Commentary
Abstract
Infantile cortical hyperostosis (also known as Caffey disease) is characterized by hyperirritability, acute inflammation of soft tissues, and profound alterations of the shape and structure of the underlying bones, particularly the long bones, mandible, clavicles, or ribs. In this issue of the JCI, Gensure et al. undertook fine mapping of the genetic locus for this disease in a large kindred of individuals with the autosomal dominant form of the condition. The authors found a novel missense mutation in COL1A1, the gene encoding the α1 chain of type I collagen, in all affected individuals in 3 discrete pedigrees. This is a surprising finding, as all other reported mutations affecting the synthesis of type I collagen lead to conditions such as osteogenesis imperfecta and Ehlers-Danlos syndrome, in which quantitative or qualitative defects in type I collagen synthesis give rise to bone fragility and/or connective tissue hyperextensibility. The deleterious effect of the mutation on collagen fibril morphology is demonstrated; however, the precise functional link between the reported missense mutation and the localized inflammation and hyperostosis seen in Caffey disease awaits future studies.
Authors
Francis H. Glorieux
Abstract
Almost a quarter of a century ago, Oldstone and colleagues proposed that infection of cells by noncytopathic viruses may lead to an alteration of the cells’ ability to produce certain products or perform certain tasks, i.e., inhibition of “luxury function.” In this issue of the JCI, this topic has been revisited by Yamano et al., who demonstrate that human T cell lymphotropic virus type I (HTLV-I) infection of CD4+CD25+ Tregs in patients with HTLV-I–associated myelopathy/tropical spastic paraparesis (HAM/TSP) results in a decrease in FOXP3 mRNA and protein expression. This leads to the inability of HTLV-I–infected CD4+CD25+ Tregs to inhibit the proliferation of CD4+CD25− Tregs, due to the effect of the HTLV-I tax gene. Defects in the Treg population could be responsible for the large numbers of virus-specific T cells and occurrence of lymphoproliferation and inflammatory autoimmune disease in HAM/TSP patients.
Authors
Robert S. Fujinami
Abstract
T and NK cells collaborate to control viral infections, discerning minute differences between infected and uninfected cells. At the same time, viruses have evolved to escape this discovery. In this issue of the JCI, Ganem and colleagues show that Kaposi sarcoma–associated herpesvirus (KSHV) inhibits CD1d presentation to T cells. This novel immune evasion strategy highlights the importance of CD1d-restricted T cells in controlling viral infection and raises an interesting question: how do T cells recognize viruses in the context of CD1 molecules that bind lipids? In the case of herpesviruses, alterations in endosomal trafficking might trigger redistribution of CD1/lipid complexes to cell surfaces, thereby promoting recognition by CD1d-restricted T cells.
Authors
Nagendra R. Hegde, David C. Johnson
Abstract
Knowledge of the pathophysiology of immunobullous diseases has been advanced by the demonstration that passive transfer of antibodies against skin autoantigens can induce blisters in experimental animals with clinical, histologic, and immunopathologic features similar to those seen in human patients. In this issue of the JCI, Liu et al. extend their earlier observations regarding an experimental murine model of bullous pemphigoid by showing that the plasminogen/plasmin signaling cascade synergizes with MMP-9 during the early phase of antibody-induced blister formation in vivo. In a separate study, Sitaru et al. show for the first time to my knowledge that passive transfer of experimental antibodies against type VII collagen create subepidermal blisters in mice that mimic those seen in patients with epidermolysis bullosa acquisita (see the related article beginning on page 870). While the articles by Liu, Sitaru, and their colleagues identify pathways of inflammation and tissue injury that, if interrupted, may abrogate blister formation, in a third study, Payne et al. utilized phage display technologies to isolate human anti-desmoglein monoclonal antibodies from a patient with pemphigus vulgaris and show that such antibodies have restricted patterns of heavy and light chain gene usage — findings suggesting that autoantibodies may represent an additional target for therapeutic interventions in patients with immunobullous diseases (see the related article beginning on page 888).
Authors
Kim B. Yancey
Abstract
Every cell in the body expresses a set of proteins designed to trigger permeabilization of the mitochondria and cell death. Inactivation or inappropriate triggering of these pathways is increasingly recognized as a contributor to human disease. A study in this issue of the JCI demonstrates that IL-6 exerts its protective effect against the development of lung injury following exposure of mice to 95% O2 by increasing the expression of a Bcl-2–related protein, A1. This protein acts to prevent mitochondrial membrane permeabilization and cell death following exposure to hyperoxia. The data in this study lend support to the hypothesis that inappropriate triggering of cell-death pathways may contribute to the development of hyperoxic pulmonary edema, lung injury, and respiratory failure.
