A Patient with Eosinophilic Esophagitis and Herpes Simplex Esophagitis: A Case Report and Literature Review.

Acute herpes simplex esophagitis (HSE) is common in immunocompromised patients. Eosinophilic esophagitis (EoE) is characterized by immune-mediated eosinophil-predominant esophageal inflammation. We report a patient with human immunodeficiency virus infection who presented with dysphagia and odynophagia and was found to have HSE and EoE. The combination of these two relatively rare conditions suggests possible predisposition.

Post-developmental extracellular proteoglycan maintenance in attractin-deficient mice.

OBJECTIVE: Neurodegeneration and hair pigmentation alterations in mice occur consequent to aberrations at the Atrn locus coding for the transmembrane form of attractin. Earlier results pointed to a possible involvement in intracellular trafficking/export of secretory vesicles containing proteoglycan. Here we examined kidney and liver, both heavily dependent upon proteoglycan, of attractin-deficient mice to determine whether abnormalities were observed in these tissues. RESULTS: Histological and histochemical analysis to detect glycosylated protein identified a severe loss in attractin-deficient mice of extracellular proteoglycan between kidney tubules in addition to a loss of glycosylated material within the intratubular brush border. In the liver, extracellular matrix material was significantly depleted between hepatocytes together with swollen sinuses and aberrations in the proteoglycan-dependent space of Disse. These results are consistent with a generalized defect in extracellular proteoglycan deposition in Atrn-mutant mice and support previous reports suggesting a role for attractin in the secretory vesicle pathway.

Breast lymphoma complicating anti-tumor necrosis factor therapy in rheumatoid arthritis.

The relationship between anti-TNF therapy and development of lymphoma in Rheumatoid arthritis (RA) patients is controversial. However lymphomas of unusual types and sites have been reported among RA patients receiving anti-TNF therapy. Primary lymphoma of the breast is a rare entity and has never been reported to occur among RA patients taking anti-TNF therapy. This is the first case of primary lymphoma of the breast reported among RA patients on anti-TNF therapy. Rheumatoid arthritis patients currently on anti-TNF therapy should undergo routine gynecological examination.

Hepatic colorectal cancer metastases: imaging initial steps of formation in mice.

PURPOSE: To prospectively use optical imaging to study the cell-specific mechanisms of entrapment and subsequent growth of two human colon cancer cell lines differing in their propensity to form hepatic metastases. MATERIALS AND METHODS: In this Animal Care Committee-approved study, intravital optical imaging was performed in exteriorized livers of three groups of mice after intrasplenic inoculation of human colon cancer cells. Group 1 mice (control group; n=12) received a cell-maintaining solution only. Groups 2 and 3 (n=12 in each) were administered poorly (MIP-101 colon cancer cells) or highly (CX-1 colon cancer cells) metastatic cells. Imaging was performed on postinoculation days 0, 1, 3, and 6 to document sites and mechanisms of tumor cell entrapment and presence and sites of endothelial cell activation and of tumor cell interactions with systemic macrophages and Kupffer cells. Fluorescence intensity of Kupffer cells was compared by using the Mann-Whitney test. Immunohistochemistry served as the reference standard for all in vivo observations. RESULTS: Whereas both MIP-101 and CX-1 colon cancer cells adhered to periportal Kupffer cells, the CX-1 cells resulted in Kupffer cell activation, evidenced in vivo by increased visible peroxidase activity (P<.05). Only CX-1 cells were associated with subsequent downstream endothelial cell activation, evidenced by in vivo expression of E-selectin. By day 6, regression of periportal MIP-101 tumor growth correlated with ingrowth of systemic macrophages, while CX-1 tumor growth, originating in the outflow venous regions, correlated with translobular migration and ingrowth of activated Kupffer cells. CONCLUSION: Formation of hepatic colon cancer metastases is cancer cell-type specific, with cell lines differing in their mechanisms and intrahepatic locations of initial entrapment and Kupffer cell activation and subsequent growth.

Juvenile-onset loss of lipid-raft domains in attractin-deficient mice.

