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International Journal of Molecular... Aug 2021Dendritic cells (DCs) dictate the outcomes of tissue-specific immune responses. In the context of autoimmune diseases, DCs instruct T cells to respond to antigens (Ags),... (Review)
Review
Dendritic cells (DCs) dictate the outcomes of tissue-specific immune responses. In the context of autoimmune diseases, DCs instruct T cells to respond to antigens (Ags), including self-Ags, leading to organ damage, or to becoming regulatory T cells (Tregs) promoting and perpetuating immune tolerance. DCs can acquire tolerogenic properties in vitro and in vivo in response to several stimuli, a feature that opens the possibility to generate or to target DCs to restore tolerance in autoimmune settings. We present an overview of the different subsets of human DCs and of the regulatory mechanisms associated with tolerogenic (tol)DC functions. We review the role of DCs in the induction of tissue-specific autoimmunity and the current approaches exploiting tolDC-based therapies or targeting DCs in vivo for the treatment of autoimmune diseases. Finally, we discuss limitations and propose future investigations for improving the knowledge on tolDCs for future clinical assessment to revert and prevent autoimmunity. The continuous expansion of tolDC research areas will lead to improving the understanding of the role that DCs play in the development and treatment of autoimmunity.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Dendritic Cells; Humans; Immune Tolerance; T-Lymphocytes, Regulatory
PubMed: 34445143
DOI: 10.3390/ijms22168415 -
Best Practice & Research. Clinical... Feb 2020Microbial contributions to the immunopathogenesis of autoimmune rheumatic diseases have been studied since the advent of germ theory in the 19th century. With the... (Review)
Review
Microbial contributions to the immunopathogenesis of autoimmune rheumatic diseases have been studied since the advent of germ theory in the 19th century. With the exception of Group A Streptococcus in rheumatic fever, early studies failed to establish causal relationships between specific pathobionts and rheumatic disease. Today, systemic autoimmune diseases are thought to result from a complex interplay of environmental factors, individual genetic risk, and stochastic events. Interactions of microbiota and the immune system have been shown to promote and sustain chronic inflammation and autoimmunity. In mechanistic studies, microbe-immune cell interactions have been implicated in the initiation of autoimmune rheumatic diseases, e.g., through the posttranslational modification of autoantigens in rheumatoid arthritis or through neutrophil cell death and cross-reactivity with commensal orthologs in systemic lupus erythematosus. In parallel, modern molecular techniques have catalyzed the study of the microbiome in systemic autoimmune diseases. Here, I review current insights gained into the skin, oral, gut, lung, and vascular microbiome in connective tissue diseases and vasculitis. Mechanism relevant to the development and propagation of autoimmunity will be discussed whenever explored. While studies on autoimmune rheumatic disease have almost invariably shown abnormal microbiome structure (dysbiosis), substantial variability in microbial composition between studies makes generalization difficult. Moreover, an etiopathogenic role of specific pathobionts cannot be inferred by association alone. Integrating descriptive studies of microbial communities with hypothesis-driven research informed by immunopathogenesis will be important in elucidating targetable mechanisms in preclinical and established rheumatic disease.
