The conundrum of iron in multiple sclerosis – time for an individualised approach

Abstract

Although the involvement of immune mechanisms in multiple sclerosis (MS) is undisputed, some argue that there is insufficient evidence to support the hypothesis that MS is an autoimmune disease, and that the difference between immune- and autoimmune disease mechanisms has yet to be clearly delineated. Uncertainties surrounding MS disease pathogenesis and the modest efficacy of currently used disease modifying treatments (DMTs) in the prevention of disability, warrant the need to explore other possibilities. It is evident from the literature that people diagnosed with MS differ widely in symptoms and clinical outcome - some patients have a benign disease course over many years without requiring any DMTs. Attempting to include all patients into a single entity is an oversimplification and may obscure important observations with therapeutic consequences. In this review we advocate an individualised approach named Pathology Supported Genetic Testing (PSGT), in which genetic tests are combined with biochemical measurements in order to identify subgroups of patients requiring different treatments. Iron dysregulation in MS is used as an example of how this approach may benefit patients. The theory that iron deposition in the brain contributes to MS pathogenesis has caused uncertainty among patients as to whether they should avoid iron. However, the fact that a subgroup of people diagnosed with MS show clinical improvement when they are on iron supplementation emphasises the importance of individualised therapy, based on genetic and biochemical determinations.

Acute-Phase Protein Hemopexin Is a Negative Regulator of Th17 Response and Experimental Autoimmune Encephalomyelitis Development

“…Thus, it is possible that the exacerbated demyelination we observed in Hx 2/2 mice with EAE was due not only to massive Th17 cell infiltration, but also to the impairment of Hx-deficient oligodendrocytes to respond to exogenous insults. This conclusion is consistent with data showing that iron deposition in the brain contributes to MS pathogenesis (38). Thus, Hx would control, on one hand, systemic signals driving Th17 differentiation and, on the other hand, local signals in CNS affecting oligodendrocyte function.…”

Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities

“…Finally, a subgroup of adult and pediatric patients showing MS signs that appear to be provoked by iron deficiency has been identified. The symptoms are usually alleviated by iron supplementation (446). This can not only be easily explained by the high amount of iron needed for normal ODC development and function (159), but also substantiates the fact that iron excess is not responsible for MS initiation.…”

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

“…Increased iron levels (attributable to age pathology) have been connected to the disruption of the brain iron homeostasis leading to neurodegeneration, including MS [ 9 , 202 ]. MS patients have further been shown to exhibit increased levels of soluble transferrin (main iron transporter protein in the brain [ 204 , 205 ]) receptor associated with reinforced iron turnover [ 10 , 205 , 210 ]. Another study has reported an increased level of ferritin in the cerebrospinal fluid and serum of SPMS patients [ 211 ], providing the possible reason for extra iron delivery, since the H-ferritin receptor in neurons and oligodendrocytes is transferrin [ 205 , 212 ].…”

“…However, its diagnosis and treatment strategies are complicated by the presence of disease heterogeneity with distinct courses and diverse therapy responses. Patients are diagnosed as having early MS (formerly clinicaly isolated syndrome suspected of being MS (CIS)), clinicaly definite multiple sclerosis (CDMS), relapsing-remitting multiple sclerosis (RRMS), progressive-relapsing MS (PRMS), and primary- and secondary-progressive multiple sclerosis (PPMS, SPMS) [ 2 , 4 , 10 ]. Moreover, the disease causes variable degrees of motor, sensory, behavioral, mental, emotional, and cognitive impairment [ 11 , 12 , 13 ].…”

“…However, recent research has shown that the neurodegenerative process is not clearly related to inflammatory lesions but is instead associated with diffuse neuro-axonal loss caused by various pathological phenomena [ 9 , 14 ]. Some authors have suggested that a cell-mediated autoimmune response occurs against extraneous or even the body’s own components, with the consequent damage of oligodendrocytes and progressive axonal degeneration [ 10 , 15 ]. One mechanism of this neurodegeneration might be associated with the production of reactive oxygen species from activated microglia and macrophages with a subsequent inadequate energy supply to the CNS [ 9 , 16 ].…”