In order to characterize the regulation of the gene encoding the p50 subunit of the transcription factor NF‐kappa B, we have isolated a human genomic clone, and sequenced the promoter of this gene. By in situ hybridization we have mapped the gene encoding the p50 subunit of NF‐kappa B to the 4q23‐4q25 region of the human genome and the H1‐H3 region of the murine chromosome 3. The p50 promoter lacks TATA and CAAT elements, but contains NF‐kappa B, AP‐1 and HIP‐1 binding sequence. The kappa B motif binds NF‐kappa B, KBF1, and heterodimers of p50 and c‐rel, suggesting that the gene is regulated by members of this family. Co‐transfection experiments demonstrate that the p50 promoter can be activated by either of the two subunits of NF‐kappa B (p50 and p65), and more strongly by the combination of both. The promoter of p50 can be activated by phorbol esters and tumor necrosis factor alpha but not by forskolin and these responses are mediated through the NF‐kappa B binding sequence. The involvement of NF‐kappa B in the regulation of the p50 gene is also supported by the inhibition of the PMA activation of the promoter by an NF‐kappa B transdominant negative mutant, as well as the product of the v‐rel oncogene.

BackgroundHypertrophic cardiomyopathy is the most prevalent heart disorder in cats and principal cause of cardiovascular morbidity and mortality. Yet, the impact of preclinical disease is unresolved.Hypothesis/ObjectivesObservational study to characterize cardiovascular morbidity and survival in cats with preclinical nonobstructive (HCM) and obstructive (HOCM) hypertrophic cardiomyopathy and in apparently healthy cats (AH).AnimalsOne thousand seven hundred and thirty client‐owned cats (430 preclinical HCM; 578 preclinical HOCM; 722 AH).MethodsRetrospective multicenter, longitudinal, cohort study. Cats from 21 countries were followed through medical record review and owner or referring veterinarian interviews. Data were analyzed to compare long‐term outcomes, incidence, and risk for congestive heart failure (CHF), arterial thromboembolism (ATE), and cardiovascular death.ResultsDuring the study period, CHF, ATE, or both occurred in 30.5% and cardiovascular death in 27.9% of 1008 HCM/HOCM cats. Risk assessed at 1, 5, and 10 years after study entry was 7.0%/3.5%, 19.9%/9.7%, and 23.9%/11.3% for CHF/ATE, and 6.7%, 22.8%, and 28.3% for cardiovascular death, respectively. There were no statistically significant differences between HOCM compared with HCM for cardiovascular morbidity or mortality, time from diagnosis to development of morbidity, or cardiovascular survival. Cats that developed cardiovascular morbidity had short survival (mean ± standard deviation, 1.3 ± 1.7 years). Overall, prolonged longevity was recorded in a minority of preclinical HCM/HOCM cats with 10% reaching 9‐15 years.Conclusions and Clinical ImportancePreclinical HCM/HOCM is a global health problem of cats that carries substantial risk for CHF, ATE, and cardiovascular death. This finding underscores the need to identify therapies and monitoring strategies that decrease morbidity and mortality.

Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1β), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS) white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.

OBJECTIVESThere is a growing understanding of the complexity of interplay between renal and cardiovascular systems in both health and disease. The medical profession has adopted the term “cardiorenal syndrome” (CRS) to describe the pathophysiological relationship between the kidney and heart in disease. CRS has yet to be formally defined and described by the veterinary profession and its existence and importance in dogs and cats warrant investigation. The CRS Consensus Group, comprising nine veterinary cardiologists and seven nephrologists from Europe and North America, sought to achieve consensus around the definition, pathophysiology, diagnosis and management of dogs and cats with “cardiovascular-renal disorders” (CvRD). To this end, the Delphi formal methodology for defining/building consensus and defining guidelines was utilised.METHODSFollowing a literature review, 13 candidate statements regarding CvRD in dogs and cats were tested for consensus, using a modified Delphi method. As a new area of interest, well-designed studies, specific to CRS/CvRD, are lacking, particularly in dogs and cats. Hence, while scientific justification of all the recommendations was sought and used when available, recommendations were largely reliant on theory, expert opinion, small clinical studies and extrapolation from data derived from other species.RESULTSOf the 13 statements, 11 achieved consensus and 2 did not. The modified Delphi approach worked well to achieve consensus in an objective manner and to develop initial guidelines for CvRD.DISCUSSIONThe resultant manuscript describes consensus statements for the definition, classification, diagnosis and management strategies for veterinary patients with CvRD, with an emphasis on the pathological interplay between the two organ systems. By formulating consensus statements regarding CvRD in veterinary medicine, the authors hope to stimulate interest in and advancement of the understanding and management of CvRD in dogs and cats. The use of a formalised method for consensus and guideline development should be considered for other topics in veterinary medicine.

