The team was led by Samar M. Hammad, Ph.D., associate professor in the MUSC College of Medicine, and the study was funded in part by a pilot project grant from the South Carolina Clinical & Translational Research Institute.

“The most exciting finding of this study is that we may be able to find another way to better diagnose and eventually treat the African American lupus patients who are at increased risk of developing heart disease,” said Hammad.

Systemic lupus erythematosus (SLE), or lupus, is a chronic autoimmune disease that can affect many different organs in the body. Our immune system typically acts like our personal bodyguard. When it senses danger from a virus or infection, it attacks and eliminates the threat. In patients with SLE, the “bodyguard” attacks and damages the person’s own cells, mistaking them as foreign invaders. As a result, patients with SLE can develop complications, such as cardiovascular disease (CVD).

Cholesterol, a type of fat circulating in our blood, is carried on lipid particles called high-density lipoproteins (HDL, the good cholesterol carrier) and low-density lipoprotein (LDL, the bad cholesterol carrier) and typically used to screen for CVD. High levels of LDL cholesterol are commonly used to predict a patient’s risk for developing heart disease because this fat accumulates in the walls of blood vessels.

Despite being at an increased risk of CVD, healthy African Americans have a lipid profile with higher HDL (good) cholesterol and lower triglyceride levels compared with healthy persons of European ancestry. Therefore, the efficacy of the standard screening method for CVD has been called into question for African American patients. Further, approximately 90% of lupus patients are females, and African American women are three times more likely than white women to develop severe symptoms associated with SLE. Thus, the standard screening panels, developed with the white patient in mind, lack efficacy for the African American patient. With the standard method of screening for CVD potentially being unreliable for African American SLE patients, additional biomarkers are needed to improve health outcomes in this group.

Sphingolipids are molecules carried in the blood on lipoproteins. They are important structural components of cells, can act as key signaling molecules and, when disrupted, are associated with several diseases. Recently, serum sphingolipids have been shown to be potential biomarkers for clinical lupus complications.

Notably, the Hammad lab previously found that the sphingolipid profile of healthy African Americans differs from that of healthy whites. They also observed differences in the sphingolipid profiles of African American lupus patients with or without heart disease.

“Treatments for SLE and heart disease are often given as a one-size-fits-all, and they can have major side effects for the patient,” said Hammad.

The purpose of this study was to determine whether sphingolipids are predictive biomarkers for preclinical CVD and CVD severity in African American patients with SLE. At study start (visit 1) and after one year (visit 2), the researchers measured levels of five different sphingolipid classes, with several sphingolipid species in each class, in plasma samples of 51 patients with SLE but without a history of clinical heart disease.

Hammad and her lab established a methodology for profiling sphingolipids in human plasma in 2010 that is now widely used in sphingolipid studies. Using this method, Hammad and her team found that a particular class of sphingolipid in the plasma samples, called lactosylceramide (Lac-Cer), was positively correlated with the change in plaque area over one year. Plaques are clumps of cholesterol found at injury sites of walls of major arteries. Thus, higher levels of Lac-Cer are associated with increased disease activity in African American patients with SLE.

“This finding showed us that the Lac-Cer levels in the circulation could have predictive value for a patient,” explained Hammad. “We could use this as a readout for how a patient is progressing while on medication and get a good indication of his or her heart disease.”

High LDL cholesterol content in the serum is typically used to determine the risk of developing heart disease. The study found no correlation between LDL concentrations and the concentrations of the measured Lac-Cer species, indicating that the traditional biomarker for heart disease was ineffective in predicting disease severity in the African American lupus population.

Ultimately, Hammad believes that studies like these emphasize the need for teamwork between basic scientists and clinicians.

“I’m a basic scientist who has almost 20 years of experience in investigating the role of sphingolipids in health and disease,” said Hammad. “This study was possible, thanks to the organized and well thought out collection and banking of patient samples from the clinical side, led by Dr. Jim Oates, division director of Rheumatology and Immunology.”

Future objectives of the team will include determining whether their findings can be applied to the general population.