Topics: Autoimmune Diseases; Autoimmunity; Dysbiosis; Humans; Lupus Erythematosus, Systemic; Microbiota; Rheumatic Diseases
PubMed: 32044247
DOI: 10.1016/j.berh.2019.101473 -
Cytokine & Growth Factor Reviews Apr 2021Interferons are the best antiviral agents in vitro against SARS-CoV-2 so far and genetic defects in their signaling cascade or neutralization of alfa-interferons by... (Review)
Review
Interferons are the best antiviral agents in vitro against SARS-CoV-2 so far and genetic defects in their signaling cascade or neutralization of alfa-interferons by autoantibodies come with more severe COVID-19. However, there is more, as the SARS-CoV-2 dysregulates not only innate immune mechanisms but also T and B cell repertoires. Most genetic, hematological and immunological studies in COVID-19 are at present phenomenological. However, these and antecedent studies contain the seed grains to resolve many unanswered questions and a whole range of testable hypotheses. What are the links, if existing, between genetics and the occurrence of interferon-neutralizing antibodies? Are NAGGED (neutralizing and generated by gene defect) antibodies involved or not? Is the autoimmune process cause or consequence of virus infection? What are the roles played by cytokine posttranslational modifications, such as proteolysis, glycosylation, citrullination and others? How is systemic autoimmunity linked with type 1 interferons? These questions place cytokines and growth factors at pole positions as keys to unlock basic mechanisms of infection and (auto)immunity. Related to cytokine research, (1) COVID-19 patients develop neutralizing autoantibodies, mainly against alpha interferons and it is not yet established whether this is the consequence or cause of virus replication. (2) The glycosylation of recombinant interferon-beta protects against breaking tolerance and the development of neutralizing antibodies. (3) SARS-CoV-2 induces severe inflammation and release of extracellular proteases leading to remnant epitopes, e.g. of cytokines. (4) In the rare event of homozygous cytokine gene segment deletions, observed neutralizing antibodies may be named NAGGED antibodies. (5) Severe cytolysis releases intracellular content into the extracellular milieu and leads to regulated degradation of intracellular proteins and selection of antibody repertoires, similar to those observed in patients with systemic lupus erythematosus. (6) Systematic studies of novel autoimmune diseases on single cytokines will complement the present picture about interferons. (7) Interferon neutralization in COVID-19 constitutes a preamble of more studies about cytokine-regulated proteolysis in the control of autoimmunity. Here we reformulate these seven conjectures into testable questions for future research.
Topics: Autoimmune Diseases; Autoimmunity; COVID-19; Cytokines; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Humans; Interferons
PubMed: 33563543
DOI: 10.1016/j.cytogfr.2021.01.004 -
Frontiers in Immunology 2022A dysregulated immune response toward self-antigens characterizes autoimmune and autoinflammatory (AIF) disorders. Autoantibodies or autoreactive T cells contribute to... (Review)
Review
A dysregulated immune response toward self-antigens characterizes autoimmune and autoinflammatory (AIF) disorders. Autoantibodies or autoreactive T cells contribute to autoimmune diseases, while autoinflammation results from a hyper-functional innate immune system. Aside from their differences, many studies suggest that monocytes and macrophages (Mo/Ma) significantly contribute to the development of both types of disease. Mo/Ma are innate immune cells that promote an immune-modulatory, pro-inflammatory, or repair response depending on the microenvironment. However, understanding the contribution of these cells to different immune disorders has been difficult due to their high functional and phenotypic plasticity. Several factors can influence the function of Mo/Ma under the landscape of autoimmune/autoinflammatory diseases, such as genetic predisposition, epigenetic changes, or infections. For instance, some vaccines and microorganisms can induce epigenetic changes in Mo/Ma, modifying their functional responses. This phenomenon is known as trained immunity. Trained immunity can be mediated by Mo/Ma and NK cells independently of T and B cell function. It is defined as the altered innate immune response to the same or different microorganisms during a second encounter. The improvement in cell function is related to epigenetic and metabolic changes that modify gene expression. Although the benefits of immune training have been highlighted in a vaccination context, the effects of this type of immune response on autoimmunity and chronic inflammation still remain controversial. Induction of trained immunity reprograms cellular metabolism in hematopoietic stem cells (HSCs), transmitting a memory-like phenotype to the cells. Thus, trained Mo/Ma derived from HSCs typically present a metabolic shift toward glycolysis, which leads to the modification of the chromatin architecture. During trained immunity, the epigenetic changes facilitate the specific gene expression after secondary challenge with other stimuli. Consequently, the enhanced pro-inflammatory response could contribute to developing or maintaining autoimmune/autoinflammatory diseases. However, the prediction of the outcome is not simple, and other studies propose that trained immunity can induce a beneficial response both in AIF and autoimmune conditions by inducing anti-inflammatory responses. This article describes the metabolic and epigenetic mechanisms involved in trained immunity that affect Mo/Ma, contraposing the controversial evidence on how it may impact autoimmune/autoinflammation conditions.
