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Axial spondyloarthritis (axSpA) is an important cause of chronic low back pain and affects approximately 1% of the US population. The back pain associated with axSpA has a characteristic pattern referred to as inflammatory back pain (IBP). Features of IBP include insidious onset before age 45 years, association with morning stiffness, improvement with exercise but not rest, alternating buttock pain, and good response to treatment with nonsteroidal anti-inflammatory drugs. In patients with IBP, it is essential to look for other features associated with spondyloarthritis (SpA), such as enthesitis, dactylitis, peripheral arthritis, extra-articular manifestations (eg, psoriasis, uveitis, or inflammatory bowel disease), human leukocyte antigen B27 positivity, and a family history of SpA. Axial SpA is underrecognized, and a delay of several years between symptom onset and diagnosis is common. However, with new and effective therapies available for the treatment of active axSpA, early recognition and diagnosis are of critical importance. For this narrative review, we conducted a literature search of English-language articles using PubMed. Individual searches were performed to identify potential articles of interest related to axSpA (search terms: ["axSpA" OR "axial SpA" OR "axial spondyloarthritis" OR "ankylosing spondylitis"]) in combination with terms related to IBP ("inflammatory back pain" OR "IBP" OR "chronic back pain" OR "CBP" OR "lower back pain" OR "LBP"), diagnosis (["diagn∗" OR "classification"] AND ["criteria" OR "recommend∗" OR "guidelines"]), and referral ("refer∗"). No date range was formally selected, as we were interested in providing an overview of the evolution of these concepts in clinical practice. We supplemented the review with insights based on our clinical expertise. Patients with chronic back pain should be screened for IBP and other SpA features; suspicion for axSpA should trigger referral to a rheumatologist for further evaluation.

Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4+ T cell regulatory elements1–3. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity4,5. Here, we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4+ T cell activation with high-depth RNA-seq in healthy individuals. We discovered widespread, dynamic allele-specific expression across the genome, where the balance of alleles changes over time. These genes were enriched fourfold within autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes. HLA-DQB1 alleles had one of three distinct transcriptional regulatory programs. Using CRISPR–Cas9 genomic editing we demonstrated that a promoter variant is causal for T cell–specific control of HLA-DQB1 expression. Our study shows that genetic variation in cis-regulatory elements affects gene expression in a manner dependent on lymphocyte activation status, contributing to the interindividual complexity of immune responses.

ObjectivesStudies in axial spondyloarthritis (axSpA) have yielded conflicting results regarding the identity of the major IL-17A-producing lymphocyte populations. The goal of this study was to comprehensively assess the production of IL-17A and related cytokines by peripheral blood lymphocytes in axSpA.MethodsPeripheral blood mononuclear cells were isolated from patients with axSpA and healthy controls matched for age, sex and HLA-B27 status. Unstimulated cells and cells activated with PMA/Ionomycin were analyzed by 25-parameter fluorescent flow cytometry. Data were analyzed by hierarchical gating, UMAP and SPICE.ResultsExcept for a reduced frequency of mucosal-associated invariant T (MAIT) cells and natural killer (NK) cells, there were no other significant differences in abundance of major lymphocyte populations in axSpA patients compared with controls. Increased IL-17A production in axSpA was observed in total non-B lymphocytes and in MAIT cells. The fraction of MAIT cells expressing the tissue residency markers CD69 and CD103 was increased in axSpA. CD103 positive MAIT cells were enriched for IL-17A producers. axSpA patients demonstrated an expansion of MAIT cell subsets producing IL-17A, IL-17F, GM-CSF and TNF. This expansion was only observed in HLA-B27+ patients.ConclusionsWe document an expansion of polyfunctional IL-17A+ MAIT cells in the peripheral blood of HLA-B27+ patients with axSpA. These results are consistent with the implied role of intestinal dysbiosis or inflammation in axSpA pathogenesis.Key messagesWhat is already known about this subject? Various IL-17A-producing lymphocyte populations have been implicated in the pathogenesis of axSpA.What does this study add? Polyfunctional MAIT cells capable of producing IL-17A, IL-17F, GM-CSF and TNF are expanded in the peripheral blood of HLA-B27+ patients with axSpA.How might this impact on clinical practice or future developments? Overproduction of IL-17A by MAIT cells is the most consistent finding of peripheral blood lymphocyte studies in axSpA.Our data support the pathogenetic link between intestinal and axial inflammation in axSpA.

