RESUMO
Basic science investigations and clinical observations in recent years indicate that hemoglobins (Hbs) may have important roles in the pathogenesis of multiple sclerosis (MS). These findings can be summarized as follows: 1- Erythrocyte fragility is higher in MS patients, the released free Hb damages blood-brain barrier, myelin basic protein and also triggers iron overload and inflammation. 2- Free Hb may further activate the inflammatory responses through Toll-like receptor 4 (TLR4), present on microglia and other innate immunocytes. 3- Hbs are expressed in neural cells including dopaminergic neurons. Also, several studies have demonstrated that Hbs are expressed in astrocytes and oligodendroglia. 4- Hb overexpression in neural cells upregulate mitochondrial complex I-V subunits. The comparison of the mitochondrial proteome between healthy and patients with MS revealed only four differentially expressed proteins including Hb ß-chain. 5- Microarray analysis of 8300 genes in monocytes of twins with and without MS showed a difference in 25 genes that include genes encoding α- and ß-globins as well. 6- ß- and α-globin gene clusters reside at chromosomal regions 11p15.5 and 16p13.3, respectively. Whole genome screen (WGS) in Sardinian MS families using 327 markers revealed linkage in 3 regions including 11p15.5 loci. Further, 11p15.5 and 16p13.3 were part of the 17 regions identified in the WGS study of 136 sibling-pairs in Nordic countries analyzing 399 microsatellite markers. In the light of these findings, we propose that free Hb released from dying erythrocytes is detrimental. On the contrary, intracellular Hbs in neural cells are protective in MS. The genomic linkage findings can be explained by common haematologically-silent Hb variants that may lower the protective function of intracellular Hbs, and therefore, enhance the risk for MS. In the absence of such variants, aberrations in the translational and post-translational mechanisms controlling synthesis of neural Hbs may also enhance the vulnerability to MS. Alternatively, such genetic variants may perturb the metabolism of anti-inflammatory hemorphins produced via cleavage of Hbs.
