PubMed · 15080840
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D Zauli, G Vukatana, A Grassi, G Ballardini. 2004. Urticaria.. https://doi.org/10.1111/j.1398-9995.2004.00482.x
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Identifying and monitoring autoreactive T cells that drive beta cell destruction remains a major obstacle to developing effective immunotherapies for type 1 diabetes (T1D). These cells are extremely rare in peripheral blood and cannot be accessed directly from the pancreas. We used intradermal injection of Glutamic Acid Decarboxylase (GAD)-Alum to recruit GAD-specific T cells to accessible sites in the skin and skin-draining lymph nodes (LNs), sampled by skin suction blisters and ultrasound-guided LN aspiration. Peripheral blood samples obtained before GAD injection were restimulated with GAD in vitro to detect reactive CD4+ T cells. Single-cell RNA sequencing (scRNAseq) followed by re-expression of selected T cell receptors (TCRs) confirmed antigen specificity. Up to 70% of T cells at the skin injection site were clonally-expanded and 4 of 14 (28%) re-expressed TCRs were GAD-reactive. In LNs 1 of 14 (4%) clonally-expanded TCRs was GAD-reactive, representing ~0.08% of all T-cells. GAD-reactive cells across compartments displayed Th1 and Th17-associated transcription signatures. These results demonstrate the intradermal autoantigen challenge and scRNAseq, enable direct identification and molecular profiling of autoreactive T cells in vivo. This minimally invasive approach provides a powerful platform for tracking antigen-specific T cells to monitor disease activity and evaluate immune interventions in T1D.
Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.
After a large myocardial infarction (MI) a progressive remodeling process can occur that results in a severe mechanical dysfunction of the heart. Among the determinants of remodeling, immune mediated inflammation has been suggested as an important contributor. However, the role of autoimmunity to cardiac antigens that are released to the circulation has not been sufficiently addressed. Cardiac myosin is a contractile protein that is unique to the myocardium and has been shown to induce a humoral immune response in patients after MI, and to trigger an autoimmune myocarditis in experimental rats and mice. In the current study, we evaluated humoral and cellular immune responses to myosin in patients with and without a history of recent MI. Eighteen patients with MI, 2 weeks to 4 months prior to initiation of the study, and eighteen control subjects were enrolled. Peripheral blood mononuclear cells (PMBC) were obtained and subjected to priming with different concentrations of cardiac myosin. Interferon-gamma and TNF-alpha were measured in conditioned medium obtained from the cultured PMBC upon priming with cardiac myosin. Humoral immune responses were also assessed by evaluating IgG anti-myosin antibodies. We have found that a third of the patients with the recent history of MI and none of the control subjects had a proliferative response to cardiac myosin evident by stimulation indices greater than 1.5. No differences were detected between the patients and controls with regard to IFN-gamma and TNF-alpha secreted by their PMBC, nor were there differences in the serum levels of IgG anti-myosin antibodies. Thus, in patients with a recent history of MI, cellular autoimmunity to cardiac myosin is present as compared with controls. It remains to be determined whether this autoimmune response is associated with an adverse outcome.