Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease.

Gestational vitamin A (retinol) deficiency poses a risk for ocular birth defects and blindness. We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia. The mutant phenotypes exhibit dominant inheritance, but incomplete penetrance. Maternal transmission significantly increases the probability of phenotypic expression. RBP normally delivers retinol from hepatic stores to peripheral tissues, including the placenta and fetal eye. The disease mutations greatly reduce retinol binding to RBP, yet paradoxically increase the affinity of RBP for its cell surface receptor, STRA6. By occupying STRA6 nonproductively, the dominant-negative proteins disrupt vitamin A delivery from wild-type proteins within the fetus, but also, in the case of maternal transmission, at the placenta. These findings establish a previously uncharacterized mode of maternal inheritance, distinct from imprinting and oocyte-derived mRNA, and define a group of hereditary disorders plausibly modulated by dietary vitamin A.

Pars plana vitrectomy with endoscope-guided sutured posterior chamber intraocular lens implantation in children and adults.

PURPOSE: To describe a novel method for placement of a sulcus-fixated, sutured posterior chamber intraocular lens (sf-SPC-IOL) using endoscopic guidance during pars plana vitrectomy surgery. DESIGN: A retrospective case-series by a single surgeon in both pediatric and adult patients undergoing sf-SPC-IOL in the setting of posterior segment surgery. METHODS: Seventy-four eyes of 71 patients had pars plana vitrectomy and placement of an sf-SPC-IOL in an academic, outpatient setting. Preoperative diagnosis included trauma (42%), subluxated lenses with no capsular support (24%), uveitis (15%), congenital cataract (11%), Marfan syndrome or ectopia lentis (6%), and other (2%). Fifty-one adults and 20 children (<18 years of age) were reviewed from cases performed from 1999 through 2007. The sf-SPC-IOL sutures were placed using endoscopic visualization of ab interno scleral fixation. RESULTS: The mean follow-up time was nearly 3 years (3 months to 9 years) and most patients experienced an improvement in visual function. Many eyes had advanced posterior segment disorders. Only 2 broken sutures occurred, both attributable to repeat trauma. Advantages of this technique include: excellent visualization and haptic localization, optimal lens centration, buried knots, broad scleral imbrication, and minimal vitreous- and hemorrhage-related complications. Disadvantages include the learning curve, increased operative time, long-term suture stability issues, and limited availability of intraocular endoscopes. CONCLUSIONS: Endoscopic-guided sf-SPC-IOL using this approach, in the setting of posterior segment disease, is a reasonable option for visual rehabilitation in both pediatric and adult patients.

Multiple intracranial meningiomas causing papilledema and visual loss in a patient with nevoid Basal cell carcinoma syndrome.

A 27-year-old man with nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) who had undergone craniospinal irradiation for a childhood brain stem medulloblastoma complained of progressive binocular visual loss. Ophthalmologic examination disclosed subnormal visual acuity and visual fields in both eyes attributed to chronic papilledema. Brain MRI demonstrated mass effect from multiple large meningiomas. After embolization and surgical resection of the largest meningioma, papilledema disappeared and visual dysfunction resolved partially. This is the sixth reported patient with NBCCS, medulloblastoma, and craniospinal radiation who has developed intracranial meningioma, further documenting the fact that such patients have a relatively high likelihood of developing meningiomas, especially multiple meningiomas. Because patients with NBCCS are often mentally impaired and because papilledema can progress silently before causing irreversible visual loss, periodic ophthalmologic examination is advisable after craniospinal radiation.

Integrins and T cell-mediated immunity.

Integrin receptors mediate adhesive events that are critical for a specific and effective immune response to foreign pathogens. Integrin-dependent interactions of lymphocytes and antigen-presenting cells (APCs) to endothelium regulate the efficiency and specificity of trafficking into secondary lymphoid organs and peripheral tissue. Within these sites, integrins facilitate cell movement via interactions with the extracellular matrix, and promote and stabilize antigen-specific interactions between T lymphocytes and APCs that are critical for initiating T cell-activation events. In this review, we discuss the role of integrins in T cell-mediated immunity, with a focus on how these receptors participate in lymphocyte recirculation and T cell activation, how antigen stimulation regulates integrin activity, and how integrins define functionally unique subsets of T cells and APCs.

The alpha 1 beta 1 and alpha E beta 7 integrins define a subset of dendritic cells in peripheral lymph nodes with unique adhesive and antigen uptake properties.

Dendritic cells (DCs) are a heterogeneous population of APCs with critical roles in T cell activation and immune regulation. We report in this study the identification and characterization of a novel subset of DCs resident in skin-draining peripheral lymph nodes of normal mice. This subset of CD11c(high)CD40(high)CD8alpha(intermediate (int)) DCs expresses the collagen-binding integrin, alpha1beta1, and the E-cadherin-binding integrin, alphaEbeta7. Although alpha1beta1 and alphaEbeta7 are also expressed on CD11c(high)CD40(int)CD8alpha(high) lymphoid DCs, CD11c(high)CD40(high)CD8alpha(int) DCs demonstrate preferential integrin-mediated adhesion to collagen and fibronectin. This DC subset most likely acquires expression of these integrins in peripheral lymph node, as this subset is not found in the spleen or mesenteric lymph node, and recent DC migrants from the skin lack expression of alpha1beta1 and alphaEbeta7 integrins. Resident CD40(high) DCs express alpha1beta1 integrin and colocalize with collagen in lymph nodes. When compared with CD11c(high)CD40(high)CD8alpha(int) DCs lacking expression of these integrins, the alpha1beta1+alphaEbeta7+DC subset exhibits more efficient formation of Ag-independent conjugates with T cells, and a decreased ability to acquire soluble Ag. Thus, the alpha1beta1 and alphaEbeta7 integrins define a unique population of peripheral lymph node-derived DCs with altered functional properties and adhesive potential that localizes these cells to sites in lymph nodes where Ag presentation to T cells occurs.

Signal transduction events regulating integrin function and T cell migration: new functions and complexity.

Integrin receptors facilitate T cell function by mediating adhesive events critical for T cell trafficking and recognition of foreign antigen, including interactions with vascular endothelium, extracellular matrix components, and antigen-presenting cells. Consequently, the functional activity of integrin receptors is acutely regulated by various intracellular signals delivered by other cell surface receptors, resulting in rapid changes in T cell adhesion and migration. This review highlights recent insights into our understanding of the signaling events by which the CD3/T cell receptor complex and chemokine receptors regulate integrin function and T cell migration. These studies highlight novel functions for several signaling molecules, including the tyrosine kinases Itk and ZAP-70, and the adapter protein SLAP-130/Fyb. In addition, analysis of the regulation of integrin function and chemokine-mediated migration has highlighted the critical role that spatial localization of signaling molecules plays in signal transduction, and the importance of the actin cytoskeleton in T cell function.