Vasileios Mastorodemos

Crucial Role of Granulocytic Myeloid-Derived Suppressor Cells in the Regulation of Central Nervous System Autoimmune Disease

There is a need in autoimmune diseases to uncover the mechanisms involved in the natural resolution of inflammation. In this article, we demonstrate that granulocytic myeloid-derived suppressor cells (G-MDSCs) abundantly accumulate within the peripheral lymphoid compartments and target organs of mice with experimental autoimmune encephalomyelitis prior to disease remission. In vivo transfer of G-MDSCs ameliorated experimental autoimmune encephalomyelitis, significantly decreased demyelination, and delayed disease onset through inhibition of encephalitogenic Th1 and Th17 immune responses. Exposure of G-MDSCs to the autoimmune milieu led to up-regulation of the programmed death 1 ligand that was required for the G-MDSC–mediated suppressive function both in vitro and in vivo. Importantly, myeloid-derived suppressor cells were enriched in the periphery of subjects with active multiple sclerosis and suppressed the activation and proliferation of autologous CD4+ T cells ex vivo. Collectively, this study revealed a pivotal role for myeloid-derived suppressor cells in the regulation of multiple sclerosis, which could be exploited for therapeutic purposes.

Rising incidence of multiple sclerosis in females associated with urbanization

Objective: To design and perform a case-control study of multiple sclerosis (MS) in Crete, an island of 0.6 million people, that has experienced profound socioeconomic changes in recent decades. Methods: All MS cases occurring on Crete from 1980 to 2008 were ascertained. To search for putative risk factors, a structured questionnaire of 71 variables was employed, with patients with MS (n = 657) being compared to random controls (n = 593) matched for age, gender, and current place of residence. Results: MS incidence rose markedly on Crete over the past 3 decades. This increase was associated with a major shift in MS distribution among genders (1980: F/M = 0.9; 2008: F/M = 2.1), with females living in towns or having relocated at a young age from the countryside to urban centers being mainly affected. In rural Crete, MS showed lesser increases and gender preference. Of the major changes that accompanied urbanization, smoking among women with MS increased dramatically, while imported pasteurized cow milk virtually replaced fresh goat milk produced locally. Compared to controls, female patients with MS more often used contraceptives and were older at first childbirth. Besides smoking, alcohol drinking and vitamin intake was more common among female patients with MS. Also, the distribution of childhood diseases and chronic medical conditions differed significantly between patients with MS and controls. Conclusions: MS incidence rose markedly over 3 decades in a genetically stable population in tandem with a transition from rural to urban living, thus possibly implicating environmental factors introduced by urbanization.

A case report of motor neuron disease in a patient showing significant level of DDTs, HCHs and organophosphate metabolites in hair as well as levels of hexane and toluene in blood.

Motor neuron disease is a devastating neurodegenerative condition, with the majority of sporadic, non-familial cases being of unknown etiology. Several epidemiological studies have suggested that occupational exposure to chemicals may be associated with disease pathogenesis. We report the case of a patient developing progressive motor neuron disease, who was chronically exposed to pesticides and organic solvents. The patient presented with leg spasticity and developed gradually clinical signs suggestive of amyotrophic lateral sclerosis, which was supported by the neurophysiologic and radiological findings. Our report is an evidence based case of combined exposure to organochlorine (DDTs), organophosphate pesticides (OPs) and organic solvents as confirmed by laboratory analysis in samples of blood and hair confirming systematic exposure. The concentration of non-specific dialkylphosphates metabolites (DAPs) of OPs in hair (dimethyphopshate (DMP) 1289.4 pg/mg and diethylphosphate (DEP) 709.4 pg/mg) and of DDTs (opDDE 484.0 pg/mg, ppDDE 526.6 pg/mg, opDDD 448.4 pg/mg, ppDDD+opDDT 259.9 pg/mg and ppDDT 573.7 pg/mg) were considerably significant. Toluene and n-hexane were also detected in blood on admission at hospital and quantified (1.23 and 0.87 μg/l, respectively), while 3 months after hospitalization blood testing was found negative for toluene and n-hexane and hair analysis was provided decrease levels of HCHs, DDTs and DAPs.

