Immune dysbalance in childhood multiple sclerosis: a ‘chicken or the egg’ conundrum

This scientific commentary refers to ‘Abnormal effector and regulatory T cell subsets in paediatric-onset multiple sclerosis’, by Mexhitaj et al. (doi:10.1093/brain/awz017).

‘The problem about the egg and the chicken, which of them came first, was dragged into our talk, a difficult problem which gives investigators much trouble. And Sulla my comrade said that with a small problem, as with a tool, we were rocking loose a great and heavy one, that of the creation of the world’ Plutarch, Moralia.

Paediatric-onset and adult-onset multiple sclerosis presumably share similar, if not identical, mechanisms of pathogenesis. Like adult-onset multiple sclerosis, childhood-onset multiple sclerosis has a prodromal phase that precedes the clinical onset by an unknown, variable time span. In paediatric-onset multiple sclerosis, this prodromal phase may be considerably shorter, although there is no formal proof for this assumption. Furthermore, children with multiple sclerosis are less likely to receive treatment immediately after clinical onset. For these reasons, paediatric multiple sclerosis offers a very special window into early disease mechanisms. In this issue of Brain, Mexhitaj and co-workers—on behalf of the Canadian Pediatric Demyelinating Disease Network (CPDDN)—report that children with multiple sclerosis have pronounced changes in circulating immune cells (Mexhitaj et al., 2019). Specifically, the authors observed decreased frequencies and reduced function of putatively anti-inflammatory, regulatory T cells, as well as increased activity of putatively pro-inflammatory T cells (Fig. 1). These results indicate that an ‘immune dysbalance’, especially of T cells, represents an early, and therefore probably important, element of the immune pathogenesis of paediatric, and by extrapolation, adult multiple sclerosis.

Figure 1

Immune dysbalance in childhood multiple sclerosis. As reported by Mexhitaj et al., putatively pro-inflammatory subsets of T cells [marked red; CD4+ effector T cells (T eff) and CD8+ mucosal-associated invariant T cells (MAIT cells)] are increased in frequency and function, whereas putatively anti-inflammatory CD4+ regulatory T cells (T reg; green) are decreased. The different T cell subsets are defined by a combination of cell surface markers revealed by monoclonal antibody staining and flow cytometry (Glossary). The markers include differentiation and activation molecules (CD4, CD8, CD161, CD127), chemokine receptors (CCR2, CCR5), transcription factors (FOXP3), and T cell receptors for antigen (TCR-V-alpha 7.2). For a detailed review of T cell immunity, see Korn and Kallies (2017).

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In a logistical and methodological tour de force, the investigators longitudinally collected blood samples from 23 children with multiple sclerosis, 26 with monophasic demyelinating disease, and 22 healthy control subjects. The diagnosis of multiple sclerosis, as opposed to monophasic illness, required a sufficient length of prospective follow-up. Furthermore, the investigators had to develop and implement rigorous standard operating procedures to guarantee high-quality conditions for the sophisticated immunological studies, which included multiparametric flow cytometry as well as functional in vitro assays of selected immune cell subsets. This formidable task would not have been possible without the infrastructures of the CPDDN.

The core findings are shown in Fig. 1: putatively pro-inflammatory subsets of T cells [CD4+ effector T cells and CD8+ mucosal-associated invariant T cells (MAIT cells)] are increased in frequency and function, whereas putatively anti-inflammatory CD4+ regulatory T cells are decreased. These findings are consistent with earlier reports of disturbed ‘T-cell homeostasis’ in adult multiple sclerosis (reviewed in Venken et al., 2010; Kleinewietfeld and Hafler, 2014). Although some of the previous studies have remained controversial, the present results lend further support and credence to the notion that disturbances of T cell homeostasis may be an early and fundamental mechanism in the pathogenesis of multiple sclerosis across the entire age spectrum.

The most obvious next question is whether the observed changes constitute a primary mechanism, or are merely secondary to a still undefined triggering event. In fact, pondering this issue poses a classical ‘chicken or the egg’ conundrum. It may be helpful to approach the issue of a primary versus secondary ‘immune dysbalance’ by considering different settings of viral infection as an analogy (Table 1). An acute viral infection of a healthy person results in massive activation of pro-inflammatory immune mechanisms and (at least transient) downregulation of anti-inflammatory mechanisms to overcome the infection with maximal speed and efficiency (scenario A in Table 1). For example, in infectious mononucleosis, primary infection of B cells with Epstein-Barr virus (EBV) leads to a massive defensive anti-EBV T cell response. Eventually the immune system of the host is left with lifelong immunity against EBV, and the virus remains dormant in B cells without harmful consequences for the host.

Progressive multifocal leukoencephalopathy (PML) provides an example of a distinctly different scenario of viral infection (scenario B in Table 1). Here, the disease-triggering mechanism is not the acute primary infection, but rather a profound disturbance of the immune system, namely a state of immunodeficiency caused by infection (HIV), immunosuppressive therapy (e.g. natalizumab), or genetically determined alterations. During such a prolonged state of immunodeficiency, a latent, otherwise harmless infection with John Cunningham (JC) virus turns into a devastatingly destructive process. The latent archetype virus mutates into a pathogenic variant that infects the brain and causes PML (Major et al., 2018).

These two different settings of viral infection may help us to imagine potential scenarios of autoimmunity in multiple sclerosis. In scenario A (Table 1), a definable ‘auto-sensitizing event’ coaxes the immune system into attacking the patient’s own body. The hypothetical initial triggering event may involve some viral or bacterial infection, and it may occur at different immunologically important sites, such as lymph nodes, gut or lung. This triggering event will induce a state of heightened pro-inflammatory and dampened anti-inflammatory immunity, resulting in autoimmune destruction of the CNS.

In an equally hypothetical autoimmune scenario B (Table 1), the pathogenic cascade of multiple sclerosis is triggered by an initial state of ‘immune dysbalance’, characterized by dampened anti-inflammatory and enhanced pro-inflammatory mechanisms. This state of dysbalance could be caused by genetic factors or by environmental influences (e.g. vitamin D deficiency), or by any combination of genetic and environmental factors. The initial state of immune hyper-reactivity would set the stage for—perhaps even multiple independent—auto-sensitizing events, possibly involving different peripheral organs and tissues.

When thinking about these hypothetical scenarios, it becomes clear that scenarios A and B pose a classical ‘chicken or the egg’ dilemma: the postulated triggering events and the postulated secondary mechanisms are so intimately intertwined that they can only be separated in certain extreme settings such as the ones discussed here.

What is also very clear is that the new Canadian study opens up many more questions than it provides final answers. Obviously, one of the most important future challenges is to determine the nature of the auto-sensitizing antigens (Hohlfeld et al., 2016). Are these myelin autoantigens as might be predicted by many animal models? Are they viral antigens that might stimulate cross-reactive autoimmune responses by molecular mimicry? Or might they belong to a novel category of autoantigens, e.g. intracellular proteins released during cellular damage or decay (Brändle et al., 2016; Winger and Zamvil, 2016; Planas et al., 2018)? All these possibilities are completely open at the moment, suggesting an important and challenging direction for future research.

Competing interests

The author reports no competing interests.

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