Monday, September 30, 2013

The Power of the MHC

 HLA MHC Complex on

 Human Chromosome 6

Infectious diseases threaten us and our animals on a daily basis. However, inside the human body on chromosome 6, there is a group of genes that is essential for your protection and health. A May 2013 paper by Kubinak et al. examined viral evolution in the context of the major histocompatibility complex (MHC). The MHC is one of the most gene-dense regions in the vertebrate genome (Kubinak et al. 2013). Although in humans, it is only approximately 3600 kb in length, it contains roughly 224 genes, 40% of which have been found to have immunological functions (Garrigan 2003). Therefore, despite making up only 0.1% of the genome, it contains a disproportionate number of genes associated with immunity. It is evident that the MHC is crucial to the immune system.

Infectious and autoimmune diseases have been correlated to polymorphisms within the MHC. Polymorphisms are defined as different alleles of a gene existing in a population. The high levels of polymorphisms in the MHC are suggested to be due to co-evolution between host genotypes and pathogens. In other words, the “pathogen bad guys” evolve to avoid detection by the “good guys” in our bodies. The “good guys” respond though a process by which MHC genes encode cell surface proteins which bind and present peptide antigens (in the form of peptide MHC complexes) to T cells. A T cell mediated immune response (“good guys” spring into action) is then triggered if the antigen is recognized as foreign. Specifically, pathogen adaptation and virulence evolution seem to be locked in a battle with polymorphic antigen-presenting MHC genes for control of the health of the human body. It is primarily the interaction effect between the virus genotype and the host genotype that dictates variation in viral fitness and virulence, not the individual effects of virus genotype or host genotype (Table 1). This leads to specialization between a particular pathogen and host genotype.

General Overview of MHC Function

A key technique used in this paper is serial passage. In this context, passage refers to the introduction of an infectious agent followed by recovery. Serial passage is defined as repeated passage, generally with the purpose of altering the virulence of the agent. Serial passage was performed in this experiment using the Friend virus (FV) complex to examine pathogen/MHC variability co-evolution and how these adaptations can lead to fitness tradeoffs between new pathogens or new MHC polymorphisms. For example, a pathogen may evolve (becomes specialized) to overcome a particular MHC polymorphism very well, but will respond poorly to other polymorphisms. This study found that serial passage of FV complex resulted in significant increases in pathogen fitness and virulence, indicating that the virus was adapting to the same MHC polymorphisms (Figures 1 & 2). However, novel MHC polymorphisms led to decreases in viral fitness and virulence, suggesting that a virus, although adapted to one polymorphism well, was poorly adapted to a new one (Figure 3). This process is comparable to how in a soccer game, you may develop one style of play that is very effective at beating a certain team, yet works very poorly against another team that plays the game differently. If the teams play each other multiple time, each will be continuously trying to adapt their style of play to put them in a better position to beat the other.
Schematic of a Single
 Nucleotide Polymorphism 
Experiments were performed using mice with three different genotypes (A/WySn, DBA/2J, and BALB/c). MHC polymorphisms alone were found to account for 71% and 83% of the total observed reductions in viral fitness and virulence in unfamiliar host genotypes, respectively (Kubinak et al. 2013). This data was obtained by comparing fitness and virulence tradeoffs incurred by adaptive viruses that were exposed to hosts with novel MHC polymorphisms alone versus hosts possessing novel MHC and non-MHC polymorphisms. This experiment allowed us to estimate the relative additive effect of non-MHC gene polymorphisms on fitness tradeoffs. It demonstrates that novel MHC polymorphisms alone were able to account for the majority of fitness and virulence tradeoffs, while non-MHC polymorphisms had minor effects. To continue the soccer analogy, novel MHC polymorphisms are like adding some new talented players to the team with a different style of play that the pathogens aren’t used to, while altering non-MHC polymorphisms has a minimal effect and could be equated to the team switching from white jerseys to black jerseys in the hope that they would be more intimidating to the pathogen. These findings highlight the importance of genetic polymorphisms within the MHC for mitigating pathogen adaptation and virulence evolution.
This study illustrated that pathogens and hosts evolve together and become specialized. If only one evolves, it can overcome the other. The themes of this study tie into the fact that the secondary immune response is more efficient than the primary immune response, since an immunological memory has already been established and antibodies (IgG, IgA, IgE) can be produced immediately. However, the key point of this study was the striking importance of the MHC for immunity despite representing such a small part of the genome. As the global population continues to grow, it will be essential to limit exposure to diseases to avoid a plague. This study demonstrates the importance of genetic variation in the MHC as a deterrent to pathogens. As pathogens develop antimicrobial resistance, we must develop alternatives to control rapidly evolving pathogens. This paper suggests that introducing MHC variation could be a potential solution.

Further studies could more definitely measure the contribution of MHC polymorphisms versus non-MHC polymorphisms in terms of their influence on pathogen adaptation and virulence evolution. Studies could also look into the impacts of different viruses/pathogens on different organisms. The paper mentioned that commercial livestock facilities with closely related animals in close proximity to each other might be a possibility. Introducing MHC variation could be a solution to control rapidly evolving pathogens. For now, the evolutionary arms race between the host and the pathogen will continue. We should continue to investigate MHC polymorphisms. It raises the interesting point as to whether we could genetically alter the MHC to better protect ourselves from diseases. This would likely spark an ethical debate.

Primary Reference:
Kubinak, J.L., Ruff, J.S., Cornwall, D.H., Middlebrook, E.A., Hasenkrug, K.J., & Potts, W.K. (2013).
Experimental viral evolution reveals major histocompatibility complex polymorphisms as the primary host factors controlling pathogen adaptation and virulence. Genes and Immunity, 14, 365-372.
Link to paper:
Secondary Reference:
Garrigan, D.H.P. (2003). Perspective: Detecting adaptive molecular polymorphism: lessons from the MHC. Evolution, 57, 1707-1722. 
HLA MHC Complex on Human Chromosome 6:
General Overview of MHC Function:
Schematic of a Single Nucleotide Polymorphism:
Host/Pathogen Arms Race:

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