Mouse and human data implicate the NOD1 and NOD2 sensors of the intestinal microbiome and the associated signal transduction via the receptor interacting protein kinase 2 (RIPK2) as a potential key signaling node for the development of inflammatory bowel disease (IBD) and an attractive target for pharmacological intervention. The TRUC mouse model of IBD was strongly indicated for evaluating RIPK2 antagonism for its effect on intestinal inflammation based on previous knockout studies with NOD1, NOD2, and RIPK2. We identified and profiled the BI 706039 molecule as a potent and specific functional inhibitor of both human and mouse RIPK2 and with favorable pharmacokinetic properties. We dosed BI 706039 in the spontaneous TRUC mouse model from age 28 to 56 days. Oral, daily administration of BI 706039 caused dose-responsive and significant improvement in colonic histopathological inflammation, colon weight, and terminal levels of protein-normalized fecal lipocalin (all

To critically appraise study designs evaluating spondyloarthritis (SpA) phenotypes in patients with inflammatory bowel disease (IBD). A systematic literature review of PubMed, Ovid, Scopus, Cinahl, Medline, Web of Science, and Cochrane databases was performed. Articles published from January 2000 - March 2020 were included if they evaluated the prevalence/incidence of musculoskeletal disease in cohorts of IBD patients. Most of the 69 included studies were clinic based (54/69, 78%), single center (47/69, 68%) and cross-sectional (60/69, 87%). The median prevalence of axial and peripheral SpA in IBD was 5% (range 1 - 46%) and 16% (range 1 - 43%), respectively. In 38 studies that evaluated axial disease in prospectively enrolled patients, inflammatory back pain was analyzed in 53%. SpA classification criteria were used in 68% and imaging was performed in 76%. In 35 studies that evaluated peripheral disease in prospectively enrolled patients, SpA classification criteria were used in 46%. A physical exam was performed in 74%, and it was performed by a rheumatologist in 54% of studies with a physical exam. Sub-phenotypes of peripheral SpA (mono- or oligo-arthritis, polyarthritis, enthesitis, dactylitis) were variably reported. Seventy-four percent of studies did not mention whether osteoarthritis and fibromyalgia had been assessed or excluded. The spectrum of SpA phenotypes in IBD patients remains incompletely characterized. Future studies should focus on standardizing the variables collected in IBD-SpA cohorts and defining musculoskeletal phenotypes in IBD-SpA in order to better characterize this disease entity and advance the field for clinical and research purposes.

Serum bone turnover markers show diurnal variation in humans, suggesting that circadian rhythms contribute to normal bone physiology. This conclusion is corroborated by bone phenotypes in mice with genetic disruption of the circadian molecular clock mechanism, for instance via deletion of the transcription factor Brain and Muscle Arntl-like 1 (Bmal1). To dissect the contribution of circadian molecular clocks in individual bone cell types, we generated mice with conditional deletion of Bmal1 in osteoclasts (Ctsk-cre) and in mesenchymal cells of the limbs (Prx1-cre). We report that deletion of Bmal1 in osteoclasts had no effect on trabecular or cortical bone parameters in vivo or on osteoclast differentiation in vitro. In contrast, Bmal1(f/f).Prx1-cre mice had significantly less trabecular and cortical bone than Bmal1(f/f) littermate controls, recapitulating the bone phenotype of Bmal1 germline deficient mice. The number of osteoblast precursors in the bone marrow of Bmal1(f/f).Prx1-cre mice was similar to wild-type controls, while the in vitro differentiation capacity of Bmal1-deficient osteoblast precursors, measured as induction of alkaline phosphatase activity, was significantly lower. Despite this, serum procollagen type 1 N-terminal propeptide (P1NP), a measure of bone formation in vivo, was higher in Bmal1(f/f).Prx1-cre mice than in Bmal1(f/f) mice. Consistent with a high bone turnover state in the mutant mice, the bone resorption marker serum C-terminal telopeptides of Type I collagen (CTX-I) was also elevated, and Bmal1(f/f).Prx1-cre mice had a higher number of tartrate resistant acid phosphatase (TRAP) positive osteoclasts than Bmal1(f/f) controls. These results demonstrate that adult bone mass in mice is controlled by the intrinsic circadian molecular clock in mesenchymal cells but not osteoclasts. The effect of the mesenchymal cell clock on bone turnover appears to involve osteoblast-osteoclast cross-talk.

Objective.Pannus formation in the atlanto-axial joint is a well-recognized complication of rheumatoid arthritis (RA). Occasionally, atlanto-axial pannus is reported when patients without a history of RA undergo magnetic resonance imaging (MRI) of the cervical spine. We sought to further characterize these patients.Methods.The Partners HealthCare Research Patient Data Registry was free-text searched for “atlanto-axial” AND “pannus” in cervical spine MRI reports from 2001 to 2015. Cases with MRI reports describing pannus were reviewed. Clinical data were extracted by chart review in cases with confirmed atlanto-axial pannus (n = 105).Results.Twenty-nine patients (27.6%) had RA, all of whom except one carried this diagnosis at the time of the MRI scan. Only 1 of 77 patients without a history of RA was subsequently diagnosed with RA (1.3%, 95% CI 0.1–7.0%, median followup 3.6 yrs). Non-RA patients were significantly older (median age 79 vs 63 yrs, p < 0.0001), less frequently female (55% vs 86%, p = 0.0032), and more likely to have undergone prior cervical spine surgery (18% vs 0%, p = 0.016) compared with RA patients. Thirty-four non-RA patients (44.7%) either had a clinical diagnosis of calcium pyrophosphate dihydrate disease (CPPD) or imaging evidence for tissue calcification. There were no significant differences in age or sex between the CPPD subgroup and other non-RA patients. Twenty-eight patients (26.7%) underwent cervical spine surgery.Conclusion.Patients without RA diagnosis and incidental atlanto-axial pannus on cervical spine MRI are unlikely to have previously unrecognized RA. Degenerative disease and tissue calcification may contribute to pannus formation in these patients.

BackgroundOverexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated.MethodsWe compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8-12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA.FindingsMale B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight.ConclusionsSystemic IL-23 overexpression results in spondyloarthritis-like disease in B10.RIII mice. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests organ-specific genetic control mechanisms of IL-23 driven inflammation. Discrepancies regarding the phenotype of IL-23 induced disease in different labs and the sexual dimorphism observed in this study warrant further exploration.

Background Overexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated. Methods We compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8–12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA. Findings Male B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight. Conclusions The phenotype of IL-23 induced disease in mice is controlled by genetic background and sex of the animals. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests that organ-specificity of IL-23 driven inflammation is genetically determined. The mechanisms behind the strain-specific differences and the sexual dimorphism observed in this study may be relevant for human spondyloarthritis and warrant further exploration.

Purpose of review This review encompasses a detailed history of spondyloarthritis (SpA) evolution as early as the 17th century, continues on to the current concept of SpA, and ends with current gaps in our understandings of SpA. Recent findings Until the early 1960s, ankylosing spondylitis and other SpA family members were considered to be variants of rheumatoid arthritis (RA). The formal medical community separated them from RA at that time, and shortly thereafter they were recognized to be inter-connected based on shared clinical, laboratory, and imaging features. The last two decades have witnessed the formal distinction between axial and peripheral SpA and the connections that exist between nonradiographic and radiographic axial SpA. Recent studies have revealed different microbial compositions among patients with SpA and healthy controls and also between HLA-B27 positive and negative healthy individuals. Summary Further investigation of the roles of intestinal microbiome and physical force transduction toward SpA pathogenesis, strategies to improve delay in SpA diagnosis, biomarkers to better predict radiographic progression, and modification of current classification criteria to better address the axial and peripheral groups are gaps in our understandings that pose top priorities for SpA research.

Scientific breakthroughs have culminated in the development of the spondyloarthritis (SpA) concept as a family of rheumatic diseases, distinct from rheumatoid arthritis. The demonstration of inflammatory lesions in the sacroiliac joints and spine of patients with axial symptoms of SpA who lacked radiographic features of ankylosing spondylitis (AS) helped refine the SpA concept. Axial SpA includes patients with AS and patients with axial symptoms previously categorized as undifferentiated SpA. This review examines the sources of knowledge that inform axial SpA pathogenesis, highlighting current limitations, and a basic working model of axial SpA pathogenesis.

Background:Ixekizumab (IXE), a high-affinity anti-interleukin-17A monoclonal antibody, is effective in patients (pts) with active non-radiographic axial spondyloarthritis (nr-axSpA), who had elevated C-reactive protein (CRP) and/or active sacroiliitis on magnetic resonance imaging (MRI).1Objectives:To determine if disease activity and patient-reported outcomes at Week 16 were similar between groups after stratifying pts by CRP/sacroiliac joint (SIJ) MRI status at baseline.Methods:COAST-X (NCT02757352) included pts with active nr-axSpA and objective signs of inflammation, i.e. presence of sacroiliitis on MRI (Assessment of Spondyloarthritis International Society [ASAS]/ Outcome Measures in Rheumatology criteria) or elevation of serum CRP (>5.0 mg/L). Pts were randomized 1:1:1 to receive subcutaneous 80 mg IXE every 4 weeks (Q4W) or Q2W, or placebo (PBO). Depending on the baseline values of CRP and MRI SIJ (Spondyloarthritis Research Consortium of Canada [SPARCC] score), pts in the intent-to-treat population (N=239) were divided into 3 subgroups (CRP >5 and MRI ≥2; CRP ≤5 and MRI ≥2; CRP >5 and MRI Results:The proportion of pts achieving ASAS40 (primary endpoint), ASDAS 5 and MRI ≥2; CRP ≤5 and MRI ≥2; CRP >5 and MRI Conclusion:Pts with active nr-axSpA and objective signs of inflammation at baseline who were treated with IXE showed an overall improvement in the signs and symptoms of the disease. The efficacy was not different between pts with both elevated CRP and active sacroiliitis on MRI and pts with either elevated CRP or active sacroiliitis on MRI.References:[1]Deodhar A, et al.Lancet.2020.Disclosure of Interests:Walter P Maksymowych Grant/research support from: Received research and/or educational grants from Abbvie, Novartis, Pfizer, UCB, Consultant of: WPM is Chief Medical Officer of CARE Arthritis Limited, has received consultant/participated in advisory boards for Abbvie, Boehringer, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Received speaker fees from Abbvie, Janssen, Novartis, Pfizer, UCB., Helena Marzo-Ortega Grant/research support from: Janssen, Novartis, Consultant of: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Takeda, UCB, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Lianne S. Gensler Grant/research support from: Pfizer, Novartis, UCB, Consultant of: AbbVie, Eli Lilly, GSK, Novartis, UCB, Joerg Ermann Grant/research support from: Boehringer-Ingelheim, Pfizer, Consultant of: Abbvie, Eli Lilly, Janssen, Novartis,Pfizer, Takeda, UCB, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Denis Poddubnyy Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, David Sandoval Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Rebecca Bolce Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Andris Kronbergs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Soyi Liu Leage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Gabriel Doridot Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Vladimir Geneus Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Ann Leung: None declared, David Adams Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Martin Rudwaleit Consultant of: AbbVie, BMS, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB Pharma