The human GLUD2 glutamate dehydrogenase: Localization and functional aspects

In all mammals, glutamate dehydrogenase (GDH), an enzyme central to the metabolism of glutamate, is encoded by a single gene (GLUD1 in humans) which is expressed widely (housekeeping). Humans and other primates also possess a second gene, GLUD2, which encodes a highly homologous GDH isoenzyme (hGDH2) expressed predominantly in retina, brain and testis. There is evidence that GLUD1 was retro-posed <23 million years ago to the X chromosome, where it gave rise to GLUD2 through random mutations and natural selection. These mutations provided the novel enzyme with unique properties thought to facilitate its function in the particular milieu of the nervous system. hGDH2, having been dissociated from GTP control (through the Gly456Ala change), is mainly regulated by rising levels of ADP/l-leucine. To achieve full-range regulation by these activators, hGDH2 needs to set its basal activity at low levels (<10% of full capacity), a property largely conferred by the evolutionary Arg443Ser change. Studies of structure/function relationships have identified residues in the regulatory domain of hGDH2 that modify basal catalytic activity and regulation. In addition, enzyme concentration and buffer ionic strength can influence basal enzyme activity. While mature hGDH1 and hGDH2 isoproteins are highly homologous, their predicted leader peptide sequences show a greater degree of divergence. Study of the subcellular sites targeted by hGDH2 in three different cultured cell lines using a GLUD2/EGFP construct revealed that hGDH2 localizes mainly to mitochondria and to a lesser extent to the endoplasmic reticulum of these cells. The implications of these findings for the potential role of this enzyme in the biology of the nervous system in health and disease are discussed.

White matter and deep gray matter hemodynamic changes in multiple sclerosis patients with clinically isolated syndrome

The dynamic susceptibility contrast magnetic resonance imaging perfusion technique was used to investigate possible hemodynamic changes in normal appearing white matter and deep gray matter (DGM) of 30 patients with clinically isolated syndrome (CIS) and 30 patients with relapsing–remitting multiple sclerosis. Thirty normal volunteers were studied as controls. Cerebral blood volume, cerebral blood flow (CBF), and mean transit time values were estimated. Normalization was achieved for each subject with respect to average values of CBF and mean transit time of the hippocampis dentate gyrus. Measurements concerned three regions of normal white matter of normal volunteers, normal appearing white matter of CIS and patients with relapsing–remitting multiple sclerosis, and DGM regions, bilaterally. All measured normal appearing white matter and DGM regions of the patients with CIS had significantly higher cerebral blood volume and mean transit time values, while averaged DGM regions had significantly lower CBF values, compared to those of normal volunteers (P < 0.001). Regarding patients with relapsing–remitting multiple sclerosis, all measured normal appearing white matter and DGM regions showed lower CBF values than those of normal volunteers and lower cerebral blood volume and CBF values compared to patients with CIS (P < 0.001). These data provide strong evidence that hemodynamic changes—affecting both white and DGM—may occur even at the earliest stage of multiple sclerosis, with CIS patients being significantly different than relapsing–remitting multiple sclerosis patients. Magn Reson Med, 2012.

Cell-based modulation of autoimmune responses in multiple sclerosis and experimental autoimmmune encephalomyelitis: therapeutic implications.

Multiple sclerosis (MS) is a prototypic autoimmune inflammatory disorder of the central nervous system (CNS). MS pathogenesis is a complex phenomenon that is influenced by genetic and environmental factors that lead to the dysregulation of immune homeostasis and tolerance. It has been shown that pathogenic T lymphocyte subsets, such as T helper 1 (Th1) and Th17 cells, play a crucial role in the autoimmune cascade influencing disease initiation, progression and subsequent tissue damage during MS. On the other hand, several mechanisms have been described in both patients and animal models of MS with the potential to modulate myelin-specific autoimmune responses and to facilitate amelioration of disease pathology. To this end, regulatory T cells (Tregs) are considered to be a powerful cell subset not only in the maintenance of homeostasis but also in the re-establishment of tolerance. Along these lines, other cell subsets such as dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), γδ T cells and natural killer (NK) cells have been shown to regulate the autoimmune response in the CNS under certain circumstances. This review will attempt to summarize the relevant knowledge of the regulatory mechanisms exerted by immune cells in MS that could hold the promise for the design of novel therapeutic strategies.

