. Li, O. Borschukova, L. Xiao, P. Pumpens and J. Holoshitz, “The Rheumatoid Arthritis Shared Epitope Increases Cellular Susceptibility to Oxidative Stress by Antagonizing an Adenosine-Mediated Anti-Oxidative Pathway,” Arthritis Research & Therapy, Vol. 9, No. 1, 2006, p. R5. doi:10.1186/ar2111

[31]   H. S. Ko, S. M. Fu, R. J. Winchester, D. T. Yu and H. G. Kunkel, “Ia determinants on stimulated human T lymphocytes. Occurrence on mitogen-and antigen-activated T cells,” The Journal of Experimental Medicine, Vol. 150, No. 2, 1979, pp. 246-255. doi:10.1084/jem.150.2.246

[32]   D. T. Yu, R. J. Winchester, S. M. Fu, A. Gibofsky, H. S. Ko and H. G. Kunkel, “Peripheral blood Ia-Positive T Cells. Increases in Certain Diseases and after Immunization,” The Journal of Experimental Medicine, Vol. 151, No. 1, 1980, pp. 91-100. doi:10.1084/jem.151.1.91

[33]   A. Mangalam, M. Rodriguez and C. David, “Role of MHC Class II Expressing CD4+ T Cells in Proteolipid Protein91-110-Induced EAE in HLA-DR3 Transgenic mice,” European Journal of Immunology, Vol. 36, No. 12, 2006, pp. 3356-3370. doi:10.1002/eji.200636217

[34]   M. D. Smith and P. J. Roberts-Thomson, “Lymphocyte Surface Marker Expression in Rheumatic Diseases: Evidence for Prior Activation of Lymphocytes in Vivo,” Annals of the Rheumatic Diseases, Vol. 49, No. 2, 1990, pp. 81-87.

[35]   M. A. Zhang, D. Rego, M. Moshkova, H. Kebir, A. Chruscinski, H. Nguyen, R. Akkermann, F. Z. Stanczyk, A. Prat, L. Steinman and S. E. Dunn, “Peroxisome Proliferator-Activated Receptor (PPAR) α and -γ Regulate IFNγ and IL-17A Production by Human T Cells in a Sex-Specific Way,” Proceedings of the National Academy of Sciences, Vol. 109, No. 24, 2012, pp. 9505-9510. doi:10.1073/pnas.1118458109

[36]   S. E. Dunn, S. S. Ousman, R. A. Sobel, L. Zuniga, S. E. Baranzini, S. Youssef, A. Crowell, J. Loh, J. Oksenberg and L. Steinman, “Peroxisome Proliferators-Activated Receptor (PPAR)α Expression in T Cells Mediates Gender Differences in Development of T Cell-Mediated Autoimmunity,” The Journal of Experimental Medicine, Vol. 204, No. 2, 2007, pp. 321-330. doi:10.1084/jem.20061839

[37]   J. Yan, J. Greer, R. Hull, J. O’Sullivan, R. Henderson, S. Read and P. McCombe, “The Effect of Ageing on Human Lymphocyte Subsets: Comparison of Males and Females,” Immunity & Ageing, Vol. 7, No. 1, 2010, p. 4. doi:10.1186/1742-4933-7-4

[38]   E. M. Moran, R. Heydrich, C. T. Ng, T. P. Saber, J. McCormick, J. Sieper, H. Appel, U. Fearon and D. J. Veale, “IL-17A Expression Is Localised to Both Mono-nuclear and Polymorphonuclear Synovial Cell Infiltrates,” PLoS One, Vol. 6, No. 8, 2011, Article ID: e24048. doi:10.1371/journal.pone.0024048

[39]   A. J. Hueber, D. L. Asquith, A. M. Miller, J. Reilly, S. Kerr, J. Leipe, A. J. Melendez and I. B. McInnes, “Cutting Edge: Mast Cells Express IL-17A in Rheumatoid Arthritis Synovium,” The Journal of Immunology, Vol. 184, No. 7, 2010, pp. 3336-3340. doi:10.4049/jimmunol.0903566

