Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of observations have led to the hypothesis that normal intestinal microbiota in patients with rheumatoid arthritis may harbour, for genetic reasons, bacteria with cell walls capable of inducing arthritis. Differences occur between bacterial species, and even between strains of a single species, because some cell walls induce experimental chronic arthritis, whereas some others induce only a transient acute arthritis or no arthritis at all. In susceptible subjects, with continuous seeding of bacterial products from the gut, the synovial inflammation is followed by erosion, exposition of cartilage antigens, and self perpetuating chronic arthritis.
 ...
PMID:Normal intestinal microbiota in the aetiopathogenesis of rheumatoid arthritis. 1292 50

Oral tolerance (OT) consists of the oral administration of antigens (Ag) that could alter the response of the immune system. This is a form of peripheral immune tolerance in which mature lymphocytes in the peripheral lymphoid tissues are rendered non functional or hyporesponsive by prior oral administration of Ag. It was first described in 1911 in animal models of anaphylaxis. This therapeutic approach requires the orally administration of Ag and the active participation of the gut-associated lymphoid tissue (GALT), a tissue comprising Peyer's patches, intraepitelial cells and villi containing epithelials cells which is a well organized immune network. The mechanisms by which OT is mediated included deletion or anergy and active cellular suppression. The primary factor determining which form of tolerance will be developed after oral administration of Ag is the Ag dosage. Thus, it is thought that low doses of Ag induce the generation of active suppression, via regulatory T cells in the GALT, which then migrate to the systemic immune system. These regulatory T cells produce down-regulatory cytokines such as IL4, IL10 and TGFbeta, a Th2 / Th3 cytokine pattern. Conversely, high dose of Ag favors anergy or clonal deletion. The phenomenon in which regulatory cells, as generated by oral tolerization, are primed in an Ag specific manner, but act in the respective microenvironment in a non-Ag specific manner is called bystander suppression. This phenomenon is of particular interest and explained the use of OT in T cell mediated autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS) and type I diabetes, some diseases in which the autoAg remains unknown or where there are reactivities to multiple autoAgs. There were several studies demonstrating the effectiveness of orally administered Ag in different animal models of autoimmune diseases, such as experimental allergic encephalomyelitis, collagen induced arthritis, diabetes, but also uveitis, myastenia gravis and transplantation. These mouse or rat models of autoimmune diseases gave the rationale for the therapeutic use of OT in human and this therapeutic approach has been tried in MS and RA, using oral myelin or oral collagen, respectively. In RA, 4 trials of oral type II collagen (CII) in RA have been published. Taken together, these studies suggested that oral CII in RA gave a trend toward clinical improvement, with significance in only 2 studies. Bacterial extract from Escherichia coli containing heat shock proteins has been tried in oral treatment for RA. Two placebo controlled trials and 2 comparative studies gave favorable results for this bacterial extract with no or mild adverse events. Although oral/mucosal tolerance has given successful results in animal models of autoimmune diseases, the enthusiasm for this therapeutic approach in human diseases must be tempered. The discrepancies between the effectiveness of OT in animal models and the results in human trials raise some questions, the identification of the subgroup of patients who might respond to this treatment and the source (or nature) of the administered Ag (homologous versus heterologous), for instance.
 ...
PMID:Oral tolerance in the treatment of rheumatoid arthritis. 1456 Dec 5

Commensal microflora (normal microflora, indigenous microbiota) consists of those micro-organisms, which are present on body surfaces covered by epithelial cells and are exposed to the external environment (gastrointestinal and respiratory tract, vagina, skin, etc.). The number of bacteria colonising mucosal and skin surfaces exceeds the number of cells forming human body. Commensal bacteria co-evolved with their hosts, however, under specific conditions they are able to overcome protective host responses and exert pathologic effects. Resident bacteria form complex ecosystems, whose diversity is enormous. The most abundant microflora is present in the distal parts of the gut; the majority of the intestinal bacteria are Gram-negative anaerobes. More than 50% of intestinal bacteria cannot be cultured by conventional microbiological techniques. Molecular biological methods help in analysing the structural and functional complexity of the microflora and in identifying its components. Resident microflora contains a number of components able to activate innate and adaptive immunity. Unlimited immune activation in response to signals from commensal bacteria could pose the risk of inflammation; immune responses to mucosal microbiota therefore require a precise regulatory control. The mucosal immune system has developed specialised regulatory, anti-inflammatory mechanisms for eliminating or tolerating non-dangerous, food and airborne antigens and commensal micro-organisms (oral, mucosal tolerance). However, at the same time the mucosal immune system must provide local defense mechanisms against environmental threats (e.g. invading pathogens). This important requirement is fulfilled by several mechanisms of mucosal immunity: strongly developed innate defense mechanisms ensuring appropriate function of the mucosal barrier, existence of unique types of lymphocytes and their products, transport of polymeric immunoglobulins through epithelial cells into secretions (sIgA) and migration and homing of cells originating from the mucosal organised tissues in mucosae and exocrine glands. The important role of commensal bacteria in development of optimally functioning mucosal immune system was demonstrated in germ-free animals (using gnotobiological techniques). Involvement of commensal microflora and its components with strong immunoactivating properties (e.g. LPS, peptidoglycans, superantigens, bacterial DNA, Hsp) in etiopathogenetic mechanism of various complex, multifactorial and multigenic diseases, including inflammatory bowel diseases, periodontal disease, rheumatoid arthritis, atherosclerosis, allergy, multiorgan failure, colon cancer has been recently suggested. Animal models of human diseases reared in defined gnotobiotic conditions are helping to elucidate the aetiology of these frequent disorders. An improved understanding of commensal bacteria-host interactions employing germ-free animal models with selective colonisation strategies combined with modern molecular techniques could bring new insights into the mechanisms of mucosal immunity and also into pathogenetic mechanisms of several infectious, inflammatory, autoimmune and neoplastic diseases. Regulation of microflora composition (e.g. by probiotics and prebiotics) offers the possibility to influence the development of mucosal and systemic immunity but it can play a role also in prevention and treatment of some diseases.
 ...
PMID:Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. 1515 4

Ankylosing spondylitis (AS) is a member of the family of spondyloarthropathies, which are inflammatory arthritides largely involving the axial skeleton and commonly accompanied by peripheral arthritis. Genetic factors, particularly the presence of HLA-B27, are major contributors to the susceptibility for AS. Despite some therapeutic advances, the treatment options for patients with AS and related disorders have been limited. Several lines of evidence have led to the hypothesis that patients with AS might benefit from treatment with tumor necrosis factor (TNF). Specifically, TNF concentrations are known to be significantly elevated in the synovium of patients with rheumatoid arthritis (RA), in the inflamed gut of patients with inflammatory bowel disease, and in the inflamed sacroiliac joints of patients with AS. The anti-TNF agents have been shown to be of benefit in, and currently have indications for, RA (etanercept, infliximab, adalimumab), Crohn's disease (infliximab), and psoriatic arthritis (etanercept). Because the spondyloarthropathies share pathogenetic mechanisms with the above-specified disease states, studies have been conducted to evaluate the effectiveness of anti-TNF agents in several disorders, including AS. Data from clinical trials so far with infliximab and etanercept show that patients with AS and related disorders achieve significant improvement in clinical signs and symptoms based on validated outcomes measures. Computed tomography and magnetic resonance imaging (MRI) can facilitate the early diagnosis of AS. Studies with infliximab using MRI together with updated scoring methods demonstrated significant decreases in associated spinal inflammation. TNF antagonist therapy is well tolerated in patients with AS, with a side effect profile consistent with the prior experience of patients with RA.
 ...
PMID:Expanding the armamentarium for the spondyloarthropathies. 1522 20

Most molecules involved in the recognition and elimination of pathogens by the immune system are glycoproteins. Oligosaccharides attached to glycoproteins initiate biological functions through mechanisms that involve multiple interactions of the monosaccharide residues with receptors. For example, calreticulin, a quality-control lectin-like chaperone, interacts with glucosylated mannose glycans presented by empty major histocompatibility complex (MHC) class I molecules, retaining them in the endoplasmic reticulum (ER) until antigenic peptide is loaded. Clusters of specific IgG glycoforms, present in increased amounts in rheumatoid arthritis, bind mannose-binding lectin (MBL), providing a potential route to inflammation through activation of the complement pathway. Secretory IgA glycans bind gut bacteria, and an unusual cluster of mannose residues on gp120, the surface coat protein of the HIV virus, is recognized by the novel 'domain-swapped' IgG 2G12 serum antibody.
 ...
PMID:Sugar-mediated ligand-receptor interactions in the immune system. 1545 Jul 46

Several studies have shown decreased synovial inflammation after treatment of patients with rheumatoid arthritis (RA) with infliximab. Recent data indicate that these effects can be detected as soon as 48 hours after first infusion. Although there are strong indications that infliximab exerts its effects in patients with Crohn's disease by induction of apoptosis in the gut, there are as yet no studies that convincingly show the same mechanism of action in RA. Conceivably, neutralization of tumor necrosis factor-alpha may be sufficient to induce clinical improvement in RA, even without induction of apoptosis at the site of inflammation. This hypothesis could explain the observation that both infliximab and etanercept are effective in RA, whereas apoptosis induction by infliximab might be required in Crohn's disease. Future studies should focus on the evaluation of apoptosis within the first 48 hours after initiation of therapy in RA to exclude the possibility that the effects occur very early after infliximab infusion.
 ...
PMID:Effects of infliximab treatment on rheumatoid synovial tissue. 1574 62

