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Why do jawed vertebrates have intermediate numbers of MHC molecules? - A modelling approach

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons57009

Wölfing,  Benno
Department Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons56825

Milinski,  Manfred
Department Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Max Planck Society;

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woelfing_diplom.pdf
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Citation

Wölfing, B. (2007). Why do jawed vertebrates have intermediate numbers of MHC molecules? - A modelling approach. Diploma Thesis, Christian-Albrechts-Universität, Kiel.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000F-D76A-B
Abstract
The major histocompatibility complex (MHC) is famous for containing the most polymorphic loci in the genome of jawed vertebrates. Immunological research has centered on the MHC, because a response of the adaptive immune system usually can only be initiated if a MHC molecule binds a peptide derived from a pathogen and if the resulting peptide-MHC complex is recognized by a T-cell. Given that each MHC molecule type can only present peptides that match its peptide-binding groove, it seems advantageous for an individual to express many different MHC molecules so that any foreign peptide can be presented and consequently every pathogen be attacked. Therefore the question arises why each individual only expresses an intermediate number of different MHC molecules that pales into insignificance beside the extensive diversity of MHC alleles at the population level. In this thesis selection pressures that may set an upper limit to intraindividual MHC diversity are discussed. MHC molecules do not only present foreign peptides but also self-peptides, so that T-cells which recognize self-peptide – MHC complexes have to be eliminated during their maturation in order to avoid autoimmune diseases. Increasing intraindividual MHC diversity is therefore expected to lead to an increased loss of mature T-cells, entailing reduced immunocompetence. While some existing models suggest that this rational can explain why individuals usually do not have more than 20 MHC class I and II alleles, other models conclude that different explanations must be true. Based on findings of recent experimental studies I develop a new model and conclude that the number of MHC alleles present in individuals may be optimal to balance the advantages of presenting an increased range of peptides and the disadvantages of an increased loss of T-cells. How the model predictions can be tested on threespined sticklebacks (Gasterosteus aculeatus) is shown in the outline of an experimental approach, which may allow to directly measure TCR repertoire diversity before and after negative selection. A better understanding of the stickleback adaptive immune system is a precondition for this experiment. The stickleback thymus – which so far has only been mentioned in a brief communication by Bigaj et al. (1987) – has been clearly identified and characterized in this thesis.