A new Yale study may lead to a cure for lupus.

Researchers at the Yale School of Medicine identified a genetic mutation that causes lupus, an autoimmune disease without a known cure. The gene typically repairs errors in DNA sequences, and the researchers observed symptoms of lupus in mice when the gene became mutated. While the finding opens new avenues of research, the study — published in Cell Reports on Jan. 16 — did not name the precise mechanism linking the mutation to the disease.

“For a long time people thought that mutations in DNA repair genes could be linked to lupus, and this is actually one of the first demonstrations that a mutation in a DNA repair gene is actually linked to lupus,” said Joann Sweasy, study senior author and professor of therapeutic radiology and genetics at the Yale School of Medicine.

The researchers did not set out to investigate the genetics of lupus — instead, they first tried to identify how a DNA repair mechanism distinguishes between correct and incorrect DNA bases. To answer this question, the research team mutated the DNA repair gene POLB in mice, thinking that the mice would exhibit symptoms of cancer.

But instead cancer, the researchers began to see symptoms of lupus. Most conspicuously, they noticed that the mice had elevated levels of antinuclear antibodies, a classic marker of lupus. According to Sweasy, the reason for this elevation might be that the mutated POLB gene was creating antibodies that attacked the animals’ own cells, leading to lupus.

The finding holds promise for helping physicians diagnose lupus and researchers develop treatments, said Alireza Senejani, study lead author and a research scientist in therapeutic radiology at the Yale School of Medicine.

“I think that the contribution to the science community is going to be high because [lupus] is a very complex disease and there is a lot to be learned,” he said. “What we found in this study was how important DNA pathways are.”

According to Betty Diamond, head of the Center of Autoimmune and Musculoskeletal Diseases at the Feinstein Institute for Medical Research in New York who was not involved with the study, nanotechnology may hold the key to locating the source of the antinuclear antibodies the study researchers observed. Pinpointing the origin of the antibodies will enable researchers to develop minimally toxic treatments, she said.

But for Eric Meffre, a professor of immunobiology at the Yale School of Medicine, the correlational nature of the study leaves much in question.

“I think that one of the major questions that remains to be addressed is that despite some of the observations that are recorded in this manuscript, it really does not explain why the mice developed lupus,” he said.

According to the Lupus Research Institute, the disease currently affects more than 1.5 million Americans.

  • charliewalls

    What on earth is a “DNA pathway”? Surely the author means DNA repair pathway. And “nanotechnology”? A little rational connecting would be much appreciated. Surely the author read the publication and leaned that POLB means a DNA polymerase associate with certain aspects of DNA repair. And also the paper must have mentioned the possibility of apoptosis, which could have caused release of nuclear antigens. Altogether an odd article — but about an interesting finding. Students in a liberal arts college must these days have some understanding of current science knowledge and writers should push a bit more than this one.

    • yalengineer

      It was a quote from Senejani. The author did use the correct term “DNA repair gene” although it really is an enzyme. I too hate the generic use of the nanotechnology buzzword but you and I both know they really meant gene therapy.

      I do find it interesting that what started off as a fishing expedition for an oncogene was able to be tied back to a GWAS suggesting a link to Lupus. Good work by the authors to dissect what was going on.

      • Rachel PM

        I agree– that is an incredibly unclear use of a buzzword… Actually, I don’t see how “nanotechnology” could mean “gene therapy” in this case. Diamond is describing an approach to “locating the source of the antinuclear antibodies”, while gene therapy would be a treatment, not a method to determine how the antibodies arise. Even on the treatment end, Diamond’s own work has dealt with small molecule peptidomimetics that mimic proteins and block the autoantibody binding– could this be what they call “nanotechnology”? I am not sure what the point of saying “nanotechnology could be useful” is unless there is some idea of what that technology might be– that is kind of like saying “computers might help solve this problem”…

  • yalengineer

    I’ll give the YDN credit. At least they mentioned the journal and the date. But what about the link or at least the title!!!!

    Mutation of POLB Causes Lupus in Mice

  • Faith Morgan

    Been 35 years since my diagnosis, 32 for my sister. I am really glad that future generations may have an easier time – as my diagnosis took years and was endlessly questioned by new physicians.

    • New to genetics

      Your sister also has Lupus…any more with autoimmune disease in your family? I really do not have a concrete LUPUS diagnosis but a more generalized diagnosis of autoimmune disease- mixed connective plus PMR. I have been sick for 20+ years and three of my cousins have similar disease. Actually half of the descendants of my geat grandmother have diagnosed autoimmune disease, some RA, some Lupus, some impacting Thyroid etc. IF I remember my genetics this means that we have a dominant gene mutation, one that causes multiple autoimmune disease. This POLB mutation makes sense to me for my illness, it may not be the only cause but it appears it may be one cause of LUPUS and other autoimmune diseases.

      Right now the thinking of researchers is that it takes many genes to cause Lupus or other autoimmune disease but families like mine and possibly yours contradict this yet do the doctors even pay attention to families with large numbers of people with autoimmune disease? I can’t get any researcher to even talk to me, much less test my family for a potential gene mutation..I gave this report to my Rheumatologist Friday but he is not linked to research. He did test me for one gene and it was negative. Have you been tested for any genes linked to LUPUS? Have you heard that some of the genes they have linked to LUPUS were from Neanderthal? Google LUPUS and Neanderthal and see what you find.

  • LupieLori

    I’ve had SLE for 37 years, I pray that others don’t have to endure what I’ve had with this disease. Sounds promising.

  • Nina Atté

    It is true this autoimmune disease, lupus is very mysterious. It is unbelievale antibodies to attack the organs.

  • New to genetics

    Mutated POLB gene is the cause of LUPUS or other autoimmune diseases too? These were mice how could they tell if they had other autoimmune disease, did they test for RA or Sclederma or PMR? Also is this the gene that they linked to Neanderthal?