Key players in the body’s defenses, macrophages ...
Arthritis comprises over 100 diseases. Some, like osteoarthritis, are the breakdown, “wear and tear” of joint tissues due to age, repetitive use or injury. Some, like gout, involve chemical imbalances in the body. But, some involve autoimmunity, which is the body attacking self tissues, mistaking your own joint tissues for a foreign substance such as bacteria, causing the immune system to go into action.
The normal human immune system protects us from infection; when its regulation is impaired, it gives rise to these diseases in which normal tissues are attacked and damaged. Attacking self-tissues, beginning in the joints, is the definition of autoimmune arthritis.
The most prevalent forms of autoimmune arthritis are rheumatoid arthritis, juvenile forms of arthritis and lupus. However, there are many other autoimmune forms of arthritis that can be just as debilitating and dangerous.
Understanding and developing effective therapies for these other forms of autoimmune arthritis may provide the key to understanding immune system disorders for arthritis and in other autoimmune diseases such as MS and Type 1 Diabetes.
Some of the autoimmune forms of arthritis studied by ANRF-funded researchers include:
Neutrophils are white blood cells that migrate into joints during inflammatory arthritis. Studies in mice confirm that neutrophils are absolutely necessary for the normal evolution of arthritis, but little is known about the mechanisms by which neutrophils reach the joint, what they do once they arrive, and how this can be manipulated therapeutically.
Dr. Peter Nigrovic, Arthritis National Research Foundation Scientific Advisory Board member, former grantee and Professor at Brigham & Women’s Hospital at Harvard Medical School has found that a particular protein on the surface of mouse neutrophils appears to play a role in this process, since binding of this protein with antibodies blocks arthritis despite the presence of neutrophils in the blood. His current studies focus on the mechanisms by which this protein acts, including its effects on the interaction between neutrophils and platelets.
Potential: These experiments will help elucidate the mechanisms by which neutrophils reach the inflamed joint, and could define a novel mechanism by which neutrophil recruitment can be targeted to treat inflammatory arthritis.
Antiphospholipid syndrome (APS) is a serious autoimmune clotting disorder in which the immune system mistakenly attacks a self-protein in the blood of certain patients with autoimmune arthritis. The blood clots that form can lodge in tissues causing stroke, heart attack and death.
Dr. Martin Kriegel at Yale University has found that certain bacteria living in the digestive tract of patients with APS trick the immune system to react against the self molecules.
Potential: These are important findings for they reveal 1) how this disease starts which may serve as a model of how other types of autoimmune disease can start and, 2) how to diagnose, prevent and stop the progression of this particular disease.
While acute inflammation is mostly beneficial, unchecked or dysregulated inflammation can have devastating consequences leading to a wide range of diseases including Rheumatoid Arthritis, Systemic Lupus Erythematous, and other autoimmune forms of arthritis.
In the 10 years since the human genome was sequenced, there have been huge improvements in our ability to carry out sequencing. The classical understanding of the genome was that DNA is transcribed into RNA, which makes proteins that carry out various biological functions. However, sequencing studies have shown that only a small portion (2%) of the genome results in protein, yet there are very large amounts of RNA being produced (85% of the genome). This 85% of RNA molecules produced from the genome is called long noncoding RNA (lncRNA and are emerging as fundamental mediators of innate immune signaling pathways.
Dr. Susan Carpenter at the University of California, Santa Cruz is working on research that has identified a specific lincRNA as a highly inducible gene in response to inflammatory stimuli while also being required for the induction of other inflammatory genes. Dr. Carpenter is studying how these RNA molecules are involved in the pathogenesis of inflammatory arthritis.
Potential: Obtaining a better understanding of the role of these RNA molecules in inflammatory conditions could lead to the development of new biomarkers for disease and unveil new therapeutic targets for inflammatory arthritis and other autoimmune, inflammatory diseases.
Salvatore Albani, M.D., Ph.D., Professor with the Duke-NUS Graduate Medical School Singapore and Director of the SingHealth Translational Immunology and Inflammation Centre, has completed a Phase II clinical trial for a treatment he developed for autoimmune inflammatory diseases. The treatment re-educates the cells of the immune system that are causing the disease to restore them to their normal function in a healthy individual.
Potential: If successful in subsequent patient clinical trials, this may become a new treatment for patients with autoimmune forms of arthritis and other autoimmune inflammatory diseases.
Judith Smith, M.D., Ph.D., University of Wisconsin, Madison, Wisconsin is studying
Ankylosing Spondylitis (AS), a progressive arthritis involving the spine that causes significant disability and decreased quality of life. Dr. Smith’s study will determine if AS macrophages overproduce IL-23 and other inflammatory cytokines in response to a variety of infection-related stimuli.
Potential: The better understanding of excess IL-23 production may lead to earlier diagnosis and more efficacious therapy for AS.
Elaine Husni, M.D., MPH, of Cleveland Clinic/Case Western Reserve University, Cleveland, Ohio will examine evidence that psoriatic arthritis patients are at increased risk for heart disease by studying the connections between joint inflammation and cardiovascular inflammation.
Potential: This study will help identify and characterize the cardiovascular biomarkers in psoriatic arthritis that may allow earlier detection of those patients at risk for atherosclerosis (heart disease).
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