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Nature Immunology Sep 2021The immunosuppressive function of regulatory T (T) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced...
The immunosuppressive function of regulatory T (T) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of T cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from T cell paucity, highlighting a vital function of T cells in preventing fatal autoimmune inflammation. However, a major question remains whether T cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate T cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued T cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, T cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Cell Differentiation; Female; Forkhead Transcription Factors; Gene Expression Regulation; Homeostasis; Inflammation Mediators; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Systemic Inflammatory Response Syndrome; T-Lymphocytes, Regulatory
PubMed: 34426690
DOI: 10.1038/s41590-021-01001-4 -
Neurotherapeutics : the Journal of the... Oct 2021In the last 25 years, intravenous immunoglobulin (IVIg) has had a major impact in the successful treatment of previously untreatable or poorly controlled autoimmune... (Review)
Review
In the last 25 years, intravenous immunoglobulin (IVIg) has had a major impact in the successful treatment of previously untreatable or poorly controlled autoimmune neurological disorders. Derived from thousands of healthy donors, IVIg contains IgG1 isotypes of idiotypic antibodies that have the potential to bind pathogenic autoantibodies or cross-react with various antigenic peptides, including proteins conserved among the "common cold"-pre-pandemic coronaviruses; as a result, after IVIg infusions, some of the patients' sera may transiently become positive for various neuronal antibodies, even for anti-SARS-CoV-2, necessitating caution in separating antibodies derived from the infused IVIg or acquired humoral immunity. IVIg exerts multiple effects on the immunoregulatory network by variably affecting autoantibodies, complement activation, FcRn saturation, FcγRIIb receptors, cytokines, and inflammatory mediators. Based on randomized controlled trials, IVIg is approved for the treatment of GBS, CIDP, MMN and dermatomyositis; has been effective in, myasthenia gravis exacerbations, and stiff-person syndrome; and exhibits convincing efficacy in autoimmune epilepsy, neuromyelitis, and autoimmune encephalitis. Recent evidence suggests that polymorphisms in the genes encoding FcRn and FcγRIIB may influence the catabolism of infused IgG or its anti-inflammatory effects, impacting on individualized dosing or efficacy. For chronic maintenance therapy, IVIg and subcutaneous IgG are effective in controlled studies only in CIDP and MMN preventing relapses and axonal loss up to 48 weeks; in practice, however, IVIg is continuously used for years in all the aforementioned neurological conditions, like is a "forever necessary therapy" for maintaining stability, generating challenges on when and how to stop it. Because about 35-40% of patients on chronic therapy do not exhibit objective neurological signs of worsening after stopping IVIg but express subjective symptoms of fatigue, pains, spasms, or a feeling of generalized weakness, a conditioning effect combined with fear that discontinuing chronic therapy may destabilize a multi-year stability status is likely. The dilemmas of continuing chronic therapy, the importance of adjusting dosing and scheduling or periodically stopping IVIg to objectively assess necessity, and concerns in accurately interpreting IVIg-dependency are discussed. Finally, the merit of subcutaneous IgG, the ineffectiveness of IVIg in IgG4-neurological autoimmunities, and genetic factors affecting IVIg dosing and efficacy are addressed.
Topics: Autoantibodies; Autoimmune Diseases of the Nervous System; Autoimmunity; COVID-19; Dose-Response Relationship, Immunologic; Humans; Immunoglobulins, Intravenous; SARS-CoV-2; Treatment Outcome; Withholding Treatment
PubMed: 34766257
DOI: 10.1007/s13311-021-01108-4 -
The Journal of Investigative Dermatology Mar 2022Sex bias in immune function has been well-described, and women have been shown to counter immunologically stimulating phenomena such as infection, malignancy, and trauma... (Review)
Review
Sex bias in immune function has been well-described, and women have been shown to counter immunologically stimulating phenomena such as infection, malignancy, and trauma with more protective responses than men. Heightened immunity in women may also result in a predisposition for loss of self-tolerance and development of autoimmunity, reflected by the overwhelming female sex bias of patients with autoimmune diseases. In this review, we discuss the postulated evolutionary etiologies for sexual dimorphism in immunity. We also review the molecular mechanisms underlying divergent immune responses in men and women, including sex hormone effects, X chromosome dosage, and autosomal sex-biased genes. With increasing evidence that autoimmune disease susceptibility is influenced by numerous hormonal and genetic factors, a comprehensive understanding of these topics may facilitate the development of much-needed targeted therapeutics.
