In this podcast, Mariana Kaplan, MD, and Sarthak Gupta, MD, both from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, discuss their findings on how sex differences in neutrophil functions may help in the understanding of differences seen in autoimmunity and, in turn, aid in the personalization of treatment approaches for men vs women with autoimmune diseases. Read the full transcript below.
Mariana J. Kaplan, MD, is senior investigator and chief of the Systemic Autoimmunity Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). She is also Deputy Scientific Director at NIAMS.
Sarthak Gupta, MD, is an assistant research physician for the Lupus Clinical Trials Unit and the Systemic Autoimmunity Branch at NIAMS.
Gupta S, Nakabo S, Blanco LP, et al. Sex differences in neutrophil biology modulate response to type I interferons and immunometabolism. Proc Natl Acad Sci U S A. 2020;117(28):16481-16491. doi:10.1073/pnas.2003603117
Colleen Murphy: Hello, everyone. Welcome to another installment of the Autoimmune Learning Network’s podcast series. I’m your moderator, Colleen Murphy, with the Autoimmune Learning Network. Today, I have the pleasure of being joined by 2 autoimmune experts, Dr Mariana Kaplan and Dr Sarthak Gupta.
Dr Kaplan is senior investigator and chief of the Systemic Autoimmunity Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr Gupta is also from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Systemic Autoimmunity Branch, where he serves as an assistant research physician. Thank you both for joining me.
Mariana Kaplan: Thank you.
Sarthak Gupta: Thank you for having us.
CM: We know there are clear differences between men and women when it comes to their clinical experience with autoimmune diseases. We know that neutrophils play key roles in homeostasis and disease. I’m excited to get your insight about a recent study you’re both involved with.
Along with the team of researchers from the National Institutes of Health, you investigated how sex differences modulate neutrophils’ phenotype and function. First, let’s get a little background. Why did you conduct the study? What knowledge gaps were you hoping to bridge?
MK: Thank you again for having us. To answer to your question, we know that women in general present with more robust immune responses to, for example, vaccines or to certain infections, and they may have decreased rates for certain cancers compared to men. These may potentially be driven by better ability for immune surveillance.
Conversely, women also present with enhanced immune responses to cells, which may promote them or give them higher susceptibility to develop inflammatory and autoimmune diseases such as systemic lupus erythematosus, Sjogren syndrome, and rheumatoid arthritis.
SG: The underlying mechanisms that drive these clearing distinctions between male and female immune systems remain insufficiently characterized, especially when concerning to the innate immune system.
CM: Your study showed that there are key sex differences in neutrophils’ functions. Can you provide a brief overview of these differences?
SG: Yes. In a previous study, we had shown that neutrophil from young adult females are more mature and activated compared to their male counterparts. In this study, we found that female neutrophils have a striking upregulation of type I interferon‑stimulated gene, suggesting enhanced response to this group of crucial antiviral cytokine.
These sex differences in type I interferon responses were very specific to neutrophil. We did not see them in any other immune cell types, and these are likely related to the enhanced maturation and activation status for female cells when compared to male neutrophils.
MK: In addition, we note the differences in the metabolism of female and male neutrophils which suggested that this was driven by the fact that female neutrophils are more mature. These appear to be explained by sex hormones such as estradiol, which was the main hormone we identify as playing a role in changing cellular metabolism.
Further supporting our role for sex hormones rather than these being due to women having an extra X chromosome in driving this enhanced response to type I interferons and the increase in maturation status of the female neutrophils, we found that the differences in the neutrophil phenotype and function between adult males and females are not observed in kids when we looked at pre‑pubertal boys and girls.
In addition, neutrophils from patients with Klinefelter syndrome which are XXY, that will not be fair in their type I interferon response when compared to young males without Klinefelter.
CM: You said that understanding the sex differences in neutrophil functions that you just mentioned may help in the understanding of differences seen in autoimmunity, cancers, and infections. In regard to autoimmunity, what differences might these findings help reveal?
MK: Neutrophils are the most abundant, circulating innate immune cells in the human body and are the first ones to respond to infection. Recent reports have also shown that they may play a key role in the initiation and perpetuation of systemic or immunity in several diseases — lupus, rheumatoid arthritis, inflammatory myopathies, vasculitis, etc. And since females have a higher prevalence of many of these autoimmune diseases. For a long time, it was unclear why they are more predisposed to getting autoimmune diseases.
SG: Our findings showed that neutrophils from even healthy females have a more activated phenotype. This may be due to the effects of sex hormones as we discussed. We also identified several subsets of neutrophils. These findings would help in the management of patients with autoimmune diseases.
CM: You wrote that this research may lead to more individualized, sex‑specific therapeutic options in a variety of disease states. Can you expand on this? In what other ways may your research impact future treatment or management?
SG: One of the things that we could think of would be, what are the effects of hormones on neutrophil responses? Can we modulate these effects, and can these be used for possible therapeutics in autoimmune diseases as well as in infectious diseases, where we do see sex differences and responses?
MK: The fact that we have recently emphasized that there isn’t just one type of neutrophil but that there are distinct subsets of neutrophils, even in healthy people and certainly in different diseases such as autoimmune diseases.
Because neutrophils are so important in fighting infections, these may help in designing more direct targeting to specifically try to fight the other answer to the responses and inflammatory conditions while leaving alone other subsets of neutrophils that may be important to fight infections. This may bring new opportunities for precision medicine in autoimmune diseases.
CM: Sounds very exciting and promising. As we wrap up here, do either of you have parting takeaways you want to leave the audience with?
MK: There is still much work to do. This study, in our view, is important because it highlights that characterizing in better ways and more refined ways how the female and male immune system develop and play a role in driving the different diseases is key in personalizing approaches that may work in women but not in men and vice versa.
Therefore, further research will be needed to try to better understand other changes in the immune system that may be driven by sex differences.
SG: I agree. The other thing we also need to look is, during the human lifespan, these neutrophil differences, how do they develop and what’s the role of age on these differences that we essentially saw in young, healthy adults?
The other thing would be looking at in vivo studies following healthy people over the course of a lifetime and trying to see how these differences stay or disappear. How that could be informative? How patients respond to different therapies, different stimuli?
CM: Great. Doctors, thank you so much again.
SG: Thank you for having us.
MK: Thank you for the opportunity.