Objectives This study aimed to compare comorbidities and biologic DMARD (bDMARD) use between AS and non-radiographic axial SpA (nr-axSpA) patients, using a large cohort of patients from routine clinical practice in the United States. Methods We performed a cross-sectional study using electronic medical records from two academic hospitals in the United States. Data were extracted using automated searches (⩾3 ICD codes combined with text searches) and supplemented with manual chart review. Patients were categorized into AS or nr-axSpA according to classification criteria. Disease features, comorbidities (from a list of 39 chronic conditions) and history of bDMARD prescription were compared using descriptive statistics. Results Among 965 patients identified, 775 (80%) were classified as having axSpA. The cohort was predominantly male (74%) with a mean age of 52.5 years (s.d. 16.8). AS patients were significantly older (54 vs 46 years), more frequently male (77% vs 64%) and had higher serum inflammatory markers than those with nr-axSpA (median CRP 3.4 vs 2.2 mg/dl). Half of all patients had at least one comorbidity. The mean number of comorbidities was 1.5 (s.d. 2.2) and similar between AS and nr-axSpA groups. A history of bDMARD-use was seen in 55% of patients with no difference between groups. The most commonly prescribed bDMARDs were adalimumab (31%) and etanercept (29%). Ever-prescriptions of individual bDMARDs were similar between AS and nr-axSpA. Conclusion Despite age differences, nr-axSpA patients had similar comorbidity burdens as those with AS. Both groups received comparable bDMARD treatment in this United States clinic-based cohort.

ObjectivesTo develop classification algorithms that accurately identify axial SpA (axSpA) patients in electronic health records, and compare the performance of algorithms incorporating free-text data against approaches using only International Classification of Diseases (ICD) codes.MethodsAn enriched cohort of 7853 eligible patients was created from electronic health records of two large hospitals using automated searches (⩾1 ICD codes combined with simple text searches). Key disease concepts from free-text data were extracted using NLP and combined with ICD codes to develop algorithms. We created both supervised regression-based algorithms—on a training set of 127 axSpA cases and 423 non-cases—and unsupervised algorithms to identify patients with high probability of having axSpA from the enriched cohort. Their performance was compared against classifications using ICD codes only.ResultsNLP extracted four disease concepts of high predictive value: ankylosing spondylitis, sacroiliitis, HLA-B27 and spondylitis. The unsupervised algorithm, incorporating both the NLP concept and ICD code for AS, identified the greatest number of patients. By setting the probability threshold to attain 80% positive predictive value, it identified 1509 axSpA patients (mean age 53 years, 71% male). Sensitivity was 0.78, specificity 0.94 and area under the curve 0.93. The two supervised algorithms performed similarly but identified fewer patients. All three outperformed traditional approaches using ICD codes alone (area under the curve 0.80–0.87).ConclusionAlgorithms incorporating free-text data can accurately identify axSpA patients in electronic health records. Large cohorts identified using these novel methods offer exciting opportunities for future clinical research.

Understanding how genetic regulatory variation affects gene expression in different T cell states is essential to deciphering autoimmunity. We conducted a high-resolution RNA-seq time course analysis of stimulated memory CD4+T cells from 24 healthy individuals. We identified 186 genes with dynamic allele-specific expression, where the balance of alleles changes over time. These genes were four fold enriched in autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes, particularly for a major autoimmune risk gene,HLA-DQB1. EachHLA-DQB1allele had one of three distinct transcriptional regulatory programs. Using CRISPR/Cas9 genomic editing we demonstrated that a single nucleotide variant at the promoter is causal for T cell-specific control ofHLA-DQB1expression. Our study in CD4+T cells shows that genetic variation incisregulatory elements may affect gene expression in a lymphocyte activation status-dependent manner contributing to the inter-individual complexity of immune responses.

