Genetic variation of innate immune receptor genes in Systemic Lupus Erythematosus

Student thesis: Doctoral ThesisDoctor of Philosophy


Genetic variations within loci encoding cell surface receptors of the innate immune system, such as Complement Receptor 3 (CR3) and Fc gamma Receptors (FcγRs), are strongly associated with Systemic Lupus Erythematosus (SLE). Such genetic associations implicate the functional importance of these receptors in disease pathogenesis.
CR3 (also known as CD18/CD11b) is an integrin receptor found on multiple immune cell types, including monocytes/macrophages, neutrophils, and Natural Killer (NK) cells. CR3 is a promiscuous receptor with many natural ligands, including complement fraction iC3b, ICAM-1, and β-glucan, and functions as a phagocytic receptor, leukocyte adhesion molecule, and immune regulator. ITGAM encodes the α-chain (CD11b) of CR3, and a common polymorphism (rs1143679) within ITGAM, which results in a non-synonymous amino acid substitution (R77H) in CD11b, is robustly associated with SLE (OR=1.76).
In this thesis I demonstrate that the SLE-associated R77H common polymorphism does not affect the cell surface expression of CR3 on ex vivo monocytes and neutrophils in a healthy cohort of European ancestry. Additionally, a collaborative resequencing project identified two case-specific non-synonymous coding variants in ITGAM, which I demonstrate result in the under-functioning of CR3-mediated phagocytosis using an in vitro model. Finally, using a CR3-specific small molecule drug, which has therapeutic potential in inflammatory disease, I observed a CR3-dependent significant reduction in STAT5 phosphorylation following NK cell activation with cytokines.
There are two genetic variants found within the FCGR locus on chromosome 1 which are robustly associated with SLE; homozygosity of the I232T (rs1050501) polymorphism within FcγRIIb (FCGR2B), and decreased gene copy number of FCGR3B. Recent work demonstrated that a consequence of a deletion at the FCGR locus, spanning the entire FCGR3B gene and parts of the upstream FCGR2C and downstream FCGR2B genes, results in ectopic expression of FcγRIIb on NK cells. In this thesis I explored the possibility of a genetic interaction between the two – copy number variation (FCGR3B) and rs1050501 (FCGR2B) - SLE-associated variants, but failed to detect such an effect within the European cohort used.
Date of Award2015
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorTimothy Vyse (Supervisor) & Benjamin Rhodes (Supervisor)

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