Macrophage migration inhibitory factor in Nodding syndrome.

Nodding syndrome (NS) is a catastrophic and enigmatic childhood epilepsy, accompanied by multiple neurological impairments and neuroinflammation. Of all the infectious, environmental and psychological factors associated with NS, the major culprit is Onchocerca Volvulus (Ov)–a parasitic worm transmitted to human by blackflies. NS seems to be an 'Autoimmune Epilepsy' in light of the recent findings of deleterious autoimmune antibodies to Glutamate receptors and to Leiomodin-I in NS patients. Moreover, we recently found immunogenetic fingerprints in HLA peptide-binding grooves associate with protection or susceptibility to NS. Macrophage migration inhibitory factor (MIF) is an immune-regulatory cytokine playing a central role in modulating innate and adaptive immunity. MIF is also involved in various pathologies: infectious, autoimmune and neurodegenerative diseases, epilepsy and others. Herein, two functional polymorphisms in the MIF gene, a −794 CATT5–8 microsatellite repeat and a −173 G/C single-nucleotide polymorphism, were assessed in 49 NS patients and 51 healthy controls from South Sudan. We also measured MIF plasma levels in established NS patients and healthy controls. We discovered that the frequency of the high-expression MIF -173C containing genotype was significantly lower in NS patients compared to healthy controls. Interestingly however, MIF plasma levels were significantly elevated in NS patients than in healthy controls. We further demonstrated that the HLA protective and susceptibility associations are dominant over the MIF association with NS.Our findings suggest that MIF might have a dual role in NS. Genetically controlled high-expression MIF genotype is associated with disease protection. However, elevated MIF in the plasma may contribute to the detrimental autoimmunity, neuroinflammation and epilepsy. Author summary: Nodding syndrome (NS) is a devastating and enigmatic childhood disease, accompanied by multiple neurological impairments and neuroinflammation. NS is associated with the parasite Onchocerca volvulus (Ov) and other environmental factors. It was shown that NS seems to be an "Autoimmune-Epilepsy". However, it is still not clear why only some children, within the same family, tribe and district, develop this malady in South-Sudan. Recently, we hypothesized that immunogenetic factors might address this question, and indeed demonstrated that few amino acids in human leukocyte antigen (HLA) peptide-binding grooves associate with either protection or susceptibility to NS. In the current study, we evaluate the contribution of macrophage migration inhibitory factor (MIF) to NS pathology. MIF is an immune-regulatory cytokine that is involved in numerous pathologies, which vary from infectious diseases, autoimmunity to neurodegenerative diseases. Immunogenetic analysis of MIF in South-Sudanese NS patients and healthy controls shed new light on the epidemiology of this disease. Our findings suggest that MIF promoter genotypes that are linked with high-protein expression are associated with disease protection. However, in affected patients, with established NS, MIF plasma levels are elevated compared to control subjects and might be involved with autoimmunity and neuroinflammation. [ABSTRACT FROM AUTHOR]