Development of a Disease Activity Index for Juvenile Spondyloarthritis In collaboration with Pam Weiss (CHOP), we used a modified Delphi consensus technique to establish potential disease activity measures for juvenile SpA. Following retrospective validation, 80% percent consensus was reached on 10 items. Peripheral disease, axial disease, and uveitis were the 3 primary domains that explained 58% of the variance. The Juvenile SpA Disease Activity index (JSpADA) discriminates between subjects with active versus inactive disease. Prospective validation studies are planned. The Microbiome and Spondyloarthritis In a study published last year we demonstrated that HLA-B27 and human β2-microglobulin (hβ2m) transgenic rats (B27-Tg) that serve as a model of human SpA exhibit changes in their gut microbiota (Lin et al., PLoS One 2014; 9:e105684). This collaborative effort was the first demonstration that HLA-B27 is associated with altered gut microbiota, and provided the basis for a large-scale study aimed at determining whether specific microbial communities are linked to colitis and arthritis in this animal model. Results from these ongoing studies will enable us to build and test hypotheses to understand how normal commensal microbiota may influence SpA pathogenesis. Bone Biology and Spondyloarthritis We recently demonstrated that HLA-B27-induced ER stress promotes the formation of osteoclasts from monocytes in B27-Tg rats stimulated with TNFα (Layh-Schmitt et al., Arthritis Rheum 2013; 65:2123-2131). The effect was mediated by increased IL-1α production. Interestingly, IFNβ secretion was also increased and had an inhibitory effect, which was insufficient to override the effects of IL-1α. This work was extended in a collaborative study with M. Rauner and colleagues who demonstrated increased bone remodeling in B27-Tg rats with SpA. While bone formation was also increased (3-fold), resorption was 6-fold greater with a net bone loss. We found greater numbers of osteoclast precursors in B27-Tg rats, and enhanced responsiveness to RANKL and TNFα. Trabecular vertebral bone loss in B27-Tg rats mimics the osteoporotic phenotype in humans with SpA, and suggests that HLA-B27 may play a direct role in the bone phenotype. Functional Genomics of ERAP1 To evaluate the interaction between ERAP1 and HLA-B27, and determine whether ERAP1 promotes or protects from SpA, we produced gene-edited rats that lack ERAP1 expression. Cohorts of B27-Tg rats with ERAP1+/+, ERAP1+/-, and ERAP1-/- genotypes have been generated and are being monitored over 6 months to determine the frequency and severity of arthritis and gastrointestinal inflammation. Similar experiments are being performed with B7-Tg and wild type rats as controls. The effects of ERAP1 deficiency on the immunobiology of HLA-B27 and cytokine production are also being evaluated. It is anticipated that these experiments will establish whether ERAP1 loss-of-function is protective for SpA, and should shed light on mechanisms by which HLA-B27 contributes to SpA pathogenesis. Induced Pluripotent Stem Cells Aberrant bone formation in SpA involves cell types such as osteoblasts and their precursors, mesenchymal stem cells (MSCs) that are not readily accessible for study. To circumvent this obstacle a major goal of our research has been to develop induced pluripotent stem cell (iPSC) technology to support functional genomics studies. This enables evaluation of cell lineages from affected patients that form bone and fat (osteoblasts and adipocytes), as well as early hematopoietic precursors that may be important in bone marrow edema. In a submitted manuscript we have demonstrated the feasibility of producing iPSCs from SpA patient fibroblasts and differentiating them into multiple disease-relevant cell lineages including MSCs, mineralizing osteoblasts, adipocytes, and myeloid lineage monocytes and macrophages. Gene expression analysis has revealed several AS risk genes that are expressed predominantly in MSCs and two that are prominent in iPSCs, supporting the utility of this approach. Skin fibroblast-derived iPSCs will provide a powerful tool to explore the functional genomics of certain AS risk genes that may impact bone formation and other aspects of SpA pathogenesis. IL-1β-Producing Cells in NOMID Mutations in the NLRP3 inflammasome cause a group of autoinflammatory diseases that present in childhood known as cryopyrin-associated periodic syndromes (CAPS), with neonatal onset multisystem inflammatory disease (NOMID) being the most severe. Inappropriate overproduction of IL-1β is a key pathogenic mechanism, however, and the cells predominantly responsible for IL-1β overproduction and their fate has not been elucidated. We developed and utilized a novel bead-based capture assay and combined this with intracellular cytokine staining to simultaneously measure IL-1β expression in cells and release into supernatants. We identified a population of CD14hi/CD16low peripheral blood monocytes in NOMID patients that produce excessive IL-1β in response to LPS alone (without the need for a second signal). Moreover, these cells die rapidly after LPS stimulation, exhibiting features of pyronecrosis and releasing pro-inflammatory proteins such as ASC. IL-1β itself can trigger pyronecrotic cell death, suggesting that part of the benefit of IL-1 receptor blockade may be to close a positive feedback loop.
| 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 |
| 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 |
| 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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