How Rare Disease Research Benefits Autoimmune Disorders


Research into rare autoinflammatory diseases is driving a new understanding of autoimmune disorders and the inflammatory process in general.

Research into rare autoinflammatory diseases is driving a new understanding of autoimmune disorders and the inflammatory process in general. Autoinflammatory diseases, such as cryopyrin associated periodic syndrome (CAPS) and TNF receptor-associated periodic syndrome (TRAPS) are diseases of the innate immune system. They're caused by genetic mutations and can be difficult to diagnose, because of their symptoms - fever, rashes and achiness - are so common, especially in the pediatric population.  Autoimmune disorders, by contrast, are caused by the malfunction of the adaptive immune system. But autoimmune diseases typically trigger innate immune responses too. And a new understanding of these innate responses provided by rare autoinflammatory markers is helping shed light on the field as a whole, according to a new review of research. [[{"type":"media","view_mode":"media_crop","fid":"43917","attributes":{"alt":"©designer491/","class":"media-image media-image-right","id":"media_crop_3437080485746","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4874","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":" ","typeof":"foaf:Image"}}]] "Understanding the inflammatory pathways of these rare pediatric diseases also helps understand more common diseases, like rheumatoid arthritis," said Dirk Holzinger, M.D., a specialist in pediatrics and clinical immunology at University Children's Hospital Münster in Germany, who co-authored the review.  Bench to Bedside and Back Again In the past two decades, translational work in pediatric rheumatology has yielded a "huge leap forward" in the field, Holzinger said. A prime example is the bench-to-bedside work on the inflammasome, a multiprotein complex in the cytoplasm. The inflammasome's assembly is directed by NOD-like receptor, or NLR, proteins. Mutations involving these proteins can kick inflammasome assembly into high gear, which in turn leads to the secretion of inflammatory cytokines such as IL-1β.  Laboratory work on this and other cytokines has led to the development of treatments that antagonize the IL-1 pathway for CAPS and other diseases, Holzinger and his colleagues report in Nature Reviews: Rheumatology. Similarly, cell-culture and mouse studies revealed the importance of the cytokine IL-6 in systemic juvenile idiopathic arthritis (sJIA). This research has led to promising clinical studies of the monoclonal antibody drug tocilizumab targeting IL-6 receptors - a treatment than would skirt the side effects of previous steroid treatments for this debilitating form of juvenile arthritis.  Sometimes, insight starts in the clinic. TRAPS is caused by defective TNF-a receptors, so doctors initially tried treating the disorder with TNF blockers, Holzinger said. It didn't work. So clinicians turned to IL-1β blockers in an attempt to halt the inflammatory process. "People tried to give IL-1β blockers to these patients, and it was just case reports, but in some of these patients the disease suddenly stopped," Holzinger said.  As a result, researchers took the question back to the lab bench, where they found that cells with dysfunctional TNF receptors are stressed, which results in an uptick in IL-1β secretion. This was an example of "backward translation" that led to a better understanding of the disease mechanism, Holzinger said.  Rare diseases, broad lessons "In general, studying these rare diseases helps a lot to understand how inflammation works," Holzinger said. "We understand parts of it, but by finding diseases where you have a certain overactivation or underactivation of parts of this pathway, it helps us to understand how the inflammatory process itself works." In particular, basic research can turn up useful biomarkers for a broad array of autoinflammatory and autoimmune diseases. S100 proteins, for example, are a type of damage-associated molecular pattern molecule (DAMP) also known as myeloid-related proteins. They're secreted by activated phagocytes and form a positive feedback loop with IL-1β, Holzinger and his colleagues wrote.  S100 protein levels are particularly high in systemic juvenile idiopathic arthritis and in familial Mediterranean fever, two autoinflammatory disorders, which makes these proteins a useful biomarker to differentiate these diseases from other autoinflammatory disorders. Elevated S100 proteins are also present in systemic juvenile idiopathic arthritis and CAPS even when the disease is clinically inactive.  The understanding of the role of these proteins has moved beyond pediatric disease, however. They're expressed in the synovial membrane in rheumatoid arthritis and are important in the inflammation process associated with that disorder, a 1999 study published in The Journal of Rheumatology found. According to a 2011 review in the International Journal of Inflammation, these S100 proteins induce macrophage migration to the affected region, playing a basic role in encouraging the inflammatory response in adult rheumatoid arthritis. Elevated levels of these proteins have been linked with vascular and organ damage in the disorder.  


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