The immune system senses and responds to changes in physiologic health, and a new tool called the immune health metric (IHM) can measure and even predict some of these changes, an NIAID study has found. If doctors could use the IHM to detect health problems long before symptoms appear, they could potentially act early to prevent disease, the investigators suggest. Their findings are published in the journal Nature Medicine. 

The researchers developed the IHM starting with extensive analyses of biological samples from nearly 230 people who have one of 22 rare, severe immune disorders caused by a mutation in just one gene. The scientists also included samples from 42 healthy people matched to the others by age and sex. The analyses involved many elements, including gene transcripts in immune cells, blood-based proteins, and the frequency of various blood cells, all related to the immune system. The initial goal was to learn if there were immune-system similarities among people with the diverse array of diseases.

To the researchers’ surprise, the disparate diseases had many similar features when viewed through the lens of the immune system as a whole, rather than only the mutated gene and its effects. The primary source of immune variation came from aspects of the individual, irrespective of their disease or the medication they were taking. 

To explore this observation further, the scientists fed their gene-transcript and blood-based protein data into artificial intelligence (AI) tools. The first tool assessed differences among the people in the study without knowing their disease or symptoms. This analysis yielded a numeric measurement called jPC1 that was based on a specific combination of key gene transcripts and proteins. jPC1 correlated negatively with inflammation and related markers, and positively with parameters not linked to inflammation. This suggested that jPC1 could be used to measure immune health. Further supporting this finding, the group of healthy participants had a significantly higher mean jPC1 score than people grouped by severe immune disorder. 

The second AI tool the researchers tested is a machine-learning model that they taught to distinguish between healthy people and those with severe immune disorders. The investigators did this using the gene transcripts, blood-based proteins, and blood cells from the original biological samples. The scientists used their model to compute the probability that a person belonged to the immunologically healthy group. Each person received a score based on that probability. The researchers called this scoring system the immune health metric, or IHM. The IHM scores correlated highly with the jPC1 scores, suggesting that the gene transcripts and proteins key to jPC1 drive immune health differences among individuals.

When the scientists applied the IHM to the healthy people in their study and data from an independent study of healthy aging conducted by NIH’s National Institute on Aging, the one variable the metric correlated with was age. There was an inverse relationship between IHM score and age, with ages ranging from 22 to 93. This indicated that aging, like disease, distances people from optimal immune health. 

The authors validated the IHM by showing it could reflect immune health status and treatment outcomes and even predict some health outcomes when applied to gene transcript data, blood-based protein data, or both from studies previously conducted by other scientists. For instance, IHM and jPC1 scores accurately distinguished people with common autoimmune and inflammatory diseases from healthy people. IHM scores also reflected variability in disease activity among people with lupus, an autoimmune disease, during periods with symptoms of differing severity and periods without symptoms. Among people with rheumatoid arthritis, IHM scores reflected differences in the immune health of people whose symptoms responded to treatment compared to those whose symptoms did not. In vaccine studies and a heart failure study, people with higher baseline IHM scores had better antibody responses to vaccines and better future heart health than people with lower baseline scores. Finally, there was an inverse relationship between IHM score and body-mass index (BMI) in a study of sedentary adults, even after controlling for age, sex, race, and levels of C-reactive protein, which the liver releases in response to inflammation. 

While there are many tools available to measure physiologic and organ-system function and health, few tools measure immune-system health. The IHM could help fill this gap. The investigators hope that clinicians will one day be able to use the predictive capacity of the IHM to detect diseases early enough for preventive medicine to halt disease progression and preserve health.

John S. Tsang, Ph.D., and Rachel Sparks, M.D., M.P.H., led the study. Dr. Tsang was co-director of the NIH Center for Human Immunology at NIAID and chief of the Multiscale Systems Biology Section in the NIAID Laboratory of Immune System Biology when most of the research was conducted. He is now the founding director of the Yale Center for Systems and Engineering Immunology, a professor of immunobiology and biomedical engineering at Yale University, and an adjunct investigator in the NIAID Laboratory of Immune System Biology. 

Dr. Sparks was an assistant clinical investigator in the NIAID Laboratory of Immune System Biology and an attending physician at the NIH Clinical Center when she conducted the research. She is now an experimental medicine physician at Astra Zeneca in Gaithersburg, Maryland, and a special volunteer in the NIAID Laboratory of Immune System Biology. 

Reference: R Sparks et al. A unified metric of human immune health. Nature Medicine DOI: 10.1038/s41591-024-03092-6 (2024).     

Malaria, one of the deadliest infectious diseases on the planet, has had a profound impact on humanity throughout history. This disease has even left its mark in our DNA: Many scientists believe it has had a strong selective pressure on the human genome over time. Because malaria is often fatal in children, babies born with some degree of resistance to the parasite that causes malaria have a better likelihood of growing up and passing those traits along to their own children. Unfortunately, some of these traits may come at a price: For more than 50 years, scientists have documented that malaria infection is associated with high levels of autoantibodies—antibodies that recognize and attack the person’s own tissues and are associated with autoimmune disorders.

To investigate the link between autoantibodies and malaria immunity, NIAID researchers, along with their colleagues, have studied the molecular mechanisms of these malaria defense systems. Their findings, recently published in Immunity, reveal the associations between malaria, human resistance to it, and autoantibodies that are linked to certain autoimmune disorders—specifically, systemic lupus erythematosus (SLE).

