Gender-biased regulation of human IL-17-producing cells in vitro by peptides corresponding to distinct HLA-DRB1 allele-coded sequences.

Susceptibility to rheumatoid arthritis (RA) is associated with HLA-DRB1 alleles coding a 5-amino acid sequence motif called the shared epitope (SE). To explore the potential mechanisms that lead to RA susceptibility, we analyze the 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 (an HLA-DRB1*04:01-coded sequence carrying the SE motif, QKRAA); 65-79*0402 (an HLA-DRB1*04:02-coded sequence carrying a SE-negative motif, DERAA); 65-79*0403 (an HLA-DRB1*04:03-coded sequence carrying a 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.

[1]  R. Cecchini,et al.  12: Common Features of Oxidative Stress and Metabolic Impairments in Human Erythrocytes and Nucleated Cells , 2014 .

[2]  Song Ling,et al.  Citrullinated calreticulin potentiates rheumatoid arthritis shared epitope signaling. , 2013, Arthritis and rheumatism.

[3]  R. Taichman,et al.  An HLA-DRB1–Coded Signal Transduction Ligand Facilitates Inflammatory Arthritis: A New Mechanism of Autoimmunity , 2013, The Journal of Immunology.

[4]  Christopher A Hunter,et al.  Interleukin-27: balancing protective and pathological immunity. , 2012, Immunity.

[5]  J. Anaya,et al.  Gender differences in Latin-American patients with rheumatoid arthritis. , 2012, Gender medicine.

[6]  H. Erlich,et al.  HLA DNA typing: past, present, and future. , 2012, Tissue antigens.

[7]  L. Steinman,et al.  Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way , 2012, Proceedings of the National Academy of Sciences.

[8]  Y. Shoenfeld,et al.  The role of gender and organ specific autoimmunity. , 2012, Autoimmunity reviews.

[9]  S. Stohlman,et al.  Peritoneal macrophage from male and female SJL mice differ in IL‐10 expression and macrophage maturation , 2012, Journal of leukocyte biology.

[10]  Song Ling,et al.  New insights into the functional role of the rheumatoid arthritis shared epitope , 2011, FEBS letters.

[11]  J. Barrett,et al.  A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population , 2011, Genes and Immunity.

[12]  V. Taneja,et al.  To B or not to B: role of B cells in pathogenesis of arthritis in HLA transgenic mice. , 2011, Journal of autoimmunity.

[13]  D. Veale,et al.  IL-17A Expression Is Localised to Both Mononuclear and Polymorphonuclear Synovial Cell Infiltrates , 2011, PloS one.

[14]  C. Loddenkemper,et al.  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 , 2011, Arthritis research & therapy.

[15]  T. Huizinga,et al.  Genetics of rheumatoid arthritis: what have we learned? , 2011, Immunogenetics.

[16]  J. Holoshitz,et al.  A role for calreticulin in the pathogenesis of rheumatoid arthritis , 2010, Annals of the New York Academy of Sciences.

[17]  P. Pumpens,et al.  Immune Dysregulation by the Rheumatoid Arthritis Shared Epitope , 2010, The Journal of Immunology.

[18]  P. Pumpens,et al.  Identification of the Rheumatoid Arthritis Shared Epitope Binding Site on Calreticulin , 2010, PloS one.

[19]  J. Holoshitz.  The rheumatoid arthritis HLA–DRB1 shared epitope , 2010, Current opinion in rheumatology.

[20]  M. Genovese,et al.  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. , 2010, Arthritis and rheumatism.

[21]  Ashley M. Miller,et al.  Mast cells express IL-17A in rheumatoid arthritis synovium. , 2010, Journal of immunology.

[22]  Pamela A McCombe,et al.  The effect of ageing on human lymphocyte subsets: comparison of males and females , 2010, Immunity & Ageing.

[23]  P. Miossec,et al.  IL-17 as a future therapeutic target for rheumatoid arthritis , 2009, Nature Reviews Rheumatology.

[24]  Martin Horlitz,et al.  Optimized Quantification of Fragmented, Free Circulating DNA in Human Blood Plasma Using a Calibrated Duplex Real-Time PCR , 2009, PloS one.

[25]  N. Carrier,et al.  The DERAA HLA-DR alleles in patients with early polyarthritis: protection against severe disease and lack of association with rheumatoid arthritis autoantibodies. , 2009, Arthritis and rheumatism.