Medical treatment with thiamine, coenzyme Q, vitamins E and C, and carnitine improved obstructive sleep apnea in an adult case of Leigh disease.

PurposeThe multi-organ involvement of mitochondrial diseases means that patients are likely to be more vulnerable to sleep disturbances. We aimed to assess if early recognition and treatment of obstructive sleep apnea (OSA) in patients with Leigh disease may influence primary disease outcome.MethodsWe describe a case of adult-onset Leigh disease presenting as severe brainstem encephalopathy of subacute onset. Based on the clinical symptoms that developed after the appearance of the neurological disease, an attended overnight polysomnography examination was performed.ResultsA marked clinical recovery was seen after administration of high doses of thiamine, coenzyme Q, L-carnitine, and vitamins C and E, combined with effective treatment with continuous positive airway pressure for the underlying severe obstructive sleep apnea (OSA). The latter condition was diagnosed on the basis of suggestive symptoms that appeared a few weeks before the establishment of the neurological disease. The improvement in the neurological disease (based on clinical and brain MRI features) with the appropriate medical treatment also resulted in a significant improvement in the OSA.ConclusionsEarly recognition and treatment of sleep apnea may not only improve sleep and overall quality of life but also ameliorate the deleterious effects of nocturnal desaturations on the neurological features. This may be crucial for disease outcome when added to the generally advised pharmacological therapy.

Hemodynamic evidence linking cognitive deficits in clinically isolated syndrome to regional brain inflammation

To investigate the relation between hemodynamic measurements and memory function in patients with clinically isolated syndrome (CIS).

Regional MRI Perfusion Measures Predict Motor/Executive Function in Patients with Clinically Isolated Syndrome

Background. Patients with clinically isolated syndrome (CIS) demonstrate brain hemodynamic changes and also suffer from difficulties in processing speed, memory, and executive functions. Objective. To explore whether brain hemodynamic disturbances in CIS patients correlate with executive functions. Methods. Thirty CIS patients and forty-three healthy subjects, matched for age, gender, education level, and FSIQ, were administered tests of visuomotor learning and set shifting ability. Cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) values were estimated in normal-appearing white matter (NAWM) and normal-appearing deep gray Matter (NADGM) structures, using a perfusion MRI technique. Results. CIS patients showed significantly elevated reaction time (RT) on both tasks, while their CBV and MTT values were globally increased, probably due to inflammatory vasodilation. Significantly, positive correlation coefficients were found between error rates on the inhibition condition of the visuomotor learning task and CBV values in occipital, periventricular NAWM and both thalami. On the set shifting condition of the respective task significant, positive associations were found between error rates and CBV values in the semioval center and periventricular NAWM bilaterally. Conclusion. Impaired executive function in CIS patients correlated positively with elevated regional CBV values thought to reflect inflammatory processes.

Emotion regulation contributes to the well-being of patients with autoimmune diseases through illness-related emotions: A prospective study:

This prospective study aimed to examine whether illness-related negative emotions mediate the relationship of cognitive reappraisal and expressive suppression to the well-being of 99 patients with rheumatoid arthritis or multiple sclerosis. After adjusting for disease and patient-related parameters, only cognitive reappraisal was associated with physical and psychological well-being through emotions. Expressive suppression was associated with psychological well-being only for patients reporting less use of cognitive reappraisal. These results underscore the need for prospective studies that will investigate the long-term impact of emotion regulation on adaptation to chronic illness and the conditions under which this impact takes place.