Systemic lupus erythematosus (SLE) is a complicated autoimmune disease affecting multiple systems and organs. It is highly heterogeneous, and it preferentially affects women at childbearing age, causing worldwide social burden. The pathogenesis of SLE mostly involves genetic predisposition, epigenetic dysregulation, overactivation of the immune system, and environment factors. Human microbiome, which is mostly composed of microbiota colonized in the gut, skin, and oral cavity, provides a natural microbiome barrier against environmental risks. The past decade of research has demonstrated a strong association between microbiota and metabolic diseases or gastrointestinal diseases. However, the role of microbiota in autoimmunity remains largely unknown until recently, when the technological and methodological progress facilitates further microbiota research in SLE. In this review, the latest research about the role and mechanisms of microbiota in SLE and the advances in the development of diagnostic and therapeutic strategies based on microbiota for SLE were summarized.
Humans ; Female ; Gastrointestinal Microbiome ; Lupus Erythematosus, Systemic/therapy* ; Microbiota ; Autoimmunity ; Immune System

IL-17 is produced by RAR-related orphan receptor gamma t (RORγt)-expressing cells including Th17 cells, subsets of γδT cells and innate lymphoid cells (ILCs). The biological significance of IL-17-producing cells is well-studied in contexts of inflammation, autoimmunity and host defense against infection. While most of available studies in tumor immunity mainly focused on the role of T-bet-expressing cells, including cytotoxic CD8⁺ T cells and NK cells, and their exhaustion status, the role of IL-17-producing cells remains poorly understood. While IL-17-producing T-cells were shown to be anti-tumorigenic in adoptive T-cell therapy settings, mice deficient in type 17 genes suggest a protumorigenic potential of IL-17-producing cells. This review discusses the features of IL-17-producing cells, of both lymphocytic and myeloid origins, as well as their suggested pro- and/or anti-tumorigenic functions in an organ-dependent context. Potential therapeutic approaches targeting these cells in the tumor microenvironment will also be discussed.
Animals ; Autoimmunity ; Child ; Child, Orphaned ; Friends ; Humans ; Inflammation ; Interleukin-17 ; Killer Cells, Natural ; Lymphocytes ; Mice ; T-Lymphocytes ; Th17 Cells ; Tumor Microenvironment

Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disorder that affects mainly salivary and lacrimal glands, but its cause remains largely unknown. Clinical data indicating that SS occurs in a substantial proportion of patients with lupus points to common pathogenic mechanisms underlying the two diseases. To address this idea, we asked whether SS develops in the lupus-prone mouse strain sanroque (SAN). Owing to hyper-activation of follicular helper T (Tfh) cells, female SAN mice developed lupus-like symptoms at approximately 20 wk of age but there were no signs of SS at that time. However, symptoms typical of SS were evident at approximately 40 wk of age, as judged by reduced saliva flow rate, sialadenitis, and IgG deposits in the salivary glands. Increases in serum titers of SS-related autoantibodies and numbers of autoantibody-secreting cells in cervical lymph nodes (LNs) preceded the pathologic manifestations of SS and were accompanied by expansion of Tfh cells and their downstream effector cells. Thus, our results suggest that chronic dysregulation of Tfh cells in salivary gland-draining LNs is sufficient to drive the development of SS in lupus-prone mice.
Animals ; Autoantibodies ; Autoimmunity ; Disease Models, Animal ; Female ; Humans ; Immunoglobulin G ; Lacrimal Apparatus ; Lupus Erythematosus, Systemic ; Lymph Nodes ; Mice ; Saliva ; Salivary Glands ; Sialadenitis

Long noncoding RNAs (lncRNAs) are non-protein coding RNAs of more than 200 nucleotides in length. Despite the term “noncoding”, lncRNAs have been reported to be involved in gene expression. Accumulating evidence suggests that lncRNAs play crucial roles in the regulation of immune system and the development of autoimmunity. lncRNAs are expressed in various immune cells including T lymphocytes, B lymphocytes, macrophages, neutrophils, dendritic cells, and NK cells, and are also involved in the differentiation and activation of these immune cells. Here, we review recent studies on the role of lncRNAs in immune regulation and the differential expression of lncRNAs in various autoimmune diseases.
Autoimmune Diseases ; Autoimmunity ; B-Lymphocytes ; Clinical Coding ; Dendritic Cells ; Gene Expression ; Immune System ; Killer Cells, Natural ; Macrophages ; Neutrophils ; Nucleotides ; RNA ; RNA, Long Noncoding ; T-Lymphocytes

