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Nature Communications Feb 2024Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus...
Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. Here we identify a HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identify high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduce our lead Sm-specific TCR into Tregs derived from patients with SLE who are anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppress Sm-specific pro-inflammatory responses in vitro and suppress disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE.
Topics: Mice; Animals; Humans; Lupus Nephritis; T-Lymphocytes, Regulatory; Lupus Erythematosus, Systemic; Autoantigens
PubMed: 38321013
DOI: 10.1038/s41467-024-45056-x -
The Journal of Investigative Dermatology Aug 2023Mucous membrane pemphigoid is an autoimmune disease with variable clinical presentation and multiple autoantigens. To determine whether disease endotypes could be...
Mucous membrane pemphigoid is an autoimmune disease with variable clinical presentation and multiple autoantigens. To determine whether disease endotypes could be identified on the basis of the pattern of serum reactivity, the clinical and diagnostic information of 70 patients with mucous membrane pemphigoid was collected, and reactivity to dermal or epidermal antigens, using indirect immunofluorescence, and specific reactivity to bullous pemphigoid (BP) autoantigens BP180 and BP230, collagen VII, and laminin 332 were evaluated. Most patients had lesions at multiple mucosae, with the most prevalent being oropharyngeal (mouth, gingiva, pharynx; 98.6%), followed by ocular (38.6%), nasal (32.9%), genital or anal (31.4%), laryngeal (20%), and esophageal (2.9%) sites and skin (45.7%). Autoantigen profiling identified BP180 (71%) as the most common autoantigen, followed by laminin 332 (21.7%), collagen VII (13%), and BP230 IgG (11.6%). Reactivity to dermal antigens predicted a more severe disease characterized by a higher number of total sites involved, especially high-risk sites, and a decreased response to rituximab. In most cases, identification of dermal indirect immunofluorescence reactivity is an accurate predictor of disease course; however, confirmation of laminin 332 reactivity is important, with dermal indirect immunofluorescence positivity because of an increased risk of solid tumors. In addition, the ocular mucosae should be monitored in patients with IgA on direct immunofluorescence.
Topics: Humans; Pemphigoid, Bullous; Autoantibodies; Collagen; Autoantigens; Mucous Membrane; Non-Fibrillar Collagens; Pemphigoid, Benign Mucous Membrane
PubMed: 36870557
DOI: 10.1016/j.jid.2023.02.012 -
Current Opinion in Organ Transplantation Aug 2016Allo- and autoantibodies have been found to play important roles in both acute and chronic allograft rejection in organ transplantation, although only recently have... (Review)
Review
PURPOSE OF REVIEW
Allo- and autoantibodies have been found to play important roles in both acute and chronic allograft rejection in organ transplantation, although only recently have non-human leukocyte antigen (non-HLA), nondonor-specific antibodies been given a more in-depth treatment. This review summarizes recent reports about investigations and proteomic approaches to identify self-antigens and corresponding autoantibodies that are associated with acute and chronic allograft rejection. Finally, we discuss the insights gained from these, challenges, and future prospects.
RECENT FINDINGS
Significant discoveries have been made regarding the presence and role of autoantibodies and alloantibodies, both those formed pretransplant and posttransplant, in acute and chronic rejection. These discoveries are made possible because of the publication of the human genome and subsequent development in the ability of expression and analysis of human proteome.
SUMMARY
Antibodies play a critical role in survival and dysfunction of a transplanted kidney. Even though HLA antibodies have been given the majority of the scientific community's attention for the past few decades, antibodies against autoantigens and that of non-HLA origin are gaining attention. Recent publications have identified novel self-antigens that are associated with acute and chronic rejection that have added to our understanding of new players in immune-related transplant rejection.
Topics: Autoantigens; Graft Rejection; Humans; Proteomics
PubMed: 27214090
DOI: 10.1097/MOT.0000000000000328 -
Frontiers in Immunology 2023T Regulatory type-1 (TR1) cells represent an immunosuppressive T cell subset, discovered over 25 years ago, that produces high levels of interleukin-10 (IL-10) but,... (Review)
Review
T Regulatory type-1 (TR1) cells represent an immunosuppressive T cell subset, discovered over 25 years ago, that produces high levels of interleukin-10 (IL-10) but, unlike its FoxP3+ T regulatory (Treg) cell counterpart, does not express FoxP3 or CD25. Experimental evidence generated over the last few years has exposed a promising role for TR1 cells as targets of therapeutic intervention in immune-mediated diseases. The discovery of cell surface markers capable of distinguishing these cells from related T cell types and the application of next generation sequencing techniques to defining their transcriptional make-up have enabled a more accurate description of this T cell population. However, the developmental biology of TR1 cells has long remained elusive, in particular the identity of the cell type(s) giving rise to TR1 cells . Here, we review the fundamental phenotypic, transcriptional and functional properties of this T cell subset, and summarize recent lines of evidence shedding light into its ontogeny.
Topics: Autoantigens; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Gene Expression Regulation; Forkhead Transcription Factors
PubMed: 37818381
DOI: 10.3389/fimmu.2023.1267697 -
Frontiers in Immunology 2023The thymus is a highly specialized organ that plays an indispensable role in the establishment of self-tolerance, a process characterized by the "education" of... (Review)
Review
The thymus is a highly specialized organ that plays an indispensable role in the establishment of self-tolerance, a process characterized by the "education" of developing T-cells. To provide competent T-cells tolerant to self-antigens, medullary thymic epithelial cells (mTECs) orchestrate negative selection by ectopically expressing a wide range of genes, including various tissue-restricted antigens (TRAs). Notably, recent advancements in the high-throughput single-cell analysis have revealed remarkable heterogeneity in mTECs, giving us important clues for dissecting the mechanisms underlying TRA expression. We overview how recent single-cell studies have furthered our understanding of mTECs, with a focus on the role of Aire in inducing mTEC heterogeneity to encompass TRAs.
