The American Society for Clinical Investigation has selected renowned lupus researcher and rheumatologist Judith James for the 2020 Stanley J. Korsmeyer Award, which is given annually in recognition of scientific excellence and outstanding mentorship of future researchers. Dr. James, member and chair of the Oklahoma Medical Research Foundation and Professor of Medicine at the University of Oklahoma Health Sciences Center, has dedicated her career to understanding the pathogenesis of systemic lupus erythematosus (SLE) and related autoimmune conditions and has made key contributions to the concepts of humoral epitope spreading and preclinical autoimmunity (Figure 1). Subsequently, her work expanded to include clinical studies aimed at preventing or delaying SLE development in high-risk populations. Her research group is also seeking to better understand immune imbalances that contribute to flares in patients with SLE. The JCI recently spoke with Dr. James about her remarkable research career and dedication to mentoring trainees in Oklahoma.

Judith James is the recipient of the 2020 Stanley J. Korsmeyer award.

JCI: What attracted you to a career in medicine and research?

James: I am a fifth-generation Oklahoman from a farming community, and I had horrible asthma as a child. When I was about five years old, I told my pediatrician that I really wanted to be a doctor. He responded that if I became a nurse, he would be happy to hire me. I told him, “That’s okay, I am going to be a doctor, and I can come back and take over this practice.” He recorded this in my medical chart and left a note to look up this precocious five-year old in 20 years. Later, he actually showed that small redacted part of my medical record to my medical school class, because he came and lectured on pediatric dermatologic conditions.

As an undergraduate, I did everything I could to become a perfect medical school candidate. I was rotating with a family physician, and I would accompany him on house calls. One day, he stopped the car, pulled to the side of the road, and told me that I asked way too many questions and would never be happy just being a physician. He suggested that I find some research opportunities. I went to a small liberal arts school that didn’t have any bench research, but I was able to participate in a summer research program at the Oklahoma Medical Research Foundation in the lab of John Harley, who was an MD-PhD. He was my first mentor and very supportive of my career. When I was 19, I saw my first patient with lupus who was also 19. That’s when I decided I really wanted to be a physician-scientist.

JCI: Can you tell us more about your early work?

James: I was the first student in the MD-PhD Program at the University of Oklahoma. I worked on epitope mapping of humoral immune targets in lupus autoantigens. That research led to the work that has been my mission in life, which is understanding the early events of disease transition, including genetics, environmental factors, as well as changes in the immune system and regulators of the immune system in the pathway to human lupus. That led to our role in the first lupus prevention trial.

JCI: How did you transition from working on a more basic understanding of disease susceptibility to clinical treatments aimed at prevention?

James: When I started my career, I was more of a basic immunologist. I did mouse experiments and in vitro work, but we still conducted a lot of studies using human samples to dissect what was changing in patients’ immune systems over time. My entire career has focused on patients and dissecting mechanisms, and then going back to see which of those mechanisms are important in human disease. As my career has evolved, I have become increasingly involved in the clinical research side. I still take care of patients, and I am very passionate about making sure we do research that helps change the lives of current and future patients.

We have a wonderful partnership with military rheumatologists who are part of the Department of Defense. Through those collaborations, we were able to access the Department of Defense serum repository, which has longitudinal samples from millions of active duty military personnel. We were able to identify individuals who came into the military completely healthy but later went on to develop SLE, and then we went to the serum repository to access samples obtained before these individuals ever became clinically ill. We saw autoantibodies many years before specific disease manifestations, and then we were able to follow changes in their immune system as they were transitioning to disease.

We have followed up that work with studies looking at family members who have increased disease risk, enrolling them in genetic studies and then recontacting them years later to see who did and didn’t transition. We’ve been very interested in identifying the family members who will go on to develop lupus, but equally important are the family members who have significant genetic risk factors and make autoantibodies but never become clinically ill. One of the major focuses of our current research involves trying to understand how these healthy individuals regulate immune responses even after they have lupus-associated autoantibodies.

Through partnerships with clinical trialists like Joan Merrill, we have built the Oklahoma Lupus Cohort, which follows about 650 lupus patients. I have taken care of some of those patients for more than 20 years. I am now enrolling multiple children of my patients or former patients who have passed away into our first-ever lupus prevention trial, and they are so excited to be part of it.

JCI: SLE has been a particularly challenging disease, in part because the clinical symptoms are so heterogeneous. How do you think that modern tools and approaches might help shape our understanding of this moving forward?

James: This is an extremely important area, and dissecting lupus heterogeneity to aid in clinical trials is the primary focus of the recently renewed Autoimmunity Center of Excellence that I lead. In lupus, we have had — which I consider a travesty — many molecules that make complete sense for intervening in lupus pathogenesis, but trials targeting those molecules have not met their primary endpoint in large-scale studies. We think this lack of success is multifactorial, and we have multiple investigators who are working on different pieces of this puzzle. One of those pieces is that lupus is clinically heterogeneous, but in the past, the field has not tried to rigorously dissect the molecular heterogeneity that is happening in patients at the time we are putting them into trials.

