Modulation of Intestinal ILC3 for the Treatment of Type 1 Diabetes

Gut-associated lymphoid tissue (GALT) is crucial for the maintenance of the intestinal homeostasis, but it is also the potential site of the activation of autoreactive cells and initiation/propagation of autoimmune diseases in the gut and in the distant organs. Type 3 innate lymphoid cells (ILC3) residing in the GALT integrate signals from food ingredients and gut microbiota metabolites in order to control local immunoreactivity. Notably, ILC3 secrete IL-17 and GM-CSF that activate immune cells in combating potentially pathogenic microorganisms. ILC3 also produce IL-22 that potentiates the strength and integrity of epithelial tight junctions, production of mucus and antimicrobial peptides thus enabling the proper function of the intestinal barrier. The newly discovered function of small intestine ILC3 is the secretion of IL-2 and the promotion of regulatory T cell (Treg) generation and function. Since the intestinal barrier dysfunction, together with the reduction in small intestine ILC3 and Treg numbers are associated with the pathogenesis of type 1 diabetes (T1D), the focus of this article is intestinal ILC3 modulation for the therapy of T1D. Of particular interest is free fatty acids receptor 2 (FFAR2), predominantly expressed on intestinal ILC3, that can be stimulated by available selective synthetic agonists. Thus, we propose that FFAR2-based interventions by boosting ILC3 beneficial functions may attenuate autoimmune response against pancreatic β cells during T1D. Also, it is our opinion that treatments based on ILC3 stimulation by functional foods can be used as prophylaxis in individuals that are genetically predisposed to develop T1D.

The rationale for targeting the JAK/STAT pathway in scleroderma-associated interstitial lung disease

The etiopathogenesis of systemic sclerosis (SSc)-associated interstitial lung disease (ILD) is still debated and no therapeutic options have proved fully effective to date. The intracellular Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is highly conserved among either immune or nonimmune cells and involved in inflammation and fibrosis. Evidence from preclinical studies shows that the JAK/STAT signaling cascade has a crucial role in the differentiation of autoreactive cells as well as in the extracellular matrix remodeling that occurs in SSc. Therefore, it is likely that the use of oral small molecule JAK-inhibitors, especially if prescribed early, may prevent or slow the progression of SSc-associated ILD, but few clinical studies currently support this hypothesis.

Differentiating MHC-dependent and -independent mechanisms of lymph node stromal cell regulation of proinsulin-specific CD8+ T-cells in type 1 diabetes

Lymph node stromal cells (LNSC) are essential for providing and maintaining peripheral self-tolerance of potentially autoreactive cells. In type 1 diabetes, proinsulin-specific CD8⁺T-cells, escaping central and peripheral tolerance, contribute to beta-cell destruction. Using G9Cα^-/-CD8⁺T-cells specific for proinsulin, we studied the mechanisms by which LNSC regulate low-avidity autoreactive cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes. Whereas MHC-matched NOD-LNSC significantly reduced G9Cα^-/-CD8⁺T-cell cytotoxicity and DC-induced proliferation, they failed to sufficiently regulate T-cells stimulated by anti-CD3/CD28. In contrast, non-MHC matched, control C57BL/6 mouse LNSC suppressed T-cell receptor engagement by anti-CD3/CD28 via MHC-independent mechanisms. This C57BL/6-LNSC suppression was maintained even after removal of the LNSC, demonstrating a direct effect of LNSC on T-cells, modifying antigen sensitivity and effector function. Thus, our results suggest that a loss of NOD-LNSC MHC-independent suppressive mechanisms may contribute to diabetes development.