Macrophage migration inhibitory factor (MIF) is a unique protein, participating in inflammation, immune response, and cell growth. MIF was first discovered as a lymphokine involved in delayed hypersensitivity and various macrophage functions, including phagocytosis, spreading, and tumoricidal activity. It has been reported that MIF is associated with the pathogenesis of a variety of diseases. MIF expression was increased at inflammatory sites in diseases such as rheumatoid arthritis and glomerulonephritis. In experimental inflammatory disease, blockade of MIF bioactivity inhibited the severity of disease activity. On the other hand, MIF expression is also increased in tumor lesions, and MIF plays a role as a cell growth factor. MIF has been reported to be constitutively expressed in gut, liver, and pancreas. In patients with gastritis, inflammatory bowel disease, hepatitis, and pancreatitis, MIF expression was remarkably increased in both the serum and the local lesions. Blockade of MIF bioactivity inhibited and prevented inflammation in experimental gastritis, colitis, hepatitis, and pancreatitis. On the other hand, MIF expression was higher than that in normal tissues in colonic carcinomas and hepatocellular carcinoma both in vivo and in vitro. Blockade of MIF bioactivity successfully inhibited tumor cell growth in vivo and in vitro. MIF plays important roles in the pathogenesis of gastrointestinal, hepatic, and pancreatic disorders.
 ...
PMID:Pathophysiological roles of macrophage migration inhibitory factor in gastrointestinal, hepatic, and pancreatic disorders. 1577 Mar 93

Citrulline (Cit, C6H13N3O3), which is a ubiquitous amino acid in mammals, is strongly related to arginine. Citrulline metabolism in mammals is divided into two fields: free citrulline and citrullinated proteins. Free citrulline metabolism involves three key enzymes: NO synthase (NOS) and ornithine carbamoyltransferase (OCT) which produce citrulline, and argininosuccinate synthetase (ASS) that converts it into argininosuccinate. The tissue distribution of these enzymes distinguishes three "orthogonal" metabolic pathways for citrulline. Firstly, in the liver, citrulline is locally synthesized by OCT and metabolized by ASS for urea production. Secondly, in most of the tissues producing NO, citrulline is recycled into arginine via ASS to increase arginine availability for NO production. Thirdly, citrulline is synthesized in the gut from glutamine (with OCT), released into the blood and converted back into arginine in the kidneys (by ASS); in this pathway, circulating citrulline is in fact a masked form of arginine to avoid liver captation. Each of these pathways has related pathologies and, even more interestingly, citrulline could potentially be used to monitor or treat some of these pathologies. Citrulline has long been administered in the treatment of inherited urea cycle disorders, and recent studies suggest that citrulline may be used to control the production of NO. Recently, citrulline was demonstrated as a potentially useful marker of short bowel function in a wide range of pathologies. One of the most promising research directions deals with the administration of citrulline as a more efficient alternative to arginine, especially against underlying splanchnic sequestration of amino acids. Protein citrullination results from post-translational modification of arginine; that occurs mainly in keratinization-related proteins and myelins, and insufficiencies in this citrullination occur in some auto-immune diseases such as rheumatoid arthritis, psoriasis or multiple sclerosis.
 ...
PMID:Almost all about citrulline in mammals. 1608 1

Extracts of lysed pathogenic bacteria were developed approximately 4 decades ago as oral vaccines in order to stimulate efficient specific immune and proinflammatory responses in patients experiencing recurrent infections, the ultimate aim being to rid the patient of the pathogen responsible for the infections. OM-89, a lysate of Escherichia coli, is clinically effective in patients who experience recurrent urinary tract infections by activating both innate and adaptive immunity. If immune activation is necessary to combat infectious pathogens, it may appear at first sight to be detrimental in patients with autoimmune diseases. However, OM-89 has also shown clear efficacy in patients with rheumatoid arthritis or with undifferentiated spondyloarthropathies, probably through oral tolerance and the long-term activation of regulatory cells. These phenomena may be explained by a hypothesis that immune exclusion and oral tolerance, both key functions of the gut, may be boosted by adjuvant-like molecules within orally administered OM-89.
 ...
PMID:An hypothesis to link the opposing immunological effects induced by the bacterial lysate OM-89 in urinary tract infection and rheumatoid arthritis. 1672 62

A staggering 4000 million people cannot digest lactose, the sugar in milk, properly. All mammals, apart from white Northern Europeans and few tribes in Africa and Asia, lose most of their lactase, the enzyme that cleaves lactose into galactose and glucose, after weaning. Lactose intolerance causes gut and a range of systemic symptoms, though the threshold to lactose varies considerably between ethnic groups and individuals within a group. The molecular basis of inherited hypolactasia has yet to be identified, though two polymorphisms in the introns of a helicase upstream from the lactase gene correlate closely with hypolactasia, and thus lactose intolerance. The symptoms of lactose intolerance are caused by gases and toxins produced by anaerobic bacteria in the large intestine. Bacterial toxins may play a key role in several other diseases, such as diabetes, rheumatoid arthritis, multiple sclerosis and some cancers. The problem of lactose intolerance has been exacerbated because of the addition of products containing lactose to various foods and drinks without being on the label. Lactose intolerance fits exactly the illness that Charles Darwin suffered from for over 40 years, and yet was never diagnosed. Darwin missed something else--the key to our own evolution--the Rubicon some 300 million years ago that produced lactose and lactase in sufficient amounts to be susceptible to natural selection.
 ...
PMID:The molecular basis of lactose intolerance. 1680 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>