Topics: Autoimmune Diseases; Autoimmunity; Hereditary Autoinflammatory Diseases; Humans; Immunity, Innate; Killer Cells, Natural
PubMed: 35464438
DOI: 10.3389/fimmu.2022.868343 -
Frontiers in Immunology 2023The process of aging is accompanied by a dynamic restructuring of the immune response, a phenomenon known as immunosenescence. This mini-review navigates through the... (Review)
Review
The process of aging is accompanied by a dynamic restructuring of the immune response, a phenomenon known as immunosenescence. This mini-review navigates through the complex landscape of age-associated immune changes, chronic inflammation, age-related autoimmune tendencies, and their potential links with immunopathology of Long COVID. Immunosenescence serves as an introductory departure point, elucidating alterations in immune cell profiles and their functional dynamics, changes in T-cell receptor signaling, cytokine network dysregulation, and compromised regulatory T-cell function. Subsequent scrutiny of chronic inflammation, or "inflammaging," highlights its roles in age-related autoimmune susceptibilities and its potential as a mediator of the immune perturbations observed in Long COVID patients. The introduction of epigenetic facets further amplifies the potential interconnections. In this compact review, we consider the dynamic interactions between immunosenescence, inflammation, and autoimmunity. We aim to explore the multifaceted relationships that link these processes and shed light on the underlying mechanisms that drive their interconnectedness. With a focus on understanding the immunological changes in the context of aging, we seek to provide insights into how immunosenescence and inflammation contribute to the emergence and progression of autoimmune disorders in the elderly and may serve as potential mediator for Long COVID disturbances.
Topics: Humans; Aged; Immunosenescence; Autoimmunity; Post-Acute COVID-19 Syndrome; COVID-19; Aging; Autoimmune Diseases; Inflammation
PubMed: 37942323
DOI: 10.3389/fimmu.2023.1298004 -
Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency.The Journal of Allergy and Clinical... Aug 2023Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections,...
BACKGROUND
Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step.
OBJECTIVES
This study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance.
METHODS
Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed.
RESULTS
A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4 T cells and low TCR-Vα7.2 T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient.
CONCLUSIONS
This study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.
Topics: Humans; DNA Ligases; Autoimmunity; Haploinsufficiency; DNA Ligase ATP; Immunologic Deficiency Syndromes; Mutation; DNA
PubMed: 37004747
DOI: 10.1016/j.jaci.2023.03.022 -
Immunity, Inflammation and Disease Feb 2024Molecular mimicry is hypothesized to be a mechanism by which autoimmune diseases are triggered. It refers to sequence or structural homology between foreign antigens and... (Review)
Review
BACKGROUND
Molecular mimicry is hypothesized to be a mechanism by which autoimmune diseases are triggered. It refers to sequence or structural homology between foreign antigens and self-antigens, which can activate cross-reactive lymphocytes that attack host tissues. Elucidating the role of molecular mimicry in human autoimmunity could have important clinical implications.
OBJECTIVE
To review evidence for the role of molecular mimicry in major autoimmune diseases and discuss potential clinical implications.
METHODS
Comprehensive literature review of clinical trials, observational studies, animal models, and immunology studies on molecular mimicry in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, lupus, Guillain-Barre syndrome, autoimmune myocarditis, and primary biliary cirrhosis published from 2000-2023.
RESULTS
Substantial indirect evidence supports molecular mimicry as a contributor to loss of self-tolerance in several autoimmune conditions. Proposed microbial triggers include Epstein-Barr virus, coxsackievirus, Campylobacter jejuni, and bacterial commensals. Key mechanisms involve cross-reactive T cells and autoantibodies induced by epitope homology between microbial and self-antigens. Perpetuation of autoimmunity involves epitope spreading, inflammatory mediators, and genetic factors.
CONCLUSIONS
Molecular mimicry plausibly explains initial stages of autoimmune pathogenesis induced by infection or microbiota disturbances. Understanding mimicry antigens and pathways could enable improved prediction, monitoring, and antigen-specific immunotherapy for autoimmune disorders. However, definitive proof of causation in humans remains limited. Further research should focus on establishing clinical evidence and utility.
