Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action

In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-gamma+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCR alpha beta- microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCR alpha beta- cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage

Blood parasites in dogs from the Belgrade area in the period 2014-2015

Prevalence of blood parasites in dogs in the Belgrade area has been investigated continuously during the last 20 years, especially in clinically suspicious dogs. In the period from 2014 to 2015, 249 blood samples of pets (182) and shelter dogs (67) were examined. Using Giemsa-stained blood smears, the presence of Babesia spp. was examined in erythrocytes and the presence of morulae of Ehrlichia spp. and Anaplasma spp. in circu­lating monocytes and granulocytes. To confirm positive findings of ehrlichiosis and ana­plasmosis in blood smears, CaniV-4 Test Kit or IDEXX SNAP 4DX test was used. Infection with two pathogens was found in 78/249 (31.32%) cases; in all cases, the infection with one of the protozoa or bacteria was in combination with heartworms. In blood-smears, babesiosis was found in 39.75% of pet dogs and in 71.64% of shelter dogs, ehrlichiosis in 15.93% and 28.35%, and anaplasmosis in 6.04% and 19.40%, respectivelly. From colected ticks, relative abundance analysis revealed that the species Ixodes ricinus was absolutely dominant and found in 50.53% (47/93), followed by Rhipicephalus sanguineus ‒ 38.70% (36/93), Derma­centor marginatus ‒ 9.67% (9/93), D. reticulatus, and Ixodes persulcatus found in 3.22% (3/93), which for the first time occurred in dogs in the Belgrade area and in Serbia

Nucleoside analogues effect on glial response in experimental autoimmune encephalomyelitis

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A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis

In multiple sclerosis, a common inflammatory disease of the central nervous system, immune-mediated axon damage is responsible for permanent neurological deficits. How axon damage is initiated is not known. Here we use in vivo imaging to identify a previously undescribed variant of axon damage in a mouse model of multiple sclerosis. This process, termed 'focal axonal degeneration' (FAD), is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation. Notably, most swollen axons persist unchanged for several days, and some recover spontaneously. Early stages of FAD can be observed in axons with intact myelin sheaths. Thus, contrary to the classical view, demyelination-a hallmark of multiple sclerosis-is not a prerequisite for axon damage. Instead, focal intra-axonal mitochondrial pathology is the earliest ultrastructural sign of damage, and it precedes changes in axon morphology. Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD. Indeed, neutralization of ROS and RNS rescues axons that have already entered the degenerative process. Finally, axonal changes consistent with FAD can be detected in acute human multiple sclerosis lesions. In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy