Background Infections may be associated with exacerbation of allergic and autoimmune diseases. Paradoxically, epidemiological and experimental data have shown that some microorganisms can also prevent these pathologies. This observation is at the origin of the hygiene hypothesis according to which the decline of infections in western countries is at the origin of the increased incidence of both Th1-mediated autoimmune diseases and Th2-mediated allergic diseases over the last decades. We have tested whether Toll-like receptor (TLR) stimulation can recapitulate the protective effect of infectious agents on allergy and autoimmunity. Methods and Findings Here, we performed a systematic study of the disease-modifying effects of a set of natural or synthetic TLR agonists using two experimental models, ovalbumin (OVA)-induced asthma and spontaneous autoimmune diabetes, presenting the same genetic background of the non obese diabetic mouse (NOD) that is highly susceptible to both pathologies. In the same models, we also investigated the effect of probiotics. Additionally, we examined the effect of the genetic invalidation of MyD88 on the development of allergic asthma and spontaneous diabetes. We demonstrate that multiple TLR agonists prevent from both allergy and autoimmunity when administered parenterally. Probiotics which stimulate TLRs also protect from these two diseases. The physiological relevance of these findings is further suggested by the major acceleration of OVA-induced asthma in MyD88 invalidated mice. Our results strongly indicate that the TLR-mediated effects involve immunoregulatory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β and different subsets of regulatory T cells, notably CD4+CD25+FoxP3+ T cells for TLR4 agonists and NKT cells for TLR3 agonists. Conclusions/Significance These observations demonstrate that systemic administration of TLR ligands can suppress both allergic and autoimmune responses. They provide a plausible explanation for the hygiene hypothesis. They also open new therapeutic perspectives for the prevention of these pathologies.

Europe PMC is an archive of life sciences journal literature.

A Study of JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against B-cell Maturation Antigen (BCMA) in Participants With Multiple Myeloma - Full Text View.

Background Toll-like receptors (TLRs) are an important family of receptors that constitute the first line of defense system against microbes. They can recognize both invading pathogens and endogenous danger molecules released from dying cells and damaged tissues and play a key role in linking innate and adaptive immunity. TLRs are widely distributed in both immune and other body cells. The expressions and locations of TLRs are regulated in response to specific molecules derived from pathogens or damaged host cells. The binding of ligands to TLR activates specific intracellular signaling cascades that initiate host defense reactions. Such binding is ligand-dependent and cell type-dependent and leads to production of pro-inflammatory cytokines and type 1 interferon. TLR-dependent signaling pathways are tightly increased during innate immune responses by a variety of negative regulators. Overactivation of TLRs can ultimately lead to disruption of immune homeostasis and thus increase the risk for inflammatory diseases and autoimmune disorders. Antagonists/inhibitors targeting the TLR signaling pathways have emerged as novel therapeutics to treat these diseases. Aim of work The present review summarizes the structure, characterizations, and signaling of TLRs and their regulators, as well as describes the implication of TLRs in many diseases with a brief idea about the inhibitors that target TLR signaling pathways. Conclusion We conclude that TLRs are the main elements of our immune system, and they should be maintained functioning to keep the integrity of innate immunity. Targeting of TLR signaling represents a new challenge for treatment of many diseases.

Abstract. Toll-like receptors (TLRs) are known primarily as pathogen recognition receptors of the innate immunity, initiating inflammatory pathways to organize

Prevention of disease can in principle be accomplished by identification of environmental and/or lifestyle risk and protective factors followed by public health measures (such as for smoking and lung cancer), or by modification of the individual's reactions to disease-inducing factors (such as in vaccinations against microbes). This review discusses both options based on emerging understanding of aetiologies in inflammatory rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The major current opportunity for public health-based prevention lies in avoiding smoking. In RA, recent studies have calculated that, in Sweden (a country characterised by a low frequency of smoking), 20% of all RA cases and 33% of all cases of ACPA-positive RA would not have occurred in a smoke-free society. Smoking is also a major risk factor for SLE but no population attribution is yet available. New avenues for individualised and biology-based prevention are provided by the demonstration that several autoimmune rheumatic diseases are preceded by emergence of subclinical autoimmunity followed by laboratory-based signs of inflammation and finally overt disease. Examples of this process are provided from studies of autoimmunity to citrullinated proteins (in RA), to dsDNA (in SLE in general) and to Ro52 epitopes (in the case of neonatal heart block). The recognition of this sequence of events provides opportunities to intervene specifically and potentially curatively before onset of full-blown disease. Such prevention can be accomplished by modification of inciting antigens (environment), by modification of immunity (more or less specific immunomodulation) or by modification of specific gene functions. In all cases, prevention will be different in different subsets of disease and differ at different time points of disease development. Thus, the road map towards prevention of autoimmune rheumatic diseases includes increased understanding of how genes, environment and immunity interact.

The CMQB Training Program (CMQBTP) supports 30 predoctoral students per year from the Departments of Molecular Biophysics & Biochemistry, Genetics, Cell Biology

Abstract. Objective: The transmembrane receptor family of Toll-like receptors (TLRs) may play a role in initiating early inflammatory and functional responses t

As visibility of the killing of unarmed black men by police has increased, a movement to address Manu Platt, PhD

Students that are accepted in to the Predoctoral Pharmacology Training Program (PPTP) will be offered a unique training experience focused in the pharmaceutical sciences. The objectives of the PPTP are to train graduate students for a research career in academia, pharmaceutical and biotechnology industries, or

What’s the price you pay when you walk into a room? For Black STEM students and professionals—as Tyrone Porter, PhD

D’Anne Duncan will discuss the critical importance and value of centering graduate student advocacy D’Anne Duncan, PhD

The Medical Research Scholars Program (MRSP) at Yale University bridges barriers between traditional predoctoral and medical training by providing Yale Ph.D.

The Yale BBS Diversity and Inclusion Collective (YBDIC) is committed to fostering the intellectual and personal growth of underrepresented minority (URM)

Yale University’s Chemical Biology Training Program draws upon the strengths of several departments to provide interdisciplinary training at the interface of

The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a …

The objective of our study was to investigate the effects of excess Methionine (Met) on the growth performance, serum homocysteine levels, apoptotic rates, and Bax and Bcl-2 protein levels in geese and to study the role of Bet (betaine) in relieving excess Met-induced hyperhomocysteinemia (HHcy). In …

Methionine is an essential amino acid for animals and is typically considered one of the first limiting amino acids in animal feed formulations. Methionine deficiency or excess in animal diets can lead to sub-optimal animal performance and increased environmental pollution, which necessitates its ac …

Dietary methionine is indispensable for animal maintenance, growth and development. L-methionine (L-Met), and its synthetic forms DL-methionine (DL-Met) and 2-hydroxy-4 (methylthio) butanoic acid (HMTBA) are common supplemental methionine sources in animal diets. There are different characteristics …

Drugs given in combination may produce effects that are greater than or less than the effect predicted from their individual potencies. The historical basis for predicting the effect of a combination is based on the concept of dose equivalence; i.e., an equally effective dose (a) of one will add to …