Innate immunity in progressive multiple sclerosis

Abstract

Multiple sclerosis is (MS) is a chronic inflammatory autoimmune disease of central nervous system (CNS) leading to demyelination, axonal damage and neurological handicap, often affecting young adults. A majority of patients with MS initiate their disease with clinical bouts and relapses, but with time convert to a progressive course with dampened signs of CNS inflammation but increasing neurological deficits. This thesis is focused on highlighting the differences in levels of key immune mediators, neurofilament-light (NFL), and kynurenine pathway in different phases of MS and in an animal model of neurodegeneration.

In Study I , we determined levels of NFL, complement C3 and activity of the two main acetylcholine hydrolyzing enzymes, AChE and BChE, in cerebrospinal fluid (CSF) from patients with MS and controls. Levels of C3 were higher in MS patients compared to controls and correlated with MS disease disability and NFL. The BChE activity was correlated with C3 and NFL in individual samples suggesting a potential link between intrathecal cholinergic activity and complement activation. The results motivate further studies on the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

In Study II , we identified a strong naturally occurring cis -regulatory influence on the local expression of complement receptor 2 (Cr2) in the rat spinal cord and increased soluble CR2 (sCR2) in the CSF of nerve injured rates. In transgenic mice loss of Cr2 resulted in increased loss of synapses in the axotomized motor neuron pool. In humans increased sCR2 levels were detected in the CSF of patients with MS as compared to controls, identifying CR2 as a potential novel biomarker of CNS inflammation. These results propose a new role for CR2/sCR2 as a modulator of innate immune reactions and synaptic plasticity in the CNS.

In Study III , we determined levels of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) in CSF. The absolute QUIN levels and the QUIN/KYN ratio were increased in MS during relapse (RRMS). Interestingly, secondary progressive MS (SPMS) displayed lower TRP and KYNA, while primary progressive (PPMS) patients displayed increased levels of all metabolites, similar to a group of inflammatory neurological disease controls. In addition, MS patients with active disease and short disease duration were prospectively evaluated for neuropsychiatric symptoms. Depressed patients displayed higher KYNA/TRP and KYN/TRP ratios, mainly due to low TRP levels. These results demonstrate that clinical disease activity and differences in disease courses are reflected by changes in KP metabolites. Increased QUIN levels of RRMS patients in relapse and generally decreased levels of TRP in SPMS may relate to neurotoxicity and failure of remyelination, respectively.

In Study IV , we analyzed the main monocytes subsets and/or expression of the chemokine receptors CCR2 or CX3CR1 in relation to different MS disease courses, and after treatment with dimethyl fumarate (DMF). In contrast to the prior studies we could not detect significant quantitative or qualitative differences in the monocyte population between different MS disease stages. DMF treatment resulted in a heterogeneous response, with both expansion and reduction of non-classical monocyte subsets in a proportion of patients.

In summary and in context of current knowledge, my findings suggest that later stages of MS is characterized less of adaptive and innate cellular alterations in the periphery, also supported by the relative lack of efficacy of current therapies in MS directed mainly at modulating the adaptive immune defense. However, findings of altered complement expression and metabolic changes involving the KP may reflect low grade widespread tissue responses that can exert effects on synaptic remodeling and neuronal transmission. These pathways deserve attention as potential therapeutic targets in later stages of MS.