Pre-clinical development of a tolerogenic peptide from glutamate decarboxylase as a candidate for antigen-specific immunotherapy in type 1 diabetes.

Dysregulation and loss of immune tolerance towards pancreatic β-cell autoantigens are features of type 1 diabetes (T1D). Until recently, life-long insulin injection was the only approved treatment for T1D, and this does not address the underlying disease pathology. Antigen-specific immunotherapy (ASI) seeks to restore tolerance and holds potential as a new therapeutic strategy for treating autoimmune diseases with well characterised antigens.

Incidence of immune-mediated inflammatory diseases following COVID-19: a matched cohort study in UK primary care.

Background: Some patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) go on to experience post-COVID-19 condition or long COVID. Preliminary findings have given rise to the theory that long COVID may be due in part to a deranged immune response. In this study, we assess whether there is an association between SARS-CoV-2 infection and the incidence of immune-mediated inflammatory diseases (IMIDs).

SARS-CoV-2 infection is associated with anti-desmoglein 2 autoantibody detection.

Post-acute cardiac sequelae, following SARS-CoV-2 infection, are well recognized as complications of COVID-19. We have previously shown the persistence of autoantibodies against antigens in skin, muscle, and heart in individuals following severe COVID-19; the most common staining on skin tissue displayed an inter-cellular cement pattern consistent with antibodies against desmosomal proteins. Desmosomes play a critical role in maintaining the structural integrity of tissues.

Symptoms and risk factors for long COVID in non-hospitalized adults.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection.

SARS-CoV-2 Spike- and Nucleoprotein-Specific Antibodies Induced After Vaccination or Infection Promote Classical Complement Activation.

Antibodies specific for the spike glycoprotein (S) and nucleocapsid (N) SARS-CoV-2 proteins are typically present during severe COVID-19, and induced to S after vaccination. The binding of viral antigens by antibody can initiate the classical complement pathway. Since complement could play pathological or protective roles at distinct times during SARS-CoV-2 infection we determined levels of antibody-dependent complement activation along the complement cascade.

Therapies for Long COVID in non-hospitalised individuals: from symptoms, patient-reported outcomes and immunology to targeted therapies (The TLC Study).

Introduction: Individuals with COVID-19 frequently experience symptoms and impaired quality of life beyond 4-12 weeks, commonly referred to as Long COVID. Whether Long COVID is one or several distinct syndromes is unknown. Establishing the evidence base for appropriate therapies is needed.

Adaptive T cell tuning in immune regulation and immunotherapy of autoimmune diseases.

Lymphocyte receptors confer antigen specificity on the adaptive immune response. Increasing evidence points to the role of adaptive tuning particularly amongst CD4 T cell responses. This review summarises how T cell tuning impacts on critically important aspects of immune regulation including thymic selection, the immune response to chronic antigen exposure and antigen-specific immunotherapy of autoimmune conditions.

Induction of Tolerance to Therapeutic Proteins With Antigen-Processing Independent T Cell Epitopes: Controlling Immune Responses to Biologics.

The immune response to exogenous proteins can overcome the therapeutic benefits of immunotherapies and hamper the treatment of protein replacement therapies. One clear example of this is haemophilia A resulting from deleterious mutations in the FVIII gene. Replacement with serum derived or recombinant FVIII protein can cause anti-drug antibodies in 20-50% of individuals treated.

Serological responses to SARS-CoV-2 following non-hospitalised infection: clinical and ethnodemographic features associated with the magnitude of the antibody response.

Objective: To determine clinical and ethnodemographic correlates of serological responses against the SARS-CoV-2 spike glycoprotein following mild-to-moderate COVID-19.

Design: A retrospective cohort study of healthcare workers who had self-isolated due to COVID-19.

Setting: University Hospitals Birmingham NHS Foundation Trust, UK (UHBFT).

Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength.

How T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice, we characterized early quantitative and qualitative changes that occur in CD4 T cells in relation to TCR signaling strength. We captured how dose- and time-dependent programming of distinct co-inhibitory receptors rapidly recalibrates T cell activation thresholds and visualized the immediate effects of ICB on T cell re-activation.

Antigen-specific immunotherapy with apitopes suppresses generation of FVIII inhibitor antibodies in HLA-transgenic mice.

Hemophilia A (HA) is a blood clotting disorder that is caused by various genetic deficiencies in the factor VIII (FVIII)-encoding F8 gene. Patients receiving FVIII-replacement therapy are at risk for developing neutralizing antibodies (FVIII inhibitors), rendering the FVIII-replacement therapy ineffective. Immunological tolerance toward FVIII can be achieved through immune tolerance induction protocols in some patients, but this is a lengthy and costly desensitization program.

Preclinical models of arthritis for studying immunotherapy and immune tolerance.

Increasingly earlier identification of individuals at high risk of rheumatoid arthritis (RA) (eg, with autoantibodies and mild symptoms) improves the feasibility of preventing or curing disease. The use of antigen-specific immunotherapies to reinstate immunological self-tolerance represent a highly attractive strategy due to their potential to induce disease resolution, in contrast to existing approaches that require long-term treatment of underlying symptoms.Preclinical animal models have been used to understand disease mechanisms and to evaluate novel immunotherapeutic approaches.

Establishing the prevalence of common tissue-specific autoantibodies following severe acute respiratory syndrome coronavirus 2 infection.