Topics: Animals; Humans; Molecular Mimicry; Autoimmunity; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Autoimmune Diseases; Epitopes; Autoantigens
PubMed: 38415936
DOI: 10.1002/iid3.1178 -
Frontiers in Immunology 2020T cells are indisputably critical mediators of atherosclerotic cardiovascular disease (CVD), where they secrete pro-inflammatory cytokines that promote vascular... (Review)
Review
T cells are indisputably critical mediators of atherosclerotic cardiovascular disease (CVD), where they secrete pro-inflammatory cytokines that promote vascular pathology. Equally well-established is the fact that autoimmune diseases, which are mediated by autoreactive T cells, substantially increase the risk of developing CVD. Indeed, as immunomodulatory treatments have become more effective at treating end-organ pathology, CVD has become a leading cause of death in patients with autoimmune diseases. Despite this, investigators have only recently begun to probe the mechanisms by which autoreactive T cells promote CVD in the context of autoimmune diseases. T cells are best-studied in the pathogenesis of systemic vasculitides, where they react to self-antigen in the vessel wall. However, newer studies indicate that T cells also contribute to the increased CVD risk associated with lupus and rheumatoid arthritis. Given the central role of T-cell-derived cytokines in the pathogenesis of psoriasis, the role of these factors in psoriatic CVD is also under investigation. In the future, T cells are likely to represent major targets for the prevention and treatment of CVD in patients with autoimmune diseases.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Cardiovascular Diseases; Humans; T-Lymphocytes
PubMed: 33117403
DOI: 10.3389/fimmu.2020.588776 -
Journal of Immunology (Baltimore, Md. :... Jan 2023DNA topoisomerases (TOPs) are complex enzymatic machines with extraordinary capacity to maintain DNA topology during torsion-intensive steps of replication and... (Review)
Review
DNA topoisomerases (TOPs) are complex enzymatic machines with extraordinary capacity to maintain DNA topology during torsion-intensive steps of replication and transcription. Recently, TOPs have gained significant attention for their tissue-specific function, and the vital role of TOPs in immune homeostasis and dysfunction is beginning to emerge. TOPs have been implicated in various immunological disorders such as autoimmunity, B cell immunodeficiencies, and sepsis, underscoring their importance in immune regulation. However, much remains unknown about immunological underpinnings of TOPs, and a deeper understanding of the role of TOPs in the immune system will be critical for yielding significant insights into the etiology of immunological disorders. In this review, we first discuss the recent literature highlighting the contribution of TOPs in the development of immune cells, and we further provide an overview of their importance in immune cell responses.
Topics: Humans; DNA; Autoimmunity; Immunologic Deficiency Syndromes
PubMed: 36596219
DOI: 10.4049/jimmunol.2200650 -
Frontiers in Immunology 2023Cytotoxic T lymphocyte has been a concern for the etiopathogenesis of alopecia areata (AA), some recent evidence suggests that the regulatory T (T) cell deficiency is... (Review)
Review
Cytotoxic T lymphocyte has been a concern for the etiopathogenesis of alopecia areata (AA), some recent evidence suggests that the regulatory T (T) cell deficiency is also a contributing factor. In the lesional scalp of AA, T cells residing in the follicles are impaired, leading to dysregulated local immunity and hair follicle (HF) regeneration disorders. New strategies are emerging to modulate T cells' number and function for autoimmune diseases. There is much interest to boost T cells in AA patients to suppress the abnormal autoimmunity of HF and stimulate hair regeneration. With few satisfactory therapeutic regimens available for AA, T cell-based therapies could be the way forward. Specifically, CAR-T cells and novel formulations of low-dose IL-2 are the alternatives.
Topics: Humans; Alopecia Areata; T-Lymphocytes, Regulatory; Autoimmune Diseases; Autoimmunity
PubMed: 37205097
DOI: 10.3389/fimmu.2023.1111547