Interferon γ, interleukin 4 and transforming growth factor β in experimental autoimmune encephalomyelitis in lewis rats: Dynamics of cellular mrna expression in the central nervous system and lymphoid cells

Abstract

The potential role of certain important immunoregulatory and effector cytokines in autoimmune neuroinflammation have been studied. We have examined the expression of mRNA, with in situ hybridization, of interferon gamma (IFN-gamma), interleukin 4 (IL-4) and transforming growth factor beta (TGF-beta) both in sections of spinal cords and the antigen-induced expression of these cytokines by lymphoid cells after stimulation with a dominant encephalitogenic peptide of MBP (MBP 63-88) during the course of actively induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats. In spinal cords, the target organ in EAE, cells expressing mRNA for IFN-gamma, first appeared at the onset of clinical signs, i.e., day 10 postimmunization (p.i.), peaked at the height of disease (day 13 p.i.) and then gradually decreased concomitant with recovery. Very few IL-4 mRNA-expressing cells appeared in the spinal cord with no clear relation to clinical signs or histopathology. In contrast, expression of mRNA for TGF-beta did not increase until day 13 p.i., at height of the disease, shortly preceding recovery. These data are consistent with a disease upregulating role of IFN-gamma, while TGF-beta may act to limit central nervous system (CNS) inflammation. In lymphoid organs, primed MBP 63-88 reactive T cells showed an interesting time-dependent evolution of their cytokine production in vitro. Thus, early after immunization there was a conspicuous MBP 63-88-induced production of both IFN-gamma and IL-4. Such cells may act in the initiation and promotion of the disease. Later, in the recovery phase, MBP 63-88 induced lymphoid cells to TGF-beta production. Thus, an autoantigen-specific production of TGF-beta occurred during EAE and hypothetically such a mechanism may serve to downregulate aggressive autoimmunity systemically.

Cytokine expression by inflammatory cells obtained from the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis induced by inoculation with myelin basic protein and adjuvants

“…Issazadeh et al (1995b) found only low numbers of IL-4 mRNA-expressing cells in the spinal cord of rats with EAE. However, in mice, Kennedy et al (1992) found that IL-4 was present in the CNS and reached a peak before the peak of the clinical disease.…”

“…These results may be compared with those of Tanuma et al (1997), who used competitive PCR in a study of cells extracted from the spinal cord of Lewis rats with EAE. We have also presented the results as cytokine mRNA expression per gram of spinal cord (Table 3), which can be compared with the results of Issazadeh et al (1995a) and Issazadeh et al (1995b), who used in situ hybridization to study cytokine mRNA expression per unit area of spinal cord section.…”

IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis

“…Similarly, the I1(761)*CA 12 , which is in strong LD with 3 0 (325)*G, was negatively associated with susceptibility to MS in men from USA (cases 52% vs controls 70%, P ¼ 0.022; OR: 0.46, 95% CI: 0.23-0.90). The marker I1(761)*CA n was not associated with MS in the other populations, even after stratifying by gender.…”

“…When the populations of men were combined and the analysis was adjusted for populations, carriers for 3 0 (325)*A (P ¼ 0.001; OR: 2.02, 95% CI: 1.31-3.14) and I1(761)*CA 13 (P ¼ 0.034; OR: 1.48, 95% CI: 1.03-2.12) had increased susceptibility to MS. If the effect of the alleles was considered protective, homozygotes for the 3 0 (325)*G (P ¼ 0.001; OR: 0.49, 95% CI: 0.32-0.77) and I1(761)*CA 12 (P ¼ 0.015; OR: 0.58, 95% CI: 0.37-0.90) alleles had reduced susceptibility to MS.…”

“…9 Interferon-gamma (IFNg) stimulates Th-1 clonal expansion and inhibits Th-2 expansion. The balance between Th-1 and Th-2 CD4 cells is relevant to autoimmunity and to MS. 10,11 IFNg expression is increased in experimental allergic encephalomyelitis (EAE) 12 and parallels disease severity. 13 However, it is unclear whether the increased IFNg expression is a deleterious or a disease limiting response in EAE, as IFNg receptor knockout mice are more susceptible to EAE than wild-type mice.…”