Coronavirus 19 (COVID-19) has been associated with both transient and persistent systemic symptoms that do not appear to be a direct consequence of viral infection. The generation of autoantibodies has been proposed as a mechanism to explain these symptoms. To understand the prevalence of autoantibodies associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we investigated the frequency and specificity of clinically relevant autoantibodies in 84 individuals previously infected with SARS-CoV-2, suffering from COVID-19 of varying severity in both the acute and convalescent setting.

Advancement of antigen-specific immunotherapy: knowledge transfer between allergy and autoimmunity.

Targeted restoration of immunological tolerance to self-antigens or innocuous environmental allergens represents the ultimate aim of treatment options in autoimmune and allergic disease. Antigen-specific immunotherapy (ASI) is the only intervention that has proven disease-modifying efficacy as evidenced by induction of long-term remission in a number of allergic conditions. Mounting evidence is now indicating that specific targeting of pathogenic T cells in autoinflammatory and autoimmune settings enables effective restoration of immune homeostasis between effector and regulatory cells and alters the immunological course of disease.

The Mechanism of Action of Antigen Processing Independent T Cell Epitopes Designed for Immunotherapy of Autoimmune Diseases.

Immunotherapy with antigen-processing independent T cell epitopes (apitopes) targeting autoreactive CD4 T cells has translated to the clinic and been shown to modulate progression of both Graves' disease and multiple sclerosis. The model apitope (Ac1-9[4Y]) renders antigen-specific T cells anergic while repeated administration induces both Tr1 and Foxp3 regulatory cells. Here we address why CD4 T cell epitopes should be designed as apitopes to induce tolerance and define the antigen presenting cells that they target .

Manipulating antigen presentation for antigen-specific immunotherapy of autoimmune diseases.

Current treatments for autoimmune diseases do not address the immune pathology underlying their initiation and progression and too often rely on non-specific immunosuppressive drugs for control of symptoms. Antigen-specific immunotherapy aims to induce tolerance selectively among the cells causing the disease while leaving the rest of the adaptive immune system capable of protecting against infectious diseases and cancers. Here we describe how novel approaches for antigen-specific immunotherapy are designed to manipulate antigen presentation and promote tolerance to specific self-antigens.

A LAT-Based Signaling Complex in the Immunological Synapse as Determined with Live Cell Imaging Is Less Stable in T Cells with Regulatory Capability.

Peripheral immune regulation is critical for the maintenance of self-tolerance. Here we have investigated signaling processes that distinguish T cells with regulatory capability from effector T cells. The murine Tg4 T cell receptor recognizes a peptide derived from the self-antigen myelin basic protein.

Peptide allergen-specific immunotherapy for allergic airway diseases-State of the art.

Allergen-specific immunotherapy (AIT) is the only means of altering the natural immunological course of allergic diseases and achieving long-term remission. Pharmacological measures are able to suppress the immune response and/or ameliorate the symptoms but there is a risk of relapse soon after these measures are withdrawn. Current AIT approaches depend on the administration of intact allergens, often comprising crude extracts of the allergen.

Serological responses to SARS-CoV-2 following non-hospitalised infection: clinical and ethnodemographic features associated with the magnitude of the antibody response.

Objective: To determine clinical and ethnodemographic correlates of serological responses against the SARS-CoV-2 spike glycoprotein following mild-to-moderate COVID-19.

Design: A retrospective cohort study of healthcare workers who had self-isolated due to COVID-19.

Setting: University Hospitals Birmingham NHS Foundation Trust, UK (UHBFT).

Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration.

Nr4a receptors are activated by T cell receptor (TCR) signaling and play key roles in T cell differentiation. Which TCR signaling pathways regulate Nr4a receptors and their sensitivities to TCR signal strength and duration remains unclear. Using Nr4a1/Nur77-GFP and Nr4a3-Timer of cell kinetics and activity (Tocky) mice, we elucidate the signaling pathways governing Nr4a receptor expression.

Autoantigens in rheumatoid arthritis and the potential for antigen-specific tolerising immunotherapy.

Autoimmune diseases, including rheumatoid arthritis, develop and persist due to impaired immune self-tolerance, which has evolved to regulate inflammatory responses to injury or infection. After diagnosis, patients rarely achieve drug-free remission, and although at-risk individuals can be identified with genotyping, antibody tests, and symptoms, rheumatoid arthritis cannot yet be successfully prevented. Precision medicine is increasingly offering solutions to diseases that were previously considered to be incurable, and immunotherapy has begun to achieve this aim in cancer.

SARS-CoV-2 seroprevalence and asymptomatic viral carriage in healthcare workers: a cross-sectional study.

Objective: To determine the rates of asymptomatic viral carriage and seroprevalence of SARS-CoV-2 antibodies in healthcare workers.

Design: A cross-sectional study of asymptomatic healthcare workers undertaken on 24/25 April 2020.

Setting: University Hospitals Birmingham NHS Foundation Trust (UHBFT), UK.

Antigen-Specific Immunotherapy for Treatment of Autoimmune Liver Diseases.

The liver is a critical organ in controlling immune tolerance. In particular, it is now clear that targeting antigens for presentation by antigen presenting cells in the liver can induce immune tolerance to either autoantigens from the liver itself or tissues outside of the liver. Here we review immune mechanisms active within the liver that contribute both to the control of infectious diseases and tolerance to self-antigens.