Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines

Lack of association of the CIITA -168A→G promoter SNP with myasthenia gravis and its role in autoimmunity

<p>Abstract</p> <p>Background</p> <p>The major histocompatibility complex class II transactivator (CIITA) regulates MHC class II gene expression. A promoter SNP -168A→G (rs3087456) has previously been shown to be associated with susceptibility to several immune mediated disorders, including rheumatoid arthritis (RA), multiple sclerosis (MS) and myocardial infarction (MI). Myasthenia gravis (MG) is an autoimmune disorder which has previously been shown to be associated with polymorphisms of several autoimmune predisposing genes, including <it>IL-1</it>, <it>PTPN22</it>, <it>TNF-α </it>and the <it>MHC</it>. In order to determine if allelic variants of rs3087456 increase predisposition to MG, we analyzed this SNP in our Swedish cohort of 446 MG patients and 1866 controls.</p> <p>Results</p> <p>No significant association of the SNP with MG was detected, neither in the patient group as a whole, nor in any clinical subgroup. The vast majority of previous replication studies have also not found an association of the SNP with autoimmune disorders.</p> <p>Conclusions</p> <p>We thus conclude that previous findings with regard to the role of the <it>CIITA </it>-168A→G SNP in autoimmunity may have to be reconsidered.</p

Correlation of Circulating Omentin-1 with Bone Mineral Density in Multiple Sclerosis: The Crosstalk between Bone and Adipose Tissue

BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of osteoporosis and fractures. Adipose tissue-derived adipokines may play important roles in the osteoimmunology of MS. In order to determine whether omentin-1 and vaspin may be related to bone health in MS patients, we compared circulating levels of these recently identified adipokines, between MS patients and healthy controls. METHODS: A total of 35 ambulatory MS patients with relapsing-remitting courses were compared with 38 age- and sex-matched healthy controls. Bone mineral density (BMD) was determined for the lumbar spine (L2-L4) and the proximal femur using dual-energy x-ray absorptiometry. Circulating omentin-1, vaspin, osteocalcin, osteopontin, osteoprotegerin, the receptor activator of nuclear factor-κB ligand, matrix metalloproteinase 9, C-reactive protein and 25-hydroxy vitamin D levels were evaluated by highly specific enzyme-linked immunosorbent assay methods. RESULTS: There was no significant difference between the two groups regarding bone-related cytokines, adipocytokines, and the BMD measurements of patients with MS and the healthy controls. However, in multiple regression analysis, serum omentin-1 levels were positively correlated with BMD at the femoral neck (β = 0.49, p = 0.016), total hip (β = 0.42, p = 0.035), osteopontin (β = 0.42, p = 0.030) and osteocalcin (β = 0.53, p = 0.004) in MS patients. No correlations were found between vaspin, biochemical, and BMD measures in both groups. CONCLUSIONS: Elevated omentin-1 serum levels are correlated with BMD at the femoral neck and the serum levels of osteocalcin and osteopontin in MS patients. Therefore, there is crosstalk between adipose tissue and bone in MS

Interaction Analysis between HLA-DRB1 Shared Epitope Alleles and MHC Class II Transactivator CIITA Gene with Regard to Risk of Rheumatoid Arthritis

HLA-DRB1 shared epitope (SE) alleles are the strongest genetic determinants for autoantibody positive rheumatoid arthritis (RA). One of the key regulators in expression of HLA class II receptors is MHC class II transactivator (CIITA). A variant of the CIITA gene has been found to associate with inflammatory diseases

AB1287 DESIGN OF A GLOBAL PHASE 2/3 RANDOMIZED, PLACEBO-CONTROLLED TRIAL EVALUATING THE EFFICACY AND SAFETY OF RAVULIZUMAB IN ADULTS WITH DERMATOMYOSITIS