Topics: Mice; Animals; Mice, Inbred C57BL; Thymus Gland; Epithelial Cells; T-Lymphocytes; Autoantigens
PubMed: 37207224
DOI: 10.3389/fimmu.2023.1176450 -
Journal of the American Society of... Nov 2018
Topics: Anti-Glomerular Basement Membrane Disease; Autoantigens; Extracellular Matrix Proteins; Glomerulonephritis; Humans; Peroxidase; Syndrome; Peroxidasin
PubMed: 30314979
DOI: 10.1681/ASN.2018090946 -
Hormone and Metabolic Research =... Dec 2019Thyroid peroxidase (TPO) is an enzyme that participates in thyroid hormone biosynthesis. TPO is also a major autoantigen in autoimmune thyroid diseases (AITD). In this... (Review)
Review
Thyroid peroxidase (TPO) is an enzyme that participates in thyroid hormone biosynthesis. TPO is also a major autoantigen in autoimmune thyroid diseases (AITD). In this review, we summarize the latest developments in the field of TPO research. We present the current understanding of immunodominant serologic determinants, frequency of TPO-specific autoantibodies in the population, as well as genetic and environmental factors contributing to their development. Moreover, we report recent progress in the clinical utilities of TPO autoantibody testing, including thyroid dysfunctions and extra-thyroidal disorders.
Topics: Animals; Autoantibodies; Autoantigens; Humans; Iodide Peroxidase; Thyroid Diseases
PubMed: 31826271
DOI: 10.1055/a-1057-9469 -
Autoimmunity Reviews Mar 2015The precise cause of the antineutrophil cytoplasmic antibodies (ANCA) autoimmunity is not known and is likely to be multifactorial. Infections may trigger formation of... (Review)
Review
The precise cause of the antineutrophil cytoplasmic antibodies (ANCA) autoimmunity is not known and is likely to be multifactorial. Infections may trigger formation of ANCA and a fraction of the patients with infection-triggered ANCA develop ANCA-associated vasculitis. Here we discuss some of the proposed mechanisms of ANCA formation during the course of infection. They include initiation of autoimmune response by microbial peptides that are complementary to autoantigens; epigenetic silencing and antigen complementarity leading to upregulation of autoantigen genes; molecular mimicry between bacterial and self-antigens; formation of neutrophil extracellular traps that stimulate immune processes including production of ANCA; and interaction of bacterial components with Toll-like receptors, which leads to formation of mediators affecting the immune responses to infections and can trigger ANCA production. Further work is needed to clarify these mechanisms and develop preventive measures and therapeutic interventions.
Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Epigenesis, Genetic; Humans; Infections; Toll-Like Receptors
PubMed: 25448042
DOI: 10.1016/j.autrev.2014.10.020 -
Current Opinion in Immunology Dec 2017AIRE is a well-established master regulator of central tolerance. It plays an essential role in driving expression of tissue-specific antigens in the thymus and shaping... (Review)
Review
AIRE is a well-established master regulator of central tolerance. It plays an essential role in driving expression of tissue-specific antigens in the thymus and shaping the development of positively selected T-cells. Humans and mice with compromised or absent AIRE function have markedly variable phenotypes that include a range of autoimmune manifestations. Recent evidence suggests that this variability stems from cooperation of autoimmune susceptibilities involving both central and peripheral tolerance checkpoints. Here we discuss the broadening understanding of the factors that influence Aire expression, modify AIRE function, and the impact and intersection of AIRE with peripheral immunity. This rapidly expanding body of knowledge will force a reexamination of the definition and clinical management of APS-1 patients as well as provide a foundation for the development of immunomodulatory strategies targeting central tolerance.
Topics: Animals; Autoantigens; Gene Expression Regulation; Humans; Immune Tolerance; Mice; Phenotype; Polyendocrinopathies, Autoimmune; Thymus Gland; Transcription Factors; AIRE Protein
PubMed: 29065385
DOI: 10.1016/j.coi.2017.10.003 -
Digestive Diseases (Basel, Switzerland) 2015Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye. (Review)
Review
BACKGROUND
Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye.
KEY MESSAGES
Endocrine autoimmunity is prevalent in patients with CD and their relatives. The genes that predispose to endocrine autoimmune diseases, e.g. type 1 diabetes, autoimmune thyroid diseases, and Addison's disease, i.e. DR3-DQ2 and DR4-DQ8, are also the major genetic determinants of CD, which is the best understood HLA-linked disease. Thus, up to 30% of first-degree relatives both of patients with CD and/or endocrine autoimmunity are affected by the other disease. In CD, certain gluten proteins bind with high affinity to HLA-DQ2 or -DQ8 in the small-intestinal mucosa, to activate gluten-specific T cells which are instrumental in the destruction of the resorptive villi. Here, the autoantigen tissue transglutaminase increases the T cell response by generating deamidated gluten peptides that bind more strongly to DQ2 or DQ8. Classical symptoms such as diarrhea and consequences of malabsorption like anemia and osteoporosis are often absent in patients with (screening-detected) CD, but this absence does not significantly affect these patients' incidence of endocrine autoimmunity. Moreover, once autoimmunity is established, a gluten-free diet is not able to induce remission. However, ongoing studies attempt to address how far a gluten-free diet may prevent or retard the development of CD and endocrine autoimmunity in children at risk.
CONCLUSIONS
The close relationship between CD and endocrine autoimmunity warrants a broader immune genetic and endocrine screening of CD patients and their relatives.
Topics: Autoantigens; Autoimmunity; Celiac Disease; Endocrine System; Humans
PubMed: 25925917
DOI: 10.1159/000369535