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Title: The role of FcγRIIb in infection and autoimmunity
Author: Clatworthy, M. R.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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A number of deletions have been identified within regulatory regions of the FcγRIIb gene in autoimmune-prone inbred mouse strains, such as NZB and NOD, which are associated with reduced expression of the receptor on macrophages and B cells. The FcγRIIb gene was sequenced in a number of inbred and wild mouse strains. Surprisingly, the autoimmune-prone FcγRIIblow haplotype predominated in wild mice, suggesting that deficiency of FcγRIIb in the immune response to two important pathogens, Streptococcus pneumoniae and malaria. In pneumococcal infection, unimmunized FcγRIIb-deficient mice show increased bacterial phagocytosis and survival. Similarly, these mice have lower levels of parasitaemia following Plasmodium chabaudi chabaudi infection. In contrast, immunized FcγRIIb-deficient mice challenged with large inocula of Streptococcus pneumoniae showed reduced survival, correlating with increased TNFα production. Therefore FcγRIIb controls the balance between efficient pathogen clearance and the cytokine-mediated consequences of sepsis. This supports the hypothesis that the FcγRIIblow haplotype predominates in wild mice because it confers increased resistance to important pathogens. Thus, autoimmunity may be an unfortunate evolutionary consequence of selecting an immune system that can better deal with infection. A polymorphism of human FcγRIIb has recently been described wit a single amino acid substitution (from isoleucine to threonine) at position 232 within its transmembrane domain (FcγRIIbT232). In several racial groups, the frequency of homozygosity for this polymorphism (T/T) is doubled in SLE patients compared to healthy controls suggesting possible dysfunction of FcγRIIbT232. I investigated the functional consequences of this amino acid substitution. The amino acid substitution appeared to prevent the inhibitory receptor from partitioning into sphingolipid rafts.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available