PolygenicBlog: arthritis

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Researchers add to evidence that common bacterial cause of gum disease may drive rheumatoid arthritis -- ScienceDaily

In a report on the work, published in the Dec. 14 edition of the journal Science Translational Medicine, the investigators say the common denominator they identified in periodontal disease (gum disease) and in many people with rheumatoid arthritis is Aggregatibacter actinomycetemcomitans. An infection with A. actinomycetemcomitans appears to induce the production of citrullinated proteins, which are suspected of activating the immune system and driving the cascade of events leading to rheumatoid arthritis."

Translational Medicine paper:-

Aggregatibacter actinomycetemcomitans–induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

Commensal intestinal microbiota drives spontaneous interleukin-1- and T helper 17-mediated arthritis in mice.

BACKGROUND: Altered composition of intestinal microbiota in recent-onset rheumatoid arthritis (RA) and possible efficacy of oral antibiotics suggest a role of intestinal microbiota in RA. This study aimed to investigate the involvement of commensal intestinal microbiota in T cell-dependent experimental arthritis.
METHODS: IL-1 receptor antagonist deficient (IL-1Ra(-/-)) mice spontaneously developing T cell-driven IL-17-dependent autoimmune arthritis were used. Intestinal and systemic T cell differentiation and arthritis development were studied in conventional and germ-free (GF) mice. Contribution of intestinal microbiota was investigated using oral broad-spectrum and selective antibiotic treatments, combined with recolonization by specific microbiota. Multiplex 454 pyrosequencing of V5 and V6 hyper-variable regions of fecal bacterial 16S rRNA was used to identify specific microbiota associated with arthritis.
RESULTS: Compared to wild-type mice, small intestinal lamina propria of IL-1Ra(-/-) mice contained increased Th17 and to lower extent Th1 percentages, both of which significantly correlated with arthritis severity. Importantly, GF IL-1Ra(-/-) mice had a marked abrogation of arthritis along with reduced intestinal Th1 and in particular Th17. GF IL-1Ra(-/-) mice exhibited a notable decrease in IL-1b and IL-17 production by splenocytes upon CD3 and Toll-like receptor stimulations, suggesting abolishment of systemic Th17 response. Relevance of intestinal microbiota was underlined by significant long-term suppression of arthritis by one-week oral treatment with Metronidazole, Neomycin and Ampicillin (each 1g/l). Interestingly, recolonization of antibiotic-treated IL-1Ra(-/-) mice by segmented filamentous bacteria, previously reported as a prominent intestinal Th17 inducer, was sufficient to cause full-blown arthritis. Selective elimination of Gram-negative bacteria, but not Gram-positive, suppressed arthritis, indicating members of intestinal Gram-negative commensals may drive arthritis. High-throughput pyrosequencing revealed lower microbiota abundance (operational taxonomic units) and reduced species richness and diversity (Chao and Shannon indices, resp.) in arthritic IL-1Ra(-/-) compared to wild-type mice. The genus Helicobacter, belonging to Gram-negative bacteria, was found associated with arthritis severity (0.0% in wild-type versus 1.1% in arthritic mice). Validation of microbiota alterations and studies on T cell-modulatory and disease-inducing characteristics in GF mice are in progress.
CONCLUSION: The presence of commensal intestinal microbiota is critical for the development of autoimmune T cell-driven arthritis, probably via shaping the T cell differentiation by Gram-negative bacteria. Understanding the molecular and cellular mechanisms linking the intestinal T cell response with extra-intestinal disease may help identify novel therapeutic targets in RA.

Exposure to mimivirus collagen promotes arthritis.

Mimivirus diagram (Photo credit: Wikipedia)

Collagens, the most abundant proteins in animals, also occur in some recently described nucleocytoplasmic large DNA viruses such as Mimiviridae, which replicate in amoebae. To clarify the impact of viral collagens on the immune response of animals exposed to Mimiviridae, we have investigated the localization of collagens in Acanthamoeba polyphaga mimivirus particles and the response of mice to immunization with mimivirus particles. Using protein biotinylation, we have first shown that viral collagen encoded by open reading frame L71 is present at the surface of mimivirus particles. Exposure to mimivirus collagens elicited the production of anti-collagen antibodies in DBA/1 mice immunized intradermally with mimivirus protein extracts. This antibody response also targeted mouse collagen type II and was accompanied by T-cell reactivity to collagen and joint inflammation, as observed in collagen-induced arthritis following immunization of mice with bovine collagen type II. The broad distribution of nucleocytoplasmic large DNA viruses in the environment suggests that humans are constantly exposed to such large virus particles. A survey of blood sera from healthy human subjects and from rheumatoid arthritis patients indeed demonstrated that 30% of healthy-subject and 36% of rheumatoid arthritis sera recognized the major mimivirus capsid protein L425. Moreover, whereas 6% of healthy-subject sera recognized the mimivirus collagen protein L71, 22% of rheumatoid arthritis sera were positive for mimivirus L71. Accordingly, our study shows that environmental exposure to mimivirus represents a risk factor in triggering autoimmunity to collagens.

