Individual differences in the human immune system are mostly due to environmental influences, which tend to outweigh hereditary influences, with the imbalance between the two becoming more lopsided as we age. Ordinarily, environmental and hereditary contributions are so entangled that they cannot be neatly separated and “put on the scales.” Yet even with something as complex and as variable as the immune system, an old trick sufficed: a study of twins.

At the Stanford University School of Medicine, scientists led by Mark Davis, Ph.D., compared pairs of monozygotic (identical) twins and dizygotic (fraternal) twins. Monozygotic twins inherit the same genome. Despite inevitable copying errors when cells divide, which cause tiny genetic divergences to accumulate between monozygotic twins over time, they remain almost 100% genetically identical. Dizygotic twins are no more alike genetically than regular siblings, on average sharing 50% of their genes.

Because both types of twins share the same environment in utero and usually share the same environment in childhood, they make excellent subjects for contrasting hereditary versus environmental influence. More than 200 healthy twins between 8 and 82 years of age were assessed in the current study, the results of which appeared January 15 in the journal Cell, in an article entitled, “Variation in the Human Immune System Is Largely Driven by Non-Heritable Influences.”

“We measured 204 different parameters, including cell population frequencies, cytokine responses, and serum proteins, and found that 77% of these are dominated (>50% of variance) and 58% almost completely determined (>80% of variance) by nonheritable influences,” wrote the authors. “In addition, some of these parameters become more variable with age, suggesting the cumulative influence of environmental exposure.”

Nonheritable influences included previous microbial or toxic exposures, vaccinations, diet, and dental hygiene. For example, Dr. Davis and colleagues observed considerable environmental influence over the quantities of antibodies produced in members of twin pairs who had been vaccinated for influenza in a separate Stanford investigation directed by study co-author Cornelia Dekker, M.D. While many previous studies have suggested a powerful genetic component in vaccine responsiveness, Dr. Davis noted that those studies typically were performed in very young children who had not yet undergone the decades of environmental exposure that appears to reshape the immune system over time.

The scientists also found that immune system plasticity could be profoundly influenced by the presence or absence of a single chronic infection: “In monozygotic twins discordant for cytomegalovirus infection, more than half of all parameters are affected.”

The results of this study may help explain why so few individual genetic variants have been shown to contribute much to particular health conditions. “The idea in some circles has been that if you sequence someone’s genome, you can tell what diseases they’re going to have 50 years later,” said Dr. Davis, who is a professor of microbiology and immunology and director of Stanford's Institute for Immunity, Transplantation, and Infection. He added that while genomic variation clearly plays a key role in some diseases, the immune system has to be tremendously adaptable in order to cope with unpredictable episodes of infection, injury, and tumor formation.

“The immune system has to think on its feet,” concluded Dr. Davis. “A healthy human immune system continually adapts to its encounters with hostile pathogens, friendly gut microbes, nutritional components, and more, overshadowing the influences of most heritable factors.”