[40]   H. Appel, R. Maier, P. Wu, R. Scheer, A. Hempfing, R. Kayser, A. Thiel, A. Radbruch, C. Loddenkemper and J. Sieper, “Analysis of IL-17+ Cells in Facet Joints of Patients with Spondyloarthritis Suggests That the Innate Immune Pathway Might be of Greater Relevance than the Th17-Mediated Adaptive Immune Response,” Arthritis Research & Therapy, Vol. 13, No. 3, 2011, p. R95. doi:10.1186/ar3370

[41]   C. Barragán-Martínez, J. Amaya-Amaya, R. Pineda-Tamayo, R. D. Mantilla, J. Castellanos-de la Hoz, S. Bernal-Macías, A. Rojas-Villarraga and J.-M. Anaya, “Gender Differences in Latin-American Patients With Rheumatoid Arthritis,” Gender Medicine, Vol. 9, No. 6, 2012, pp. 490-510.

[42]   G. Afshan, “CD4 CD25(hi) Regulatory T Cells in Healthy Males and Females Mediate Gender Difference in the Prevalence of Autoimmune Diseases,” Clinical Laboratory, Vol. 58, No. 5-6, 2012, pp. 567-571.

[43]   A. L. Feitsma, A. H. M. van der Helm-van Mil, T. W. J. Huizinga, R. R. P. de Vries and R. E. M. Toes, “Protection Against Rheumatoid Arthritis by HLA: Nature and Nurture,” Annals of the Rheumatic Diseases, Vol. 67, Suppl. 3, 2008, pp. iii61-iii63.

[44]   T. M. Holling, E. Schooten and P. J. van Den Elsen, “Function and Regulation of MHC Class II Molecules in T-Lymphocytes: Of Mice and Men,” Human Immunology, Vol. 65, No. 4, 2004, pp. 282-290. doi:10.1016/j.humimm.2004.01.005

[45]   J.-P. Truman, M. L. Ericson, C. J. M. Choqueux-Séébold, D. J. Charron and N. A. Mooney, “Lymphocyte Programmed Cell Death Is Mediated via HLA Class II DR,” International Immunology, Vol. 6, No. 6, 1994, pp. 887-896. doi:10.1093/intimm/6.6.887

[46]   L. DiMolfetto, H. A. Neal, A. Wu, C. Reilly and D. Lo, “The Density of the Class II MHC T Cell Receptor Ligand Influences IFN-γ/IL-4 Ratios in Immune Responses in Vivo,” Cellular Immunology, Vol. 183, No. 1, 1998, pp. 70-79. doi:10.1006/cimm.1997.1231

[47]   S. Hussain and S. A. Stohlman, “Peritoneal Macrophage from Male and Female SJL Mice Differ in IL-10 Expression and Macrophage Maturation,” Journal of Leukocyte Biology, Vol. 91, No. 4, 2012, pp. 571-579. doi:10.1189/jlb.0711351

[48]   S. C. Wilcoxen, E. Kirkman, K. C. Dowdell and S. A. Stohlman, “Gender-Dependent IL-12 Secretion by APC Is Regulated by IL-10,” The Journal of Immunology, Vol. 164, No. 12, 2000, pp. 6237-6243.

[49]   C. A. Hunter and R. Kastelein, “Interleukin-27: Balancing Protective and Pathological Immunity,” Immunity, Vol. 37, No. 6, 2012, pp. 960-969. doi:10.1016/j.immuni.2012.11.003

[50]   H. G. Evans, T. Suddason, I. Jackson, L. S. Taams and G. M. Lord, “Optimal Induction of T Helper 17 Cells in Humans Requires T Cell Receptor Ligation in the Context of Toll-Like Receptor-Activated Monocytes,” Proceedings of the National Academy of Sciences, Vol. 104, No. 43, 2007, pp. 17034-17039. doi;10.1073/pnas.0708426104

 
 
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