#histocompatibility

Precision in Transplantation: Navigating the HLA Typing for Transplant Market

A Tool to Simulate Immune Response to Biologics Developed by FDA

By compiling and analysing a large database of MHC allotype frequencies from human populations worldwide, we were able to confirm and expand previous findings (Prugnolle et al. 2005b). Diversity at all three class I MHC loci was shown to be affected both by ancient demography and pathogen-driven selection. Furthermore, the use of sequence-based measures of diversity provides evidence for past coevolution between HLA-C and KIR.

The unprecedented genetic diversity found at vertebrate MHC (major histocompatibility complex) loci influences susceptibility to most infectious and autoimmune diseases. The evolutionary explanation for how these polymorphisms are maintained has been controversial. One leading explanation, antagonistic coevolution (also known as the Red Queen), postulates a never-ending molecular arms race where pathogens evolve to evade immune recognition by common MHC alleles, which in turn provides a selective advantage to hosts carrying rare MHC alleles. This cyclical process leads to negative frequency-dependent selection and promotes MHC diversity if two conditions are met: (i) pathogen adaptation must produce trade-offs that result in pathogen fitness being higher in familiar (i.e., host MHC genotype adapted to) vs. unfamiliar host MHC genotypes; and (ii) this adaptation must produce correlated patterns of virulence (i.e., disease severity).

Genome-wide variation from the HapMap European American dataset are compatible with the hypothesis of MHC-dependent mate choice, which adds to previous evidence of MHC-disassortative mating among Hutterites 14. These findings do not imply that the MHC influences mate choice in every human population, but rather that its influence may be restricted to certain populations, depending on the importance of socio-cultural factors, the level of genetic diversity and the strength of pathogenic pressures. Hopefully, future studies, based on larger datasets, may help untangle the relative importance of both socio-cultural and biological factors in shaping the human genome.

Both classical mechanisms of parasite-mediated balancing selection can drive the evolution of MHC introgression: negative frequency-dependent selection and heterozygote advantage. Assuming the first mechanism, if a resistance allele exists in one species, introgressing it into the second species may confer a longer-term advantage. This is because it will have already been tested by selection in the first species, but will be rare by definition in the second. This MHC allele may then confer a selective advantage until the frequency increase of this allele causes prevalent parasites of the second species to counter adapt. Under heterozygote advantage, it becomes clear that maintaining the possibility of introgression allows the newt species to maintain larger inter- and intraindividual MHC diversity and therefore increases the possibility for individuals to fight a broader range of parasites and pathogens. Both mechanisms would result in higher survival and reproductive output of locally adapted individuals allowing introgressed MHC alleles to be maintained in the species’ populations. In this context, it is remarkable to note that Lm showed higher allelic richness probably resulting from directional introgression from Lv to Lm. It is also interesting to speculate about the potential adaptive reasons for this pattern of directional introgression. Obvious candidates are higher parasite richness or different genomic architecture (i.e. lower number of loci) of Lm that could potentially change the trade-off between immunogenetic diversity and auto-immunity (Woelfing et al. 2009) into a trade-off between immunogenetic diversity and cost of hybridization.

Here we show in six experimental populations of sticklebacks, each exposed to one of two different parasites, that only those major histocompatibility complex alleles providing resistance to the respective specific parasite increased in frequency in the next host generation. This result demonstrates experimentally that varying parasite selection causes rapid adaptive evolutionary changes, thus facilitating the maintenance of major histocompatibility complex polymorphism.

We organize recent findings from the literature and discuss them in relation to four nonmutually exclusive models wherein MHC functions as a signal of (i) individuality, (ii) relatedness, (iii) genetic compatibility and (iv) quality. We also synthesize current mechanistic studies, showing how knowledge about the molecular basis of MHC signaling can lead to elegant and informative experimental manipulations. Finally, we discuss current evidence relating to the primordial functions of the MHC, including the possibility that its role in social signaling may be ancestral to its central role in adaptive immunity.