Overexpression of the ubiquitin-editing enzyme A20 in the brain lesions of Multiple Sclerosis patients: moving from systemic to central nervous system inflammation.

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) in which inflammation plays a key pathological role. Recent evidences showed that systemic inflammation induces increasing cell infiltration within meninges and perivascular spaces in the brain parenchyma, triggering resident microglial and astrocytic activation. The anti-inflammatory enzyme A20, also named TNF associated protein 3 (TNFAIP3), is considered a central gatekeeper in inflammation and peripheral immune system regulation through the inhibition of NF-kB. The TNFAIP3 locus is genetically associated to MS and its transcripts is downregulated in blood cells in treatment-naïve MS patients. Recently, several evidences in mouse models have led to hypothesize a function of A20 also in the CNS. Thus, here we aimed to unveil a possible contribution of A20 to the CNS human MS pathology. By immunohistochemistry/immunofluorescence and biomolecular techniques on post-mortem brain tissue blocks obtained from control cases (CC) and progressive MS cases, we demonstrated that A20 is present in CC brain tissues in both white matter (WM) regions, mainly in few parenchymal astrocytes, and in grey matter (GM) areas, in some neuronal populations. Conversely, in MS brain tissues, we observed increased expression of A20 by perivascular infiltrating macrophages, resident-activated astrocytes, and microglia in all the active and chronic active WM lesions. A20 was highly expressed also in the majority of active cortical lesions compared to the neighboring areas of normal-appearing grey matter (NAGM) and control GM, particularly by activated astrocytes. We demonstrated increased A20 expression in the active MS plaques, particularly in macrophages and resident astrocytes, suggesting a key role of this molecule in chronic inflammation.

The Footprints of Poly-Autoimmunity: Evidence for Common Biological Factors Involved in Multiple Sclerosis and Hashimoto's Thyroiditis.

Autoimmune diseases are a diverse group of chronic disorders and affect a multitude of organs and systems. However, the existence of common pathophysiological mechanisms is hypothesized and reports of shared risk are emerging as well. In this regard, patients with multiple sclerosis (MS) have been shown to have an increased susceptibility to develop chronic autoimmune thyroid diseases, in particular Hashimoto's thyroiditis (HT), suggesting an autoimmune predisposition. However, studies comparing such different pathologies of autoimmune origin are still missing till date. In the present study, we sought to investigate mechanisms which may lead to the frequent coexistence of MS and HT by analyzing several factors related to the pathogenesis of MS and HT in patients affected by one or both diseases, as well as in healthy donors. In particular, we analyzed peripheral blood mononuclear cell gene-expression levels of common candidate genes such as TNFAIP3, NR4A family, BACH2, FOXP3, and PDCD5, in addition to the regulatory T cell (Treg) percentage and the 25-hydroxy vitamin D serum levels. Our findings support the plausibility of the existence of common deregulated mechanisms shared by MS and HT, such as BACH2/PDCD5-FOXP3 pathways and Tregs. Although the biological implications of these data need to be further investigated, we have highlighted the relevance of studies comparing different autoimmune pathologies for the understanding of the core concepts of autoimmunity.

The increase in plasma C19Delta5 steroids in subcutaneous abdominal and jugular veins of dairy cattle during pregnancy is unrelated to estrogenic activity.

Plasma concentrations of dehydroepiandrosterone (DHEA), 5-androstene-3beta,17beta-diol (AED), and 17beta-estradiol (E2) in dairy cows and heifers and AED binding to uterine cytosolic estrogen receptor (ER) were studied. Plasma samples were collected from the subcutaneous abdominal (SA) and jugular (J) veins of heifers and cows in the non-pregnant state and at 15-45, 90-120, 180-210, and 250-280 days of pregnancy (N = 5-12). Plasma DHEA, AED, and E2 were determined by RIA. DHEA and AED significantly increased (P < 0.001) in heifers and cows throughout pregnancy. The stage of pregnancy significantly (P < 0.001) affected the three steroids in heifers and cows. Plasma DHEA increased throughout pregnancy in both heifers and cows, and in heifers it was significantly greater in SA than in J veins at 90-120 days (P < 0.01). Plasma AED was greater in heifers than in cows in J veins at 90-120 days (P < 0.01) and 180-210 days (P < 0.05), and in SA veins, at 15-45 days (P < 0.01) and 90-120 days (P < 0.05). In heifers, circulating AED showed concentration values significantly greater than those in non-pregnant animals from 90 to 120 days (P < 0.05) and was significantly greater in SA than in J veins at 90-120 days (P < 0.05). In cows, plasma AED was significantly greater than in non-pregnant animals at 250-280 days (P < 0.01). In heifers, plasma E2 was significantly greater in the SA than in the J veins from 180-210 to 250-280 days (P < 0.01). In cows, differences between E2 plasma concentrations in J and SA veins were observed only at 250-280 days of pregnancy. At 250-280 days, in both animal types plasma E2 was significantly greater than in non-pregnant animals (P < 0.001). We suggest that AED originates primarily from the feto-placental unit, while mammary E2 synthesis near term can affect plasma concentrations. Binding data showed that AED is a weak competitor for cytosolic ER (IC50 range: 1.44 x 10(-5) to 3.71 x 10(-5) M). These results suggest that a direct estrogenic activity for AED is unlikely in dairy cattle, and the physiological role of AED needs to be elucidated.