Topics: Autoimmune Diseases; Autoimmunity; Female; Humans; Male; Sex Characteristics; Sex Factors; Sexism
PubMed: 34362556
DOI: 10.1016/j.jid.2021.06.008 -
Pharmacological Research Jun 2023Nicotinic acetylcholine receptors (nAChRs) are widely expressed in many and diverse cell types, participating in various functions of cells, tissues and systems. In this... (Review)
Review
Nicotinic acetylcholine receptors (nAChRs) are widely expressed in many and diverse cell types, participating in various functions of cells, tissues and systems. In this review, we focus on the autoimmunity against neuronal nAChRs, the specific autoantibodies and their mechanisms of pathological action in selected autoimmune diseases. We summarize the current relevant knowledge from human diseases as well as from experimental models of autoimmune neurological disorders related to antibodies against neuronal nAChR subunits. Despite the well-studied high immunogenicity of the muscle nAChRs where autoantibodies are the main pathogen of myasthenia gravis, autoimmunity to neuronal nAChRs seems infrequent, except for the autoantibodies to the ganglionic receptor, the α3 subunit containing nAChR (α3-nAChR), which are detected and are likely pathogenic in Autoimmune Autonomic Ganglionopathy (AAG). We describe the detection, presence and function of these antibodies and especially the recent development of a cell-based assay (CBA) which, contrary to until recently available assays, is highly specific for AAG. Rare reports of autoantibodies to the other neuronal nAChR subtypes include a few cases of antibodies to α7 and/or α4β2 nAChRs in Rasmussen encephalitis, schizophrenia, autoimmune meningoencephalomyelitis, and in some myasthenia gravis patients with concurrent CNS symptoms. Neuronal-type nAChRs are also present in several non-excitable tissues, however the presence and possible role of antibodies against them needs further verification. It is likely that the future development of more sensitive and disease-specific assays would reveal that neuronal nAChR autoantibodies are much more frequent and may explain the mechanisms of some seronegative autoimmune diseases.
Topics: Humans; Autoimmunity; Receptors, Nicotinic; Myasthenia Gravis; Autoimmune Diseases of the Nervous System; Autoantibodies
PubMed: 37164280
DOI: 10.1016/j.phrs.2023.106790 -
Science Translational Medicine Jul 2020The autoimmune disease systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies. It has been postulated that gut microbial...
The autoimmune disease systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies. It has been postulated that gut microbial dysbiosis may be one of the mechanisms involved in SLE pathogenesis. Here, we demonstrate that the dysbiotic gut microbiota of triple congenic (TC) lupus-prone mice (B6.) stimulated the production of autoantibodies and activated immune cells when transferred into germfree congenic C57BL/6 (B6) mice. Fecal transfer to B6 mice induced autoimmune phenotypes only when the TC donor mice exhibited autoimmunity. Autoimmune pathogenesis was mitigated by horizontal transfer of the gut microbiota between co-housed lupus-prone TC mice and control congenic B6 mice. Metabolomic screening identified an altered distribution of tryptophan metabolites in the feces of TC mice including an increase in kynurenine, which was alleviated after antibiotic treatment. Low dietary tryptophan prevented autoimmune pathology in TC mice, whereas high dietary tryptophan exacerbated disease. Reducing dietary tryptophan altered gut microbial taxa in both lupus-prone TC mice and control B6 mice. Consequently, fecal transfer from TC mice fed a high tryptophan diet, but not a low tryptophan diet, induced autoimmune phenotypes in germfree B6 mice. The interplay of gut microbial dysbiosis, tryptophan metabolism and host genetic susceptibility in lupus-prone mice suggest that aberrant tryptophan metabolism may contribute to autoimmune activation in this disease.
