Metabolic alterations and increased liver mTOR expression precede the development of autoimmune disease in a murine model of lupus erythematosus

Although metabolic syndrome (MS) and systemic lupus erythematosus (SLE) are often associated, a common link has not been identified. Using the BWF1 mouse, which develops MS and SLE, we sought a molecular connection to explain the prevalence of these two diseases in the same individuals. We determined SLE- markers (plasma anti-ds-DNA antibodies, splenic regulatory T cells (Tregs) and cytokines, proteinuria and renal histology) and MS-markers (plasma glucose, non-esterified fatty acids, triglycerides, insulin and leptin, liver triglycerides, visceral adipose tissue, liver and adipose tissue expression of 86 insulin signaling-related genes) in 8-, 16-, 24-, and 36-week old BWF1 and control New-Zealand-White female mice. Up to week 16, BWF1 mice showed MS-markers (hyperleptinemia, hyperinsulinemia, fatty liver and visceral adipose tissue) that disappeared at week 36, when plasma anti-dsDNA antibodies, lupus nephritis and a pro-autoimmune cytokine profile were detected. BWF1 mice had hyperleptinemia and high splenic Tregs till week 16, thereby pointing to leptin resistance, as confirmed by the lack of increased liver P-Tyr-STAT-3. Hyperinsulinemia was associated with a down-regulation of insulin related-genes only in adipose tissue, whereas expression of liver mammalian target of rapamicyn (mTOR) was increased. Although leptin resistance presented early in BWF1 mice can slow-down the progression of autoimmunity, our results suggest that sustained insulin stimulation of organs, such as liver and probably kidneys, facilitates the over-expression and activity of mTOR and the development of SLE.

Primary Sjogren syndrome.

Sjögren syndrome is a systemic autoimmune disease causing secretory gland dysfunction. This leads to dryness of the main mucosal surfaces such as the mouth, eyes, nose, pharynx, larynx, and vagina. 1 Sjögren syndrome may be a serious disease, with excess mortality caused by haematological cancer. 2 The cause of Sjögren syndrome is unknown, but factors postulated to play a role are both genetic and environmental .....

Anàlisis dels immunofenotips dels NKR de les cèl·lules Natural Killer en pacients amb Esclerosi Múltiple (MS).

La MS és una malaltia autoimmunitària les causes de la qual són encara desconegudes. Entre altres efectes, els pacients d’aquesta malaltia veuen reduït el nombre de limfòcits, així com el percentatge d’aquests ocupats pel compartiment NK. Tot i que molts estudis es centren en investigar aquesta malaltia, el motiu d’aquesta reducció, continua essent un misteri. En el present estudi s’ha plantejat una hipòtesi, la qual apunta a què aquesta reducció, pugui venir causada pel fet que les cèl·lules NK s’hagin vist eliminades de la circulació; a la qual cosa s’esperaria trobar una població de NK més joves per aquells pacients que tinguessin en un percentatge menor de NK, ja que aquesta pèrdua s’hauria hagut de compensar amb cèl·lules NK de nova formació. Per tal de determinar l’antiguitat de les cèl·lules NK s’analitzen els receptors ILT2 (present en cèl·lules més antigues, ja que s’acumula amb el temps), NKG2A (molt present en cèl·lules NK joves), i en la subpoblació CD56bright, (estat de maduració precoç, ja que aquestes amb el temps esdevindran CD56dim). Després de molts anàlisis, s’ha pogut comprovar com la presència de CMV influeix en els receptors de les cèl·lules NK, igual que també influeix la presència de tractament amb immunomoduladors. Però a part d’aquestes influències les quals ja s’havien descrit en altres estudis previs, s’ha pogut trobar que aquells pacients CMV- sense tractament, presenten una correlació significativament negativa entre el percentatge de les cèl·lules CD56bright respecte al total del compartiment NK, la qual al no estar sota la influència de CMV ni de tractament, està causada per algun factor estrictament lligat a la malaltia, fet del qual no se’n havien presentat evidències significatives fins ara. Tot i que aquests resultats, a la vegada de ser molt interessants, recolzen la hipòtesi base, no s’han trobat resultats significatius per a NKG2A i els resultats per a ILT2 són significatius però no concloents. Igualment però, aquests resultats són molt prometedors, i pensem que seria interesant continuar treballant en aquestes troballes.

Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

Background Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (KATP) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of KATP channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Methods Anti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNy)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration. Results Diazoxide inhibited in vitro nitric oxide (NO), tumor necrosis factor alpha (TNF-¿) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord. Conclusion Taken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease.