Female offspring gestated in hypothyroxinemia and infected with human Metapneumovirus (hMPV) suffer a more severe infection and have a higher number of activated CD8+ T lymphocytes.

Maternal thyroid hormones (THs) are essential for the appropriate development of the fetus and especially for the brain. Recently, some studies have shown that THs deficiency can also alter the immune system development of the progeny and their ability to mount an appropriate response against infectious agents. In this study, we evaluated whether adult mice gestated under hypothyroxinemia (Hpx) showed an altered immune response against infection with human metapneumovirus (hMPV). We observed that female mice gestated under Hpx showed higher clinical scores after seven days of hMPV infection. Besides, males gestated under Hpx have higher lung viral loads at day seven post-infection. Furthermore, the female offspring gestated in Hpx have already reduced the viral load at day seven and accordingly showed an increased proportion of activated (CD71+ and FasL+) CD8+ T cells in the lungs, which correlated with a trend for a higher histopathological clinical score. These results support that T4 deficiency during gestation might condition the offspring differently in males and females, enhancing their ability to respond to hMPV.

Trained Immunity Contribution to Autoimmune and Inflammatory Disorders.

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.

S100A8 alarmin supports IL-6 and metalloproteinase-9 production by fibroblasts in the synovial microenvironment of peripheral spondyloarthritis.

Introduction: Spondyloarthritis (SpA) is a common autoinflammatory disease. S100A8/ S100A9 alarmin is strongly expressed in the synovial sublining layers of psoriatic arthritis. S100A8/ S100A9 is the most abundant protein in rheumatoid arthritis synovial fluid (SF) and has a key role in promoting IL-6 expression in fibroblast-like synoviocytes (FLS). The molecular mechanisms and the role of S100-alarmins in the synovial microenvironment of SpA have never been demonstrated. Methods and Results: Here, we confirm the effect of the synovial microenvironment of peripheral SpA on interleukin-6 (IL-6) and metalloproteinase (MMP)-9 production by FLS. MMP-9 expression and activity were detected, which were reduced in the presence of anti-IL-6R. Analyzing cell signaling mechanisms, we found that stimulation with IL-6 co-triggered MMP-9 and IL-10 secretion. MMP-9 secretion depended on JNK and p38 MAPKs, whereas IL-10 secretion was dependent on the JAK pathway as a potential feedback mechanism controlling IL-6-induced MMP-9 expression. Using a proteomic approach, we identified S100A8 in the peripheral SpA SF. This presence was confirmed by immunoblotting. S100A8 increased the IL-6 secretion via ERK and p38 MAPK pathways. Furthermore, anti-S100A8/A9 reduced both IL-6 and MMP-9 production induced by SpA SF in FLS. Discussion: Our data reveal a marked relationship between S100A8 alarmin with IL-6 and MMP-9 secretion by FLS in the real synovial microenvironment of peripheral SpA. These results identify a mechanism linking S100A8 to the pathogenesis of peripheral SpA.

Contribution of Dysregulated DNA Methylation to Autoimmunity.

Epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs are known regulators of gene expression and genomic stability in cell growth, development, and differentiation. Because epigenetic mechanisms can regulate several immune system elements, epigenetic alterations have been found in several autoimmune diseases. The purpose of this review is to discuss the epigenetic modifications, mainly DNA methylation, involved in autoimmune diseases in which T cells play a significant role. For example, Rheumatoid Arthritis and Systemic Lupus Erythematosus display differential gene methylation, mostly hypomethylated 5'-C-phosphate-G-3' (CpG) sites that may associate with disease activity. However, a clear association between DNA methylation, gene expression, and disease pathogenesis must be demonstrated. A better understanding of the impact of epigenetic modifications on the onset of autoimmunity will contribute to the design of novel therapeutic approaches for these diseases.

Naturally Derived Heme-Oxygenase 1 Inducers and Their Therapeutic Application to Immune-Mediated Diseases.