“Using sphingolipids as a tool to complement other diagnostic modalities will be important because SLE is often hard to diagnose,” said Hammad. “I think sphingolipids can play a major role in the diagnosis, prognosis and treatment of lupus.”

The finding runs counter to many scientists’ hypothesis that cities would trigger mammals to get smaller over time. Buildings and roads trap and re-emit a greater degree of heat than green landscapes, causing cities to have higher temperatures than their surroundings, a phenomenon known as the urban heat island effect. Animals in warmer climates tend to be smaller than the same species in colder environments, a classic biological principle called Bergmann’s Rule.

But Florida Museum of Natural History researchers discovered an unexpected pattern when they analyzed nearly 140,500 measurements of body length and mass from more than 100 North American mammal species collected over 80 years: City-dwelling mammals are both longer and heftier than their rural counterparts.

“In theory, animals in cities should be getting smaller because of these heat island effects, but we didn’t find evidence for this happening in mammals,” said study lead author Maggie Hantak, a Florida Museum postdoctoral researcher. “This paper is a good argument for why we can’t assume Bergmann’s Rule or climate alone is important in determining the size of animals.”

Hantak and her collaborators created a model that examined how climate and the density of people living in a given area — a proxy for urbanization — influence the size of mammals. As temperatures dropped, both body length and mass increased in most mammal species studied, evidence of Bergmann’s Rule at work, but the trend was stronger in areas with more people.

Surprisingly, mammals in cities generally grew larger regardless of temperature, suggesting urbanization rivals or exceeds climate in driving mammal body size, said Robert Guralnick, Florida Museum curator of biodiversity informatics.

“That wasn’t what we expected to find at all,” he said. “But urbanization represents this new disturbance of the natural landscape that didn’t exist thousands of years ago. It’s important to recognize that it’s having a huge impact.”

About a decade ago, scientists began to raise the alarm that warmer temperatures brought by climate change are causing many animal species to grow smaller over time. While many of the consequences of shifting body size are unknown, researchers cautioned that smaller animals may have smaller or fewer offspring, creating a feedback loop, and shrinking prey could also put pressure on meat-eaters to find more resources.

Guralnick and Hantak said they hope their findings will lead more researchers to add urbanization to their analyses of changing body size.

“When we think about what’s going to happen to mammalian body size over the next 100 years, a lot of people frame that as global warming causing animals to get smaller,” Guralnick said. “What if that isn’t the biggest effect? What if it’s that urbanization is going to lead to fatter mammals?”

Not all animals respond to human-induced environmental changes in the same way, Hantak added. The researchers also investigated how the effects of climate and urbanization may be tempered or amplified by the behavior and habits of certain species.

They found animals that use hibernation or torpor, a temporary way of slowing metabolic rate and dropping body temperature, shrank more dramatically in response to increases in temperature than animals without these traits. The finding could have important implications for conservation efforts, Hantak said.

“We thought species that use torpor or hibernation would be able to hide from the effects of unfavorable temperatures, but it seems they’re actually more sensitive,” she said.

While cities radically transform the landscape, they provide animals with new opportunities as well as threats, Guralnick said. The abundance of food, water and shelter and relative lack of predators in cities may help certain species succeed in comparison with their neighbors in rural areas. The results of the 2020 U.S. Census show that almost all human population growth over the past decade has occurred in the nation’s metro areas. As urbanization ramps up, animals could be divided into “winners and losers,” and mammal distributions may shift, he said.

“Animals that like living in urban environments could have a selective advantage while other species may lose out because of the continued fragmentation of landscapes,” Guralnick said. “This is relevant to how we think about managing suburban and urban areas and our wildlands in 100 years.”

While bigger is often better biologically, the long-term consequences to urban mammals of eating a diet of human food waste have yet to be determined, Hantak said.

“When you change size, it could change your whole lifestyle,” she said.

Hantak and her collaborators were able to conduct the study thanks to thousands of measurements collected by natural historians in the field and museums. The research team used information from three databases: VertNet, the National Science Foundation’s National Ecological Observatory Network (NEON) and the North American Census of Small Mammals (NASCM). Cumulatively, this data offers a broadscale view of how increasing urbanization is impacting mammals with very different life histories, from wolves, bobcats and deer to bats, shrews and rodents, Guralnick said.

