New evidence has been discovered by biologists at the University of Utah as to why people, mice and other vertebrate animals carry thousands of different genes to create major histocompatibility complex (MHCs) proteins, despite the fact that some of those genes make humans vulnerable to autoimmune diseases and infections. Findings from the study will be published online the week of February 6, 2012, in the journal Proceedings of the National Academy of Sciences.

MHC proteins are found on the surface of most cells in vertebrates and define an individual’s tissue type. MHC proteins control the immune system through recognition of “self” and “non-self” and trigger an immune response against foreign invaders. MHCs reject or accept transplanted organs, recognize invading germs, and play a role in helping individuals smell compatible mates. Invertebrates don’t have MHCs.

Biology Professor and senior author of the study, Wayne Potts, explained:

“This study explains why there are so many versions of the MHC genes, and why the ones that cause susceptibility to disease are being maintained and not eliminated. They are involved in a never-ending arms race that causes them, at any point in time, to be good against some infections but bad against other infections and autoimmune diseases.”

The researchers discovered the new evidence for the arms race between genes and germs (antagonistic coevolution) by allowing a disease virus to progress rapidly in mice.

The study was conducted by Potts and first author and former doctoral student Jason Kubinak, now a postdoctoral fellow in pathology. Other researchers include biology doctoral student James Ruff, biology undergraduate C. Whitney Hyzer and Patricia Slev, a clinical assistant professor of pathology. The National Science Foundation and the National Institute of Allergy and Infectious Diseases funded the study.

The majority of genes in humans and other vertebrate only have 1 or 2 varieties or variants of a single gene (alleles). Although individuals carry no more than 12 alleles of the 6 human MHC genes, the varieties of each of the 6 human genes that generate MHC proteins ranges from hundreds to 2,300 in the human population.

Kubinak explains:

“The mystery is why there are so many different versions of the same [MHC] gene in the human population,” especially as the majority of individuals carry MHCs that make them vulnerable to several pathogens, including malaria, hepatitis B and C, the AIDS virus, as well as autoimmune diseases, such as lupus, multiple sclerosis, type 1 diabetes, rheumatoid arthritis, ankylosing spondylitis, and irritable bowel disease.

Researchers have come up with three theories as to why so many MHC gene variants exist in vertebrate animal populations. According to the researchers all three theories contribute to maintaining the enormous variety of MHCs:

Prior studies suggest that individuals and other animals are attracted to the scent of possible mates with MHCs that are “foreign” rather than “self”. Parents with different MHC variants produce children with more MHCs, creating stronger immune systems.

Organisms with fewer MHC varieties have weaker immune response than an organism with more varieties. Over time, organisms with more MHCs are more likely to survive. This theory however, cannot explain the full extent of MHC diversity.

Kubinak explains:

“We have an organism and the microbes that infect it. Microbes evolve to better exploit the organism, and the organism evolves better defenses to fight off the infection. One theory to explain this great diversity in MHC genes is that those competing interests over time favor retaining more diversity.”

Kubinak explains:

“You naturally keep genes that fight disease. They help you survive, so those MHC genes become more common in the population over time because the people who carry them live to have offspring.”

Pathogens are disease-causing viruses, parasites or bacteria that are able to infect animals. Once an animal is infected, it defends itself with MHCs that identify the invader and activate an immune response to kill the foreign pathogen.

However, some pathogens mutate and evolve over time to become less identifiable by the MHCs, and thus avoid an immune response, allowing the pathogens to thrive. MHCs incapable of fighting germs become less prevalent as they now predispose individuals who carry them to get sick and potentially die. Researchers believed that such disease-vulnerability MHC genes eventually should disappear from the human population, however, they generally do not.

Although some of those MHCs vanish, others do not. This is due to two reasons:

  • Some rare MHCs can produce an effective immune response against different microbes.
  • Some now-rare MHCs regain an ability to identify and fight the same germ that previously defeated them (after that germ mutates yet again) as they are no longer targeted by evolving microbes.

In the study, the team examined 60 mice that were genetically identical. The researchers divided the mice into three groups, each with a different variety of MHC genes – b, d and k.

The researchers infected two mice from each of the three MHC types with a mouse leukemia virus named Friend virus. Friend virus was grown in tissue culture. The rapidly progressing virus grew within the mice for 12 days, attacking, replicating and enlarging within the liver and spleen. The researchers gathered virus particles in the spleen and measured the severity of the illness by weighing the enlarged spleen.

The researchers then infected another three pairs of mice with the same MHC types (b, d, and k) from the virus taken from each of the first three pairs of mice. The team repeated this process until 10 pairs of mice in each MHC type were infected, giving the virus time to mutate.

The researchers demonstrated that they could get the Friend virus to adjust to and therefore avoid the MHC variants (b, d, or k) in the mouse cells it attacked.

Following this, the team demonstrated that the virus adjusted only to certain MHC proteins. For instance, viruses that adjusted to and sickened mice with the MHC type b protein still were attacked effectively in mice that had type d and k MHCs.

Furthermore, the biologists demonstrated that pathogen fitness (measured by the number of virus particles in the spleen) was associated with pathogen virulence (as measured by spleen enlargement and thus weight). So the virus that avoided MHC type b made mice with that MHC more ill.

Potts explains:

“Together, the experiments demonstrate the first step in the antagonistic coevolutionary dance between a virus and MHC genes.”

The following findings have some important implications says Potts:

  • Endangered species have less genetic diversity, making them more susceptible for germs as their populations are diminished. According to Potts it would be desirable to breed protective MHCs back into endangered species to boost their disease defenses.
  • The main reason human diseases are increasingly resistant to antibiotics is because antibiotics are used to increase productivity in dairy herds and other livestock. Genetic diversity in livestock, including their MHCs, has been reduced to do selective breeding to produce more milk and beef. Thereby breeding more MHCs back into herds may boost their resistance to disease and therefore reduce the need for antibiotics.
  • In individuals and other organisms, genetic MHC variation is important for preventing evolution and spread of emerging disease. Potts and his team developed emerging diseases by making virus evolve in mice. “It’s a model to identify what things change in viruses to make them more virulent and thus an emerging disease.”

Written by Grace Rattue