PLOS Pathogens: Porphyromonas gingivalis Facilitates the Development and Progression of Destructive Arthritis through Its Unique Bacterial Peptidylarginine Deiminase (PAD)

Rheumatoid arthritis and periodontitis are two prevalent chronic inflammatory diseases in humans and are associated with each other both clinically and epidemiologically. Recent findings suggest a causative link between periodontal infection and rheumatoid arthritis via bacteria-dependent induction of a pathogenic autoimmune response to citrullinated epitopes. Here we showed that infection with viable periodontal pathogen Porphyromonas gingivalis strain W83 exacerbated collagen-induced arthritis (CIA) in a mouse model, as manifested by earlier onset, accelerated progression and enhanced severity of the disease, including significantly increased bone and cartilage destruction. The ability of P. gingivalis to augment CIA was dependent on the expression of a unique P. gingivalis peptidylarginine deiminase (PPAD), which converts arginine residues in proteins to citrulline. Infection with wild type P. gingivalis was responsible for significantly increased levels of autoantibodies to collagen type II and citrullinated epitopes as a PPAD-null mutant did not elicit similar host response. High level of citrullinated proteins was also detected at the site of infection with wild-type P. gingivalis. Together, these results suggest bacterial PAD as the mechanistic link between P. gingivalisperiodontal infection and rheumatoid arthritis.

Scientists Warn Of The Dangers Of Toxoplasma Gondii In Cat Faeces

Each year in the United States, cats deposit about 1.2 million metric tons of feces into the environment, and that poop is carrying with it what may be a vast and underappreciated public health problem, say scientists in the journal Trends in Parasitology, a Cell Press publication.

Some of that poop is laden with an infectious parasite known as Toxoplasma gondii, a protozoan that has recently caused toxoplasmosis epidemics in otherwise healthy people, not just in pregnant women or people with immune deficiencies. Additional concerns have been raised by studies linking T. gondii to schizophrenia, obsessive-compulsive disorder, rheumatoid arthritis, brain cancer, and even to kids' trouble in school.

Did evolution give us inflammatory disease?

"The findings suggest that in the past these variants rose in frequency in the human population to help protect us against viruses, bacteria and other pathogens. But now in our modern world, the environment and exposure to pathogens has changed, and the genetic variants that were originally meant to protect us, now make an autoimmune reaction more likely. These results are consistent with the hygiene hypothesis in which our cleaner environment is thought to contribute to the increasing prevalence of inflammatory diseases."

Common chemicals linked to osteoarthritis

"A new study has linked exposure to two common perfluorinated chemicals (PFCs) with osteoarthritis. PFCs are used in more than 200 industrial processes and consumer products including certain stain- and water-resistant fabrics, grease-proof paper food containers, personal care products, and other items. Because of their persistence, PFCs have become ubiquitous contaminants of humans and wildlife. The study, published in Environmental Health Perspectives, is the first to look at the associations between perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), and osteoarthritis, in a study population representative of the United States."

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Scientists discover an epigenetic cause of osteoarthritis

In what could be a breakthrough in the practical application of epigenetic science, U.K. scientists used human tissue samples to discover that those with osteoarthritis have a signature epigenetic change (DNA methylation) responsible for switching on and off a gene that produces a destructive enzyme called MMP13. This enzyme is known to play a role in the destruction of joint cartilage, making MMP13 and the epigenetic changes that lead to its increased levels, prime targets for osteoarthritis drug development. In addition to offering a new epigenetic path toward a cure for osteoarthritis, this research also helps show how epigenetic changes play a role in diseases outside of cancer. This finding was recently published online in the FASEB Journal.

Bartonella infection associated with rheumatoid illnesses in humans

A bacterium historically associated with cat scratch fever and transmitted predominately by fleas may also play a role in human rheumatoid illnesses such as arthritis, according to new research from North Carolina State University. Bartonella is a bacterium that is maintained in nature by fleas, ticks and other biting insects. It can be transmitted to humans both by these parasites as well as by bites or scratches from infected cats and dogs.

