We should focus more on finding therapeutic targets for the non-inflammatory damage in MS – No

There may be several reasons why the majority of registered drugs as well as most new drug candidates in development pipelines for multiple sclerosis (MS) target inflammation. Inflammation is arguably the most visible pathological feature in MS diagnosis with magnetic resonance imaging (MRI). Moreover, the strong effect of MHC class II in the genetic risk to MS points to an important pathogenic role of CD4+ T cells, which display the induction of inflammation as one of their main immunological functions. In active MS compared to inactive MS, there is stronger Th1 type lymphocyte reactivity to naturally presented central nervous system (CNS)-derived MHC-presented peptides. ¹ Arguing for a fundamental role of inflammation in MS is also that treatment with the B cell–depleting agent ocrelizumab shows beneficial effects in primary-progressive MS in which the role of inflammation has been debated for a long time. ² Finally, the CNS pathology in the most frequently used MS animal model in the translational research of MS pathogenesis and therapy, rodent experimental autoimmune encephalomyelitis (EAE), is dominated by inflammation. Nevertheless, despite several successes, anti-inflammatory drugs often failed to reproduce promising effects observed in the EAE model, when they were tested in MS. Two notorious examples are monoclonal antibodies against tumour necrosis factor alpha (TNFα) or interleukin (IL)-12p40, which failed in MS but do show satisfactory activity in typical inflammatory diseases, such as rheumatoid arthritis or psoriasis. Understandably, the disappointing efficacy of anti-inflammatory treatments in MS thus far stimulates the search for other therapeutic targets.

The implicit assumption in the title of this controversy is that there is tissue damage in MS with and without inflammation. Inflammation refers to the biological response of body tissues to harmful stimulants, which initially involves activation of the innate arm of the immune system. The term innate inflammatory response (IIR) seems appropriate here. The triggers of tissue inflammation can be diverse, including damage-associated molecular patterns (DAMPs; e.g. DNA, mitochondria) released from necrotic cells or pathogen-associated molecular patterns (PAMPs) expressed in bacteria or viruses (e.g. lipopolysaccharide (LPS), dsRNA, flagellin). Innate immune cells are equipped with a variety of pattern recognition receptors (PRRs) via which PAMPs or DAMPs relay their activation signals. This implies that tissue damage and inflammation are not separate pathological entities, but should be viewed as two sides of the same coin. The real question is therefore: Should MS research be more focused on the cause(s) of tissue damage than on the (tissue) response to damage? Also here an assumption is made, namely, that the primary CNS tissue damage in MS is pathological and should be prevented with new medication. What is the evidence?

Wilkin ³ proposed that autoimmune reactions of T and B cells, named here the adaptive inflammatory response (AIR), may comprise a normal physiological response of the immune system against excess release of antigens from a hypothetical primary lesion. Based on the work in a marmoset EAE model, we later proposed a modification of this ‘primary lesion hypothesis’, namely, that CNS autoimmunity is due to a hyper-reaction of the immune system against antigens released from a primary lesion of CNS myelin. Conceptually, the immune hyper-reactivity is due to the interaction of genetic and environmental risk factors, infection with herpesviruses such as cytomegalovirus (CMV) and Epstein–Barr virus (EBV) in particular (reviewed in ’t Hart et al.^4,5).

The nature of the primary lesion has not been exactly defined, but could well be the microglia aggregates that have been found as earliest histological manifestation of neuroinflammation in the otherwise normal-appearing white matter in the MS brain. ⁶ In a subset of these pre-active lesions, evidence of inflammation, namely inflammasome activation and expression of IL-1β, was found. ⁷ Whether these aspects of an IIR in microglia are induced is regulated by the health status of oligodendrocytes; more specifically, by the interaction of myelin oligodendrocyte glycoprotein (MOG) expressed on myelin sheaths and oligodendrocytes with Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) expressed on microglia. ⁸ It is unclear why in MS the oligodendrocytes lose control over the IIR in microglia. Of note, MOG produced by stressed oligodendrocytes (e.g. exposure to TNFα) failed to bind DC-SIGN and therefore seems unable to suppress an IIR in pre-active lesions. ⁸

Data obtained also in marmoset EAE showed that the anti-myelin T and B cell reactions driving chronic inflammation and demyelination are directed against the quantitatively minor albeit specific constituent of CNS myelin MOG. The AIR against MOG in marmosets diverges into two distinct pathogenic pathways: (1) a rodent EAE-like pathway mediated by Th1 cells and antibodies that primarily affect the white matter and (2) a novel pathway driven by the interaction of γ1-infected B cells with effector memory cytotoxic T cells (CTL) present in the healthy repertoire, which affects the white and cortical grey matter of the brain (reviewed in ’t Hart et al. ⁹ ). The model indicates that both pathways operate in parallel, but that the Th1/antibody pathway 1 is more influential in the early phase of the disease, while the CTL pathway 2 is more dominant in the late phase. This is illustrated by the observation that treatment with the anti-IL12p40 antibody ustekinumab is highly effective in early stage disease, but much less in the late stage.^10,11 Nevertheless, both pathways carry clear, albeit different, inflammatory signatures. Even though not defined to the very end, the type of inflammation differs between early and late stage disease and should be treated accordingly.

In summary, the concept of non-inflammatory damage to the CNS is questionable as the immune system has been trained to detect disturbance of homeostasis and responds with an appropriate inflammatory reaction. Importantly, inflammation is a multifaceted pathological process that exceeds the MRI-detectable focal oedema caused by leakage of the blood–brain barrier or the formation of perivascular cuffs of inflammatory cells. Inflammation shows many faces involving activation of innate immune cells and molecules, formation of new blood vessels and the activation of tissue repair mechanisms.

Obviously, we cannot afford to reject any promising lead towards an effective treatment for MS, especially for primary and secondary progressive disease. In classical neurodegenerative diseases like Parkinson’s disease and amyotrophic lateral sclerosis (ALS), there is increasing data and consent that inflammation is a major disease driver. We should therefore continue to focus in MS research on the understanding of inflammation without neglecting secondarily induced events like mitochondrial dysfunction, axonal transport disturbances or remyelination failure, to name a few.