A genome-scale assessment of peripheral blood B-cell molecular homeostasis in patients with rheumatoid arthritis.

OBJECTIVE While rheumatoid arthritis (RA) is considered a prototypical autoimmune disease, the specific roles of B-cells in RA pathogenesis is not fully delineated. METHODS We performed microarray expression profiling of peripheral blood B-cells from RA patients and controls. Data were analysed using differential gene expression analysis and 'gene networking' analysis (characterizing clusters of functionally inter-relelated genes) to identify both regulatory genes and the pathways in which they participate. Results were confirmed by quantitative real-time polymerase chain reaction and by measuring the levels of 10 serum cytokines involved in the pathways identified. RESULTS Genes regulating and effecting the cell-cycle, proliferation, apoptosis, autoimmunity, cytokine networks, angiogenesis and neuro-immune regulation were differentially expressed in RA B-cells. Moreover, the serum levels of several soluble factors that modulate these pathways, including IL-1beta, IL-5, IL-6, IL-10, IL-12p40, IL-17 and VEGF were significantly increased in this cohort of RA patients. CONCLUSIONS These results outline aspects of the multifaceted role B-cells play in RA pathogenesis in which immune dysregulation in RA modulates B-cell biology and thereby contributes to the induction and perpetuation of a pathogenic humoral immune response.

[1]  Hong Li,et al.  Endothelial metalloprotease-disintegrin protein (ADAM) is implicated in angiogenesis in vitro , 2004, Angiogenesis.

[2]  M. Nagashima,et al.  Comparative study of symptoms and neuroendocrine-immune network mediator levels between rheumatoid arthritis patients and healthy subjects. , 2000, Clinical and experimental rheumatology.

[3]  G. Manda,et al.  Imbalance of peripheral B lymphocytes and NK cells in rheumatoid arthritis , 2003, Journal of cellular and molecular medicine.

[4]  G. Panayi,et al.  Carcinoembryonic antigen in rheumatic diseases. , 1975, Rheumatology and rehabilitation.

[5]  U. Wahn,et al.  Perturbations of peripheral B lymphocyte homoeostasis in children with systemic lupus erythematosus , 2003, Annals of the rheumatic diseases.

[6]  Igor Dozmorov,et al.  Microarray Data Analysis Toolbox (MDAT): for normalization, adjustment and analysis of gene expression data , 2004, Bioinform..

[7]  K. Tamai,et al.  Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes , 1996, Nature.

[8]  F. Breedveld,et al.  Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis. , 2001, Arthritis and rheumatism.

[9]  van der Heijde Dm,et al.  Development of a disease activity score based on judgment in clinical practice by rheumatologists. , 1993 .

[10]  M. A. van 't Hof,et al.  Development of a disease activity score based on judgment in clinical practice by rheumatologists. , 1993, The Journal of rheumatology.

[11]  Gregory J. Parker,et al.  The phosphatidylinositol 4-phosphate 5-kinase family. , 1996, Advances in enzyme regulation.

[12]  D. Littman,et al.  Requirement for CARMA1 in Antigen Receptor-Induced NF-κB Activation and Lymphocyte Proliferation , 2003, Current Biology.

[13]  P. Lipsky,et al.  The role of the T cell in autoimmune inflammation , 2005, Arthritis research & therapy.

[14]  E. Smeland,et al.  A splice variant of human ephrin-A4 encodes a soluble molecule that is secreted by activated human B lymphocytes. , 2000, Blood.

[15]  T. Nanki,et al.  Cytokine, activation marker, and chemokine receptor expression by individual CD4+ memory T cells in rheumatoid arthritis synovium , 2000, Arthritis research.

[16]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[17]  R. Lai,et al.  Immunohistochemical Expression of the Transcription Factor DP-1 and Its Heterodimeric Partner E2F-1 in Non-Hodgkin Lymphoma , 2002, Applied immunohistochemistry & molecular morphology : AIMM.

[18]  T. Martin,et al.  Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. , 2002, Bone.

[19]  P. Lipsky,et al.  Abnormalities in peripheral B cell memory of patients with primary Sjögren's syndrome. , 2004, Arthritis and rheumatism.

