Distribution Of Inflammatory Lesions Research Articles

Peripheral Joint and Enthesis Involvement in Patients With Newly Diagnosed Inflammatory Bowel Disease: Symptoms, and Clinical and Ultrasound Findings - A Population-Based Cohort Study.

Musculoskeletal [MSK] manifestations in patients with inflammatory bowel disease [IBD] are common and associated with poorer outcomes. Hence, early detection is important to optimally tailor treatment. We aimed to determine the prevalence and distribution of inflammatory lesions in peripheral joints and entheses in newly diagnosed IBD patients. Patients with newly diagnosed IBD from a prospective population-based inception cohort were consecutively included. Data on MSK symptoms were collected by questionnaires and by structured rheumatological interview. Peripheral joints and entheses were assessed clinically and by ultrasound [US], using standardized definitions. Of 110 included patients (mean age: 42 years, 40% male, 70 with ulcerative colitis [UC], 40 with Crohn's disease [CD]), a history of ≥1 peripheral musculoskeletal symptom was reported by 49%. Clinical examination revealed peripheral MSK manifestations in 56 [52.3%] patients; 29 [27.1%] had ≥1 tender and/or swollen joints and 49 [45.8%] ≥1 tender entheses. Small peripheral joints were predominantly affected. US found inflammation in ≥1 joint or enthesis in 52 [49.5 %] patients; 29 [27.4 %] had US synovitis in ≥1 joint, while 36 [34%] had US enthesitis. Fibromyalgia classification criteria were fulfilled in seven [7.9%] patients. There was no difference in clinical or US findings between patients with UC and CD, nor between patients with active and inactive IBD. Half of the patients with newly diagnosed IBD had inflammation in their peripheral joints and/or entheses, documented by rheumatological clinical and US evaluations. This indicates a need for multidisciplinary collaboration to ensure an optimal therapeutic strategy for suppressing inflammation in all disease domains.

Acquired Hematologic Disorders of Ras-MAPK Activation

Histiocytic disorders represent a collection of conditions characterized by aberrant function, differentiation and/or proliferation of cells of the mononuclear phagocyte system (MPS). “Histiocyte” is an archaic term (meaning “tissue cell”) used to describe phagocytic cells with mononuclear morphology. Clinical approaches to histiocytic disorders have historically been challenged by incomplete understanding of mechanisms of pathogenesis, with debate over classification as cancer versus immune dysregulation. Langerhans cell histiocytosis (LCH), the most common histiocytic disorder, presents with granulomatous lesions with clonal CD207+ dendritic cells (DCs) that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable regardless of disease severity. Erdheim-Chester disease (ECD) arises in adults and is characterized by distribution of inflammatory lesions with CD163+ foamy histiocytes involving bone, retroperitoneum/kidney, skin and/or brain. Juvenile xanthogranuloma (JXG), histologically similar to ECD, is typically skin-limited in children, but may also manifest as life-threatening systemic disease. Classical Rosai-Dorfman disease (RDD) presents in children as lymphadenopathy with CD163+ histiocytes and emperipolesis identified in lymph node biopsy, though RDD likely represents a spectrum of conditions in children and adults with a common histiological endpoint. Classification of histiocytic disorders has been based on phenotype of the pathologic cell: LCH (DC-like), non-LCH (macrophage-like), or malignant histiocytosis. BRAFV600E was the first recurrent somatic mutation identified in LCH and ECD. While occurring in 7% of all human cancers, BRAFV600E mutations are also frequently found in benign conditions such as melanocytic nevi and colon polyps. Whole exome sequencing of LCH, ECD, RDD and JXG biopsies has revealed mutually exclusive MAPK pathway activating mutations within otherwise “quiet” genomic landscapes. In LCH, the stage of myeloid differentiation in which the mutation arises defines the extent of disease, and MAPK activation in precursor cells drives myeloid differentiation, blocks migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic DCs that recruit and activate T cells. These new insights support reclassification of these histiocytic disorders as myeloproliferative neoplasms (MPN). Early phase trials in adults with LCH and ECD and emerging pediatric case studies demonstrate promising responses to MAPK pathway inhibitors, though potential for cure and long-term safety are not known. MAPK pathway activation clearly drives pathogenesis in histiocytic MPNs. However, it remains unclear how pathway activation, in many cases with the same mutation in the same CD34+ hematopoietic stem cell, can produce distinct cellular phenotypes with characteristic tissue distribution. While we now are beginning to understand the framework for mechanisms of pathogenesis of histiocytic disorders, continued research will uncover opportunities to identify additional targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation and inherited risk factors. DisclosuresNo relevant conflicts of interest to declare.