Differentiating MHC-dependent and -independent mechanisms of lymph node stromal cell regulation of proinsulin-specific CD8+ T-cells in type 1 diabetes

Lymph node stromal cells (LNSC) are essential for providing and maintaining peripheral self-tolerance of potentially autoreactive cells. In type 1 diabetes, proinsulin-specific CD8⁺T-cells, escaping central and peripheral tolerance, contribute to beta-cell destruction. Using G9Cα^-/-CD8⁺T-cells specific for proinsulin, we studied the mechanisms by which LNSC regulate low-avidity autoreactive cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes. Whereas MHC-matched NOD-LNSC significantly reduced G9Cα^-/-CD8⁺T-cell cytotoxicity and DC-induced proliferation, they failed to sufficiently regulate T-cells stimulated by anti-CD3/CD28. In contrast, non-MHC matched, control C57BL/6 mouse LNSC suppressed T-cell receptor engagement by anti-CD3/CD28 via MHC-independent mechanisms. This C57BL/6-LNSC suppression was maintained even after removal of the LNSC, demonstrating a direct effect of LNSC on T-cells, modifying antigen sensitivity and effector function. Thus, our results suggest that a loss of NOD-LNSC MHC-independent suppressive mechanisms may contribute to diabetes development.

The molecular basis of immune regulation in autoimmunity

Autoimmune diseases can be triggered and modulated by various molecular and cellular characteristics. The mechanisms of autoimmunity and the pathogenesis of autoimmune diseases have been investigated for several decades. It is well accepted that autoimmunity is caused by dysregulated/dysfunctional immune susceptible genes and environmental factors. There are multiple physiological mechanisms that regulate and control self-reactivity, but which can also lead to tolerance breakdown when in defect. The majority of autoreactive T or B cells are eliminated during the development of central tolerance by negative selection. Regulatory cells such as Tregs (regulatory T) and MSCs (mesenchymal stem cells), and molecules such as CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) and IL (interleukin) 10 (IL-10), help to eliminate autoreactive cells that escaped to the periphery in order to prevent development of autoimmunity. Knowledge of the molecular basis of immune regulation is needed to further our understanding of the underlying mechanisms of loss of tolerance in autoimmune diseases and pave the way for the development of more effective, specific, and safer therapeutic interventions.

Salvianolic acid B: In vitro and in vivo effects on the immune system

Type 1 diabetes (T1D) is an autoimmune disorder with a strong inflammatory component. Autoreactive cells specifically target insulin-producing ?-cells, which leads to loss of glucose homeostasis. T1D remains incurable and versatile; potentially beneficial therapeutics are being tested worldwide. Possible candidates for the treatment of autoimmune diabetes are plants and their extracts since they are rich in biophenols, substances that act as secondary metabolites, and have verified antioxidant and antiinflammatory effects. Salvianolic acid B (SalB) is a biophenol and one of the major constituents of Origanum vulgare ssp. hirtum (Greek oregano) extracts which in our previous studies was shown to exhibit an antidiabetic effect in mice. The aim of the present study was to determine whether SalB is responsible for the observed effects of Greek oregano extracts. SalB was applied in vitro to macrophages and lymphocytes isolated from C57BL/6 mice, as well as in vivo in the model of T1D induced by multiple low doses (MLD) of streptozotocin (STZ). SalB did not affect the viability of cells, but it significantly decreased secretion of nitric oxide (NO) and TNF in lipopolysaccharide (LPS)-stimulated macrophages, as well as the secretion of IFN-? in concanavalin A (ConA)-stimulated lymphocytes. However, when applied in vivo, SalB at a dose of 2.5 mg/kg b.w., applied for 10 consecutive days, failed to protect mice from diabetes development. In conclusion, SalB exerts immunomodulatory effects in vitro, but is not effective in prevention of T1D in vivo. It probably requires cooperation with some other substances for the maximum efficacy exhibited by oregano extracts.

The influence of methylprednisolone on the ability of CD4+CD95+HLA-DR+ T-cells to produce proinflammatory medators in cultures of TCR-activated CD3+CD45RO+ T-lymphocytes from patients with rheumatoid arthritis

The effect of different concentrations of the glucocorticoid (GC) methylprednisolone (MP) on CD4+CD95+HLA-DR+ T-cells and their ability to produce proinflammatory mediators in cultures of TCR-stimulated CD3+CD45RO+ T-lymphocytes in the in vitro system was investigated. T cells were obtained from healthy donors and patients with rheumatoid arthritis (RA).Under conditions of TCR-activation, MP increased the number of CD4+HLA-DR+CD95+ cells in CD3+CD45RO+ cultures obtained from RA patients and did not change their content in the control group. In general, MP decreased production of proinflammatory factors (IFN-, IL-2, IL-17, IL-21 and TNF-) by TCR-activated CD3+CD45RO+ cells from healthy donors and RA, consistent with the overall immunosuppressive mechanism of GC action. The correlation between CD4+CD45RO+HLA-DR+CD95+ T-cell contents and parameters reflecting production of proinflammatory mediators (IL-17, IL-21 and TNF-) in RA patients indicates maintenance of the pro-inflammatory potential of this T-cell population exposed to GC action. We suggest that relative resistance of CD4+CD45RO+CD95+HLA-DR+ T-cells of RA patients to the suppressor effect of GC leads to maintenance and even enhancement in the functional capacities of autoreactive cells in the pathogenesis of RA.

The gut immune system, inflammatory bowel diseases, and the body immune homeostasis: modern treatment strategies

The digestive tract is nowadays conceived as a barrier organ constituted by a mucosal membrane separating the gut lumen from the inner milieu. The gut lumen is laden by a myriad of antigens brought about by the diet, but also pertaining to the overwhelming bacterial species of the gut microbiome. The mucosal cell population comprehends epithelial cells, and a variety of immune reactive cells. Of them, the mononuclear types effecting innate responses are endowed by membrane signaling receptors and, as a rule, are sensing the polysaccharides of bacterial cell walls; non-tolerated signals may then push the chain reaction on, to end in full activation of inflammation mediators. Acquired immunity is in turn mainly effected by T-cell types, some of them, behaving as autoreactive cells, may induce metastatic inflammation beyond bowel boundaries, partly explaining the so-called extra-intestinal manifestations of inflammatory bowel disease (IBD). The scenario is further complicated by the possible influence of epigenetic factors: diet, stress, smoking, drugs. Being IBD a low-penetrance disorder, for the full phenotype to develop, a critical mass of the above listed factors (typically, a disturbed membrane permeability, an immune stimulus, and an epigenetic factor) must occur. In the century since the full description of IBD, a variegated plethora of measures have been attempted. Some updated designs are now under scrutiny. Microbiota engineering, apoptosis modulation, and diet modification are just a few of the measures that we are arbitrarily describing here.

A tobozmirigy-csecsemőmirigy rendszer szerepe az autoimmunitás, öregedés és élettartam szabályozásában

Thymus is an immunoendocrine organ, the hormones of which mainly influence its own lymphatic elements. It has a central role in the immune system, the neonatal removal causes the collapse of immune system and the whole organism. The thymic nurse cells select the bone marrow originated lymphocytes and destroy the autoreactive ones, while thymus originated Treg cells suppress the autoreactive cells in the periphery. The involution of the organ starts after birth, however, this truly happens in the end of puberty only, as before this it is overcompensated by developmental processes. From the end of adolescence the involution allows the life, proliferation and enhanced functioning of some autoreactive cells, which gradually wear down the cells and intercellular materials, causing the aging. The enhanced and mass function of autoreactive cells lead to the autoimmune diseases and natural death. This means that the involution of thymus is not a part of the organismic involution, but an originator of it, which is manifested in the lifespan-pacemaker function. In this case aging can be comprehended as a thymus-commanded slow autoimmune process. The neonatal removal of pineal gland leads to the complete destruction of the thymus and the crashing down of the immune system, as well as to wasting disease. The involution of the pineal and thymus runs parallel, because the two organs form a functional unit. It is probable that the pineal gland is responsible for the involution of thymus and also regulates its lifespan determining role. The data reviewed do not prove the exclusive role of pineal-thymus system in the regulation of aging and lifespan, however, calls attention to the suitability of solving this problem alone. Orv. Hetil., 2016, 157(27), 1065–1070.