Several years ago it was proposed that the AMP-activated protein kinase cascade might protect cells against stresses that deplete cellular ATP. Young et al. have now directly tested this by studying the effects of ischemia and reperfusion in perfused hearts from mice expressing a dominant-negative mutant that suppresses the kinase activity in cardiac muscle. Compared with control hearts, the mutant hearts showed clear evidence for increased necrotic damage and increased apoptosis. These findings may have implications for the treatment of ischemic heart disease.
D. Grahame Hardie
Most antigens expressed by human cancer cells and recognized by host T cells and antibodies are nonmutated self antigens — molecules also expressed on the surface of normal cells. These self antigens are ineffective at triggering immune responses against cancer cells, which provides one explanation for the difficulties in trying to immunize against human cancer. A new study describes how tumors can avoid recognition by the immune system and how enhancing the affinity of the interaction between a self antigen and the MHC-I molecule may lead to cancer immunity.
Alan N. Houghton, José A. Guevara-Patiño
The etiology of autoimmunity in humans remains poorly defined, and animal models provide a unique opportunity to study potential autoimmune mechanisms. A novel model of autoimmune inflammatory arthritis results from a point mutation in the ζ-associated–protein of 70 kDa (ZAP-70), which causes abnormal thymic T cell selection and survival of autoreactive clones. Although the resulting clinical and pathologic abnormalities are clearly T cell–dependent, macrophage and fibroblast cytokines such as IL-1 and TNF-α are required for full expression of the disease. The studies of Hata et al. raise the intriguing possibility that traditional proinflammatory cytokine networks represent common effector mechanisms in inflammatory joint diseases such as rheumatoid arthritis. Hence, effective therapeutic interventions can target either unique etiologic pathways related to adaptive immune responses or shared terminal mechanisms.
Gary S. Firestein
Degeneration of brain tissue following stroke leads to functional impairment with limited brain self-repair. New evidence suggests that delivery of circulating CD34+ human umbilical cord blood cells can produce functional recovery in an animal stroke model with concurrent angiogenesis and neurogenesis leading to some restoration of cortical tissue. While some alternative interpretations of this data are offered herein, the study provides encouraging evidence of functional recovery from stroke in an animal model using stem cell therapy.
Daniel A. Peterson
Failure of the pancreas to secrete sufficient insulin results in type 2 diabetes, but the pathogenesis of pancreatic β cell dysfunction is still poorly understood. New insights into β cell failure come from defining the genes involved in rare genetic subtypes of diabetes and creating appropriate animal models. A new mouse model of transient neonatal diabetes mellitus emphasizes that both the number of β cells and their function are critical for insulin secretion and may be regulated by imprinted genes.
Andrew T. Hattersley
Oxidized LDL induces changes in several facets of the immune system, although the relationships between these facets and their contributions to atherogenesis have yet to be fully elucidated. A report in this issue of the JCI provides a novel demonstration of the adaptive immune system influencing the production of natural antibodies. The results demonstrate that injection of malondialdehyde-modified LDL promotes a Th2 response that in turn increases the titers of the natural antibody T15/EO6, which recognizes the oxidized phospholipid POVPC. Atherosclerotic lesion size in LDL receptor–deficient mice is reduced as a consequence of the increase in natural antibody titers, and IL-5 is identified as the link between the adaptive and natural immune systems.
Alan Daugherty, Debra L. Rateri, Victoria L. King
Pulmonary fibrosis is a devastating condition that leads to progressive lung destruction and scarring. Previous mechanistic research has focused on the local fibroproliferative process in the lung. However, emerging evidence suggests that circulating cells of hematopoietic origin play a crucial role in the pathogenesis of this disease .
Stavros Garantziotis, Mark P. Steele, David A. Schwartz
Although it has been known for more than a decade that Marfan syndrome — a dominantly inherited connective tissue disorder characterized by tall stature, arachnodactyly, lens subluxation, and a high risk of aortic aneurysm and dissection — results from mutations in the FBN1 gene, which encodes fibrillin-1, the precise mechanism by which the pleiotropic phenotype is produced has been unclear. A report in this issue now proposes that loss of fibrillin-1 protein by any of several mechanisms and the subsequent effect on the pool of TGF-β may be more relevant in the development of Marfan syndrome than mechanisms previously proposed in a dominant-negative disease model. The model proposed in this issue demonstrates several strategies for clinical intervention.
Peter H. Byers
Lipodystrophy and insulin resistance are the core features of human PPARγ deficiency states. Metabolic complications in PPARγ deficiency, such as hypertension, have been considered to be secondary to insulin resistance. However, a new mouse model that expresses the analog of a human PPARG mutation displays minimal lipodystrophy and insulin resistance but rather severe hypertension. Furthermore, the mutant protein appears to directly modulate the renin-angiotensin system in adipose tissue, providing evidence of the pleiotropic effects of PPARγ.
Robert A. Hegele, Todd Leff
New data support the importance of the innate immune response in the resolution or progression of pulmonary fibrosis. The presence of CXC chemokine receptor 3–expressing cells, specifically pulmonary NK cells, is necessary to produce IFN-γ. This is critical in the polarization of the immune response to injury toward a favorable Th1 response and resolution. In contrast, a Th2 response is associated with progressive fibrosis.
Robert M. Strieter, Michael P. Keane
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