The researchers began by examining a collection of blood samples collected during a longitudinal study of 602 people, aged three months to 25 years, in the West African country of Mali. Malaria transmission is highly seasonal in Mali: the parasite which causes malaria, Plasmodium falciparum, is transmitted by mosquitoes, which need certain conditions to reproduce. During the dry season, which ends in May, malaria transmission rates are low. The researchers tested for autoantibodies in blood samples that were collected in May and then linked this with whether the participant had symptomatic malaria that needed treatment during the ensuing malaria season.

Participants who had very high levels of autoantibodies had a 41 percent lower risk of getting sick with malaria than people who had low levels of autoantibodies. To investigate how autoantibodies might protect from malaria, the researchers took blood samples with high levels of autoantibodies and isolated the autoantibodies. They then exposed malaria parasites to the autoantibodies in the laboratory and found that parasite growth was inhibited. The autoantibodies bound to proteins that the parasite uses to invade human red blood cells. The researchers believe that something similar may have happened to the participants of this study—their autoantibodies reduced the parasite’s ability to invade and grow in their blood cells, increasing their chances of remaining free of malaria symptoms.

Although this adaptation seems beneficial, it may come with a catch. Very similar autoantibodies can be found in the blood of people with SLE. This chronic autoimmune disorder can affect almost any organ system, but it often manifests as a rash, joint pain, and persistent fatigue. In its worst forms, it can be debilitating. While the causes of SLE are still unknown, it does appear to have a genetic component—for example, in the U.S., SLE is more common in some ethnic groups than others, including people with African ancestry. However, for unclear reasons, SLE and other autoimmune disorders are less common in Africa, suggesting that other factors alter the immune system to decrease the risk of autoimmune disorders there. Participants in the Mali study with high levels of autoantibodies had no symptoms of SLE or other autoimmune disorders.

When the researchers tested autoantibodies from people in the United States with SLE, they reacted to malaria parasites similar to the autoantibodies from the Malian study participants. These findings suggest that the overactive immune response that contributes to SLE may have evolved to defend against malaria. Even though many people with SLE today will never encounter a malaria-carrying mosquito, they still produce the antibodies that may have helped their ancestors survive malaria.

Reference:

Hagadorn, K et al. Autoantibodies inhibit Plasmodium falciparum growth and are associated with protection from clinical malaria. Immunity. DOI: https://doi.org/10.1016/j.immuni.2024.05.024 (2024)
 

An HIV drug that suppresses the activity of the CCR5 receptor—a collection of proteins on the surface of certain immune cells—was associated with better renal function in kidney transplant recipients with HIV compared to people who took a placebo in a randomized trial. Study participants taking the drug, called maraviroc, also experienced lower rates of transplant rejection than those taking placebo, but the difference was not statistically significant due to lower-than-expected rejection rates across the entire study population. The findings of the NIAID-sponsored trial were presented today at the 2024 American Transplant Congress in Philadelphia. 

The CCR5 receptor helps HIV enter CD4+ T cells. Some people have a genetic mutation that prevents the CCR5 receptor from working, and either cannot acquire HIV or experience slower HIV-related disease progression if living with the virus. It has separately been observed that people with the same CCR5 genetic mutation have better outcomes following kidney and liver transplantation. The CCR5 antagonist class of antiretroviral drugs was developed to mimic the naturally occurring CCR5 mutation and is a well tolerated component of HIV treatment, but the drugs have not been evaluated as an intervention to improve transplantation outcomes in people. Furthermore, transplant recipients with HIV more frequently experience transplant rejection and elevated CCR5 activity than transplant recipients without HIV.

A research team led by the University of California San Francisco conducted a U.S.-based Phase 2 trial to assess the safety and tolerability of the CCR5 antagonist maraviroc given daily from the time of transplant onward among kidney transplant recipients, and to compare renal function of people taking daily maraviroc to those taking a placebo one year (52 weeks) post-transplant. All study participants were living with HIV and were virally suppressed on antiretroviral therapy (ART) regimens. The study randomized 97 participants to receive maraviroc or a placebo in addition to their continued ART regimens post-transplant. Of them, only 27 participants were able to complete all necessary study examinations through 52 weeks due to logistical complications from the SARS-CoV-2 pandemic. At one-year post-transplant, the mean estimated glomerular filtration rate—a measure of how well kidneys were working—was significantly higher in participants receiving maraviroc in addition to their ART regimen compared with participants receiving ART and placebo (59.2 versus 49.3 mL/min/1.73m²). The drug was safe and well tolerated. 

Four of the 49 participants taking maraviroc and 6 of the 48 participants taking placebo experienced transplant rejection, but this difference was not statistically significant given the relatively small sample size. Transplant rejection rates were lower than expected across both study groups, which the study team suggests may be a favorable outcome of the ART regimens most participants were taking. 

The addition of maraviroc significantly improved renal function in kidney transplant recipients with HIV compared to placebo. According to the authors, these findings warrant further exploration of the benefit of CCR5 antagonists in all kidney transplant recipients regardless of HIV status.

For more information about this study, please visit ClinicalTrials.gov and use the identifier NCT02741323.

Reference:

Brown et al. Beneficial Impact of CCR5 Blockade in Kidney Transplant Recipients with HIV. American Transplant Congress in Philadelphia, Pennsylvania. Tuesday, June 4, 2024.