Autoimmune Arthritis Inflammation

(2018) Rheumatoid arthritis (RA) is a chronic, debilitating illness characterized by painful swelling of the joints, inflammation of the synovial lining of the joints, and damage to cartilage and bone. Several anti-inflammatory and disease-modifying drugs are available for RA therapy. However, the prolonged use of these drugs is associated with severe side effects. Furthermore, these drugs are effective only in a proportion of RA patients. Hence, there is a need to search for new therapeutic agents that are effective yet safe. Interestingly, a variety of natural products offer a vast resource for anti-arthritic agents.

RA is typically characterized by chronic inflammation of the the joints, damage to the cartilage, and erosion of the bone. Swelling and redness of the hands and feet is the most common sign of RA along with pain in the afflicted areas. Ulnar deviation, Swan neck deformity, and subcutaneous nodules are among the clinical manifestations of untreated severe RA. The most common serum biomarkers for RA are rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA). Furthermore, ACPA can also be used as prognostic markers for RA similarly to RF, as they are present a median of 4.5 years prior to clinical onset of the disease. A relatively new potential biomarker for RA is the oncoprotein survivin, which is already a known biomarker for cancer. In one study, survivin was detected in 50.7% of RA patients but only 5.6% in controls, which indicates its high specificity.

The Cellular and Soluble Mediators of Arthritic Inflammation

Under normal conditions, the mature T cells encounter self-antigens in the periphery all the time; however, their activation is kept under control via diverse mechanisms, including unresponsiveness due to lack of adequate interaction between the peptide-MHC (major histocompatibility complex) complex and the T cell receptor (TCR) (ignorance), induction of anergy in the absence of co-stimulation, or suppression by T regulatory (Treg) cells. The initiation of RA involves an interplay among components of the innate and adaptive immune responses leading to unintended activation of autoreactive T cells specific for potentially arthritogenic self-antigens in the peripheral lymphoid organs. Antigen-presenting cells (APCs), including dendritic cells, macrophages as well as activated B cells, present arthritogenic autoantigens to T cells that have specific TCRs that can recognize these autoantigens. At the same time, upregulation of co-stimulatory molecules expressed by the APCs under inflammatory conditions facilitates activation of these potentially arthritogenic T cells. Further, the cytokine milieu of the inflammatory environment (such as interleukin-12 (IL-12) and interferon-γ (IFN-γ) for T helper 1 (Th1), and IL6 and IL-1β for Th17) facilitates the differentiation of activated T cells into pathogenic T cell subsets (Th1, Th17), the key drivers of RA pathology.

This process results in break in tolerance leading to expansion of pathogenic T cells in the peripheral lymphoid organs.

Interplay between Dietary Products and the Host Microbiome for Maintenance of Health and Disease Modulation

The human microbiota is composed of bacteria, fungi, and viruses, whose total population exceeds that of the host cells, and whose metabolic contribution to our state of health is essential.

The microbiome is an untapped source for identification of novel natural products for the treatment and prevention of disease such as RA.

The associations between certain taxa of microbes and RA have been reported.

In addition, a variety of bioactive molecules produced by the human microbiome can have significant effects on the immune system.

There are three general approaches to harnessing the microbiome for RA prevention and treatment, namely the use of prebiotics, probiotics, and microbial-derived xenobiotics.

Prebiotics are certain dietary ingredients metabolized by the microbiome to facilitate growth of beneficial bacteria in the gut, which in turn produce substances that are optimal for the local microenvironment and health of the intestines. Probiotics consist of living strains of beneficial bacteria. Microbial-derived xenobiotics are the molecules produced by the action of the microbiome action, for example, metabolic degradation/alteration of the dietary products consumed by the host and/or of the products released from the host’s cellular processes.

These prebiotics serve as a fuel for microbiota, which then produce substances that contribute to the optimal health and function of intestinal cells. Another way for microbiota to influence immune system is via production of xenobiotic metabolites. For example, Bifidobacterium spp., including B. bifidum, convert dietary carbohydrates into butyrate. In addition to propionate and acetate, these essential short-chain fatty acids (SCFAs) affect host cells by inhibiting histone-deacetylase to promote anti-inflammatory responses. Oral administration of SCFAs has been shown to reduce arthritis severity. SCFAs were shown to inhibit osteoclastogenesis in vitro, and to prevent bone loss of arthritis when administered orally. These studies illustrate the potential benefits of xenobiotic supplementation. It also enforces the importance of a complex carbohydrate rich diet. In addition to SCFAs, unexplored microbial-derived ligands for the AhR could prove efficacious for RA treatment, as other ligands of the AhR are either currently licensed for RA treatment or have been shown to alter disease in animal models. In the dairy-derived P. freudenreichii, beneficial metabolites produced could include SCFAs as well as the metabolite 1,4-Dihydroxy-2-naphthoic acid (DHNA), a known AhR ligand.

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