The role of dietary antigens in the pathogenesis of experimental glomerulonephritis

Browning, Michael John (1987) The role of dietary antigens in the pathogenesis of experimental glomerulonephritis. PhD thesis, University of Glasgow.

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Abstract

In this thesis I have investigated the role of dietary antigens in the pathogenesis of experimental glomerulonephritis in mice. I have identified a role of dietary antigens in two forms of glomerulonephritis. Firstly, prolonged oral administration of protein antigen was associated with the induction of glomerular IgA deposition. Secondly, intragastric administration of protein antigen was shown to protect against the subsequent induction of immune complex glomerulonephritis by repeated injections of the same antigen. Prolonged oral administration of bovine gamma globulin (0.1%) in the drinking water of BALB/c mice was associated with the appearance of glomerular deposits of IgA in the kidneys of antigen fed mice. This association was not seen when ovalbumin was administered to the same strain of mouse in the drinking water (0,A05%) or by weekly intragastric intubation to the same total dose. Prolonged oral administration of ovalbumin (0.1% in the drinking water) or of sheep erythrocytes (10 cells per day by intragastric intubation) was not associated with any increase in glomerular deposition of IgA in C3H/HeJ or C3H/HeOla mice. The presence of antigen deposition in the kidneys was not detected in antigen fed mice in any of the above experiments. The role of hepatic sequestration of IgA-immune complexes in glomerular IgA deposition was investigated by the induction of experimental liver damage in mice. The administration of carbon tetrachloride to mice by weekly intragastric intubation was associated with hepatocellular damage and the induction of chronic hepatic fibrosis. There was however, no increase in glomerular IgA deposits in mice with experimentally induced liver damage as compared with controls. Repeated injections of foreign protein antigen induced an immune complex glomerulonephritis characterised by predominantly mesangial deposition of IgG, C3 and the immunising antigen in TO [low], TO [high] and BALB/c mice. Electron microscopy showed mesangial expansion, with large numbers of electron dense deposits in the mesangium and subendothelial space. Intragastric administration of single doses of protein antigen prior to the induction of glomerulonephritis in these strains of mice was associated with a reduction in the incidence and degree of glomerular immune complex deposition. The reduced incidence of immune complex glomerulonephritis was associated in antigen fed animals of all three strains with reductions in the antibody responses to the immunising antigen, and the incidence and degree of glomerular immune complex deposition correlated with the antibody titres. This protection from antigen induced immune complex glomerulonephritis was shown to be specific for the immunising antigen. Further investigation of the specificity of the response using hapten-carrier conjugates indicated that the protective effects of antigen feeding were induced at the level of the carrier protein. The degree of protection from immune complex glomerulonephritis conferred by single intragastric doses of antigen was dependent on the dose of antigen administered. Protection from antigen induced immune complex glomerulonephritis was not transferred by serum collected from donor mice 1 hour after administration of single intragastric doses of antigen. Protection from immune complex glomerulonephritis by antigen feeding was resistant to pretreatment with cyclophosphamide, and was not transferred by spleen cells from syngeneic donor mice rendered tolerant to the immunising antigen by prior intragastric administration of antigen. These results suggested that suppressor T cells did not play a major role in this effect. The model of protection from antigen induced immune complex glomerulonephritis appeared to be related to the phenomenon of oral tolerance induction, which showed a similar dose-dependent relationship with regard to systemic delayed type hypersensitivity and antibody responses. Studies on the induction of oral tolerance in 11 inbred strains of mice showed marked genetic variations in the ease of oral tolerance induction. The roles of both H2 and non H2 genes were implicated in the induction of oral tolerance. Disparate effects of single intragastric doses of antigen administration on the cell mediated and humoral limbs of the immune response were seen in certain strains of mice, suggesting that oral tolerance induction for delayed type hypersensitivity and for antibody responses were under the control of separate mechanisms. Thus a direct role of dietary antigen has been identified in the induction of glomerular IgA deposits, suggesting a possible role of dietary antigens in the pathogenesis of IgA nephropathy. In addition, antigen ingestion may protect against the induction, by systemic exposure to the same antigen, of immune complex glomerulonephritis. This latter effect appeared to be mediated by an oral tolerance mechanism, acting on the humoral limb of the immune response. The exact nature of this mechanism, however, remains obscure.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Dalphine Parrott
Keywords: Immunology, Pharmacology
Date of Award: 1987
Depositing User: Enlighten Team
Unique ID: glathesis:1987-72637
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Jun 2019 11:06
Last Modified: 11 Jun 2019 11:06
URI: http://theses.gla.ac.uk/id/eprint/72637

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