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Antibodies to Self: Have Complex Relationship with Autoimmunity

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By Anette Breindl
Science Editor

Autoimmune disease, Richard Siegel of the National Institute of Arthritis and Musculoskeletal and Skin Diseases told his audience at a recent talk at the National Institutes of Health, is "one of the final frontiers in medicine."

Compared to the scientific understanding of other disease like cancer or infectious disease, he asserted, "we don't understand a lot of the basic mechanisms. . . . We're still at a very primitive phase. We have concepts, but we don't always have molecular mechanisms that can take us all the way."

Even the phrase "autoimmune disease" does not cover every condition that can result from an individuals' immune system going on the attack. To be called autoimmune disease, a condition has to result from an attack of B and T cells.

But some autoimmune diseases have nothing to do with B and T cells. Instead, in diseases like gout, the body attacks itself via the inflammatory mechanisms of the innate immune system – an older, faster and less specific branch of the immune system that Siegel likened to an immune brainstem of sorts, reacting reflexively as opposed to the adaptive immune system's cerebral cortex of specific and considered responses to pathogens.

If not all autoimmune diseases feature auto-antibodies, not all auto-antibodies are a sign of disease, either.

Studies have shown that in some autoimmune conditions – Siegel named myasthenia gravis as an example – transferring autoantibodies to a healthy animal will cause it to develop myasthenia gravis. In rheumatoid arthritis, the autoantibody "is a great biomarker, but it cannot transfer disease."

One study followed individuals that had given a blood sample when they entered the military, some of whom later developed systemic lupus erythematosus. Going back and analyzing those blood samples after the fact, the authors could identify lupus-typical antibodies in blood samples that were given decades before the patients developed clinical signs of the disease.

In fact, at the symposium, whose title was "Demystifying Medicine 2013 – Autoimmunity: Disease and Mechanisms," Abner Notkins of the National Institute of Dental and Craniofacial Research presented data showing that an individual's chance of being diagnosed with Type I diabetes within five years if they had only one diabetes-typical antibody was less than 10 percent. Those chances rose sharply as the number of different auto-antibodies increased; those with three diabetes-typical antibodies had an 80 percent chance of being diagnosed within the same time frame.

Notkins introduced his audience to something that might seem like a contradiction in terms: polyreactive monoclonal antibodies.

The whole idea of a monoclonal antibody is that it has a laser-like focus on one particular antigen. But Notkins and his team have discovered that some monoclonal antibodies can react to several antigens. In fact, he said, "If you screen against enough antigens, – 10,000 antigens – classic, so called monoreactive antibodies can have polyreactive properties."

Polyreactive antibodies frequently have self-antigens among their targets. But, Notkins said, that does not mean they should necessarily be considered auto-antibodies in the sense of contributing to, let alone driving, autoimmune disease. Polyreactive antibodies are different from autoantibodies in everything from their binding strength to their degree of evolution away from germline center antibodies.

Despite the fact that much remains to be learned, Siegel also noted that much progress has been made in understanding autoimmune disease. His parody of what he learned about the autoinflammatory disease gout in medical school was that it results when "uric acid crystals make neutrophils angry." These days, it is clear that the Nlrp3 inflammasome, a group of proteins in the cytoplasm that controls the release of proinflammatory cytokines such as interleukin-1beta, is key in autoinflammatory disease, and interleukin-1beta itself is a key driver of inflammation.

Siegel said that although the genetics of common autoimmune diseases are complex, "We learn a huge amount from diseases that are rare." Such rare autoimmune diseases are more often caused by a single gene, and those single genes are active in the more common autoimmune disorders as well. Overproduction of interleukin-1beta, for example, characterizes gout as well as a number of extremely rare autoinflammatory diseases such as Neonatal Onset Multisystem Inflammatory Disease (NOMID).

Genomewide Association Studies, too, have been valuable for understanding the origins of autoimmune disease. His field has been "revolutionized" since the first paper on risk genes for rheumatoid arthritis was published in 2006, Siegel said. So far, only about 50 percent of the estimated genetic risk for autoimmune diseases has been pinned down. But that already amounts to more than 100 risk genes for rheumatoid arthritis and Crohn's disease, and 50 for Type I diabetes and lupus.