（盐湖城）——56岁, Roma Jean Ockler was continually afflicted with sinus infections and pneumonia, 尽管进行了治疗, 情况似乎越来越糟. 几十年来，免疫学家 哈利R. 山,米.D., 见过像她这样的病人吗. At the time he couldn't have known that her family's genetic information, combined with that of five other families from across the world, 会对一种新的疾病进行分类吗. Their subtype of common variable immunodeficiency disorder (CVID) results from mutations in IKAROS, a protein well known for its central role in immune cell development. The new findings, published online in the New England Journal of Medicine (NEJM) 3月17日, make possible a definitive genetic diagnosis for this class of CVID, opening a door to precision medicine tailored to patients with the disorder.
The research was a collaboration between Hill and his colleagues Attila Kumánovics, M.D.卡尔·沃尔克丁，m.s.D.萨拉·索斯博士.D., Nancy Augustine, and Thomas Martins, M.S.，来自 University of Utah School of Medicine and the ARUP Institute for Clinical and Experimental Pathology at ARUP Laboratories in Salt Lake City, and 26 other scientists from institutions across the U.S. 和欧洲.
One of the most frustrating aspects of CVID is that it's difficult to diagnose early before serious complications develop, 希尔说. 发生率约为1 / 20,000人, the rare condition is actually a collection of disorders that cause a susceptibility to infection, 就像在Ockler的案例中看到的那样. Her illnesses worsened considerably over time but because doctors did not diagnose her, she was not given appropriate treatment. By the time she saw Hill for the first time, she had been through 17 years of sinus surgeries, 肺炎, and a life-threatening intestinal infection. Based on experience he prescribed an immunoglobulin regimen that has since quieted her symptoms.
The genetic causes of only about 15 percent of CVID cases have been identified, and Ockler did not have any of them. When Hill learned she had relatives with similar symptoms, he saw an opportunity to define her condition.
"We knew that if we could find the cause of her and her extended family's disorder that we would have the chance to keep others from going through what she had,希尔说。, 病理学教授, 儿科学与医学.
In collaboration with molecular pathologists Kumánovics and Voelkerding, they found that many of her relatives were missing one of two copies of a gene that codes for IKAROS. 与此同时，马萨诸塞州的玛丽·艾伦·康利（Mary Ellen Conley）.D., from 洛克菲勒大学, independently came to the same conclusion with her own patients. She connected with the Utah team and coordinated what would become an international effort revealing a total of six unrelated families who share similar sets of symptoms, 以及同一基因的变化, implicating IKAROS as the culprit behind their shared disorder. "Often research tries to answer a question that is brought up by the patients," says Conley.
While some families had a change in just one DNA letter within the gene, others were missing a large piece, 或者全部. Each of the mutations cripple a region required for IKAROS to function, a result confirmed by biochemical analysis, suggesting it cannot carry out its critical role in regulating immune B cell development. Indeed, as the experiments predicted, all six families have low B cell counts. 换句话说, their immune system is misconstructed, likely explaining why they also have low levels of infection-fighting antibodies (immunoglobulins).
Yet one of the most surprising findings, 说Kumanovics, assistant 病理学教授, is that while some who carry the IKAROS mutations are prone to sickness, 其他人似乎很健康. He adds that understanding the biology that leads to this unexpected resilience could provide clues to overcoming the condition. "These rare patients don't know how valuable they are. They are providing insights into how the immune system works," he says.
在不久的将来, researchers have what they need to create definitive diagnostic criteria for this new class of CVID. "The diagnosis is rare but that makes it no less difficult for those who have it,Voelkerding说, 病理学教授. 他补充说，如果奥克勒, 现年71岁, had the benefit of a diagnosis at a young age, the information would have allowed doctors to intervene early and give the right treatment from the start.
"We think this discovery will help patients around the world," he adds. "There is no good treatment if you don't have a good diagnosis."
"Heterozygous Mutations in IKAROS in 病人 with Progressive Loss of B Cells and Hypogammaglobulinemia的文章在网上发表 New England Journal of Medicine 2016年3月17日.
The research was supported by the National Institutes of Health, the Gebert Rüf Stiftung program, Zurich Centre for Integrative Human Physiology, Gottfried und Julia Bangerter-Rhyner-Stiftung, and Fondazione Ettoree Valeria Rossi, 全国犹太人健康, 洛克菲勒大学, Institut National de la Santé et de la Recherche Médicale (INSERM), 和巴黎笛卡尔大学
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