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

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.1. Summary 5 2. Deutsche Zusammenfassung 7 3. Introduction 9 3.1 The adaptive immune system 9 3.1.1 An introduction from a theoretical perspective 9 3.1.2 Initiation of a response of the adaptive immune system 10 3.1.3 αß T-cell maturation 10 3.1.4 Types of errors in the detection system of the adaptive immune system 11 3.2 Evolutionary ecology of the MHC 11 4. Parameter estimates and scenario to be modelled 17 4.1 Quantitative estimates of positive selection efficiency 17 4.2 Quantifying negative selection 21 4.3 Estimates for other parameters 26 5. The model 27 5.1 Model development 27 5.2 Evaluation of the model 28 5.3 Comparison with other models 31 5.3.1 Model by Nowak et al. (1992) 31 5.3.2 Model by Borghans et al. (2003) 32 5.3.3 Model by DeBoer and Perelson (1993) 35 6. Other processes influenced by MHC diversity 37 6.1 Risk of autoimmune diseases 37 6.2 Level of antigen presentation 39 7. Outlook: Experimental test of the model predictions 43 7.1 Testable hypotheses and outline of experimental approach 43 7.2 Methods 45 7.2.1 Sectioning 45 7.2.2 Staining 45 7.2.3 Identification of genes of the adaptive immune system in Gasterosteus aculeatus 47 7.3 Results and discussion 47 7.3.1 Histological identification and characterization of the thymus 47 7.3.2 Identification of genes of the adaptive immune system in Gasterosteus aculeatus 52 8. Conclusion 55 9. Literature 57 10. Danksagung 65 11. Stellungnahme 6