[20]  D. Golenbock,et al.  Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. , 2005, The Journal of clinical investigation.

[21]  N. Motoyama,et al.  A novel adenovirus E1B19K-binding protein B5 inhibits apoptosis induced by Nip3 by forming a heterodimer through the C-terminal hydrophobic region , 1999, Cell Death and Differentiation.

[22]  K. Kawashima,et al.  The lymphocytic cholinergic system and its biological function. , 2003, Life sciences.

[23]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[24]  M. Pierer,et al.  B lymphocytopenia in rheumatoid arthritis is associated with the DRB1 shared epitope and increased acute phase response , 2002, Arthritis research.

[25]  G. Lombardi,et al.  Characterization of ionotropic glutamate receptors in human lymphocytes , 2001, British Journal of Pharmacology.

[26]  Kaiyu Jiang,et al.  Novel approaches to gene expression analysis of active polyarticular juvenile rheumatoid arthritis , 2003, Arthritis research & therapy.

[27]  W. Koopman.  Arthritis and allied conditions;: A textbook of rheumatology , 1972 .

[28]  Anne M. Bowcock,et al.  Identification of a RING protein that can interact in vivo with the BRCA1 gene product , 1996, Nature Genetics.

[29]  R. L. Roper,et al.  A new view of prostaglandin E regulation of the immune response. , 1991, Immunology today.

[30]  R. Dziarski,et al.  Peptidoglycan Recognition Proteins , 2001, The Journal of Biological Chemistry.

[31]  A. Gurney,et al.  IL-17E, a Novel Proinflammatory Ligand for the IL-17 Receptor Homolog IL-17Rh1* , 2001, The Journal of Biological Chemistry.

[32]  B. Neel,et al.  Role of phosphatases in lymphocyte activation. , 1997, Current opinion in immunology.

[33]  T. Mimori,et al.  Anti-U5 small nuclear ribonucleoprotein (snRNP) antibodies: a rare anti-U snRNP specificity. , 1996, Clinical immunology and immunopathology.

[34]  J. Cawley,et al.  In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells. , 2000, Blood.

[35]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[36]  Y. Ikeda,et al.  Advances in our understanding of peroxiredoxin, a multifunctional, mammalian redox protein , 2002, Redox report : communications in free radical research.

[37]  M. Turner.  B-cell development and antigen receptor signalling. , 2001, Biochemical Society transactions.

[38]  R. Tagett,et al.  Wdr12, a mouse gene encoding a novel WD-Repeat Protein with a notchless-like amino-terminal domain. , 2002, Genomics.

[39]  R. Jonsson,et al.  Circulating Cytokines in Primary Sjögren's Syndrome Determined by a Multiplex Cytokine Array System , 2004, Scandinavian journal of immunology.

[40]  G. Bishop,et al.  CpG motifs in bacterial DNA trigger direct B-cell activation , 1995, Nature.

[41]  Loring T. Swaim.  THE AMERICAN RHEUMATISM ASSOCIATION , 1938 .

[42]  B. He,et al.  CpG DNA Induces IgG Class Switch DNA Recombination by Activating Human B Cells through an Innate Pathway That Requires TLR9 and Cooperates with IL-101 , 2004, The Journal of Immunology.

[43]  I. Lawrance,et al.  Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes. , 2001, Human molecular genetics.

[44]  E. Lubberts.  The role of IL-17 and family members in the pathogenesis of arthritis. , 2003, Current opinion in investigational drugs.

[45]  L. Parysek,et al.  The structure of the human peripherin gene (PRPH) and identification of potential regulatory elements. , 1994, Genomics.

[46]  Ronenn Roubenoff,et al.  Arthritis and Allied Conditions: A Textbook of Rheumatology , 1993 .

[47]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[48]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[49]  A. Koch,et al.  Angiogenesis: Implications for rheumatoid arthritis , 1998 .

[50]  M. Segal,et al.  Assessment of differential gene expression in human peripheral nerve injury , 2002, BMC Genomics.

[51]  Xiao-Ling Li,et al.  RNase-L-dependent Destabilization of Interferon-induced mRNAs , 2000, The Journal of Biological Chemistry.