Heme oxygenase (HO) is the primary antioxidant enzyme involved in heme group degradation. A variety of stimuli triggers the expression of the inducible HO-1 isoform, which is modulated by its substrate and cellular stressors. A major anti-inflammatory role has been assigned to the HO-1 activity. Therefore, in recent years HO-1 induction has been employed as an approach to treating several disorders displaying some immune alterations components, such as exacerbated inflammation or self-reactivity. Many natural compounds have shown to be effective inductors of HO-1 without cytotoxic effects; among them, most are chemicals present in plants used as food, flavoring, and medicine. Here we discuss some naturally derived compounds involved in HO-1 induction, their impact in the immune response modulation, and the beneficial effect in diverse autoimmune disorders. We conclude that the use of some compounds from natural sources able to induce HO-1 is an attractive lifestyle toward promoting human health. This review opens a new outlook on the investigation of naturally derived HO-1 inducers, mainly concerning autoimmunity.

Immune Modulation by Inhibitors of the HO System.

The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely studied in proinflammatory diseases because treatments that overexpress this enzyme promote the generation of anti-inflammatory products. However, neonatal jaundice (hyperbilirubinemia) derived from HO overexpression led to the development of inhibitors, such as those based on metaloproto- and meso-porphyrins inhibitors with competitive activity. Further, non-competitive inhibitors have also been identified, such as synthetic and natural imidazole-dioxolane-based, small synthetic molecules, inhibitors of the enzyme regulation pathway, and genetic engineering using iRNA or CRISPR cas9. Despite most of the applications of the HO inhibitors being related to metabolic diseases, the beneficial effects of these molecules in immune-mediated diseases have also emerged. Different medical implications, including cancer, Alzheimer´s disease, and infections, are discussed in this article and as to how the selective inhibition of HO isoforms may contribute to the treatment of these ailments.

Tolerogenic dendritic cell transfer ameliorates systemic lupus erythematosus in mice.

Current treatments for systemic autoimmune diseases partially improve the health of patients displaying low pharmacological efficacy and systemic immunosuppression. Here, the therapeutic potential of transferring tolerogenic dendritic cells (tolDCs) generated with heme-oxygenase inductor cobalt (III) protoporphyrin IX (CoPP), dexamethasone and rosiglitazone for the treatment of systemic autoimmunity was evaluated in two murine models of systemic lupus erythematosus (SLE), MRL-Faslpr and NZM2410 mice. Dendritic cells treated ex vivo with these drugs showed a stable tolerogenic profile after lipopolysaccharide stimulation. Regular doses of tolDCs were administered to anti-nuclear antibody-positive mice throughout 60-70 days, and the clinical score was evaluated. Long-term treatment with these tolDCs was well tolerated and effective to improve the clinical score on MRL-Faslpr lupus-prone mice. Additionally, decreased levels of anti-nuclear antibodies in NZM2410 mice were observed. Although tolDC treatment increased regulatory T cells, no significant reduction of renal damage or glomerulonephritis could be found. In conclusion, these results suggest that the transfer of histone-loaded tolDCs could improve only some SLE symptoms and reduced anti-nuclear antibodies. This is the first study to evaluate antigen-specific tolDC administration to treat SLE. Our report strengthens the clinical relevance of tolDC generation with CoPP, dexamethasone and rosiglitazone and the use of these modified cells as a therapy for systemic autoimmunity.

Immune checkpoints and the regulation of tolerogenicity in dendritic cells: Implications for autoimmunity and immunotherapy.

The immune system is responsible for defending the host from a large variety of potential pathogens, while simultaneously avoiding immune reactivity towards self-components. Self-tolerance has to be tightly maintained throughout several central and peripheral processes; immune checkpoints are imperative for regulating the immunity/tolerance balance. Dendritic cells (DCs) are specialized cells that capture antigens, and either activate or inhibit antigen-specific T cells. Therefore, they play a key role at inducing and maintaining immune tolerance. DCs that suppress the immune response have been called tolerogenic dendritic cells (tolDCs). Given their potential as a therapy to prevent transplant rejection and autoimmune damage, several strategies are under development to generate tolDCs, in order to avoid activation and expansion of self-reactive T cells. In this article, we summarize the current knowledge relative to the main features of tolDCs, their mechanisms of action and their therapeutic use for autoimmune diseases. Based on the literature reviewed, autologous antigen-specific tolDCs might constitute a promising strategy to suppress autoreactive T cells and reduce detrimental inflammatory processes.

