Abdominal aortic aneurysms are common and life threatening. Although CD4+ T cells are abundant in aneurysm tissue, their role in disease progression remains unclear. A new study shows that mouse aortic allografts placed in animals lacking IFN-γ receptors develop a Th2 inflammatory response with aortic aneurysms, whereas Th1 responses promote intimal hyperplasia. It is expected that these surprising findings will stimulate further efforts to clarify whether adaptive cellular immunity in aneurysm disease is detrimental or potentially beneficial.
John A. Curci, Robert W. Thompson
Although the mechanisms of immune-mediated pregnancy loss are unknown, investigations are currently focused on mediators of immune activation and tissue injury at the maternal-fetal interface. A new study, however, demonstrates that systemic inflammatory mediators can induce pregnancy failure in a different way, by inhibiting ovarian hormone production, and identifies links between the immune and reproductive endocrine systems.
Jane E. Salmon
Circulating platelets are continually replenished by fragmentation of terminally differentiated megakaryocytes. Processes disrupted in inherited thrombocytopenias frequently shed light on normal thrombopoietic mechanisms. An especially rare condition called Paris-Trousseau syndrome (PTS) seems to occur by virtue of hemizygous loss of the FLI1 transcription factor gene. Provocative new data suggest that FLI1 shows monoallelic expression during a brief window in megakaryocyte differentiation, which thus explains the dominant inheritance pattern of PTS despite the presence of one normal FLI1 allele .
Ramesh A. Shivdasani
In several clinical disorders, there are interactions between inflammation-dependent tissue injury and thrombin formation, fibrin deposition, and impaired fibrinolysis. New evidence generated from a mouse model of allergic airway hyperreactivity suggests that disordered coagulation and fibrinolysis may contribute to the pathogenesis of asthma . The inflammatory mechanisms that lead to airway smooth muscle contraction and airway hyperresponsiveness may be associated with accumulation of extravascular fibrin, plasma exudates, and inflammatory cells that can lead to airway closure.
Michael A. Matthay, John A. Clements
Increasing evidence suggests that selective neuronal loss in neurodegenerative diseases involves activation of cysteine aspartyl proteases (caspases), which initiate and execute apoptosis. In Alzheimer disease both extracellular amyloid deposits and intracellular amyloid β protein may activate caspases, leading to cleavage of nuclear and cytoskeletal proteins, including tau protein. Proteolysis of tau may be critical to neurofibrillary degeneration, which correlates with dementia.
Dennis W. Dickson
Cleft lip and palate is a common human birth defect, and its causes are being dissected through studies of human populations and through the use of animal models. Mouse models in particular have made a substantial contribution to our understanding of the gene pathways involved in palate development and the nature of signaling molecules that act in a tissue-specific manner at critical stages of embryogenesis. Related work has provided further support for investigating the role of common environmental triggers as causal covariates.
Jeffrey C. Murray, Brian C. Schutte
The genetic basis for the attenuation of polio vaccines has been known since the 1980s. Changes in the internal ribosome entry site, within the 5′ noncoding region of genomic RNAs, were presumed to reduce translation in certain target organs, leading to the conclusion that attenuation is mediated at the level of translation. A report in this issue of the JCI reveals that poliovirus tropism is, in part, determined after internal ribosome entry.
Bert L. Semler
To test the hypothesis that chronic stimulation of T cells with a weak agonistic antigen will generate regulatory T cells and immune tolerance, a study reported in this issue employed the redesign of a minor histocompatibility antigen. Using knowledge of residues at which the antigen contacts the T cell receptor, a weak agonist was produced. Pretreatment with this altered antigen produced transplant tolerance, generation of regulatory T cells, and a loss of many antigen-reactive T cells.
Terry B. Strom
Numerous signaling pathways have been shown to mediate cardioprotection, but the end effectors that mediate protection are only beginning to be elucidated. Numerous cardioprotective drugs are shown to converge on glycogen synthase kinase-3β (GSK-3β) . The phosphorylation and inhibition of GSK-3β lead to inhibition or delayed activation of the mitochondrial permeability transition, a key regulator of apoptosis.
Elizabeth Murphy
The collecting ducts of the kidney are composed of intercalated cells (responsible for acid/base transport), principal cells (mediating salt and water absorption), and inner medullary cells, which mediate all three types of transport. Forkhead box (Fox) genes are a large family of transcription factors that are important in cell-type specification during organogenesis. In this issue, Blomqvist et al. find that mice lacking Foxi1 have no intercalated cells in the kidney . The collecting ducts of the null mice contained primitive cells that expressed both intercalated cell and principal cell proteins, yet the acid/base transport function of the kidney was disrupted and the mice exhibited distal renal tubular acidosis. These findings suggest that Foxi1 plays a critical role in determining cell identity during collecting duct development.
Qais Al-Awqati, George J. Schwartz
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