Essay: Cells activating and regulating immune responses

Background
In the last half-century, researchers have made significant contributions to understanding the mechanisms and identifying the cells responsible for activating and regulating immune responses. Early immunological models were primarily based on studies conducted on human and mice populations, though research on the immunology of avian species has increased as their immune system contrasts that of other vertebrate species (Schat et al., 2013). The co-evolutionary relationship between birds and parasites has enabled birds to develop a diverse set of molecules called major histocompatibility molecules that play a crucial role? in recognizing and eliminating these constantly-changing pathogens. The discovery of major histocompatibility complex (MHC) genes has allowed researchers to examine whether the presence of certain MHC alleles impacts an individual’s fitness, measured by an increase in resistance of susceptibility to parasites.
MHC genes code for proteins called MHC molecules that are expressed on the surface of cells. MHC molecules display peptide fragments of antigens in the peptide-binding region, which can be recognized by other cells in the immune system. There are two major classes of MHC molecules, Class I and Class II, that can specifically activate T-cells of the adaptive immune system. MHC class I molecules are found on the surface of all nucleated cells and present peptide fragments of endogenous pathogens to cytotoxic T-cells. Once activated, cytotoxic T-cells can specifically target and eliminate pathogens (Zinkernagel, 1979). MHC genes are highly polymorphic and are capable of producing diverse molecular structures that determine what pathogenic peptides can be presented on MHC molecules, and ultimately what pathogens T-cells will be able to eliminate (Bonneaud et al., 2007).
Earlier research in the field of avian immunology sought to find associations between the presence of specific MHC alleles and the status of infection in malaria-infected passerine species. In the following experiments, researchers genetically screened populations of wild birds at a specific locus that plays a role in creating the diversity in the peptide-binding region in MHC class I molecules.
In 2006, Bonneaud et al. compared variations in MHC class I alleles between two populations of geographically separated House Sparrows (Passer domesticus). Since red blood cells of birds are nucleated, MHC class I molecules are found on the cell surface, making it a target for haemosporidian parasites, Plasmodium, that causes avian malaria. Bonneaud et al. discovered the presence of specific alleles found in both populations that were associated with an increase in resistance in some individuals and greater susceptibility in others (Bonneaud et al., 2006).
Similarly working with House Sparrows, Loiseau et al. showed that alleles associated with increased susceptibility can remain in a population if there is an advantageous antagonistic outcome. In their experiment, they discovered an allele from exon 3 of the MHC class I gene that correlated to susceptibility to one strain of malaria, but protection from another strain of malarial parasites (Loiseau et al., 2008). Loiseau et al.’s findings suggest that the genetic variations of the MHC class genes can lead to varying fitness outcomes.
These earlier works that found associations between MHC alleles and differences in fitness outcomes provide a qualitative basis for resistance, though in more recent research, the quantitative aspect is incorporated. To further understand the complexity of MHC genes and their interactions with parasites, the intensity of the infection should be measured in addition to its prevalence. In 2011, Westerdahl et al. provided a framework that takes into account a quantitative basis for disease resistance, by measuring the number of parasites in red blood cells, allowing them to quantify the infection intensity. By adding data on infection intensity to infection status, Westerdahl et al. were able to argue that the existence of a malaria strain in an avian host does not automatically mean it is associated with a susceptibility allele. Instead, this created a situation where MHC alleles can be associated with an increase in resistance if there are low levels of parasites, a low infection intensity, despite the positive status of parasites in the host (Westerdahl et al., 2011).
In their study on a population of Great Reed Warblers, Westerdahl et al. gathered data that followed the model for quantitative disease resistance. Compared to previous research that discovered MHC allele associations with prevalence of malaria, Westerdahl et al. found an allele in Great Reed Warblers that exhibited a high level of prevalence for disease, but low levels of intensity, suggesting that the allele conferred quantitative resistance to the disease (Westerdahl et al., 2011). This finding contributes to the diverse polymorphism of MHC genes by adding a level of compromise between resistance and susceptibility.
Recent Advances
Building on Westerdahl et al.’s research that included a quantitative basis for resistance and susceptibility, Rivero-de Aguilar et al. measured parasite prevalence, infection intensities, and screened MHC class I alleles in young and old populations of Blue tits (Cyanistes caeruleus) in central Spain. Rivero et al. employed similar methods that were used in earlier research that discovered associations between MHC class I alleles and resistance or susceptibility. They quantified the level of infection to the parasitic strains Haemoproteus and Leucocytozoon, and developed four hypotheses. The team hypothesized that a specific MHC class I allele is responsible for either total resistance or susceptibility, a MHC class I resistant allele that correlates with low infection intensity, or a MHC class I susceptibility allele that correlates with high infection intensity (Rivero-de Aguilar, 2016).
Rivero-de Aguilar et al. not only found a quantitative resistance or susceptibility to malaria strains, but they were also able to find another factor that can potentially impact the fitness of bird populations, age (Rivero-de Aguilar, 2016). Specifically, young birds with a specific MHC class I allele exhibited lower levels of infection intensity compared to birds of similar age without the allele (Rivero-de Aguilar, 2016). Similarly, adults with certain alleles were less intensely infected than their younger counterpart with the same allele. This research provides advancements to avian immunology as the researchers were able to find age-related differences in conferred protection and susceptibilities within the blue tit population by utilizing methods that studied both qualitative and quantitative bases for resistance.
Future Directions
The discovery of MHC molecules first in chickens and later in other avian species has led to many advancements to the field of avian immunology as well as to the broader field of vertebrate immunology. By first investigating the genetic basis that determines what pathogens MHC molecules can recognize, associations can be made whether specific MHC alleles can lead to increased resistance or harm from parasites.
In the previously mentioned experiments, the primary population that were genetically screened for MHC alleles and screened for parasitic infection levels were individuals in the population that had survived the malarial infections. Westerdahl et al. and Loiseau et al. mentioned that this may lead to a misinterpretation of allele frequency among the entire population because those sampled are the ones who have made it past the acute infection phase (Westerdahl et al., 2011, Loiseau et al., 2008). Parasitic infections typically matriculate in multiple stages, an acute phase where the most damage is done, and a later chronic phase. The early death of individuals during the acute phase can alter the alleles left in the population, so researchers cannot conclude that the alleles present are totally resistant or susceptible.
Though many works have shown that there is a greater complexity in MHC genes in passerine birds than in non-passerine birds, another factor that can affect the diversity of MHC alleles is the migration behavior of birds. Particularly, migratory birds that are exposed to more parasites from different environments are expected to have a more complex set of MHC alleles that can recognize and protect them from a wider range of parasites, as compared to sedentary species. Previous research has shown that allelic variants can lead to a local adaptation seen by comparing geographically isolated populations, so research between species may pose greater challenges when comparing MHC alleles.
Another direction for future research concerns MHC class II molecules, where researchers have found the genetic marker for the variability of MHC II molecules. MHC II molecules can activate a different set of T-cells which may help to explain the differential outcomes in fitness among populations. The field of avian immunology is multi-layered and complex, though through experiments such as those described in this paper, researchers are able to advance the knowledge and enhance the understanding behind the mechanisms that impact immune systems.