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Title: FcγRIIIa : tissue distribution and regulation of expression
Author: Bhatia, Ajay Singh
ISNI:       0000 0001 3463 1511
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2001
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FcγRIIIa is an IgG Fc receptor described on large granular lymphocytes, natural killer cells, approximately 5 percent of peripheral blood monocytes (Ravetch J V, Kinet J P et al, 1991), macrophages in the synovial intima of adult synovium, macrophages in dermis exposed to mechanical stretch (Edwards J C W, Blades S et al, 1997) and on Kupffer cells within normal liver tissue (Tuijnman W B, Van Wichen D F et al, 1993). The expression of FcγRIIIa by macrophages in other normal human tissues has been poorly documented. Small immune complexes are present in the sera of patients with rheumatoid arthritis (Mannik M, Nardella F A, 1985). These complexes fix complement poorly (Brown P B, Nardella F A et al, 1982) and are small enough to be expected to pass through vessel walls and access tissue macrophages. The prominent expression of FcγRIIIa on synovial intimal macrophages first led to the hypothesis that inflammation in rheumatoid arthritis might be due to an interaction between small complexes and FcγRIIIa. The cross-linking of 2 or 3 FcγRIIIa but not FcγRI or FcγRIIa receptors with respective anti-FcγR monoclonal antibodies results in the release of TNF-α, IL1-α and reactive oxygen species from mature macrophages in vitro (Abrahams V M, Cambridge G et al, 2000). Binding of small immune complexes to FcγRIIIa on macrophages with release of proinflammatory cytokines would explain inflammation in rheumatoid disease, but only if the tissue distribution of FcγRIIIa proved to be consistent with the clinical picture. The first aim of this study was to assess the distribution of FcγRIIIa in a range of normal human tissues using immunohistochemical techniques. FcγRIIIa expression in normal human tissues was assessed semiquantitatively using microdensitometry. Results from these experiments revealed high levels of FcγRIIIa expression in tissues targeted by rheumatoid arthritis. Factors responsible for the induction of FcγRIIIa on tissue macrophages have not been clearly defined. The second aim of this study was to investigate the factors responsible for the induction of FcγRIIIa on tissue monocyte-macrophages. Rheumatoid arthritis has a predilection for sites where mechanical stretch occurs. These are also sites where FcγRIIIa expression is present. Some cell types release TGFβ in response to mechanical stretch (Riser B L, Cortecs P et al, 1996). TGFβ1 has been reported to selectively induce FcγRIIIa on monocytes in vitro (Welch G R, Wong H L al, 1990). Therefore TGFβ produced as a result of mechanical stretch or mechanical stretch itself might directly induce FcγRIIIa expression on macrophages. Other cytokines, neuropeptides and/or the interaction of monocytes with extracellular matrix proteins might also be responsible for FcγRIIIa induction. To investigate the factors responsible for the induction of FcγRIIIa on tissue monocyte-macrophages, peripheral blood monocytes were isolated from normal donors and cultured on different substrates. The cytokines TGFβ and IL-10 were added to cultured monocytes at a concentration of 10 ng/ml. Stretching experiments were undertaken using the flex I, McKeesport System. Synovial fibroblasts were also subjected to stretch and the resulting conditioned medium was added to cultured monocytes. The induction of FcyRIIIa was assessed by using murine monoclonal anti-FcγRIII antibody 3G8 followed by FACS analysis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Receptors