Aging is a complex process associated with dysregulation of the immune system and low levels of inflammation, often associated with the onset of many pathologies. The lacrimal gland (LG) plays a vital role in the maintenance of ocular physiology and changes related to aging directly affect eye diseases. The dysregulation of the immune system in aging leads to quantitative and qualitative changes in antibodies and cytokines. While there is a gradual decline of the immune system, there is an increase in autoimmunity, with a reciprocal pathway between low levels of inflammation and aging mechanisms. Elderly C57BL/6J mice spontaneously show LGs infiltration that is characterized by Th1 but not Th17 cells. The aging of the LG is related to functional alterations, reduced innervation and decreased secretory activities. Lymphocytic infiltration, destruction, and atrophy of glandular parenchyma, ductal dilatation, and secretion of inflammatory mediators modify the volume and composition of tears. Oxidative stress, the capacity to metabolize and eliminate toxic substances decreased in aging, is also associated with the reduction of LG functionality and the pathogenesis of autoimmune diseases. Although further studies are required for a better understanding of autoimmunity and aging of the LG, we described anatomic and immunology aspects that have been described so far.
Aged ; Aging ; Allergy and Immunology ; Animals ; Antibodies ; Atrophy ; Autoimmune Diseases ; Autoimmunity ; Cytokines ; Dilatation ; Eye Diseases ; Humans ; Immune System ; Inflammation ; Lacrimal Apparatus ; Mice ; Ocular Physiological Phenomena ; Oxidative Stress ; Pathology ; Tears ; Th17 Cells

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease characterized by production of autoantibodies to various nuclear antigens and overexpression of genes regulated by IFN-I called IFN signature. Genetic studies on SLE patients and mutational analyses of mouse models demonstrate crucial roles of nucleic acid (NA) sensors in development of SLE. Although NA sensors are involved in induction of anti-microbial immune responses by recognizing microbial NAs, recognition of self NAs by NA sensors induces production of autoantibodies to NAs in B cells and production of IFN-I in plasmacytoid dendritic cells. Among various NA sensors, the endosomal RNA sensor TLR7 plays an essential role in development of SLE at least in mouse models. CD72 is an inhibitory B cell co-receptor containing an immunoreceptor tyrosine-based inhibition motif (ITIM) in the cytoplasmic region and a C-type lectin like-domain (CTLD) in the extracellular region. CD72 is known to regulate development of SLE because CD72 polymorphisms associate with SLE in both human and mice and CD72−/− mice develop relatively severe lupus-like disease. CD72 specifically recognizes the RNA-containing endogenous TLR7 ligand Sm/RNP by its extracellular CTLD, and inhibits B cell responses to Sm/RNP by ITIM-mediated signal inhibition. These findings indicate that CD72 inhibits development of SLE by suppressing TLR7-dependent B cell response to self NAs. CD72 is thus involved in discrimination of self-NAs from microbial NAs by specifically suppressing autoimmune responses to self-NAs.
Animals ; Antigens, Nuclear ; Autoantibodies ; Autoantigens ; Autoimmune Diseases ; Autoimmunity ; B-Lymphocytes ; Cytoplasm ; Dendritic Cells ; Discrimination (Psychology) ; Humans ; Immunoreceptor Tyrosine-Based Inhibition Motif ; Lectins, C-Type ; Lupus Erythematosus, Systemic ; Mice ; RNA

IL-32 exists as seven mRNA transcripts that can translate into distinct individual IL-32 variants with specific protein domains. These translated protein domains of IL-32 variants code for specific functions that allow for interaction with different molecules intracellularly or extracellularly. The longest variant is IL-32γ possessing 234 amino acid residues with all 11 protein domains, while the shortest variant is IL-32α possessing 131 amino acid residues with three of the protein domains. The first domain exists in 6 variants except IL-32δ variant, which has a distinct translation initiation codon due to mRNA splicing. The last eleventh domain is common domain for all seven IL-32 variants. Numerous studies in different fields, such as inflammation, autoimmunity, pathogen infection, and cancer biology, have claimed the specific biological activity of individual IL-32 variant despite the absence of sufficient data. There are 4 additional IL-32 variants without proper transcripts. In this review, the structural characteristics of seven IL-32 transcripts are described based on the specific protein domains.
Autoimmunity ; Biology ; Codon, Initiator ; Inflammation ; Protein Structure, Tertiary ; RNA, Messenger

