Objective 1: We examined peripheral blood mononuclear cells from 59 healthy children and 136 patients with juvenile idiopathic arthritis (28 with enthesitis-related arthritis, 42 with persistent oligoarthritis, 45 with rheumatoid factor (RF)-negative polyarthritis, and 21 with systemic disease). Cells were isolated from whole blood and poly(A) RNA was then purified from cells and labeled for gene expression profiles using Affymetrix microarrays (HG-U133 Plus 2.0). A total of 9,501 differentially expressed probe sets were identified among the juvenile arthritis subjects and controls with 193, 1,036, 873, and 7,595 probe sets different in the respective subtypes as listed above. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 signaling was prominent. A hemoglobin cluster was identified that was underexpressed in enthesitis-related arthritis patients but overexpressed in systemic juvenile arthritis patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic juvenile arthritis, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferatoractivated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were upregulated in systemic juvenile arthritis, with a subset of these genes being differentially expressed in other subtypes as well. These expression analyses identified differentially expressed genes in peripheral blood cells from patients with different subtypes of juvenile arthritis and healthy controls providing evidence of immunobiologic differences between these forms of childhood arthritis. Further analysis of the 873 probe sets for differentially expressed genes in polyarticular juvenile arthritis patients and healthy controls was performed in 61 children. Hierarchical clustering distinguished 3 subgroups within the polyarticular juvenile arthritis group. Prototypical patients within each subgroup were identified and used to define subgroup-specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor betainducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets. We have concluded that gene expression signatures in peripheral blood cells from patients with recent-onset polyarticular juvenile arthritis reflect discrete disease processes and offer a molecular classification of disease. Further analysis may reveal more information relevant to pathogenic mechanisms and hypotheses to be pursued. Objective 2: Previous work from our group has shown that HLA-B27 has a tendency to misfold, and that this can activate the unfolded protein response (UPR) particularly when HLA-B27 is upregulated in macrophages from HLA-B27 and human beta-2 microglobulin transgenic rats (HLA-B27 transgenic rats) that serve as an experimental model of spondyloarthritis. In these studies we asked whether HLA-B27 misfolding and the UPR result in cytokine dysregulation and whether this is associated with Th1 and/or Th17 activation. We found interleukin-23 to be synergistically upregulated in macrophages stimulated with bacterial products and undergoing a UPR induced by pharmacologic agents or by HLAB27 misfolding. Interleukin-23 was also increased in colon tissue from the transgenic rats concurrently with the development of intestinal inflammation, and interleukin-17, a downstream target of interleukin-23, exhibited robust up-regulation in a similar temporal pattern. Interleukin-23 and interleukin-17 transcripts were localized to CD11 positive antigen-presenting cells and CD4 positive T cells (Th17), respectively, from the colonic lamina propria. Colitis was associated with a 6-fold expansion of CD4 positive interleukin-17expressing T cells. The interleukin-23/interleukin-17 axis is strongly activated in the colon of HLA-B27 transgenic rats with spondylarthritis-like disease. HLA-B27 misfolding and UPR activation in macrophages can result in enhanced induction of the pro-Th17 cytokine IL-23. These results suggest a link between HLA-B27 misfolding and immune dysregulation in this animal model, with implications for human disease. In humans IL23R polymorphisms are associated with predisposition to ankylosing spondylitis, inflammatory bowel disease, and psoriasis, and studies showing Th17 activation with IL-17 overexpression are beginning to emerge.
| Navid, Fatemeh; Layh-Schmitt, Gerlinde; Sikora, Keith A et al. (2018) The Role of Autophagy in the Degradation of Misfolded HLA-B27 Heavy Chains. Arthritis Rheumatol 70:746-755 |
| Sanchez, Gina A Montealegre; Reinhardt, Adam; Ramsey, Suzanne et al. (2018) JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest 128:3041-3052 |
| Sikora, Keith A; Bennett, Joshua R; Vyncke, Laurens et al. (2018) Germline gain-of-function myeloid differentiation primary response gene-88 (MYD88) mutation in a child with severe arthritis. J Allergy Clin Immunol 141:1943-1947.e9 |
| Ritchlin, Christopher T; Colbert, Robert A; Gladman, Dafna D (2017) Psoriatic Arthritis. N Engl J Med 376:2095-6 |
| Colbert, Robert A; Navid, Fatemeh; Gill, Tejpal (2017) The role of HLA-B*27 in spondyloarthritis. Best Pract Res Clin Rheumatol 31:797-815 |
| Ritchlin, Christopher T; Colbert, Robert A; Gladman, Dafna D (2017) Psoriatic Arthritis. N Engl J Med 376:957-970 |
| Navid, Fatemeh; Colbert, Robert A (2017) Causes and consequences of endoplasmic reticulum stress in rheumatic disease. Nat Rev Rheumatol 13:25-40 |
| Barnea, Eilon; Melamed Kadosh, Dganit; Haimovich, Yael et al. (2017) The Human Leukocyte Antigen (HLA)-B27 Peptidome in Vivo, in Spondyloarthritis-susceptible HLA-B27 Transgenic Rats and the Effect of Erap1 Deletion. Mol Cell Proteomics 16:642-662 |
| Layh-Schmitt, Gerlinde; Lu, Shajia; Navid, Fatemeh et al. (2017) Generation and differentiation of induced pluripotent stem cells reveal ankylosing spondylitis risk gene expression in bone progenitors. Clin Rheumatol 36:143-154 |
| Tran, Tri M; Hong, Sohee; Edwan, Jehad H et al. (2016) ERAP1 reduces accumulation of aberrant and disulfide-linked forms of HLA-B27 on the cell surface. Mol Immunol 74:10-7 |
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