An IFN\u03b3/CXCL2 regulatory pathway determines lesion localization during EAE

BackgroundMyelin oligodendrocyte glycoprotein (MOG)-reactive T-helper (Th)1 cells induce conventional experimental autoimmune encephalomyelitis (cEAE), characterized by ascending paralysis and monocyte-predominant spinal cord infiltrates, in C57BL/6 wildtype (WT) hosts. The same T cells induce an atypical form of EAE (aEAE), characterized by ataxia and neutrophil-predominant brainstem infiltrates, in syngeneic IFNγ receptor (IFNγR)-deficient hosts. Production of ELR+ CXC chemokines within the CNS is required for the development of aEAE, but not cEAE. The cellular source(s) and localization of ELR+ CXC chemokines in the CNS and the IFNγ-dependent pathways that regulate their production remain to be elucidated.MethodsThe spatial distribution of inflammatory lesions and CNS expression of the ELR+ CXC chemokines, CXCL1 and CXCL2, were determined via immunohistochemistry and/or in situ hybridization. Levels of CXCL1 and CXCL2, and their cognate receptor CXCR2, were measured in/on leukocyte subsets by flow cytometric and quantitative PCR (qPCR) analysis. Bone marrow neutrophils and macrophages were cultured with inflammatory stimuli in vitro prior to measurement of CXCL2 and CXCR2 by qPCR or flow cytometry.ResultsCNS-infiltrating neutrophils and monocytes, and resident microglia, are a prominent source of CXCL2 in the brainstem of IFNγRKO adoptive transfer recipients during aEAE. In WT transfer recipients, IFNγ directly suppresses CXCL2 transcription in microglia and myeloid cells, and CXCR2 transcription in CNS-infiltrating neutrophils. Consequently, infiltration of the brainstem parenchyma from the adjacent meninges is blocked during cEAE. CXCL2 directly stimulates its own expression in cultured neutrophils, which is enhanced by IL-1 and suppressed by IFNγ.ConclusionsWe provide evidence for an IFNγ-regulated CXCR2/CXCL2 autocrine/paracrine feedback loop in innate immune cells that determines the location of CNS infiltrates during Th1-mediated EAE. When IFNγ signaling is impaired, myeloid cell production of CXCL2 increases, which promotes brainstem inflammation and results in clinical ataxia. IFNγ, produced within the CNS of WT recipients, suppresses myeloid cell CXCR2 and CXCL2 production, thereby skewing the location of neuroinflammatory infiltrates to the spinal cord and the clinical phenotype to an ascending paralysis. These data reveal a novel mechanism by which IFNγ and CXCL2 interact to direct regional recruitment of leukocytes in the CNS, resulting in distinct clinical presentations.

P295 Atypical distribution of inflammatory lesions in ulcerative colitis: is it really rare?

P294 Back pain in inflammatory bowel disease patients L. Brakenhoff1 *, R. van den Berg2, F. van Gaalen2, A. van der Meulen-de Jong1, T. Huizinga2, D. van der Heijde2, D. Hommes3, H. Fidder4. 1Leiden University Medical Center, Gastroenterology and Hepatology, Leiden, Netherlands, 2Leiden University Medical Center, Rheumatology, Leiden, Netherlands, 3University of California Los Angeles, Center for Inflammatory Bowel Diseases, Los Angeles, United States, 4University Medical Center Utrecht, Gastroenterology and Hepatology, Utrecht, Netherlands

Efficacy of tacrolimus in Sjögren’s syndrome-associated CNS disease with aquaporin-4 autoantibodies

Sirs, We present two patients with central nervous system (CNS) disease associated with Sjogren’s syndrome (SjS) and positive for antiaquaporin-4 water channel autoantibodies (AQP4-Ab) who were treated successfully with tacrolimus. Tacrolimus is an immunosuppressant that acts as a calcineurin inhibitor and suppresses T helper 2 (Th2) cells [1]. Tacrolimus may also act as a neuroprotectant by reducing axonal and myelin damage, as shown in a mouse model of experimental autoimmune encephalomyelitis [2]. SjS is a chronic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands. SjS-associated inflammation sometimes spreads into the CNS (CNS–SjS), occasionally mimics relapsing-remitting multiple sclerosis (MS), and inflammation often involves the brain, spinal cord, and optic nerve [3]. Neuromyelitis optica (NMO) is also a relapsing inflammatory disease of the CNS, characterized by severe attacks of optic nerve neuritis and longitudinally extensive transverse myelitis [4]. NMO is distinguished from MS by the presence of AQP4-Ab and differences in the distribution of inflammatory lesions and pathological findings. Combination therapy with a corticosteroid and azathioprine is the current standard treatment for preventing NMO relapse [5]; however, some patients are refractory to this therapy. Approximately 3% of patients with NMO have coexisting systemic lupus erythematosus (SLE) or SjS, and CNS–SjS patients with optic nerve neuritis or longitudinal myelitis (conditions called ‘‘NMO spectrum disorder’’) often present with positive findings for AQP4-Ab [4, 6, 7]. To our knowledge, this is the first reported assessment of tacrolimus in patients with CNS–SjS with AQP4-Ab. This treatment was approved by the ethical committee of our university, and the patients provided written informed consent. A 48-year-old female (Patient 1, Fig. 1) was admitted to the hospital with rapidly progressive nausea, hiccups, dysphagia, and drowsiness. Magnetic resonance imaging (MRI) revealed T2 hyperintensities of the hypothalamus bilaterally and the dorsal medulla oblongata. After three courses of intravenous high-dose methylprednisolone (IHMP, 1 g/day for 3 days in one course), the patient recovered completely, except for mild dysphagia. One year after the first attack, she developed limb weakness. Laboratory test results revealed high levels of anti-Ro (SSA) antibodies and positive antinuclear antibody. The Schirmer test and the Saxon test revealed decreased salivary secretion (Table 1). She was diagnosed with CNS–SjS [8]. She experienced nine attacks during the entire disease course, and we started treatment with oral tacrolimus during her ninth admission. No recurrent attacks have been observed for 49 months since the start of this treatment. T. Fukuda (&) H. Shiraishi H. Nakamura A. Tsujino Y. Nishiura M. Motomura K. Eguchi First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan e-mail: taku-ngs@umin.ac.jp

Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100 beta molecule, a calcium binding protein of astroglia.

The pathogenic potential of autoimmune T cell responses to nonmyelin autoantigens was investigated in the Lewis rat using the astrocyte-derived calcium binding protein S100 beta, as a model nonmyelin autoantigen. The Lewis rat mounts a vigorous RT1B1 (major histocompatibility complex class II) restricted autoimmune response to an immunodominant S100 beta epitope (amino acid residues 76-91). The adoptive transfer of S100 beta-specific T cell lines induced a severe inflammatory response in the nervous system, but only minimal neurological dysfunction in naive syngeneic recipients. The inability of S100 beta-specific T cell transfer to induce severe disease was associated with a decreased recruitment of ED1+ macrophages into the central nervous system (CNS) in comparison with that seen in severe experimental autoimmune encephalomyelitis (EAE) induced by the adoptive transfer of myelin basic protein (MBP)-specific T line cells. Moreover, unlike encephalitogenic MBP-specific T cell lines, S100 beta-specific T cell lines exhibited no cytotoxic activity in vitro. Histopathological analysis also revealed striking differences in the distribution of inflammatory lesions in MBP- and S100 beta-specific T cell-mediated disease. In contrast to the MBP paradigm, S100 beta-specific T cell transfer induces intense inflammation not only in the spinal cord, but throughout the entire CNS and also in the uvea and retina of the eye. In view of the distribution of lesions throughout the grey and white matter of the CNS we propose to term this new model experimental autoimmune panencephalomyelitis (EAP) to differentiate it from EAE. These experiments demonstrate for the first time that nonmyelin CNS autoantigens can initiate a pathogenic autoimmune T cell response, although the nature of the target autoantigen profoundly influences the clinical and histopathological characteristics of the resulting autoimmune disease. This is not simply a consequence of the distribution of the autoantigen, as both MBP and S100 beta are coexpressed in many areas of the CNS, but reflects differences in the capacity of different regions of the CNS to process and present specific autoantigens. This new model of T cell-mediated autoimmune CNS disease exhibits a number of similarities to multiple sclerosis (MS), such as its mild clinical course and the involvement of areas of the brain and eye, which are absent in myelin-mediated models of EAE. Nonmyelin autoantigens may therefore play an unexpectedly important role in the immunopathogenesis of inflammatory diseases of the CNS.

Experimental allergic orchitis in mice. VII. Preliminary characterization of the aspermatogenic autoantigens responsible for eliciting actively and passively induced disease

Experimental allergic orchitis (EAO) can be induced actively and passively in mice by either immunization with mouse testicular homogenate (MTH) in conjunction with the appropriate adjuvants or by transferring CD4 + T cells isolated from sensitized donors into non-immunized, naive recipients. The distribution of inflammatory lesions seen in active and passive EAO are markedly different. In active EAO maximal disease is observed in the seminiferous tubules, whereas in passive EAO lesions occur primarily in the straight tubules, rete testis, and ductus efferentes. These observations suggest that different immunopathogenic mechanisms and/or aspermatogenic autoantigens may be responsible for the distinct histopathologic profiles. Two murine testis-specific aspermatogenic autoantigens (mAP1 and mAP2) were partially purified from MT acetone powder by extraction in 7-M urea under reducing conditions, gel filtration, ion-exchange chromatography, and preparative isoelectric focusing from pH 3 to 10. In gel filtration on Sephacryl S-400 in 7-M urea, mAP1 is confined to the V 0 peak, while mAP2 is in the major included peak. mAP1 has an isoelectric point of 4.4–4.9, is sensitive to both pronase and DNase but not RNase, and is active at a minimal dose of 250–500 μg (dry wt). Dose-response bioassays for active and passive EAO revealed that mAP1 preferentially elicits active disease, whereas mAP2 is most effective at eliciting passive disease. These results support the concept that the different histopathologic profiles seen in active and passive EAO are, in part, the result of different immunopathologic responses elicited by separate aspermatogenic autoantigens.