Cytokine Regulation in Systemic Lupus Erythematosus (SLE)

Huang, Fang-Ping (1994) Cytokine Regulation in Systemic Lupus Erythematosus (SLE). PhD thesis, University of Glasgow.

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The origin of the defects leading to pathogenicity in systemic lupus erythematosus (SLE), an autoimmune disorder characterised by multi-system involvement, female preference, B-cell hyperactivity, autoantibody production and immune complex deposition, is still controversial. The therapeutic strategies today for treatment of lupus disease are mainly based on a general suppression of the immune system with uncertainty about their long term effects being beneficial or rather harmful to the patients. These treatments that may achieve a temporary symptomatic relief do not cure the disease and are often followed by problematic side effects including infections. The underlying mechanism for the development of the disease is yet to be clarified. There is, however, some evidence that defects in the ability of lymphocytes to produce or respond to cytokines may disturb the finely balanced immune system resulting in abnormal B-cell regulation. In contrast to the B-cell hyperactivity, deficient T-cell functional activity is another prominent feature of the disease. Many cytokine disorders have been reported in both SLE patients and the animal models but findings are often difficult to reconcile, especially differences between data from the in vitro and in vivo studies. In order to understand the mechanism of immune regulation in SLE, experiments were designed, in the present study, to give a detailed analysis of the nature and pathological relevance of those immunological abnormalities, the T-helper cell functional defects in particular. Much of the work focused on and described in this thesis was based mainly on two well established murine models of SLE including an early-life (MRL/lpr) model and a later-life (NZB/W) disease model. Both the NZB/W and the MRL/lpr strains are mutant mice which spontaneously develop a disease similar to human SLE. Female mice of different ages were used in the study and the normal control strains were sex and age-matched BALB/c and CBA mice. Results from studies using lymphocytes and serum samples from SLE patients are also described and compared with the studies on the mouse models. The study included both in vitro and in vivo approaches. Results from the in vitro studies indicate that T-cell, particularly T-helper, functions are severely impaired in the lupus mice. These include abnormal production of IL-2, IFN-gamma and IL-4, inability of T-cells to express functional high affinity IL-2R and to proliferate in response to Con A stimulation, confirming and extending previous studies by other investigators. Since the stage of development at which these defects occur is not clearly understood, efforts have been devoted to analysis of lymphocytes from lupus mice at different ages, in relation to the disease activity. Attention has been particularly focused on young lupus mice including mice of one week old, before the onset of clinical disease. Evidence is given indicating an early onset of the T-helper functional defects and the central role of IL-2 deficiency in the defective T-cell activation. The hyporesponsiveness of lupus T-cells to Con A is due to the inability of T-helper cells to produce IL-2 and this can be bypassed by exogenous IL-2 in vitro. Addition of IL-2 during Con A activation restores fully the ability of lupus T-cells to proliferate, upregulates IL-2R expression and increases the frequency of IFN-gamma secretors resulting in normalised levels of IFN-gamma secretion. T-cell phenotype analysis indicates that IL-2 preferentially promotes the expansion of the functionally more mature single positive cell population while inhibiting the growth of the characteristic CD3+CD4-CD8- (double negative) cells in MRL/lpr mice. Addition of IL-1 during Con A stimulation of T-cells did not restore the IL-2 production defect in the lupus mice. In general, the study indicates a crucial role for the Th1 functional defect and therapeutic potential of IL-2 in SLE. It sheds some doubt on the current clinical treatments by non-specific immunosuppressive drugs and favours approaches which may enhance the endogenous capacity of the immune system to carry out its proper functions in maintaining self-tolerance. The need for new insights into the underlying mechanism of the disease and more consideration of the immune deficient aspects of autoimmune phenomena as a whole for therapeutic strategies are discussed. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: David I Stott
Keywords: Immunology
Date of Award: 1994
Depositing User: Enlighten Team
Unique ID: glathesis:1994-74762
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2019 16:36
Last Modified: 27 Sep 2019 16:36

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