[52]  T G Wolfsberg,et al.  ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell- matrix interactions , 1995, The Journal of cell biology.

[53]  P. Farnham,et al.  Position-dependent transcriptional regulation of the murine dihydrofolate reductase promoter by the E2F transactivation domain , 1997, Molecular and cellular biology.

[54]  T. Martin,et al.  Involvement of receptor activator of NFκB ligand and tumor necrosis factor-α in bone destruction in rheumatoid arthritis , 2002 .

[55]  Yu-WeiZhang,et al.  Reg gene family and human diseases , 2003 .

[56]  M. Gibaldi.  Regulating Angiogenesis: A New Therapeutic Strategy , 1998, Journal of clinical pharmacology.

[57]  S. Mizel,et al.  Interleukin 1-mediated induction of kappa-light chain synthesis and surface immunoglobulin expression on pre-B cells. , 1984, Journal of immunology.

[58]  N. Olsen,et al.  In vitro synthesis of immunoglobulins and IgM-rheumatoid factor by blood mononuclear cells of patients with rheumatoid arthritis , 2004, Rheumatology International.

[59]  S. Hirohata,et al.  The role of IL-10 in human B cell activation, proliferation, and differentiation. , 1995, Journal of immunology.

[60]  N. Sugimoto,et al.  The Edg family G protein-coupled receptors for lysophospholipids: their signaling properties and biological activities. , 2002, Journal of biochemistry.

[61]  T. Mosmann.  Complexity or coherence? Cytokine secretion by B cells , 2000, Nature Immunology.

[62]  G. Chrousos,et al.  The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. , 2000, Pharmacological reviews.

[63]  Igor Dozmorov,et al.  An associative analysis of gene expression array data , 2003, Bioinform..

[64]  M. Lipinski,et al.  Core Histones and HIRIP3, a Novel Histone-Binding Protein, Directly Interact with WD Repeat Protein HIRA , 1998, Molecular and Cellular Biology.

[65]  M. Roussel,et al.  Inhibition of cell proliferation by the Mad1 transcriptional repressor , 1996, Molecular and cellular biology.

[66]  J. Wesche,et al.  Binding of FGF‐1 variants to protein kinase CK2 correlates with mitogenicity , 2002, The EMBO journal.

[67]  W. van Eden,et al.  The Human Endoplasmic Reticulum Molecular Chaperone BiP Is an Autoantigen for Rheumatoid Arthritis and Prevents the Induction of Experimental Arthritis1 , 2001, The Journal of Immunology.

[68]  N. Bessis,et al.  Recent data on the role for angiogenesis in rheumatoid arthritis. , 2003, Joint, bone, spine : revue du rhumatisme.

[69]  N. Tsopanoglou,et al.  Role of thrombin in angiogenesis and tumor progression. , 2004, Seminars in thrombosis and hemostasis.

[70]  U. Rodeck,et al.  Molecular cloning of cDNA for the human tumor-associated antigen CO-029 and identification of related transmembrane antigens. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[71]  K. Clark,et al.  Characterization of a B cell surface antigen with homology to the S100 protein MRP8. , 1999, Biochemical and biophysical research communications.

[72]  J. Moore,et al.  Human B cells express IL-5 receptor messenger ribonucleic acid and respond to IL-5 with enhanced IgM production after mitogenic stimulation with Moraxella catarrhalis. , 1996, Journal of immunology.

[73]  M. Rocchi,et al.  Interleukin-1-inducible genes in endothelial cells. Cloning of a new gene related to C-reactive protein and serum amyloid P component. , 1992, The Journal of biological chemistry.

[74]  R. Jonsson,et al.  Programmed Cell Death of Peripheral Blood B Cells Determined by Laser Scanning Cytometry in Sjögren’s Syndrome with a Special Emphasis on BAFF , 2004, Journal of Clinical Immunology.

[75]  G. Firestein,et al.  Starving the synovium: angiogenesis and inflammation in rheumatoid arthritis. , 1999, The Journal of clinical investigation.

[76]  C. Heizmann,et al.  The S100 family of EF-hand calcium-binding proteins: functions and pathology. , 1996, Trends in biochemical sciences.

