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Studies of immune mechanisms in myasthenia gravis

thesis
posted on 2024-09-03, 02:56 authored by Biying Xu

Myasthenia gravis (MG) has been considered the prototype of autoantibody-mediated autoimmune diseases. The pathogenic autoantibodies are directed against the acetylcholine receptor (AChR). Several mechanisms by which these antibodies (AChR Ab) disturb the function of the receptor have been elucidated. Besides the pathogenic AChR Ab, other autoantibodies are present, among them Ab against several skeletal muscle components and Ab against the adrenergic receptors. T cells from MG patients display increased reactivity with the AChR and the autoantibody production is considered to be T cell dependent. This thesis focuses on the different disease mechanisms in MG. A cytotoxic effect is mediated by sera and IgG fractions from MG patients. The strong correlation between the concentrations of AChR Ab and cytotoxic effect in patients with thymoma indicates that antibody-dependent cell mediated cytotoxicity via AChR Ab might be an additional pathogenic mechanism in MG. An abnormal T cell receptor (TCR) usage, with significantly decreased usage of V02 in CD8+ and Vß3 in CD4+ cells and T cell expansions that use different TCR in both CD4+ and CD8+ cell populations, was present in patients. The expanded CD4+ T cells expressed to a high extent activation markers and had a predominant Th1 cytokine profile. AChR-reactive cells were concentrated in the expanded populations indicating that the autoantigen AChR might be driving the expansions. These expanded and functionally active CD4+ cells may thus be involved in the pathogenesis of the disease. Apart from AChR Ab, ß-adrenergic receptor (ß1-AR and ß2-AR) Ab are present in MG patients with significantly higher prevalence and concentration of IgG Ab. Immunopharmacological blockade, and up-/down-regulation of the receptor by Ab are possible mechanisms of action. A decreased density of the ß2-AR on peripheral blood mononuclear cells from MG was observed. Although the prevalence of cardiovascular disease did not differ between patients with and without ß-AR Ab, patients with cardiovascular disease had significantly higher IgG Ab than the other patients and healthy individuals. These Ab might be one factor of importance in the subgroup of patients with cardiovascular disease. Certain gene polymorphisms of ß2-AR were associated with MG. Homozygous for Arg16 was associated with generalised disease and homozygous for Glu27 was negatively associated with the presence of ß2-AR Ab. The frequencies of ß2-AR gene polymorphisms did not differ in HLA-B8, DR3, DR2 or DR4 positive and negative patients. This thesis demonstrate additional mechanisms that might influence the disease. Immune reactions against the ß-AR and certain gene polymorphisms of the ß-AR are associated with the disease. The abnormal TCR usage is reflected in the expanded CD4+ autoantigen reactive cells. ADCC can be induced by AChR Ab. All these mechanism might influence the pathogenesis and/or progression of the disease.

History

Defence date

1998-12-09

Department

  • Department of Medicine, Solna

Publication year

1998

Thesis type

  • Doctoral thesis

ISBN-10

91-628-3265-4

Language

  • eng

Original publication date

1998-11-18

Author name in thesis

Xu, Biying

Original department name

Department of Medicine

Place of publication

Stockholm

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