Topics: Animals; Autoimmunity; Dysbiosis; Gastrointestinal Microbiome; Lupus Erythematosus, Systemic; Mice; Mice, Inbred C57BL; Tryptophan
PubMed: 32641487
DOI: 10.1126/scitranslmed.aax2220 -
BMC Immunology Oct 2023Digestive autoimmune conditions are a growing challenge to global health. Risk factors associated with autoimmune digestive diseases are complex, including genetic...
Digestive autoimmune conditions are a growing challenge to global health. Risk factors associated with autoimmune digestive diseases are complex, including genetic variation, immunological dysfunction, and various environmental factors. To improve our understanding of the mechanisms behind digestive autoimmune conditions, including factors causing gastrointestinal manifestations and pathogenesis, BMC Immunology has launched a new Collection "The digestive system and autoimmunity".
Topics: Humans; Autoimmunity; Autoimmune Diseases; Digestive System
PubMed: 37794375
DOI: 10.1186/s12865-023-00561-4 -
Journal of Autoimmunity May 2023Infections are known to trigger flares of autoimmune diseases in humans and serve as an inciting cause of autoimmunity in animals. Evidence suggests a causative role of... (Review)
Review
Infections are known to trigger flares of autoimmune diseases in humans and serve as an inciting cause of autoimmunity in animals. Evidence suggests a causative role of infections in triggering antigen-specific autoimmunity, previous thought mainly through antigen mimicry. However, an infection can induce bystander autoreactive T and B cell polyclonal activation, believed to result in non-pathogenic and pathogenic autoimmune responses. Lastly, epitope spreading in autoimmunity is a mechanism of epitope changes of autoreactive cells induced by infection, promoting the targeting of additional self-epitopes. This review highlights recent research findings, emphasizes infection-mediated autoimmune responses, and discusses the possible mechanisms involved.
Topics: Humans; Animals; Autoimmunity; Autoantibodies; Autoimmune Diseases; Epitopes; Communicable Diseases
PubMed: 36470769
DOI: 10.1016/j.jaut.2022.102962 -
Nature Reviews. Immunology Feb 2023Self-reactive immune responses occur in autoimmune diseases and also in chronic inflammatory and metabolic diseases that are not generally considered as autoimmune...
Self-reactive immune responses occur in autoimmune diseases and also in chronic inflammatory and metabolic diseases that are not generally considered as autoimmune diseases. How do the mechanisms of autoreactivity in the different settings overlap and how are they distinguished? Evidence indicates that while autoimmune diseases rely on both a supportive genetic background and a cooperative environment, chronic inflammatory and metabolic diseases strongly hinge on a conducive milieu for the activation of pathogenic autoreactive cells even in the absence of facilitating polygenic factors.
Topics: Humans; Autoimmunity; Autoantibodies
PubMed: 36418434
DOI: 10.1038/s41577-022-00812-2 -
Current Opinion in Structural Biology Aug 2022Bacteria are microscopic, single-celled organisms known for their ability to adapt to their environment. In response to stressful environmental conditions or in the... (Review)
Review
Bacteria are microscopic, single-celled organisms known for their ability to adapt to their environment. In response to stressful environmental conditions or in the presence of a contact surface, they commonly form multicellular aggregates called biofilms. Biofilms form on various abiotic or biotic surfaces through a dynamic stepwise process involving adhesion, growth, and extracellular matrix production. Biofilms develop on tissues as well as on implanted devices during infections, providing the bacteria with a mechanism for survival under harsh conditions including targeting by the immune system and antimicrobial therapy. Like pathogenic bacteria, members of the human microbiota can form biofilms. Biofilms formed by enteric bacteria contribute to several human diseases including autoimmune diseases and cancer. However, until recently the interactions of immune cells with biofilms had been mostly uncharacterized. Here, we will discuss how components of the enteric biofilm produced in vivo, specifically amyloid curli and extracellular DNA, could be interacting with the host's immune system causing an unpredicted immune response.
Topics: Amyloid; Amyloidogenic Proteins; Autoimmune Diseases; Autoimmunity; Bacteria; Biofilms; Humans
PubMed: 35863164
DOI: 10.1016/j.sbi.2022.102435 -
Frontiers in Immunology 2021
Topics: Animals; Autoimmunity; Bacteria; Humans; Viruses
PubMed: 34567014
DOI: 10.3389/fimmu.2021.752980