Preclinical characterization of the Toll-like receptor 7/8 antagonist MHV370 for lupus therapy.

Genetic and in vivo evidence suggests that aberrant recognition of RNA-containing autoantigens by Toll-like receptors (TLRs) 7 and 8 drives autoimmune diseases. Here we report on the preclinical characterization of MHV370, a selective oral TLR7/8 inhibitor. In vitro, MHV370 inhibits TLR7/8-dependent production of cytokines in human and mouse cells, notably interferon-α, a clinically validated driver of autoimmune diseases.

Disease Association of Anti‒Carboxyethyl Lysine Autoantibodies in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurring suppurating lesions of the intertriginous areas, resulting in a substantial impact on patients' QOL. HS pathogenesis remains poorly understood. An autoimmune component has been proposed, but disease-specific autoantibodies, autoantigens, or autoreactive T cells have yet to be described.

CARD10 cleavage by MALT1 restricts lung carcinoma growth in vivo.

CARD-CC complexes involving BCL10 and MALT1 are major cellular signaling hubs. They govern NF-κB activation through their scaffolding properties as well as MALT1 paracaspase function, which cleaves substrates involved in NF-κB regulation. In human lymphocytes, gain-of-function defects in this pathway lead to lymphoproliferative disorders.

Blockade of CD40-CD154 pathway interactions suppresses ectopic lymphoid structures and inhibits pathology in the NOD/ShiLtJ mouse model of Sjögren's syndrome.

Objective: To examine the role of CD40-CD154 costimulation and effects of therapeutic pathway blockade in the non-obese diabetic (NOD/ShiLtJ) model of Sjögren's syndrome (SS).

Methods: We assessed leucocyte infiltration in salivary glands (SGs) from NOD/ShiLtJ mice by immunohistochemistry and examined transcriptomics data of SG tissue from these animals for evidence of a CD40 pathway gene signature. Additionally, we dosed MR1 (anti-CD154 antibody) in NOD mice after the onset of SS-like disease and examined the effects of MR1 treatment on sialadenitis, autoantibody production, SG leucocyte infiltration, gene expression downstream of CD40 and acquaporin 5 (AQP5) expression.

Chronic antidepressants reverse cerebrocortical allopregnanolone decline in the olfactory-bulbectomized rat.

Olfactory bulbectomy is one of the most validated models of depression. We demonstrate that bilateral removal of the olfactory bulbs in rats produced a significant decline of allopregnanolone content in a select cerebrocortical area which was reversed by chronic (3-week) treatment with three different classes of antidepressant (desipramine, fluoxetine, and sertraline, and venlafaxine). The effects of the chronic antidepressant treatments on allopregnanolone cortical content are observed at a time which typically coincides with the drug's abilities to reverse the behavioral deficits of the bulbectomy syndrome.

Region-specific dysregulation of allopregnanolone brain content in the olfactory bulbectomized rat model of depression.

Allopregnanolone (ALLO) is one of the most potent positive endogenous allosteric modulators of the type A gamma-aminobutyric acid (GABA(A)) receptors. While the robust anxiolytic profile of ALLO has been extensively characterized in rodents and its antidepressant-like effect was recently demonstrated in mice, there have been only few reports on alterations of brain ALLO levels in putative animal models of depression and anxiety. Removal of the olfactory bulbs of rats produces one of the most predictive animal models with which to screen for drugs with potential antidepressant activity following repeated treatment.