Despite efficient antiretroviral therapy (ART), CD4+ T cell counts often remain low in HIV-1-infected patients. This has led to IL-7, a crucial cytokine involved in both thymopoiesis and peripheral T cell homeostasis, being suggested as an additional therapeutic strategy. We investigated whether recombinant simian IL-7-treatment enhanced the T cell renewal initiated by ART in rhesus macaques chronically infected with SIVmac251. Six macaques in the early chronic phase of SIV infection received antiretroviral treatment. Four macaques also received a 3-wk course of IL-7 injections. Viral load was unaffected by IL-7 treatment. IL-7 treatment increased the number of circulating CD4+ and CD8+ memory T cells expressing activation (HLA-DR+, CD25+) and proliferation (Ki-67+) markers. It also increased naive (CD45RAbrightCD62L+) T cell counts by peripheral proliferation and enhanced de novo thymic production. The studied parameters returned to pretreatment values by day 29 after the initiation of treatment, concomitantly to the appearance of anti-IL-7 neutralizing Abs, supporting the need for a nonimmunogenic molecule for human treatment. Thus, IL-7, which increases T cell memory and de novo renewal of naive T cells may have additional benefits in HIV-infected patients receiving ART.

Infection by the human immunodeficiency virus (HIV-1) causes chronic ongoing inflammation in HIV-1 seropositive individuals as shown by high plasma levels of inflammatory cytokines and production of reactive oxygen intermediates (ROIs). One source of ROIs is provided from the very early stages of HIV infection by activated polymorphonuclear neutrophils. Tat, the viral protein, is also specifically responsible for an endogenous cellular increase of ROI. In this review we also evaluate the effects of this oxidative stress on various biological parameters such as immune response and survival of T lymphocytes, virus transcription and replication. It was clearly demonstrated in ex vivo experiments that the oxidative stress due to infection itself participates in CD4+ T lymphocyte depletion by increasing their rate of apoptosis and particularly of Fas-induced apoptosis. This oxidative stress also facilitates NF-kappa B-dependent activation of HIV transcription. In vitro studies suggest that the early steps of HIV activation from its quiescent state might be subsequently facilitated by this oxidative environment. Whereas already active replication is not influenced. The data presented here lead to a better understanding of the consequences of oxidative stress on the pathophysiology of HIV infection and also enable us to evaluate the potential use of antioxidant molecules as therapeutic agents against AIDS.

The KBF1 factor, which binds to the enhancer A located in the promoter of the mouse MHC class I gene H‐2Kb, is indistinguishable from the p50 DNA binding subunit of the transcription factor NF‐kappa B, which regulates a series of genes involved in immune and inflammatory responses. The KBF1/p50 factor binds as a homodimer but can also form heterodimers with the products of other members of the same family, like the c‐rel and v‐rel (proto)oncogenes. The dimerization domain of KBF1/p50 is contained between amino acids 201 and 367. A mutant of KBF1/p50 (delta SP), unable to bind to DNA but able to form homo‐ or heterodimers, has been constructed. This protein reduces or abolishes in vitro the DNA binding activity of wild‐type proteins of the same family (KBF1/p50, c‐ and v‐rel). This mutant also functions in vivo as a trans‐acting dominant negative regulator: the transcriptional inducibility of the HIV long terminal repeat (which contains two potential NF‐kappa B binding sites) by phorbol ester (PMA) is inhibited when it is co‐transfected into CD4+ T cells with the delta SP mutant. Similarly the basal as well as TNF or IL1‐induced activity of the MHC class I H‐2Kb promoter can be inhibited by this mutant in two different cell lines. These results constitute the first formal demonstration that these genes are regulated by members of the rel/NF‐kappa B family.

IntroductionAlzheimer’s disease (AD) is associated with the accumulation of β-amyloid (Aβ) as senile plaques in the brain, thus leading to neurodegeneration and cognitive impairment. Plaque formation depends not merely on the amount of generated Aβ peptides, but more importantly on their effective removal. Chronic infections with neurotropic pathogens, most prominently the parasite Toxoplasma (T.) gondii, are frequent in the elderly, and it has been suggested that the resulting neuroinflammation may influence the course of AD. In the present study, we investigated how chronic T. gondii infection and resulting neuroinflammation affect plaque deposition and removal in a mouse model of AD.ResultsChronic infection with T. gondii was associated with reduced Aβ and plaque load in 5xFAD mice. Upon infection, myeloid-derived CCR2hi Ly6Chi monocytes, CCR2+ Ly6Cint, and CCR2+ Ly6Clow mononuclear cells were recruited to the brain of mice. Compared to microglia, these recruited mononuclear cells showed highly increased phagocytic capacity of Aβ ex vivo. The F4/80+ Ly6Clow macrophages expressed high levels of Triggering Receptor Expressed on Myeloid cells 2 (TREM2), CD36, and Scavenger Receptor A1 (SCARA1), indicating phagocytic activity. Importantly, selective ablation of CCR2+ Ly6Chi monocytes resulted in an increased amount of Aβ in infected mice. Elevated insulin-degrading enzyme (IDE), matrix metalloproteinase 9 (MMP9), as well as immunoproteasome subunits β1i/LMP2, β2i/MECL-1, and β5i/LMP7 mRNA levels in the infected brains indicated increased proteolytic Aβ degradation. Particularly, LMP7 was highly expressed by the recruited mononuclear cells in the brain, suggesting a novel mechanism of Aβ clearance.ConclusionsOur results indicate that chronic Toxoplasma infection ameliorates β-amyloidosis in a murine model of AD by activation of the immune system, specifically by recruitment of Ly6Chi monocytes and by enhancement of phagocytosis and degradation of soluble Aβ. Our findings provide evidence for a modulatory role of inflammation-induced Aβ phagocytosis and degradation by newly recruited peripheral immune cells in the pathophysiology of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0293-8) contains supplementary material, which is available to authorized users.