Conflict or Consensus? : Democratic consequences of management- and market-oriented reforms in local politics

The question under investigation in this dissertation is whether the management- and market-oriented reforms of public institutions in Sweden of the 1980s and 1990s have affected municipal politics in the direction of more or less conflict. The analysis takes its point of departure from Arend Lijphart’s model of majoritarian versus consensus democracy. Majoritarian democracy refers to a form of democracy in which the central role of electing decision-makers and holding them accountable is emphasized. Majoritarian democracy therefore underlines the importance of conflict in politics. Consensus democracy refers to a form of democracy in which the importance of representing the preferences of political minorities, not only those of the majority, is emphasized. Consensus democracy therefore underlines the concern for consensus between political actors. In this study, four municipalities with different political majorities and reform ambitions within the county of Stockholm were chosen for comparative analysis . The study shows that the reforms in all likelihood have affected the political work in a more majoritarian direction. This applies in particular to the efforts of introducing new forms of management. The political relations have become more conflict-oriented and more coordinated or centralized within each political party and between the parties of a leftist and rightist orientation respectively. The political relations within the municipal committees have also become more conflict oriented, primarily by a more public and pronounced expression of divergent views. These results clearly strengthens the argument in Swedish debate that municipal politics is increasingly becoming more similar to national politics, where it is only the political parties in parliamentary majority that governs public administration. The results of this investigation therefore have implications on the organization of municipal politics in Sweden, as it is currently based on a more consensual form of democracy

Antibody Evolution and Repertoire Development

Antibodies are key players of the immune system in higher vertebrates, which provide a defense against potentially lethal threats from the environment. Besides their importance in the immune defense, antibodies have a great potential as reagents in biological chemistry and diagnostics, and as therapeutic agents against both infectious diseases and cancer. Despite tremendous advances in all fields regarding antibodies, the understanding of the processes that shape antibody responses in vivo is far from complete. In this thesis, which is based on five original papers, I present work that deals with aspects of the evolution of antibodies and the development of antibody repertoires. By analyzing the inherited repertoires of human genes encoding the variable domains of antibodies, I have discovered regions with accumulations of repetitive trinucleotide motifs. These repeats were mainly found in the complementarity determining regions (CDR), and most likely target them with insertions and deletions during the maturation of an antibody response. In order to investigate the functional consequences of such modifications, insertions and deletions were introduced into the CDR of antibody fragments by molecular engineering. The results showed that modifications of this kind are well tolerated in the CDR of the heavy chain, and can be utilized to expand sequence and structure space of an antigen-binding site beyond what is encoded by the germline gene repertoire. Thus, insertions and deletions seem to be an efficient way of expanding antibody sequence and structure space both in vivo and in vitro, and it is conceivable that these modifications can also be used in antibody engineering to create antibodies against specific targets. I have also studied the development of antibodies reactive with a weakly immunogenic epitope on human cytomegalovirus, and what the critical parameters are that determine the neutralizing capacity of such antibodies. The results from these studies showed that the genes encoding one of the two existing human antibodies reactive with this epitope do not have the intrinsic features required for high-affinity interaction with the epitope, as mutations are required at key positions. The poor immunogenicity of this epitope may in fact be a consequence of the lack of an imprinted specificity in the human germline repertoire. Furthermore, the obtained data demonstrated that a divalent antibody format is required for effective virus neutralization via this epitope, and that the neutralizing potential of a repertoire of antibodies reactive with this epitope is determined by the reaction rate kinetics and fine-specificity of the interaction with the epitope. These results provide insights into the development of human antibody repertoires against weakly immunogenic targets, and are also discussed in the context of vaccine development

Uneven distribution of repetitive trinucleotide motifs in human immunoglobulin heavy variable genes

Insertions and deletions of entire codons have recently been discovered as a mechanism by which B cells, in addition to conventional base substitution, evolve the antibodies produced by their immunoglobulin genes. These events frequently seem to involve repetitive sequence motifs in the antibody-encoding genes, and it has been suggested that they occur through polymerase slippage. In order to better understand the process of codon deletion, we have analyzed the human immunoglobulin heavy variable (IGHV) germline gene repertoire for the presence of trinucleotide repeats. Such repeats would ensure that the reading frame is maintained in the case of a deletional event, as slippage over multiples of three bases would be favored. We demonstrate here that IGHV genes specifically carry repetitive trinucleotide motifs in the complementarity-determining regions (CDR) 1 and 2, thus making these parts of the genes that encode highly flexible structures particularly prone to functional deletions. We propose that the human IGHV repertoire carries inherent motifs that allow an antibody response to develop efficiently by targeting codon deletion events to the parts of the molecule that are likely to be able to harbor such modifications

Functional consequences of insertions and deletions in the complementarity-determining regions of human antibodies

Insertions and deletions of nucleotides in the genes encoding the variable domains of antibodies are natural components of the hypermutation process, which may expand the available repertoire of hypervariable loop lengths and conformations. Although insertion of amino acids has also been utilized in antibody engineering, little is known about the functional consequences of such modifications. To investigate this further, we have introduced single-codon insertions and deletions as well as more complex modifications in the complementarity-determining regions of human antibody fragments with different specificities. Our results demonstrate that single amino acid insertions and deletions are generally well tolerated and permit production of stably folded proteins, often with retained antigen recognition, despite the fact that the thus modified loops carry amino acids that are disallowed at key residue positions in canonical loops of the corresponding length or are of a length not associated with a known canonical structure. We have thus shown that single-codon insertions and deletions can efficiently be utilized to expand structure and sequence space of the antigen-binding site beyond what is encoded by the germline gene repertoire