Abnormal networks of immune response-related molecules in bone marrow cells from patients with rheumatoid arthritis as revealed by DNA microarray analysis

Abstract

IntroductionRheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis that progresses to destruction of cartilage and bone. Bone marrow (BM) cells have been shown to contribute to this pathogenesis. In this study, we compared differentially expressed molecules in BM cells from RA and osteoarthritis (OA) patients and analyzed abnormal regulatory networks to identify the role of BM cells in RA.MethodsGene expression profiles (GEPs) in BM-derived mononuclear cells from 9 RA and 10 OA patients were obtained by DNA microarray. Up- and down-regulated genes were identified by comparing the GEPs from the two patient groups. Bioinformatics was performed by Expression Analysis Systemic Explorer (EASE) 2.0 based on gene ontology, followed by network pathway analysis with Ingenuity Pathways Analysis (IPA) 7.5.ResultsThe BM mononuclear cells showed 764 up-regulated and 1,910 down-regulated genes in RA patients relative to the OA group. EASE revealed that the gene category response to external stimulus, which included the gene category immune response, was overrepresented by the up-regulated genes. So too were the gene categories signal transduction and phosphate metabolism. Down-regulated genes were dominantly classified in three gene categories: cell proliferation, which included mitotic cell cycle, DNA replication and chromosome cycle, and DNA metabolism. Most genes in these categories overlapped with each other. IPA analysis showed that the up-regulated genes in immune response were highly relevant to the antigen presentation pathway and to interferon signaling. The major histocompatibility complex (MHC) class I molecules, human leukocyte antigen (HLA)-E, HLA-F, and HLA-G, tapasin (TAP) and TAP binding protein, both of which are involved in peptide antigen binding and presentation via MHC class I molecules, are depicted in the immune response molecule networks. Interferon gamma and interleukin 8 were overexpressed and found to play central roles in these networks.ConclusionsAbnormal regulatory networks in the immune response and cell cycle categories were identified in BM mononuclear cells from RA patients, indicating that the BM is pathologically involved in RA.

Pathway analysis of genomic data: concepts, methods, and prospects for future development

“…Importantly, recent studies are combining enrichment and module-based methods to point to broader findings. For example, network analysis of enriched pathways revealed major roles for antigen presentation and interferon signaling in rheumatoid arthritis [58]. …”

Inflammatory lesions in the bone marrow of rheumatoid arthritis patients: a morphological perspective

“…The finding that levels of IL-6 and IL-8 were markedly elevated in BM aspirates from RA patients (compared with controls) [15] is suggestive of ongoing pathology in the BM region. DNA microarray analysis also demonstrated that BM cells from RA patients have abnormal functional networks in immune response and cell cycle when compared to those from osteoarthritis patients, with overexpression of genes that take part in the antigen presentation pathway and interferon signaling [16]. Studies in experimental arthritis have confirmed a generalized pattern of red marrow conversion with enhanced myelopoiesis in conjunction with either increased IL-1 and IL-6 activity [17] or TNF overexpression [18].…”

Upcoming value of gene expression analysis in rheumatology

“…Более того, высокая базальная экспрессия TNFa у больных, у которых концентрация С-реактивного белка (СРБ) в крови после терапии уменьшалась до уровня, наблюдаемого у здоровых лиц, оказалась маркером эффективности терапии ингибитором TNFa, инфликсимабом [20]. Отрицательная корреляция базальной экспрессии гена TNFa с числом болезненных и припухших суставов после терапии метотрексатом (МТ) у больных ранним РА также свидетельствует о прогностическом потенциале экспрессии гена TNFa для оценки эффективности 11 пар монозиготных близнецов Многочисленные гены с повышенной или пониженной экспрессией у близнецов больных РА по сравнению со здоровыми сибсами [150] 9 больных РА и 10-ОА Повышенная экспрессия генов регулирующих иммунный ответ [157] антиревматической терапии [21]. Это подтверждается сообщением о том, что повышенная экспрессия генов провоспалительных цитокинов у пациентов, чувствительных к терапии антителами к TNFa, нормализуется быстрее, чем у неответчиков [22], что может быть связано с ослаблением некоторых иммунных путей у данных больных [23].…”

“…[источник] TNFa [14] S100 Са-связывающий белок А8 [89] MMP-9 [95] IL-1b [90] ASICs [75] MMP-12 [128] IL-7R [142] TPRV1 [76,77] RANKL [116,117] IL-2 индуцируемая киназа Т-лимфоцитов [157] NGF [80] OPG [114] Регуляторы активации Т-лимфоцитов [157] Рецептор лимфотоксина [81] Катепсины В, К, L [125] Хемокины и их рецепторы [157] Эндоканнабиноиды [82] MMP-1 [129] р53-связывающий белок [150] Антагонисты PPARa [82] MMP-3 [130] Рецептор Т-лимфоцитов [157] Опиоидные рецепторы [84] MMP-13 [132] Регуляторы активации Т-лимфоцитов [157] Антагонисты опиоидных рецепторов [84] Cелектин [150] Рецептор фракталкина CX3CR1 [86] RUNX3 [113] IL6 [31] ULK1 [96,140] …”