[77]  S. Hoshino,et al.  Molecular Cloning of a Novel Member of the Eukaryotic Polypeptide Chain-Releasing Factors (eRF) , 1998, The Journal of Biological Chemistry.

[78]  T. Sugiura,et al.  B cell stimulating activity of metallothionein in vitro. , 2000, International journal of immunopharmacology.

[79]  K. Itoh,et al.  Clonal expansion is a characteristic feature of the B-cell repertoire of patients with rheumatoid arthritis , 1999, Arthritis research.

[80]  N. Olsen,et al.  Synthesis of rheumatoid factor in vitro: implications for the pathogenesis of rheumatoid arthritis. , 1985, Seminars in arthritis and rheumatism.

[81]  J. Hsuan,et al.  A new component of the transcription factor DRTF1/E2F , 1993, Nature.

[82]  V. Dixit,et al.  Mice Lacking the CARD of CARMA1 Exhibit Defective B Lymphocyte Development and Impaired Proliferation of Their B and T Lymphocytes , 2003, Current Biology.

[83]  R. Moots,et al.  Dopamine receptor expression on human T- and B-lymphocytes, monocytes, neutrophils, eosinophils and NK cells: a flow cytometric study , 2002, Journal of Neuroimmunology.

[84]  J. She,et al.  Molecular cloning and characterization of a novel gene family of four ancient conserved domain proteins (ACDP). , 2003, Gene.

[85]  M. Kuwana,et al.  Anti-U5 snRNP antibody as a possible serological marker for scleroderma-polymyositis overlap. , 2002, Rheumatology.

[86]  Monilola A. Olayioye,et al.  The ErbB signaling network: receptor heterodimerization in development and cancer , 2000, The EMBO journal.

[87]  S. Wahl,et al.  Humoral immune function in severe, active rheumatoid arthritis. , 1987, Clinical immunology and immunopathology.

[88]  M. Shlomchik,et al.  Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors , 2002, Nature.

[89]  K. Kawashima,et al.  The lymphocytic cholinergic system and its contribution to the regulation of immune activity. , 2003, Life sciences.

[90]  M. Bertagnolli,et al.  IL-12 augments antigen-dependent proliferation of activated T lymphocytes. , 1992, Journal of immunology.

[91]  S. L. Bridges,et al.  Pathogenesis of rheumatoid arthritis. Role of B lymphocytes. , 2001, Rheumatic diseases clinics of North America.

[92]  Jong Ran Lee,et al.  Cutting Edge: Induced Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, Following CD40 Stimulation and WEHI 231 B Cell Activation1 , 2003, The Journal of Immunology.

[93]  G. Burmester,et al.  The role of B cells in rheumatoid arthritis: mechanisms and therapeutic targets. , 2003, Current opinion in rheumatology.

[94]  L. Menoud,et al.  Cytokine-like factor-1, a novel soluble protein, shares homology with members of the cytokine type I receptor family. , 1998, Journal of immunology.

[95]  H. Volk,et al.  Cyclic adenosine monophosphate‐responsive elements are involved in the transcriptional activation of the human IL‐10 gene in monocytic cells , 1999, European journal of immunology.

[96]  A. Schmidt,et al.  S100P Stimulates Cell Proliferation and Survival via Receptor for Activated Glycation End Products (RAGE)* , 2004, Journal of Biological Chemistry.

[97]  Igor Dozmorov,et al.  Statistical monitoring of weak spots for improvement of normalization and ratio estimates in microarrays , 2004, BMC Bioinformatics.

[98]  R. Fanin,et al.  Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. , 2002, Arthritis and rheumatism.

[99]  Y. Ishimi.  A DNA Helicase Activity Is Associated with an MCM4, -6, and -7 Protein Complex* , 1997, The Journal of Biological Chemistry.

[100]  Michael L. Bittner,et al.  cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene. , 1999 .

[101]  A. Kehlen,et al.  Expression, modulation and signalling of IL‐17 receptor in fibroblast‐like synoviocytes of patients with rheumatoid arthritis , 2002, Clinical and experimental immunology.

[102]  A. Parker,et al.  Expression profiling of metalloproteinases and their inhibitors in cartilage. , 2004, Arthritis and rheumatism.