Viruses are the most abundant and diverse biological entities in the planet. Historically, our main interest in viruses has focused on their pathogenic role, recognized by pandemics that have decimated the world population. However, viral infections have also played a major role in the evolution of cellular organisms, both through interchanging of genes with novel functions and shaping the immune system. Examples abound of infections that seriously compromise the host integrity, but evidence of plant and insect viruses mutualistic relationships have recently surfaced in which infected hosts are better suited for survival, arguing that virus-host interactions are initially parasitic but become mutualistic over years of co-evolution. A similar mutual help scenario has emerged with commensal gut bacteria. EBV is a herpesvirus that shares more than a hundred million years of co-evolution with humans, today successfully infecting close to 100% of the adult world population. Infection is usually acquired early in childhood persisting for the host lifetime mostly without apparent clinical symptoms. Disturbance of this homeostasis is rare and results in several diseases, of which the best understood are infectious mononucleosis and several EBV-associated cancers. Less understood are recently found inborn errors of the immune system that result in primary immunodeficiencies with an increased predisposition almost exclusive to EBV-associated diseases. Puzzling to these scenarios of broken homeostasis is the co-existence of immunosuppression, inflammation, autoimmunity and cancer. Homologous to EBV, HCMV, HHV-6 and HHV-7 are herpesviruses that also latently infect most individuals. Several lines of evidence support a mutualistic equilibrium between HCMV/EBV and hosts, that when altered trigger diseases in which the immune system plays a critical role. Interestingly, these beta and gamma herpesviruses persistently infect all immune lineages and early precursor cells. In this review, we will discuss the evidence of the benefits that infection of immune cells with these herpesviruses brings to the host. Also, the circumstances in which this positive relationship is broken, predisposing the host to diseases characterized by an abnormal function of the host immune system.
The action of bradykinin was studied in rat-1 fibroblasts stably expressing alpha1b-adrenoceptors. It was observed that bradykinin and kallidin markedly increase cytosol calcium concentration, but that the B1 agonist, des-Arg9-bradykinin, only mimicked this effect to a minimal extent. Antagonists, selective for the B2 subtype, such as Hoe 140, blocked this effect of bradykinin and kallidin. Similarly, bradykinin and kallidin stimulated the production of inositol phosphates and B2 antagonists blocked their actions. The possibility that bradykinin could modulate alpha1b-adrenoceptors was studied. It was observed that bradykinin and kallidin increased alpha1b-adrenoceptor phosphorylation and that such effect was also blocked by Hoe 140. Interestingly, the ability of norepinephrine to increase intracellular calcium concentration was not altered by pretreatment of the cells with bradykinin, i.e. bradykinin induced alpha1b-adrenoceptor phosphorylation but this did not lead to receptor desensitization.
Acute lymphoblastic leukemia (ALL) is the most common cancer in children around the globe. Mexico City has one of the highest incidence rates of childhood leukemia worldwide with 49.5 cases per million children under the age of 15 which is similar to that reported for
Background Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS). Objective The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified. Methods We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2 R229Q/R229Q ( Rag2 R229Q ) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt. Results We show that memory/activated T cells from patients with OS and from the Rag2 R229Q mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad T h 1/T h 2/T h 17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2 R229Q mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2 R229Q mice results in increased frequency of Ccr4 + splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by T h 1 effector T cells. Conclusions These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS.
CD43 is an abundant cell surface sialoglycoprotein implicated in hemopoietic cell adhesion and activation. Cell stimulation through CD43 results in recruitment of different signaling proteins, including members of the Src family kinases, Syk, phospholipase Cγ2, the adapter protein Shc, the guanine nucleotide exchange factor Vav, and activation of protein kinase C. In this study, we report that in human T lymphocytes, the ζ-chain is part of the CD43 signaling pathway. Upon CD43 engagement, the ζ-chain was tyrosine-phosphorylated, generating docking sites for tyrosine-phosphorylated ζ-associated protein of 70 kDa and Vav. In vitro kinase assays suggested that ζ-associated protein of 70 kDa could account for the kinase activity associated with the ζ-chain following CD43 engagement. Cross-linking CD43 on the surface of the Lck-deficient JCaM.1 cells failed to phosphorylate the ζ-chain and associated proteins, suggesting that Lck is a key element in the CD43 signaling pathway leading to ζ phosphorylation. CD43 engagement with beads coated with anti-CD43 mAb resulted in concentration of the ζ-chain toward the bead attachment site, but interestingly, the distribution of the T cell Ag receptor complex remained unaffected. Recruitment of the ζ-chain through CD43-mediated signals was not restricted to T lymphocytes because phosphorylation and redistribution of the ζ-chain was also observed in NK cells. Our results provide evidence that the ζ-chain functions as a scaffold molecule in the CD43 signaling pathway, favoring the recruitment and formation of downstream signaling complexes involved in the CD43-mediated cell activation of T lymphocytes and other leukocytes such as NK cells.
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