Introduction Les resultats a la semaine (S) 16 de l’etude COAST-W (NCT02696798) ont montre que l’ixekizumab (IXE) etait superieur au placebo (PBO) sur l’amelioration des signes et symptomes de spondyloarthrite axiale radiographique (r-axSpA) active chez des patients (pts) ayant presente une reponse inadequate (IR) ou une intolerance aux anti-TNF [1] . L’objectif de la presente etude d’extension etait d’evaluer l’efficacite et la tolerance de l’IXE en traitement continu a S52. Patients et methodes Des pts adultes atteints de r-axSpA active (repondant aux criteres ASAS) et ayant presente une reponse inadequate ou une intolerance a 1 ou 2 anti-TNF ont ete randomises (1 :1 :1) pour recevoir un PBO ou 80 mg d’IXE toutes les 2 (IXEQ2 W) ou 4 semaines (IXEQ4 W). A S16 les pts qui recevaient de l’IXE continuaient a recevoir de l’IXE, et les pts recevant un PBO etaient randomises (1 :1) pour recevoir l’IXEQ2 W ou l’IXEQ4 W jusqu’a S52. Resultats Des 212 pts initialement randomises pour recevoir l’IXE, 169 (80 %) ont termine l’etude a S52. Les 2 posologies d’IXE ont conduit au maintien de l’amelioration de l’activite de la maladie jusqu’a S52 (ASAS40 a S16 : IXEQ4 W [n = 98] = 28,6 %, IXEQ2 W [n = 90] = 33,3 % ; ASAS40 a S52 : IXEQ4W = 39,8 %, IXEQ2W = 33,3 % ; ASDAS [1] sur la fonction, les signes objectifs d’inflammation, la qualite de vie, l’etat de sante et la fonction globale ont ete maintenues voire ameliorees jusqu’a S52. Les pts initialement randomises pour recevoir un PBO et qui ont switche sous IXE ont rapidement atteint des niveaux d’amelioration de leurs signes et symptomes similaires a ceux observes chez les pts initialement randomises pour recevoir l’IXE (PBO puis IXEQ4 W ou IXEQ2 W [n = 93] : ASAS40 a S16 = 14,0 % ; ASAS40 a S52 = 38,7 % ; ASDAS [1] . Conclusion Ces resultats sont les premieres donnees a long terme d’efficacite et de tolerance de l’IXE dans la r-axSpA chez des pts ayant presente une reponse inadequate ou une intolerance aux anti-TNF. Les 2 posologies d’IXE ont montre une amelioration similaire des signes et symptomes et maintenue jusqu’a S52, sans nouveau signal de tolerance. Ces resultats montrent que chez les patients atteints de r-axSpA et ayant presente une reponse inadequate ou une intolerance a 1 ou 2 anti-TNF, l’IXE, un anti-IL17A, constitue une alternative therapeutique.

High-dimensional single-cell analyses have improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging because of technical and interindividual variation. Here, we present mixed-effects modeling of associations of single cells (MASC), a reverse single-cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounders and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from the blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4+ T cells, identified as CD27- HLA-DR+ effector memory cells, in RA patients (odds ratio, 1.7; P = 1.1 × 10-3). The frequency of CD27- HLA-DR+ cells was similarly elevated in blood samples from a second RA patient cohort, and CD27- HLA-DR+ cell frequency decreased in RA patients who responded to immunosuppressive therapy. Mass cytometry and flow cytometry analyses indicated that CD27- HLA-DR+ cells were associated with RA (meta-analysis P = 2.3 × 10-4). Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained about fivefold higher frequencies of CD27- HLA-DR+ cells, which comprised ~10% of synovial CD4+ T cells. CD27- HLA-DR+ cells expressed a distinctive effector memory transcriptomic program with T helper 1 (TH1)- and cytotoxicity-associated features and produced abundant interferon-γ (IFN-γ) and granzyme A protein upon stimulation. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single-cell data.

Retro-odontoid pseudotumor, or mass-like retro-odontoid soft tissue thickening, is an uncommon but important imaging finding that may be associated with rheumatoid arthritis, crystal deposition diseases, as well as non-inflammatory conditions such as cervical degenerative changes and mechanical alterations. Retro-odontoid pseudotumor is commonly associated with atlantoaxial microinstability or subluxation. MRI and CT have an important role in the detection and diagnosis of retro-odontoid pseudotumor. However, due to a wide range of imaging characteristics and ambiguous etiology, it is a frequently misunderstood entity. The purpose of this article is to review relevant anatomy of the craniocervical junction; describe various imaging appearances, pathophysiology and histology in both rheumatoid and non-rheumatoid etiologies; and discuss differential diagnosis of retro-odontoid pseudotumor in order to help guide clinical management.

Multiple regulatory mechanisms control osteoblast differentiation and function to ensure unperturbed skeletal formation and remodeling. In this study we identify histone lysine-specific demethylase 1(LSD1/KDM1A) as a key epigenetic regulator of osteoblast differentiation. Knockdown of LSD1 promoted osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro and mice lacking LSD1 in mesenchymal cells displayed increased bone mass secondary to accelerated osteoblast differentiation. Mechanistic in vitro studies revealed that LSD1 epigenetically regulates the expression of WNT7B and BMP2. LSD1 deficiency resulted in increased BMP2 and WNT7B expression in osteoblasts and enhanced bone formation, while downregulation of WNT7B- and BMP2-related signaling using genetic mouse model or small-molecule inhibitors attenuated bone phenotype in vivo. Furthermore, the LSD1 inhibitor tranylcypromine (TCP) could increase bone mass in mice. These data identify LSD1 as a novel regulator of osteoblast activity and suggest LSD1 inhibition as a potential therapeutic target for treatment of osteoporosis., Epigenetics: Taking the brakes off bone formation A molecular brake controlling the differentiation of bone-forming osteoblasts has been identified, which could provide a new therapeutic target for osteoporosis. LSD1 regulates the expression of various genes by interfering with the ability of the cellular machinery to bind to DNA and transcribe it. A previous study had suggested that inhibiting LSD1 in stem cells from human fat promoted the formation of new osteoblasts. To further investigate its role in bone development, Weiguo Zou at the Shanghai Institute of Biochemistry and Cell Biology and colleagues engineered mice which lacked LSD1 in their mesenchymal cells–precursors of bone, muscle and fat cells—the animals had increased numbers of osteoblasts and greater bone mass. Further experiments revealed that blocking LSD1 resulted in increased expression of two osteoblast-stimulating factors, although it may also influence bone resorbing osteoclasts.

Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA., The treatment of inflammatory arthritis by local delivery of therapeutics is limited by short half-lives of drugs. Here the authors demonstrate a hydrogel platform that titrates drug release to arthritis activity.

Objective To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). Methods A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946–2014), PubMed (1966–2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. Results In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. Conclusion These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

Biomarkers are needed to guide treatment decisions for patients with rheumatic diseases. Although the phenotypic and functional analysis of immune cells is an appealing strategy for understanding immune-mediated disease processes, immune cell profiling currently has no role in clinical rheumatology. New technologies, including mass cytometry, gene expression profiling by RNA sequencing (RNA-seq) and multiplexed functional assays, enable the analysis of immune cell function with unprecedented detail and promise not only a deeper understanding of pathogenesis, but also the discovery of novel biomarkers. The large and complex data sets generated by these technologies--big data--require specialized approaches for analysis and visualization of results. Standardization of assays and definition of the range of normal values are additional challenges when translating these novel approaches into clinical practice. In this Review, we discuss technological advances in the high-dimensional analysis of immune cells and consider how these developments might support the discovery of predictive biomarkers to benefit the practice of rheumatology and improve patient care.

High dimensional single-cell analyses have dramatically improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging due to technical and inter-individual variation. Here we present Mixed effects modeling of Associations of Single Cells (MASC), a novel reverse single cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounds and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4+ T cells, identified as CD27- HLA-DR+ effector memory cells, in RA patients (OR = 1.7; p = 1.1 × 10−3). The frequency of CD27- HLA-DR+ cells was similarly elevated in blood samples from a second RA patient cohort, and CD27- HLA-DR+ cell frequency decreased in RA patients who respond to immunosuppressive therapy. Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained ∼5-fold higher frequencies of CD27- HLA-DR+ cells, which comprised ∼10% of synovial CD4+ T cells. We find that CD27- HLA-DR+ cells are abundant producers of IFN-γ and also express perforin and granzyme A at elevated levels. Thus MASC identified the expansion of a unique Th1 skewed effector T cell population with cytotoxic capacity in RA. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single cell data.One Sentence SummaryMixed-effects regression of single cells identifies a cytotoxic Th1-like CD4+ T cell subset while accounting for inter-individual and technical variation.

Systemic sclerosis (SSc) is a potentially fatal autoimmune disorder with limited therapeutic options. Sclerodermatous graft versus host disease (sclGvHD), induced by transfer of B10.D2 splenocytes into BALB/c Rag2–/– mice, models an inflammatory subset of SSc characterized by a prominent IL13-induced gene expression signature in the skin. Host mice deficient in IL4RA, a subunit of the type II IL4/IL13 receptor, are protected from sclGvHD. While IL4RA has a well-established role in Th2 differentiation and alternative macrophage activation, we report here a previously unappreciated function for IL4RA in lymphatic endothelial cells (LECs): regulation of activated T cell egress. Seven days after splenocyte transfer, Il4ra–/– hosts had increased numbers of activated graft CD4+ T cells in skin draining lymph nodes (dLNs) but fewer T cells in efferent lymph, blood, and skin. Sphingosine-1 phosphate (S1P), master regulator of lymphocyte egress from LNs, was lower in dLNs of Il4ra–/– hosts with a corresponding decrease of S1P kinase 1 (Sphk1) expression in LECs. Bypassing the efferent lymphatics via i.v. injection of CD4+ T cells from dLNs of Il4ra–/– sclGvHD mice restored clinical GvHD in secondary Il4ra–/– recipients. These results identify a role for IL4RA and suggest that modulation of lymphocyte egress from LNs may be effective in SSc and GvHD.

Osteochondromas are common benign osteocartilaginous tumors in children and adolescents characterized by cartilage-capped bony projections on the surface of bones. These tumors often cause pain, deformity, fracture, and musculoskeletal dysfunction, and they occasionally undergo malignant transformation. The pathogenesis of osteochondromas remains poorly understood. Here, we demonstrate that nuclear factor of activated T cells c1 and c2 (NFATc1 and NFATc2) suppress osteochondromagenesis through individual and combinatorial mechanisms. In mice, conditional deletion of NFATc1 in mesenchymal limb progenitors, Scleraxis-expressing (Scx-expressing) tendoligamentous cells, or postnatally in Aggrecan-expressing cells resulted in osteochondroma formation at entheses, the insertion sites of ligaments and tendons onto bone. Combinatorial deletion of NFATc1 and NFATc2 gave rise to larger and more numerous osteochondromas in inverse proportion to gene dosage. A population of entheseal NFATc1- and Aggrecan-expressing cells was identified as the osteochondroma precursor, previously believed to be growth plate derived or perichondrium derived. Mechanistically, we show that NFATc1 restricts the proliferation and chondrogenesis of osteochondroma precursors. In contrast, NFATc2 preferentially inhibits chondrocyte hypertrophy and osteogenesis. Together, our findings identify and characterize a mechanism of osteochondroma formation and suggest that regulating NFAT activity is a new therapeutic approach for skeletal diseases characterized by defective or exaggerated osteochondral growth.

Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1(R206H) knock-in allele recapitulate the phenotypic spectrum of FOP, including injury-responsive intramuscular HO and spontaneous articular, tendon, and ligament ossification. The cells that drive HO in these diverse tissues can be compartmentalized into two lineages: an Scx(+) tendon-derived progenitor that mediates endochondral HO of ligaments and joints without exogenous injury, and a muscle-resident interstitial Mx1(+) population that mediates intramuscular, injury-dependent endochondral HO. Expression of Acvr1(R206H) in either lineage confers aberrant gain of BMP signaling and chondrogenic differentiation in response to activin A and gives rise to mutation-expressing hypertrophic chondrocytes in HO lesions. Compared to Acvr1(R206H), expression of the man-made, ligand-independent ACVR1(Q207D) mutation accelerates and increases the penetrance of all observed phenotypes, but does not abrogate the need for antecedent injury in muscle HO, demonstrating the need for an injury factor in addition to enhanced BMP signaling. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr(1R206H) knock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. Thus, diverse phenotypes of HO found in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in nonoverlapping tissue-resident progenitor pools that may be addressed by systemic therapy or by modulating injury-mediated factors involved in their local recruitment.

The genetic basis of human autoimmune diseases remains incompletely understood, despite significant progress from genome-wide association studies (GWAS). In this review we outline how studies in mice may help filling these knowledge gaps. Forward genetic approaches including mutagenesis screens and quantitative trait locus (QTL) mapping studies can identify candidate genes for in depth analysis in human patient populations. Reverse genetic approaches utilize genetically engineered mice to analyze the function of disease-associated genes and their variants. Inbred strains are a distinctive feature of mouse genetics and we discuss their history, advantages and disadvantages. Three factors need to be considered when comparing experimental results from studies in mice and humans: In addition to species-specific differences, phenotypes are affected by the genetic background of the mouse strain being analyzed, and by microbial factors. Despite of these complexities, mice are essential discovery tools in the post GWAS era.

Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA.

Summary Background: Systemic lupus erythematosus (SLE) is a heterogenous disease with complex pathogenesis. Aim: In this review, we summarise recent progress in the understanding of SLE pathogenesis and discuss implications for the treatment of SLE patients using standard and experimental medications. Conclusions: The discovery that Toll-like receptor signalling and interferon-α abundance are central elements of the disease process has led to a new appreciation for hydroxychloroquine as an essential baseline medication. Although much needs to be learned, modulation of the immune system via B-cell depletion is entering clinical practice. Mycophenolate mofetil is an effective and safer alternative to cyclophosphamide for many patients with lupus nephritis. Several other therapeutic approaches are at various stages of preclinical and clinical development. These include anticytokine therapies, co-stimulatory blockade, antigen-specific immune modulation and haematopoietic stem cell transplantation.

There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD.

Recent advances have dramatically increased our understanding of how organ systems interact. This has been especially true for immunology and bone biology, where the term “osteoimmunology” was coined to capture this relationship. The importance of the microbiome to the immune system has also emerged as a driver of health and disease. It makes sense therefore to ask the question: how does the intestinal microbiome influence bone biology and does dysbiosis promote bone disease? Surprisingly, few studies have analyzed this connection. A broader interpretation of this question reveals many mechanisms whereby the microbiome may affect bone cells. These include effects of the microbiome on immune cells, including myeloid progenitors and Th17 cells, as well as steroid hormones, fatty acids, serotonin and vitamin D. As mechanistic interactions of the microbiome and skeletal system are revealed within and without the immune system, novel strategies to optimize skeletal fitness may emerge.

CD4+CD25+ regulatory T cells (Treg) acquire unique immunosuppressive properties while maintaining an anergy phenotype when activated in vitro under conditions that induce IL-2 production and proliferation in conventional CD4+ T cells. We investigated the mechanism underlying one component of this naturally anergic phenotype, the inability of the Treg cells to produce IL-2 following activation. Analysis of freshly isolated murine CD4+CD25+ Treg and conventional CD4+CD25− T cells following PMA/ionomycin stimulation demonstrated no differences in inducible AP-1 formation, an important transcriptional complex in regulating IL-2 gene expression. Although p38 MAPK and ERK1/2 protein kinases were phosphorylated with similar kinetics, we observed diminished activation of JNK in the CD4+CD25+ Treg cells. However, lentiviral-mediated reconstitution of the JNK pathway using a constitutively active construct did not overcome the block in IL-2 synthesis. Using a PCR-based chromatin accessibility assay we found that the minimal IL-2 promoter region of CD4+CD25+ Treg cells, unlike conventional CD4 T cells, did not undergo chromatin remodeling following stimulation, suggesting that the inability of CD4+CD25+ Treg cells to secrete IL-2 following activation is controlled at the chromatin level.

Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4(+)CD25(+) regulatory T (T(reg)) cells have recently been shown to suppress proliferative responses of CD4(+)CD25(-) T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization of donor T cells, which results in their reduced potential to induce aGVHD. Here we show that CD4(+)CD25(+) T cells isolated from the spleen or BM of donor C57BL/6 (H-2(b)) mice that have not been tolerized are still potent inhibitors of the alloresponse in vitro and of lethal aGVHD induced by C57BL/6 CD4(+)CD25(-) T cells in irradiated BALB/c (H-2(d)) hosts in vivo. The addition of the CD4(+)CD25(+) T(reg) cells at a 1:1 ratio with responder/inducer CD4(+)CD25(-) T cells resulted in a90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD. This protective effect depended in part on the ability of the transferred CD4(+)CD25(+) T cells to secrete interleukin 10 and occurred if the T(reg) cells were of donor, but not host, origin. Our results demonstrate that the balance of donor-type CD4(+)CD25(+) T(reg) and conventional CD4(+)CD25(-) T cells can determine the outcome of aGVHD.

T-bet(-/-).Rag2(-/-) (TRUC) mice spontaneously develop microbiota-driven, TNF-mediated large bowel inflammation that resembles human ulcerative colitis. We show here that IL-23 and IL-1-dependent secretion of IL-17A by innate lymphoid cells (ILCs; defined as CD45(+)lin(-)Thy1(hi)NKp46(-)) is a second critical pathway in this model. Using an in vitro coculture system of bone marrow-derived dendritic cells (DCs) and freshly isolated FACS-purified ILCs, we demonstrate that IL-23 and IL-1 secreted by DCs in response to microbial stimulation work together to induce IL-17A production by ILCs. TNF is not required for IL-17A secretion by ILCs in vitro but synergizes with IL-17A to induce the expression of neutrophil-attracting chemokines. Upstream, activation of the IL-23/IL-17A axis is regulated by nucleotide-binding oligomerization domain containing (Nod)/receptor-interacting serine-threonine kinase 2 (Ripk2) signals in DCs. Genetic ablation of the Nod/Ripk2 signaling pathway protects TRUC mice from developing colitis without affecting the colitogenicity of the intestinal microbiota. Our data provide insight into the complex network of interactions between IL-17A-secreting ILCs and other components of the innate immune system in the development of colitis.

Genetic modifier loci influence the phenotypic expression of many Mendelian traits; insight into disease pathogenesis gained from their identification in animal disease models may impact the treatment of human multigenic disorders. We previously described an innate immune-driven model of spontaneous ulcerative colitis in T-bet −/− .Rag2 −/− double-deficient mice that resembles human ulcerative colitis. On a BALB/c background, this disease is highly penetrant and results in the development of colorectal cancer. However, we observed that colitis in T-bet −/− .Rag2 −/− mice on a C57BL/6 background was significantly less severe. Quantitative trait locus analysis using an N2 backcross strategy revealed a single major quantitative trait locus on chromosome 3 that mapped to the Cdcs1 (cytokine deficiency-induced colitis susceptibility-1) locus previously identified in the Il10 −/− and Gnai2 −/− colitis models. Congenic introduction of the susceptible Cdcs1 interval from C3H/He into the C57BL/6 background restored colitis severity. Bone marrow reconstitution experiments further mapped the effect of host genetics on disease severity to the hematopoietic compartment. There were distinct differences in the expression of several Cdcs1 genes in bone marrow-derived dendritic cells from Cdcs1 congenic mice. We conclude that the Cdcs1 locus controls colitis severity in T-bet −/− .Rag2 −/− mice through innate immune cells.

The goal of this study was to compare the ability of donor naive and alloantigen-primed effector memory T cells to induce graft-vs-host disease after bone marrow transplantation in MHC-mismatched irradiated host mice. Purified CD4+ naive (CD62LhighCD44low) T cells and CD4+ effector memory (CD62LlowCD44high) T cells obtained from unprimed donors and donors primed to host alloantigens, respectively, were injected into host mice, and the rapidity, severity, and pattern of tissue injury of graft-vs-host disease was assessed. Unexpectedly, the naive T cells induced a more acute and severe colitis than the primed memory cells. Whereas the naive T cells expressing CD62L and CCR7 lymph node homing receptors vigorously expanded in mesenteric lymph nodes and colon by day 6 after transplantation, the primed memory T cells without these receptors had 20- to 100-fold lower accumulation at this early time point. These differences were reflected in the significantly more rapid decline in survival and weight loss induced by naive T cells. The primed memory T cells had a greater capacity to induce chronic colitis and liver injury and secrete IL-2 and IFN-γ in response to alloantigenic stimulation compared with memory T cells from unprimed donors. Nevertheless, the expected increase in potency as compared with naive T cells was not observed due to differences in the pattern and kinetics of tissue injury.