Researchers find joint failures potentially linked to oral bacteria

The culprit behind a failed hip or knee replacements might be found in the mouth. DNA testing of bacteria from the fluid that lubricates hip and knee joints had bacteria with the same DNA as the plaque from patients with gum disease and in need of a joint replacement.

Arthritis Research & Therapy | Abstract | A profile of immune response to herpesvirus is associated with radiographic damage in rheumatoid arthritis

Introduction

Progression of joint damage despite appropriate therapy remains a significant problem for patients with rheumatoid arthritis (RA). This study was undertaken to identify profiles of immune response that correlate with radiographic joint damage as a first step toward the discovery of new pathogenic mechanisms of joint destruction in RA.

Methods

The study included 58 patients with RA and 15 healthy controls. The profiles of cytokine release from peripheral blood mononuclear cells (PBMC) in response to stimulation for 48 hours with one of six stimuli, or in media alone, were measured. Immune response profiles identified for each stimulus were correlated with radiographic joint damage as defined by the Sharp-van der Heijde score (SHS), before and after multivariable adjustment. For profiles correlated with the SHS, the distributions of individual cytokines were evaluated in patients according to the severity of joint damage and compared to healthy controls.

Results

The immune response profile for cytomegalovirus (CMV) / Epstein-Barr virus (EBV) stimulation was correlated with both the SHS total and erosion scores (r = 0.31, p = 0.018 and r = 0.33, p = 0.011, respectively). After adjusting for age, sex, disease duration, autoantibody status, CMV/EBV serological status, current disease activity, disability, and treatments, the correlation of the CMV/EBV immune response and the SHS erosion score became stronger (r = 0.43, p < 0.003). The CMV/EBV immune response correlated with CMV IgG (r = 0.44, p < 0.001), but not with EBV IgG. The most important cytokines for the CMV/EBV immune response profile were IFN-gamma, IL-2, IL-4, IL-5, IL-13 and IL-17A, all of which are associated with T-cell immunity. Both the summary immune response score and the individual responses of IFN-gamma and IL-13 to CMV/EBV stimulation were associated with greater joint damage.

Conclusions

A profile of immune response to purified CMV/EBV lysates is associated with radiographic joint damage. The correlation of this immune response to CMV serology implies possible involvement of latent CMV infection. Therefore, the findings suggest that the immune response to latent CMV infection could play a fundamental role in the progression of inflammation and structural joint damage in patients with RA.

Toxoplasma gondii infection inhibits Th17-mediated spontaneous development of arthritis in IL-1 receptor antagonist-deficient mice.

IL-1 receptor antagonist (IL-1Ra)-deficient BALB/c mice develop spontaneous arthritis resembling human rheumatoid arthritis. We herein report that infection with Toxoplasma gondii, an intracellular protozoan, is capable of ameliorating the spontaneous development of arthritis in IL-1Ra-deficient mice. The onset of arthritis development was delayed and the severity score of arthritis was significantly suppressed in T. gondii-infected mice. Expression of IL-12p40 mRNA from CD11c(+) cells of mesenteric lymph nodes (mLN) and spleen markedly increased at 1 week after peroral infection. While CD11c(+) cells also produced IL-10, IL-1β and IL-6, CD4(+) T cells from T. gondii-infected mice expressed significantly high levels of T-bet and IFN- γ mRNA at both mLN and spleen. Levels of GATA-3/IL-4 mRNA or RORγt/IL-17 mRNA decreased in the infected mice, indicating Th1 polarization and the reduction of Th2 and Th17 polarization. The severity of arthritis was related to Th1 polarization accompanied with Th17 reduction, demonstrating the protective role of T. gondii-derived Th1 response against Th17-mediated arthritis in IL-1Ra-deficient mice.

Ultra short telomeres linked to osteoarthritis

Telomeres, the very ends of chromosomes, become shorter as we age. When a cell divides it first duplicates its DNA and, because the DNA replication machinery fails to get all the way to the end, with each successive cell division a little bit more is missed. New research published in BioMed Central's open access journal Arthritis Research & Therapy shows that cells from osteoarthritic knees have abnormally shortened telomeres and that the percentage of cells with ultra short telomeres increases the closer to the damaged region within the joint.

Commonly Used Drug (dexamethasone) Could Prevent Arthritis | Medical News and Health Information

In an animal model of #arthritis cartilage breakdown in damaged tissue that was treated immediately with the glucocorticoid, dexamethasone was halted. The drug also worked when given a day or two after the injury.
Researchers plan to test the drug's potential protective effects, in future studies.

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