CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.
“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.
To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.
Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R2 = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R2 = 0.78).
In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.
Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.
To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
Understanding the impact of measles on the immune system
“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.
Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.
More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.
“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”
The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.
SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.