Antigen Presentation by MHC Class I and CD1 Molecules

Antigen presentation is the “sine qua non” of the mammalian adaptive immune system. The assembly of MHC class I/peptide complexes in the endoplasmic reticulum (ER) relies on the orchestrated interplay between different chaperonins, which assist MHC class I folding, and the peptide loading complex (PLC). Mutant lymphoblastoid cell lines with defective MHC class I surface expression have greatly helped the functional analysis of the PLC. The TAP transporter associated with antigen processing translocates MHC class I peptide ligands from the cytosol into the ER and is critical for successful MHC class I assembly and maturation. In the first two results chapters of this thesis I will describe the identification, clinical description and molecular and genetic analysis of a new clinical syndrome in a group of patients with dramatically reduced MHC class I surface expression. The disease in these patients could be identified as primary TAP-deficiency. Mycobacterial infections were conspicuously absent in these TAP-deficient patients whereas TAP-deficient mice are known to be highly susceptible to mycobacteria. The focus of the third and fourth chapter of this thesis lies on lipid antigen presentation via CD1 molecules, which are known to present mycobacterial lipids to T lymphocytes. The first objective of this thesis was to generate recombinant mycobacterial lipid loaded CD1 molecules as tools to measure mycobacterial lipid specific T cell responses in the TAP-deficient patients. Chapters three and four describe novel protocols for the generation of recombinant human CD 1b and CD 1d molecules with loaded single lipid species

TAP deficiency syndrome: chronic rhinosinusitis and conductive hearing loss

Nose-ear-throat manifestations of immunodeficiency disorders represent a diagnostic challenge for clinicians as these diseases often constitute the initial sign for connective disorders or autoimmune disease. The history of chronic rhinosinusitis and conductive hearing loss is often non specific. Therefore attention to an HLA class I deficiency must be considered if the disease has not been diagnosed on routine examination. One of the syndromes is due to a defective TAP complex, the peptide transporter complex associated with antigen presentation. Herein, we report two sisters with TAP-deficiency. The treatment of choice for TAP-deficient patients is conservativ

Innate and adaptive T cells in asthmatic patients: relationship to severity and disease mechanisms

BackgroundAsthma is a chronic inflammatory disease involving diverse cells and mediators whose interconnectivity and relationships to asthma severity are unclear.ObjectiveWe performed a comprehensive assessment of TH17 cells, regulatory T cells, mucosal-associated invariant T (MAIT) cells, other T-cell subsets, and granulocyte mediators in asthmatic patients.MethodsSixty patients with mild-to-severe asthma and 24 control subjects underwent detailed clinical assessment and provided induced sputum, endobronchial biopsy, bronchoalveolar lavage, and blood samples. Adaptive and invariant T-cell subsets, cytokines, mast cells, and basophil mediators were analyzed.ResultsSignificant heterogeneity of T-cell phenotypes was observed, with levels of IL-13–secreting T cells and type 2 cytokines increased at some, but not all, asthma severities. TH17 cells and ??-17 cells, proposed drivers of neutrophilic inflammation, were not strongly associated with asthma, even in severe neutrophilic forms. MAIT cell frequencies were strikingly reduced in both blood and lung tissue in relation to corticosteroid therapy and vitamin D levels, especially in patients with severe asthma in whom bronchoalveolar lavage regulatory T-cell numbers were also reduced. Bayesian network analysis identified complex relationships between pathobiologic and clinical parameters. Topological data analysis identified 6 novel clusters that are associated with diverse underlying disease mechanisms, with increased mast cell mediator levels in patients with severe asthma both in its atopic (type 2 cytokine–high) and nonatopic forms.ConclusionThe evidence for a role for TH17 cells in patients with severe asthma is limited. Severe asthma is associated with a striking deficiency of MAIT cells and high mast cell mediator levels. This study provides proof of concept for disease mechanistic networks in asthmatic patients with clusters that could inform the development of new therapies

Motor control retraining exercises for shoulder impingement: effects on function, muscle activation, and biomechanics in young adults

Objective: Evidence for effective management of shoulder impingement is limited. The present study aimed to quantify the clinical, neurophysiological, and biomechanical effects of a scapular motor control retraining for young individuals with shoulder impingement signs.Method: Sixteen adults with shoulder impingement signs (mean age 22 ? 1.6 years) underwent the intervention and 16 healthy participants (24.8 ? 3.1years) provided reference data. Shoulder function and pain were assessed using the Shoulder Pain and Disability Index (SPADI) and other questionnaires. Electromyography (EMG) and 3 dimensional motion analysis was used to record muscle activation and kinematic data during arm elevation to 90? and lowering in 3 planes. Patients were assessed pre and post a 10-week motor control based intervention, utilizing scapular orientation retraining.Results: Pre-intervention, patients reported pain and reduced function compared to the healthy participants (SPADI in patients 20 ? 9.2; healthy 0 ? 0). Post intervention, the SPADI scores reduced significantly (P < .001) by a mean of 10 points (?4). EMG showed delayed onset and early termination of serratus anterior and lower trapezius muscle activity pre-intervention, which improved significantly post-intervention (P < .05). Pre intervention, patients exhibited on average 4.6-7.4? less posterior tilt, which was significantly lower in 2 arm elevation planes (P < .05) than healthy participants. Postintervention, upward rotation and posterior tilt increased significantly (P <.05) during 2 arm movements, approaching the healthy values.Conclusion: A 10-week motor control intervention for shoulder impingement increased function and reduced pain. Recovery mechanisms were indicated by changes in muscle recruitment andscapular kinematics. The efficacy of the intervention requires further examined in a randomizedcontrol trial

CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains

Tuberculosis, caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in tuberculosis granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells

Oral abstracts 1: SpondyloarthropathiesO1. Detecting axial spondyloarthritis amongst primary care back pain referrals

Background: Inflammatory back pain (IBP) is an early feature of ankylosing spondylitis (AS) and its detection offers the prospect of early diagnosis of AS. However, since back pain is very common but only a very small minority of back pain sufferers have ASpA or AS, screening of back pain sufferers for AS is problematic. In early disease radiographs are often normal so that fulfilment of diagnostic criteria for AS is impossible though a diagnosis of axial SpA can be made if MRI evidence of sacroiliitis is present. This pilot study was designed to indicate whether a cost-effective pick up rate for ASpA/early AS could be achieved by identifying adults with IBP stratified on the basis of age. Methods: Patients aged between 18 and 45 years who were referred to a hospital physiotherapy service with back pain of more than 3 months duration were assessed for IBP. All were asked to complete a questionnaire based on the Berlin IBP criteria. Those who fulfilled IBP criteria were also asked to complete a second short questionnaire enquiring about SpA comorbidities, to have a blood test for HLA-B27 and CRP level and to undergo an MRI scan of the sacroiliac joints. This was a limited scan, using STIR, diffusion-weighted, T1 and T2 sequences of the sacroiliac joints to minimize time in the scanner and cost. The study was funded by a research grant from Abbott Laboratories Ltd. Results: 50 sequential patients agreed to participate in the study and completed the IBP questionnaire. Of these 27 (54%) fulfilled criteria for IBP. Of these, 2 patients reported a history of an SpA comorbidity - 1 psoriasis; 1 ulcerative colitis - and 3 reported a family history of an SpA comorbidity - 2 psoriasis; 1 Crohn's disease. 4 were HLA-B27 positive, though results were not available for 7. Two patients had marginally raised CRP levels (6, 10 -NR ≤ 5). 19 agreed to undergo MRI scanning of the sacroiliac joints and lumbar spine; 4 scans were abnormal, showing evidence of bilateral sacroiliitis on STIR sequences. In all cases the changes met ASAS criteria but were limited. Of these 4 patients 3 were HLA-B27 positive but none gave a personal or family history of an SpA-associated comorbidity and all had normal CRP levels. Conclusions: This was a pilot study yielding only limited conclusions. However, it is clear that: Screening of patients referred for physiotherapy for IBP is straightforward, inexpensive and quick. It appears that IBP is more prevalent in young adults than overall population data suggest so that targeting this population may be efficient. IBP questionnaires could be administered routinely during a physiotherapy assessment. HLA-B27 testing in this group of patients with IBP is a suitable screening tool. The sacroiliac joint changes identified were mild and their prognostic significance is not yet clear so that the value of early screening needs further evaluation. Disclosure statement: C.H. received research funding for this study from Abbott. A.K. received research funding for this study, and speaker and consultancy fees, from Abbott. All other authors have declared no conflicts of interes

Primary Sjögren's Syndrome_Article for Patients (Lays) in German Language

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Antigen presentation by MHC class I and CD1 molecules

Antigen presentation is the "sine qua non" of the mammalian adaptive immune stem. The assembly of MHC class 1/peptide complexes in the endoplasmic reticulum (ER) relies on the orchestrated interplay between different chaperonins, which assist MHC class I folding, and the peptide loading complex (PLC). Mutant lymphoblastoid cell lines with defective MHC class I surface expression have greatly helped the functional analysis of the PLC. The TAP transporter associated with antigen processing translocates MHC class I peptide ligands from the cytoso into the ER and is critical for successful MHC class I assembly and maturation. In the first two results chapters of this thesis I will describe the identification, clinical description and molecular and genetic analysis of a new clinical syndrome in a group of patients with dramatically reduced MHC class I surface expression. The disease in these patients could be identified as primary TAP-deficiency. The focus of the third and fourth chapter of this thesis lies on lipid antigen presentation via CDl molecules, which are known to present mycobacterial lipids to T lymphocytes. The first objective of this thesis was to generate recombinant mycobacterial lipid loaded CUl molecules as tools to measure mycobacterial lipid speclfic T cell responses in the TAP-deficient patients.EThOS - Electronic Theses Online ServiceGBUnited Kingdo