Authors
G.R. Scott Budinger, Jacob I. Sznajder
Abstract
Rare mutations in MEF2A have been proposed as a cause of coronary artery disease (CAD) and myocardial infarction (MI). In this issue of the JCI, Pennacchio and colleagues report sequencing MEF2A in 300 patients with premature CAD and in controls. Only 1 CAD patient was found to carry a missense mutation not found in controls. The specific 21-bp deletion in MEF2A previously proposed as causal for CAD and/or MI was observed in unaffected individuals and did not segregate with CAD in families. These results do not support the hypothesis that mutations in MEF2A are a cause of CAD and/or MI but do illustrate general principles regarding the difficulty of connecting genetic variation to common diseases.
Authors
David Altshuler, Joel N. Hirschhorn
Abstract
In this issue of the JCI, Niedermaier and colleagues demonstrate that a chromosomal inversion in mice results in dysregulation of Sonic hedgehog (Shh), such that Shh is ectopically expressed in a skeletogenic domain typically occupied by Indian hedgehog (Ihh). This molecular reversal eliminates phalangeal joint spaces, and consequently, Short digits (Dsh) heterozygotes (Dsh/+) have brachydactyly (shortened digits). Ihh is normally downregulated in regions that will become the joint space, but in Dsh/+ mice, Shh bypasses this regulatory control and persists; accordingly, cells maintain their chondrogenic fate and the developed digits are shorter than normal. The significance of these data extends far beyond the field of skeletal biology: they hint at the very real possibility that the endogenous Shh regulatory region contains a repressor designed to segregate the activity of Shh from Ihh. The existence of such a repressor provides a window into the distant past, revealing that Shh and Ihh must once have shared responsibilities in establishing tissue boundaries and orchestrating vertebrate tissue morphogenesis.
Authors
Luis de la Fuente, Jill A. Helms
Abstract
In systemic lupus erythematosus (SLE), IL-2 production by T lymphocytes in vitro is impaired. Deficient IL-2 production may be an outcome of a primary SLE T cell disorder that is due to impaired signal transduction. In this issue of the JCI, evidence is presented that an anti-TCR/CD3 complex autoantibody present in SLE sera can bind to T cells and activate the Ca2+-calmodulin kinase IV (CaMKIV) signaling cascade, resulting in downregulation of IL-2 transcription and IL-2 production. Because IL-2 may contribute to the maintenance of T cell tolerance, deficient IL-2 production could promote a breach of T cell tolerance that results in autoantibody production in SLE.
Authors
Gary M. Kammer
Abstract
Blood pressure abnormalities are thought to originate from intrinsic changes in the kidney, a concept that has been largely unchallenged for more than 4 decades. However, recent molecular, cellular, and transgenic mouse studies support an alternative hypothesis: primary abnormalities in vascular cell function can also directly cause abnormalities of blood pressure. In this issue of the JCI, Crowley and coworkers describe the application of an elegant cross-renal transplant model to type 1A angiotensin (AT1A) receptor–deficient mice and their wild-type littermates to explore the relative contributions of renal and extrarenal tissues to the low blood pressure seen in the AT1A receptor–deficient animals. Their studies further support the emerging paradigm that primary abnormalities of the vasculature can make unique, nonredundant contributions to blood pressure regulation; the findings have potentially important implications for the ways we diagnose and treat blood pressure diseases in humans.
Authors
Michael E. Mendelsohn
Abstract
The hypothalamic-pituitary-adrenal axis (a major component of the stress system) and the immune system contribute to the maintenance of homeostasis at rest and during stress. Because of their essential roles for the survival of self and species, the activities of these systems have evolutionarily developed in parallel and are intertwined at many levels. In this issue of the JCI, Ezzat et al. demonstrate that Ikaros, a differentiation factor of leukocyte lineage, also influences the maturation of the fetal pituitary corticotroph and, hence, the secretion of adrenocorticotropic hormone before and after birth. These results indicate that Ikaros is an ontogenetic and phylogenetic integrator of the stress and immune systems and that abnormalities in its function may produce endocrine and/or immune pathologies.
Authors
George P. Chrousos, Tomoshige Kino
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