[26]  T. Huizinga,et al.  Protection against rheumatoid arthritis by HLA: nature and nurture , 2008, Annals of the rheumatic diseases.

[27]  V. Taneja,et al.  Delineating the Role of the HLA-DR4 “Shared Epitope” in Susceptibility versus Resistance to Develop Arthritis1 , 2008, The Journal of Immunology.

[28]  J. Holoshitz,et al.  The Rheumatoid Arthritis Shared Epitope Triggers Innate Immune Signaling via Cell Surface Calreticulin1 , 2007, The Journal of Immunology.

[29]  Graham M Lord,et al.  Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes , 2007, Proceedings of the National Academy of Sciences.

[30]  A. Koch.  The pathogenesis of rheumatoid arthritis. , 2007, American journal of orthopedics.

[31]  S. Youssef,et al.  Peroxisome proliferator–activated receptor (PPAR)α expression in T cells mediates gender differences in development of T cell–mediated autoimmunity , 2007, The Journal of Experimental Medicine.

[32]  S. Youssef,et al.  Peroxisome proliferator–activated receptor (PPAR)α expression in T cells mediates gender differences in development of T cell–mediated autoimmunity , 2007, The Journal of experimental medicine.

[33]  P. Pumpens,et al.  The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway , 2007, Arthritis research & therapy.

[34]  Moses Rodriguez,et al.  Role of MHC class II expressing CD4+ T cells in proteolipid protein91–110‐induced EAE in HLA‐DR3 transgenic mice , 2006, European journal of immunology.

[35]  Song Ling,et al.  Activation of nitric oxide signaling by the rheumatoid arthritis shared epitope. , 2006, Arthritis and rheumatism.

[36]  P. J. van den Elsen,et al.  Function and regulation of MHC class II molecules in T-lymphocytes: of mice and men. , 2004, Human immunology.

[37]  Vrajesh V. Parekh,et al.  Evidence That Glycoprotein 96 (B2), a Stress Protein, Functions as a Th2-Specific Costimulatory Molecule1 , 2002, The Journal of Immunology.

[38]  Kennichi C. Dowdell,et al.  Gender-Dependent IL-12 Secretion by APC Is Regulated by IL-101 , 2000, The Journal of Immunology.

[39]  A. M. Carmo,et al.  Calreticulin Is Expressed on the Cell Surface of Activated Human Peripheral Blood T Lymphocytes in Association with Major Histocompatibility Complex Class I Molecules* , 1999, The Journal of Biological Chemistry.

[40]  T. Martin,et al.  IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. , 1999, The Journal of clinical investigation.

[41]  P. Miossec,et al.  Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. , 1999, Arthritis and rheumatism.

[42]  D. Lo,et al.  The Density of the Class II MHC T Cell Receptor Ligand Influences IFN-γ/IL-4 Ratios in Immune Responsesin Vivo , 1998 .

[43]  D. Charron,et al.  Lymphocyte programmed cell death is mediated via HLA class II DR. , 1994, International immunology.

[44]  M. Smith,et al.  Lymphocyte surface marker expression in rheumatic diseases: evidence for prior activation of lymphocytes in vivo. , 1990, Annals of the rheumatic diseases.

[45]  S. Jonjić,et al.  Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes , 1989, The Journal of experimental medicine.

[46]  P. Gregersen,et al.  The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. , 1987, Arthritis and rheumatism.

[47]  R. Winchester,et al.  Peripheral blood Ia-positive T cells. Increases in certain diseases and after immunization , 1980, The Journal of experimental medicine.

[48]  R. Winchester,et al.  Ia determinants on stimulated human T lymphocytes. Occurrence on mitogen- and antigen-activated T cells , 1979, The Journal of experimental medicine.

[49]  G. Afshan,et al.  CD4+CD25(hi) regulatory T cells in healthy males and females mediate gender difference in the prevalence of autoimmune diseases. , 2012, Clinical laboratory.

[50]  V. Taneja,et al.  HLA class II transgenic mice mimic human inflammatory diseases. , 2008, Advances in immunology.

[51]  V. Taneja,et al.  New humanized HLA-DR4-transgenic mice that mimic the sex bias of rheumatoid arthritis. , 2007, Arthritis and rheumatism.

[52]  C. Turesson,et al.  Genetics of rheumatoid arthritis. , 2006, Mayo Clinic proceedings.

[53]  J J Gómez-Reino Carnota,et al.  [Genetics of rheumatoid arthritis]. , 2000, Medicina clinica.