Role of Regulatory T Cells in Infection and Vaccination During Early Infancy.

Reducing infant mortality due to infectious diseases is one of the most important public health goals worldwide. Several approaches have been implemented to reach this goal and vaccination has been an effective strategy for reducing infant and newborn mortality. However, the immunological features of neonates and infants represent a significant barrier to the effectiveness of vaccination. Since regulatory T cells (Treg cells) are known to play an active role in contributing to various mechanisms of suppression of the immune cell function. It has been proposed that these immune cells could decrease the immunogenicity of vaccines administered in newborns and infants. In this article, we discuss the various types of Treg cells, along with their suppressing and inhibitory mechanisms, which are used by these cells in the context of infectious and immunization processes in newborns and infants.

Implications of macrophage polarization in autoimmunity.

Macrophages are extremely heterogeneous and plastic cells with an important role not only in physiological conditions, but also during inflammation (both for initiation and resolution). In the early 1990s, two different phenotypes of macrophages were described: one of them called classically activated (or inflammatory) macrophages (M1) and the other alternatively activated (or wound-healing) macrophages (M2). Currently, it is known that functional polarization of macrophages into only two groups is an over-simplified description of macrophage heterogeneity and plasticity; indeed, it is necessary to consider a continuum of functional states. Overall, the current available data indicate that macrophage polarization is a multifactorial process in which a huge number of factors can be involved producing different activation scenarios. Once a macrophage adopts a phenotype, it still retains the ability to continue changing in response to new environmental influences. The reversibility of polarization has a critical therapeutic value, especially in diseases in which an M1/M2 imbalance plays a pathogenic role. In this review, we assess the high plasticity of macrophages and their potential to be exploited to reduce chronic/detrimental inflammation. On the whole, the evidence detailed in this review underscores macrophage polarization as a target of interest for immunotherapy.

Experimental Guillain-Barre syndrome induced by immunization with gangliosides: Keyhole limpet hemocyanin is required for disease triggering.

An experimental model of Guillain-Barré Syndrome has been established in recent years. Rabbits develop disease upon immunization with a single dose of an emulsion containing bovine brain gangliosides, KLH and complete Freund's adjuvant. Within a period of four to ten weeks after immunization, they began to produce anti-ganglioside IgG-antibodies first, and to show clinical signs of neuropathy afterwards. In addition to gangliosides, KLH is a requirement for antibody production and disease triggering. Although KLH is commonly used as an immunological carrier protein, an anti-KLH-specific immune response was necessary for induction of both events. KLH is a glycoprotein carrying most of the immunogenicity in its glycan moiety. Between 20% to 80% of anti-ganglioside IgG-antibodies present in sick rabbit sera cross-reacted with KLH, indicating that both immune responses are related. The terminal Gal-ß(1,3)-GalNAc glycan (present in gangliosides and KLH) is proposed as "key" antigenic determinant involved in inducing the anti-ganglioside immune response. These results are discussed in the context of the "binding site drift" hypothesis.

Novel antibodies reacting with two neighboring gangliosides are induced in rabbits immunized with bovine brain gangliosides.

Immunization of rabbits with bovine brain gangliosides induced an experimental neuropathy, with clinical signs resembling Guillain-Barré syndrome. All the immunized animals developed immunoglobulin G immunoreactivity to GM1 ganglioside. In a few (4 of 27) animals, an additional anti-ganglioside antibody population showing an unusual binding behavior was detected. Enzyme-linked immunosorbent assay and thin-layer chromatography immunostaining analyses showed that the binding of these unusual antibodies required the presence of two co-localized gangliosides. Maximal interaction was observed to a mixture of GM1 and GD1b, but the antibodies also showed "density-dependent" binding to GD1b. The antibodies were purified by affinity chromatography and displayed the ability to target antigens in biological membranes (rat synaptosomes).