“Museum collections have the power to tell us stories about the natural world,” he said. “Because we have these collections, we can ask questions about what mammals looked like before humans dominated the landscape. Digitizing specimen data unlocks these resources so that everyone can make discoveries about our planet.”

The researchers published their findings in Communications Biology.

Bryan McLean of the University of North Carolina Greensboro and Daijiang Li of Louisiana State University also co-authored the study. McLean and Li are former Florida Museum postdoctoral researchers.

In the new study, which appears in the journal Immunity, the Penn Medicine researchers analyzed the T-cell responses in 47 healthy people who received two doses of the Moderna and Pfizer/BioNTech mRNA vaccines.

The results reveal the complex details of how the T-cell response to these vaccines unfolds, and underline the importance of a second dose for people with no history of COVID-19. The findings showed, however, that in people with a history of COVID-19, the T-cell response was already robust after the first vaccine dose, with no significant increase after the second dose, which may have implications for potential future booster shots.

“Our findings underscore the fact that we need to look at T cells, not just antibodies, if we want a complete picture of the vaccine response for those who have not had COIVD-19 and for those who have recovered from the disease,” said senior author E. John Wherry, PhD, chair of the department of Systems Pharmacology and Translational Therapeutics and director of the Penn Institute of Immunology in the Perelman School of Medicine at the University of Pennsylvania.

Antibodies are forked proteins secreted by immune cells called B cells; they can bind tightly to specific viral structures on virus-infected cells. T cells also have antibody-like receptors that enable tight binding to specific viral structures, but they are whole cells, some of which — called “killer” T-cells — are capable of directly killing virus-infected cells they encounter. T cells therefore have long been regarded as the heavy armor of the immune system. Their responses to vaccines are harder to study than antibody responses, though, so less is known about those responses, including in the case of COVID-19.

Researchers examined in detail the T-cell responses to mRNA vaccination in 36 healthy people who had no history of COVID-19, and 11 people who had previously recovered from COVID-19.

In the group of participants who did not previously have COVID-19, they found that the first vaccine dose elicited a rapid and strong response from helper T cells called CD4 T cells — some of which help marshal an antibody response, while others stimulate the proliferation of CD8 killer T cells. The strengths of those initial CD4 T cell responses generally predicted the later strengths of antibody and killer T-cell responses. However, the killer T cells tended not to appear in large numbers until after the second vaccine dose — confirming the importance of that second dose for people with no COVID-19 history.

By contrast, in the prior-COVID-19 group, helper and killer T cells specific for the COVID-19 coronavirus were already substantially present before the first dose. After that first dose, T cell numbers rose somewhat, but did not significantly increase after the second dose.

“For people who haven’t had COVID-19, the first dose powerfully primes the pump, and the second dose turns on the whole engine — but having had COVID-19 is like having had that first vaccine dose already,” Wherry said. “It is important to point out, however, that a complete understanding of the relative importance of these T cell responses, compared to antibody, in protection from future infections will require larger clinical studies.”

The results also showed that the T-cell response in the weeks after mRNA vaccination includes T-cell types normally elicited by natural infection — and in general, natural viral infection is known to be capable of inducing T-cell protection that lasts years and even decades.

“We need to do follow-up studies to confirm the longevity of the T-cell response to vaccination, but our results here support the idea that that response can be long-lasting,” Wherry said.

Support for the research was provided by the National Institutes of Health (AI105343, AI082630, AI108545, AI155577, AI149680, AI152236, AI082630, HL143613, P30-AI0450080, T32 AR076951-01, T32 CA009140, T32 AI055400, U19AI082630), the Allen Institute for Immunology, the Cancer Research Institute, the Chen Family Research Fund, the Parker Institute for Cancer Immunotherapy, the Penn Center for Research on Coronavirus and Other Emerging Pathogens, the University of Pennsylvania Perelman School of Medicine COVID Fund, the University of Pennsylvania Perelman School of Medicine 21^st Century Scholar Fund, and Jeffrey Lurie, Joel Embiid, Josh Harris, and David Blitzer.