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The most satisfying solutions are for the longest-standing mysteries. Fermat’s Theorem. Amelia Earhart’s fate. The Golden State Killer. When we know the answer, how long the answer has been under our nose all long is directly proportional to the cathartic thrill. Well, now the field of rheumatology might have their moment.

Patients with systemic lupus erythematosus (SLE, “lupus”) and other related diseases, such as rheumatoid arthritis, myositis and Sjogren’s Syndrome, commonly have antibodies in their blood that bind to DNA, histones and other molecules that are normally located in the nucleus of cells, sequestered from the blood and extracellular space where antibody producing cells recognize antigens and produce cognate antibodies. This has been such a conundrum for so many years that physicians and scientists basically stopped talking about it. If these formed when cells were burst by trauma or other scorched earth kinds of events, then everyone would have these antibodies from all their scratches and cuts. But, no, they are very specific to people with autoimmune disorders. How, then, do the B-cells that produce antibodies ‘see’ the intranuclear targets? Nobody knew.

Now, researchers have revealed an elegant system, built on a sequence of discoveries, that might explain the phenomena. The first discovery some time ago was the process of apoptosis, namely a way for a cell to die in an orderly fashion. It just breaks itself down in a quiet, non-inflammatory way. Then, biologists discovered the dynamics of the plasma membrane, with blebs and microvesicles and all manner of bubbles pinching off from cells in an intentional rather than random manner. Then, those two things were put together, and, hello, part of apoptosis is to transport nuclear materials to the membrane where they are pinched off in these little bubbles so that they can be easily digested by a series of “pac-men” in the vicinity. When any one of the pac-men are deficient, the nuclear molecule containing bubble hangs around long enough to encounter an antibody producing cell and BOOM, ANA.

The last part of that is illustrated by a recent study on a deficiency in the enzyme DNASE1L3, which is one of those “pac-men.” A family tree exhibiting a clear inherited pattern of autoimmune disease was mapped to DNAS1L3. Similar alteration of DNASE1L3 in mice produced autoimmune disease and anti-DNA antibodies in the mice. It was then shown that DNASE1 could not digest the DNA in the bubbles, but DNASE1L3 could. Other data was consistent with the picture.

This story was specific for anti-DNA antibodies, but ANA and other such tests target a whole bunch of nuclear antigens. There are likely a whole host of gene products like DNASE1L3 that target different bubbles. One way to find them might be to compare the tissue expression profile of DNASE1L3 to candidate genes . . .

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