The immune system is our body’s defense against infectious microorganisms. Some of the most important players of the immune system are a group of proteins called MHC molecules. By binding to short fragments of molecules derived from pathogens, they play a crucial role in triggering an immune response. The genes encoding our MHC molecules vary greatly from person to person, and this variation has been linked to several diseases. For example, those carrying certain variants of MHC molecules might be suffering from autoimmune diseases or be more susceptible to certain pathogens.
Intriguingly, MHC molecules also differ in their geographical distributions, with some of them being prevalent in Europe while others are more prevalent in Southeast Asia. Why is this so? An interdisciplinary team of scientists, Máté Manczinger, Balázs Papp, and Csaba Pál from the Biological Research Centre of the Hungarian Academy of Sciences and collaborators in Szeged, Budapest, and Plön, proposed a new hypothesis to explain this variation.
In a nutshell, MHC molecules are known to be either specialists or generalists. The former recognize only a few types of pathogens, while the latter recognize many of them and, hence, can activate the immune response against a wide range of viruses and bacteria. According to their hypothesis, generalist MHC molecules are favored in geographical regions with a high diversity of pathogens (e.g. tropical regions). In contrast, in regions of low pathogen richness, such as in Northern Europe, specialists work well enough to sustain a proper immune defense. By analyzing publicly available data, the researchers showed that generalist MHC molecules are indeed more frequent in geographical regions of high pathogen diversity. This finding suggests that exposure to pathogens was a key driving force in the evolution of the human immune system and it shaped the prevalence of different MHC gene variants across the globe.
But why don’t all of us carry generalist MHC molecules? Researchers speculate that these molecules come at a cost: generalist MHC molecules also likely recognize more non-harmful molecules and proteins made by our own body, potentially leading to allergic and autoimmune diseases. Additionally, recognizing only a limited repertoire of molecules of only a few pathogens – which is the case for specialists – could lead to a more specific and effective immune response and might be beneficial under certain conditions. Thus, the prevalence of a particular MHC variant depends on its benefits and drawbacks, which in turn depends on the richness of pathogens in the environment.
The study will likely encourage researchers to revisit some of the key issues in immunology and genomics. For example, the genes encoding MHC molecules are the most variable regions in the human genome. Thus, different individuals of human populations carry thousands of different MHC variants. What shapes this huge genetic variation? The authors speculate that the geographic distribution of generalist MHC molecules could have a substantial impact on the genetic diversity of MHC genes, which is an interesting area of future research. In a similar vein, the diversity of MHC-encoding genes is associated with olfaction-based mate choice in human and other animals. Accordingly, it will be interesting to see whether generalist and specialist MHC molecules play a role in mating success.
Finally, genetic variation within particular MHC genes influences vaccine efficacy, rejection rates of transplanted organs, and anticancer immunity. Generalist and specialist MHC molecules could have a hitherto unrecognized impact on these immune processes. Clearly, a better understanding of the causes and consequences of genetic variation in MHC molecules will also help clinicians to customize treatment to an individual’s genetic makeup.
These findings are described in the article entitled Pathogen diversity drives the evolution of generalist MHC-II alleles in human populations, recently published in the journal PLOS Biology. Csaba Pál and Máté Manczinger contributed to this research and article as PI and postdoc, respectively at the Institute of Biochemistry, Biological Research Centre.