In the orchestra of the immune system, B cells play the antibody part, while the sex chromosomes and gonads act as conductors setting a different tempo. Until recently, scientists could not work out which of them calls the shots: the genes written into the chromosomes, or the hormones produced by the gonads. In a new study in mice, the two influences were separated, and the individual parts became audible.
The experiment used mice of the Four Core Genotype model, in which the SRY gene has been moved from the Y chromosome to another chromosome. This yielded four groups of animals: with XX or XY chromosomes and with ovaries or testes, independently of each other. The mice were crossed with the 5xFAD line, a model of Alzheimer's disease, and at the age of eight months their B cells were examined in the brain and blood.
The loudest chord sounded in mice with the combination of XY chromosomes and ovaries: in their cortex, the levels of IgG and IgM antibodies reached a maximum. This means the inflammatory score is born not from chromosomes or gonads alone, but from the two working together.
When Alzheimer's disease entered the score, the orchestra played differently. Sex differences in the brain were wiped out: nearly all B cells had switched antibody class, as if the general inflammatory noise had drowned out the individual voices. In the blood, by contrast, an unexpected interaction showed up: in mice whose chromosomes and gonads did not match (XX with testes, or XY with ovaries), the share of B1 cells, which respond quickly to a threat, was elevated.
These results change how we look at personalized therapy for Alzheimer's disease. If the inflammatory response of B cells depends on the combination of chromosomes and gonads, then drugs may need to be tuned to that combination as well. The orchestra of immunity does not play from a single score for everyone, and now we have the notes to hear the difference.
Mice with the combination of XY chromosomes and ovaries (a rare pairing made possible by the genetic model) had the highest levels of IgG and IgM in the brain, pointing to strong inflammation.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.