Recently, we took a large group of patients with lupus and characterized them from a molecular phenotype perspective. We have looked at immunophenotyping, gene expression profiling, genetics, soluble mediators, and autoantibodies and then used machine learning and clustering algorithms to identify different groups of patients. We have some preliminary data from work with clinical trial samples suggesting that if we can select patients who are in a specific cluster, we may be able to tease out which medicines should be used.

JCI: You have stayed in Oklahoma for all of your training and professional career with great success. Was it important to you to remain in Oklahoma?

James: In the beginning, all of my mentors told me I couldn’t do it this way. However, the science was going so well, as we were building patient collections and had substantial support from the institution, so I just never left. I also have a huge passion to help other Oklahoma students to understand that they can have a career in biomedical research. I’ve had well over 130 people come through the lab who were thinking about medical school, graduate school, or a combined degree, and helping those Oklahoma students (many of whom are either in high school or are undergraduates) and seeing them succeed with physician-scientist training and now with faculty positions at universities like Columbia, Duke, the University of Alabama Birmingham, Harvard, Yale and OUHSC, is something I’m really excited about.

I am also very passionate about training Native American students, because we have a significant Native American population in Oklahoma, but they account for less than 0.2% of all medical students and an even lower percentage of graduate students nationally. I have a tribe-based research clinic, currently with the Cherokee Nation and previously with the Chickasaw Nation. We are working on developing better molecular information to help improve outcomes through early diagnosis and treatment. I’ve had a number of Native American students who have come through the lab and worked on that project or other projects and who have now finished medical school or graduate school and gone on to productive careers. I’ve had two Native American trainees who have gone on to obtain independent NIH funding and are both doing really well. That’s extremely rewarding.

JCI: What does winning the Korsmeyer award mean to you?

James: I was incredibly excited but also humbled to receive this award. I was not fortunate to know Dr. Korsmeyer, but my institutional president, Steven Prescott, knew him and has shared with me how passionate Dr. Korsmeyer was about mentoring and helping train the next generation. I’m honored to receive the award, and it re-emphasizes to me how important mentoring is. The list of previous recipients is amazing, and I’m very, very honored to be added to that list.

Footnotes

Reference information: J Clin Invest. 2020;130(4):1543–1544. https://doi.org/10.1172/JCI137323.

Copyright: © 2020, American Society for Clinical Investigation.

美国临床研究学会已选出著名的狼疮研究人员和风湿病学家朱迪思·詹姆斯（Judith James）担任2020年斯坦利·J·科尔斯迈尔奖，该奖每年颁发一次，以表彰其杰出的科学成就和对未来研究者的杰出指导。詹姆斯博士是俄克拉荷马州医学研究基金会的主席兼主席，也是俄克拉荷马州大学健康科学中心的医学教授，她的职业生涯致力于了解系统性红斑狼疮（SLE）的发病机理和相关的自身免疫状况，并做出了重要贡献体液抗原表位传播和临床前自身免疫的概念（图1）。随后，她的工作扩展到包括旨在预防或延缓高危人群SLE发展的临床研究。她的研究小组还试图更好地了解导致SLE患者发作的免疫失衡。的JCI最近与James博士谈了谈她杰出的研究事业以及致力于在俄克拉荷马州指导学员的工作。

朱迪思·詹姆斯（Judith James）是2020年史丹利·J·科尔斯迈尔（Stanley J.

JCI：是什么吸引了您从事医学和研究事业？

詹姆斯：我是来自农业社区的第五代俄克拉荷马州人，小时候患有严重的哮喘。当我大约五岁时，我告诉儿科医生我真的很想成为一名医生。他回答说，如果我成为护士，他很乐意雇用我。我告诉他：“没关系，我将成为一名医生，我可以回来接受这种做法。” 他将此记录在我的病历表中，并留下了一张纸条，以查找这位20岁的早熟五岁男孩。后来，他实际上向我的医学院课堂展示了我的病历中的一小部分，因为他来了关于小儿皮肤病的讲座。

作为一名本科生，我竭尽所能成为一名完美的医学院候选人。我和一位家庭医生一起旋转，我会陪他做家务。有一天，他停了车，拉到路边，并告诉我，我问了太多的问题，仅仅当医生就不会高兴。他建议我找到一些研究机会。我去了一所没有任何基础研究的小型文科学校，但是我得以参加了俄克拉荷马州医学研究基金会约翰·哈雷实验室的夏季研究项目，他是医学博士。他是我的第一任导师，对我的职业生涯非常支持。当我19岁的时候，我看到了第一位也是19岁的狼疮患者。那时候，我决定我真的想成为一名医师医师。

JCI：您能谈谈您的早期工作吗？

詹姆斯：我是俄克拉荷马大学医学博士课程的第一位学生。我从事狼疮自身抗原中体液免疫靶标的表位作图。这项研究导致了我的人生使命，那就是了解疾病转变的早期事件，包括遗传，环境因素以及通往人类狼疮的免疫系统和免疫系统调节剂的变化。 。这导致了我们在第一次狼疮预防试验中的作用。

