Multiple sclerosis: a disorder of altered T-cell homeostasis

Abstract

Uncertainty exists as to whether similar or different mechanisms contribute to the pathogenesis of different subtypes of multiple sclerosis (MS). Detailed analysis of naive T cell homeostasis shows that patients with relapsing-remitting MS (RRMS) and with primary progressive MS (PPMS) have early-onset thymic involution that causes reduced thymic output. The reduced thymic output leads to secondary peripheral homeostatic alterations in naïve CD4 T-cells, which closely mimic T-cell alterations observed in an experimental animal model of diabetes mellitus. Homeostatic T-cell receptor (TCR) signalling and proliferation of naïve T cells are induced by self-peptides. Consequently, the findings of increased TCR signalling of naïve CD4 T-cells, without increased proliferation, in PPMS, and the increased homeostatic proliferation of naïve CD4 T-cells in RRMS favour the development of autoimmunity. Thus, it seems highly likely that peripheral T-cell alterations secondary to a thymic abnormality contribute to the pathogenesis of both MS subtypes.

Figure 1

sjTRECs in controls and patients. (a) Naïve CD4 sjTREC frequencies (sjTRECs/10⁶ naïve CD4 T-cells) decreased significantly with age only in controls (P = 0.037). (b) Naïve CD8 sjTREC frequencies decreased with age only in controls (P = 0.037). (c) Total naïve CD4 sjTREC numbers decreased exponentially with age only in controls (P = 0.048). Median sjTRECs were higher in controls than in RRMS (P = 0.03) or in PPMS (P = 0.007) with a trend towards higher sjTREC numbers in RRMS versus PPMS (P = 0.055). (d) Thymic export (naïve CD4 T-cells/day) decreased with age only in controls (r = −0.564, P = 0.05). Both RRMS (P = 0.005) and PPMS patients (P = 0.004) had significantly reduced median daily thymic export compared to controls.

Figure 2

Naive CD4 T-cell expression of CD31. The proportion of naïve CD4 T-cells expressing CD31 showed a significant decrease with age only in PPMS (P = 0.031).