Mutations at the attractin (Atrn) locus in mice result in altered pigmentation on an agouti background, higher basal metabolic rate and juvenile-onset hypomyelination leading to neurodegeneration, while studies on human immune cells indicate a chemotaxis regulatory function. The underlying biochemical defect remains elusive. In this report we identify a role for attractin in plasma membrane maintenance. In attractin's absence there is a decline in plasma membrane glycolipid-enriched rafts from normal levels at 8 weeks to a complete absence by 24 weeks. The structural integrity of lipid rafts depends upon cholesterol and sphingomyelin, and can be identified by partitioning within of ganglioside GM(1). Despite a significant fall in cellular cholesterol with maturity, and a lesser fall in both membrane and total cellular GM(1), these parameters lag behind raft loss, and are normal when hypomyelination/neurodegeneration has already begun thus supporting consequence rather than cause. These findings can be recapitulated in Atrn-deficient cell lines propagated in vitro. Further, signal transduction through complex membrane receptor assemblies is not grossly disturbed despite the complete absence of lipid rafts. We find these results compatible with a role for attractin in plasma membrane maintenance and consistent with the proposal that the juvenile-onset hypomyelination and neurodegeneration represent a defect in attractin-mediated raft-dependent myelin biogenesis.

Immunoinflammatory responses and fibrogenesis.

In response to injury, tissues adjacent to the damaged area initiate a cascade of inflammatory and matrix remodeling events that are necessary to restore tissue integrity and function. The typical features of such healing effects in adult mammals are deposition of matrix proteins, which mature to scar tissues. In general, the wound healing response demonstrates certain commonalities across organs, but there are also organ-specific mechanisms. Such organ-specific controlled healing and uncontrolled tissue scarring are partly determined by the bioactivities of resident cells and local microenvironments, which are influenced by multiple factors, including the presence of specific types of cytokines (Th1 and Th2), chemokines, growth factors, cell-cell interaction, and reorganization of matrix proteins. In this article, we briefly present the relevance of Th1 and Th2 responses and the significance of interactions between matrix-producing cells and inflammatory cells during granuloma tissue and scar tissue formation.

Attractin: cautionary tales for therapeutic intervention in molecules with pleiotropic functionality.

First discovered as a circulating secreted molecule expressed by activated T lymphocytes, attractin was examined as a potential marker of immune activity. The discovery that a transmembrane form not only controls neuropeptide regulation of hair pigmentation in animals but also affects basal metabolism led to proposals that attractin may also be an extracellular target amenable for the development of obesity-regulating drugs. Examination of several animal mutants used as models ofjuvenile-onset neurodegeneration revealed mutations at the attractin locus as the cause, and the reassessment of earlier attractin mutants demonstrated that neurodegeneration, alterations in pigmentation regulation, and basal metabolic rate were common to all the allelic variants. The presentation and severity of the symptoms differ depending upon the mutation, and some may be variably penetrant even within an allelic line. In this report, we review our rapidly altering perception of the functional activity of attractin with each further addition to its sphere of physiological involvement. We further reappraise our concepts of the subcellular location of attractin, leading to a new proposal that provides a unifying mechanism for attractin's pleiotropic activities. Progress in elucidating each new aspect of attractin function provides a case study in the evolution of possible therapeutic interventions as well as illuminating some of the pitfalls of studying molecular pathways isolated from the whole organism physiology.

SKAP-55 regulates integrin adhesion and formation of T cell-APC conjugates.

Src kinase-associated phosphoprotein of 55 kDa (SKAP-55; encoded by SCAP1) is a T cell adaptor protein of unknown function that contains a pleckstrin homology and an SH3 domain. Here we show that SKAP-55 regulates integrin-mediated adhesion and conjugate formation between T cells and antigen-presenting cells (APCs). SKAP-55 enhances adhesion to fibronectin and intercellular adhesion molecule-1 (ICAM-1), colocalizes with actin at the T cell-APC synapse and promotes the clustering of lymphocyte-associated antigen-1 (LFA-1). Enhanced conjugation is comparable to that induced by adhesion and degranulation-promoting adaptor protein (ADAP), a binding partner of SKAP-55, and is abrogated by deletion of the SKAP-55 SH3 domain. Conjugate formation is accompanied by the translocation of SKAP-55 to membrane rafts, an event that is regulated by both LFA-1 and T cell receptor ligation. Our findings identify a mechanism by which SKAP-55 modulates T cell responses to antigen.