JCI：您是如何从对疾病易感性的更基本的了解过渡到旨在预防的临床治疗的？

詹姆斯：当我开始职业生涯时，我更是一名基础免疫学家。我进行了小鼠实验和体外研究，但我们仍然使用人体样本进行了大量研究，以剖析患者免疫系统随时间变化的情况。我的整个职业生涯都集中在患者和解剖机制上，然后回头看看其中哪些机制对人类疾病很重要。随着我职业的发展，我越来越多地参与临床研究。我仍然照顾病人，并且我非常热衷于确保我们进行有助于改变当前和未来病人生活的研究。

我们与隶属于国防部的军事风湿病学家建立了良好的合作关系。通过这些合作，我们能够访问国防部血清库，该库具有数百万现役军人的纵向样本。我们能够鉴定出完全健康的军人，但后来又发展了SLE，然后我们去了血清库以获取在这些人患上临床疾病之前获得的样本。我们在特定的疾病表现出现之前已经看到了自身抗体很多年，然后我们就能够追踪到他们转变为疾病的免疫系统的变化。

我们对这项工作进行了跟踪研究，研究的对象是罹患疾病风险增加的家庭成员，将他们纳入基因研究，然后在多年后重新联系他们，以了解谁做了和不进行了过渡。我们一直对确定将继续发展狼疮的家庭成员非常感兴趣，但同样重要的是具有重要遗传风险因素并产生自身抗体但从未患上临床疾病的家庭成员。我们当前研究的主要重点之一是试图了解这些健康个体即使在患有狼疮相关自身抗体后如何调节免疫反应。

通过与Joan Merrill等临床试验专家的合作，我们建立了俄克拉荷马州狼疮队列，该队列追踪了大约650名狼疮患者。我已经照顾了其中一些患者超过20年。我现在正在招募我的患者或以前的患者的多个孩子，这些孩子已经去世了我们有史以来的首次狼疮预防试验，他们很高兴能参与其中。

JCI：SLE是一种特别具有挑战性的疾病，部分原因是临床症状如此多样。您如何看待现代工具和方法可能有助于塑造我们对这一前进方向的理解？

James：这是一个非常重要的领域，解剖狼疮异质性以协助临床试验是我领导的最近更新的自身免疫卓越中心的主要重点。在狼疮中，我们有很多分子（我认为是怪诞的）对干预狼疮发病机理完全有意义，但针对这些分子的试验尚未达到大规模研究的主要终点。我们认为这种缺乏成功的原因是多方面的，我们有多个研究人员正在研究这个难题的不同方面。其中之一是狼疮在临床上是异质性的，但是在过去，该领域尚未尝试严格剖析患者在进行试验时所发生的分子异质性。

最近，我们接受了一大批狼疮患者，并从分子表型的角度对它们进行了表征。我们研究了免疫表型，基因表达谱，遗传学，可溶性介体和自身抗体，然后使用机器学习和聚类算法来识别不同的患者群体。我们从临床试验样本中获得了一些初步数据，这些数据表明，如果我们可以选择特定人群的患者，我们也许可以弄清楚应该使用哪种药物。

JCI：您在俄克拉荷马州的所有培训和职业生涯都取得了巨大的成功。留在俄克拉何马州对您来说重要吗？

詹姆斯：一开始，我所有的导师都告诉我我不能这样做。但是，科学发展得很好，因为我们正在建立患者病历并得到了机构的大力支持，所以我就再也没有离开过。我也非常热衷于帮助其他俄克拉荷马州的学生了解他们可以从事生物医学研究。我有130多名来自实验室的人在考虑医学院，研究生院或综合学位的工作，他们正在帮助俄克拉荷马州的学生（其中许多人是高中或大学生）并看到他们取得了成功医师-科学家培训以及现在在哥伦比亚大学，杜克大学，阿拉巴马州伯明翰大学，哈佛大学，耶鲁大学和OUHSC等大学担任教职的职位让我感到非常兴奋。

我也非常热衷于培训美国原住民学生，因为我们在俄克拉荷马州有大量的美国原住民人口，但他们占所有医学生的比例不到0.2％，而全国的研究生比例甚至更低。我有一个基于部落的研究诊所，目前在切罗基族和奇卡索族中。我们正在努力开发更好的分子信息，以帮助通过早期诊断和治疗改善结果。我有许多美国原住民学生通过实验室并从事该项目或其他项目，现在已经完成医学院或研究生院的工作，并开始从事生产性职业。我有两名美国原住民培训生，他们一直获得独立的NIH资助，而且都做得很好。那是非常有益的。

JCI：赢得Korsmeyer奖对您意味着什么？

詹姆斯：我非常激动，但也很谦虚地获得了这个奖项。我不是很幸运认识Korsmeyer博士，但是我的机构总裁Steven Prescott认识了他，并与我分享了Korsmeyer博士对指导和帮助培养下一代的热情。我很荣幸获得该奖项，它再次向我强调了指导的重要性。以前的收件人列表令人赞叹，很荣幸能被添加到该列表中。

脚注

参考信息：J Clin Invest。2020; 130（4）：1543-1544。https://doi.org/10.1172/JCI137323。

版权所有： ©2020，美国临床研究学会。