PURPOSE: Immunoglobulin (Ig) E autoantibodies against thyroid antigens such as thyroid peroxidase (TPO) have been demonstrated in chronic spontaneous urticaria (CSU) patients in higher frequency than healthy subjects. However, if these IgE autoantibodies can trigger urticaria is still a matter of study. The aim of this study was to investigate the relationship between concomitant IgE autoantibodies against thyroid antigens in CSU. METHODS: Patients with CSU, healthy subjects and patients with autoimmune thyroid disease (ATD) were recruited. Total IgE and specific anti-TPO IgE and IgG were assessed in all subjects. The basophil activation test and skin tests with TPO were performed to demonstrate whether this antigen could selectively induce urticaria reaction in subjects with positive anti-TPO IgE. RESULTS: Anti-TPO IgE was present in all 3 groups (CSU: 34.0%, ATD: 16.6%, healthy subjects: 8.1%). Anti-TPO IgE levels were higher in CSU patients, whereas anti-TPO IgG were higher in ATD patients. After exposure to TPO, CD203c expression from patients with CSU and anti-TPO IgE significantly increased in comparison to the other groups; 33.0% vs. 14.0% in ATD patients and 9.0% in control subjects (P < 0.05). Skin reactions with TPO were higher in patients with CSU according to the intradermal (CSU: 18.0%, ATD: 3.3%, control: 8.0%) and skin prick tests (12.0%, 0%, 0%, respectively). Passive transfer of anti-TPO IgE from a CSU patient to the skin of control subjects without anti-TPO IgE induced a positive skin reaction. CONCLUSIONS: Anti-TPO IgE is not a specific biomarker for CSU. However, IgE against TPO plays a pathogenic role in inducing effector cell activation and skin exacerbation in some patients with CSU.
Autoantibodies ; Autoimmunity ; Basophils ; Healthy Volunteers ; Humans ; Hypothyroidism ; Immunoglobulin E* ; Immunoglobulin G ; Immunoglobulins ; In Vitro Techniques* ; Iodide Peroxidase ; Skin ; Skin Tests ; Thyroid Diseases ; Thyroid Gland ; Urticaria*

Atherosclerosis is a major cause of morbidity and mortality due to cardiovascular diseases, such as coronary artery disease, stroke, and peripheral vascular disease, that are associated with thrombosis-induced organ infarction. In Westernized countries, the high prevalence of obesity-induced insulin resistance is predicted to be a major factor leading to atherosclerotic vascular disease. Both genetic and environmental factors interfere with immune responses in atherosclerosis development with chronic and non-resolving states. The most known autoimmune disease therapy is cytokine-targeted therapy, which targets tumor necrosis factor-α and interleukin (IL)-17 antagonists. Recently, a clinical trial with the anti-IL-1β antibody (canakinumab) had shown that the anti-inflammatory effects in canakinumab-treated subjects play a critical role in reducing cardiovascular disease prevalence. Recent emerging data have suggested effective therapeutics involving anti-obesity and anti-diabetic agents, as well as statin and anti-platelet drugs, for atherothrombosis prevention. It is well-known that specialized immune differentiation and activation completely depends on metabolic reprogramming mediated by mitochondrial dynamics in distinct immune cells. Therefore, there is a strong mechanistic link between metabolism and immune function mediated by mitochondrial function. In this review, we describe that cellular metabolism in immune cells is strongly interconnected with systemic metabolism in terms of diverse phenotypes and activation.
Atherosclerosis ; Autoimmune Diseases ; Autoimmunity ; Cardiovascular Diseases ; Coronary Artery Disease ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Hypercholesterolemia ; Infarction ; Insulin Resistance ; Interleukins ; Metabolism ; Mitochondrial Dynamics ; Mortality ; Necrosis ; Peripheral Vascular Diseases ; Phenotype ; Prevalence ; Stroke ; Vascular Diseases

The commensal microbiota contributes to the maintenance of immune homeostasis in the human body. Autoimmunity can be aggravated or alleviated by the microbiota, which affects both innate and adaptive immune cells. Many studies have demonstrated the role of gut dysbiosis, the alteration of the gut microbiome, in the development and progression of numerous autoimmune diseases. Systemic sclerosis (SSc) is an autoimmune disease of the connective tissue and is characterized by skin and lung fibrosis, as well as injuries in small arteries. Recent studies have shown variable degrees of dysbiosis in SSc patients and the effect of probiotics on these patients, providing evidence for the potential link between microbiota and SSc. However, further research is needed to elucidate the key microorganisms and the mechanisms through which they affect the pathoimmunological process of SSc. This review summarizes the current knowledge regarding the association between microbiota and SSc, and discusses the changing perspectives and potential therapy strategies based on the microbiota and its products.
Arteries ; Autoimmune Diseases ; Autoimmunity ; Connective Tissue ; Dysbiosis ; Fibrosis ; Gastrointestinal Microbiome ; Homeostasis ; Human Body ; Humans ; Lung ; Microbiota ; Probiotics ; Scleroderma, Systemic ; Skin