Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease of elusive origin and characterised by polyclonal B cell hyperactivity and the production of pathogenic antibodies targeting self DNA and nucleoproteins. Clinical manifestations of SLE are highly heterogeneous and include multisystem inflammation of connective tissue and vasculitis of the central nervous system (CNS). SLE is known to have genetic associations, and is widely acknowledged to involve a profound breakdown in immune tolerance. The aim of this project was to identify whether defects in early B cell development that affect the expressed repertoire of immunoglobulin light chains could be observed and to ask whether receptor editing contributes to disease pathogenesis. Chapter 3 describes a high-throughput sequencing analysis of the human immunoglobulin kappa light chain gene repertoire in healthy and SLE mature naive peripheral B cells. We observed that involvement of gene segments as the repertoire develops is equivalent in health and SLE and that a previously described bias towards usage of the gene segment IGKV4-1 in SLE is only observed in the expressed repertoire analysed. Chapter 4 describes an inefficient function of the kappa deleting element (KDE) in SLE, which manifests as reduced frequency of KDE rearrangement status in populations of CD19+ B cells and a failure to inactivate alleles of IGK allowing them to accumulate somatic hypermutations within non-productive IGK rearrangements. Chapter 5 identifies a potential biological outcome of a failure to inactivate rearranged alleles of IGK in SLE; cell surface expression of both kappa and lambda light chains were observed by flow cytometry analyses. Efforts to disprove this were unsuccessful anddetection of both light chain transcripts was confirmed through single cell PCR amplification of cDNA. The data in this thesis suggest that the failure of the KDE to inactivate alleles of IGK efficiently in SLE permits the expression of IGK light chains that have been selected against resulting in allelic inclusion. This mechanism may account for the broader and less stringently regulated antigen-binding B cell repertoire associated with SLE.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:631334 |
| Date | January 2013 |
| Creators | Fraser, Louise |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/immunoglobulin-light-chains-in-systemic-lupus-erythematosus(759b46c1-24bc-427d-8b25-8987eec6f61f).html |
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