BackgroundDermatomyositis (DM) is a rare and life-altering chronic immune-mediated disease characterized by distinct skin rash and/or progressive muscle weakness and other systemic manifestations. Many patients are refractory and/or experience serious adverse effects when treated with currently prescribed medications, including high-dose systemic steroids and immunosuppressive therapies1-3, which are often prescribed off-label. Therefore, there is a need for new DM treatment options that offer more favorable risk-benefit profiles.The classical complement pathway is implicated in DM pathophysiology, including a close correlation between endothelial deposition of the C5b-9 membrane attack complex (MAC) and organ damage.4 Treatment with the long-acting anti-C5 monoclonal antibody ravulizumab is associated with immediate, complete, and sustained inhibition of the complement protein C5, which prevents its cleavage to form MAC, and it has proven to be a safe and effective therapeutic approach for multiple complement-mediated diseases.5ObjectivesGiven the continued unmet need in DM and the evidence implicating the terminal complement pathway in the disease pathophysiology, a global, multi-center double-blind, randomized, placebo-controlled Phase 2 (Part A)/Phase 3 (Part B) trial was designed to evaluate the efficacy and safety of the C5 inhibitor ravulizumab compared with placebo in adults with DM (ALXN1210-DM-310; NCT04999020; EudraCT2021-001200-15).MethodsA total of 180 adult patients with DM6 who have active disease with muscle weakness and inadequate responses or intolerances to two or more DM treatments including glucocorticoids will be randomized to receive either intravenous ravulizumab or placebo, delivered as loading dose followed by maintenance administration once every eight weeks. Different patients will be enrolled in Parts A and B, which each consist of a screening period, a randomized, controlled period (Part A; 26 weeks; Part B: 50 weeks), and an open-label extension period. The primary endpoints are the proportion of patients with a minimal improvement from baseline on the ACR/EULAR Myositis Response Criteria Total Improvement Score (TIS20) at 26 weeks (Part A) and 50 weeks (Part B). In addition, a wide range of key secondary and exploratory outcome measures will be evaluated, including the mean change from baseline in the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score and a novel participant-reported outcome measure, the Dermatomyositis-Disease Symptoms Questionnaire (DM-DSQ). Safety will be assessed by analyzing the incidence of treatment-related adverse events (TEAEs), including those classified as serious and/or leading to intervention discontinuation.ResultsThe ALXN1210-DM-310 trial is currently enrolling patients.ConclusionALXN1210-DM-310 is the first global, multi-center, randomized, placebo-controlled Phase 2/3 interventional trial designed to evaluate the safety and efficacy of a C5 inhibitor in adult patients with DM who continue to have active disease despite treatment with standard medications.References[1]Joffe MM, Love LA, Leff RL, et al. Am J Med.1993; 94:379.[2]Zieglschmid-Adams ME, Pandya AG, Cohen SB, et al. J Am Acad Dermatol. 1995; 32:754.[3]Kissel JT, Levy RJ, Mendell JR, Griggs RC. Neurology 1986; 36:35.[4]Yang SH, Chang C, Lian Z-X. J Transl Autoimmun. 2019;2:100018.[5]https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761108s012lbl.pdf. Accessed January 26, 2022.[6]Lundberg IE, Tjarnlund A, Bottai M, et al. Arthritis Rheumatol. 2017;69(12):2271-2282.Disclosure of InterestsLorenzo Cavagna: None declared, Rohit Aggarwal Consultant of: Alexion and AstraZeneca, Pfizer, Octapharma, Csl Behring, BMS, Argenx, Corbus, EMD, Janssen, Kezar, Kyverna, Roivant, and Mallinckrodt, Grant/research support from: Pfizer, BMS, Q32, EMD Serono, and Mallinckrodt, Noriko Iikuni Shareholder of: AstraZeneca, Employee of: Alexion/AstraZeneca Rare Disease, Pfizer, Eli Lilly, Sanjay Rakhade Shareholder of: AstraZeneca, Employee of: Alexion/AstraZeneca Rare Disease, Sanofi Genzyme</jats:sec