Suhail Aamar

Interleukin-1 activity in lesioned peripheral nerve.

The cytokine interleukin-1 (IL-1) is involved in a wide range of inflammatory and immune responses. As such, IL-1 could play a role in peripheral nerve repair mechanisms. Specifically, by its already established properties as a regulator of nerve growth factor (NGF) synthesis, and as a chemotactant to macrophages. We examined, therefore, IL-1 production in injured mouse peripheral nerve. Injured nerve segments were incubated in serum free medium to produce conditioned medium (CM) that was then tested for IL-1 activity in a thymocyte proliferation assay. CM induced thymocyte proliferation in a dose-dependent manner. Proliferation was inhibited by the M20 IL-1 inhibitor, the IL-1 receptor antagonist, and antisera raised against recombinant mouse IL-1 alpha. Inhibitions produced by these three specific inhibitors of IL-1-induced thymocyte proliferation strongly suggest that proliferation induced by CM was mediated largely by IL-1 secreted by non-neuronal cells residing in the damaged nerve. IL-1 activity was detected within hours after lesion, and 1 week thereafter. The rapid and prolonged production of IL-1 indicates that IL-1-dependent mechanisms can play roles in the response of the peripheral nerve to injury: degeneration and regeneration. The regulation of NGF synthesis, and the recruitment of white blood cells, macrophages in particular, from blood into the damaged nerve tissue, are two such mechanisms.

The Involvement of CD44 and Its Novel Ligand Galectin-8 in Apoptotic Regulation of Autoimmune Inflammation

The synovial fluid (SF) cells of rheumatoid arthritis (RA) patients express a specific CD44 variant designated CD44vRA. Using a cellular model of this autoimmune disease, we show in this study that the mammalian lectin, galectin-8 (gal-8), is a novel high-affinity ligand of CD44vRA. By affinity chromatography, flow cytometry, and surface plasmon resonance, we demonstrate that gal-8 interacts with a high affinity (Kd, 6 × 10−9 M) with CD44vRA. We further demonstrate that SF cells from RA patients express and secrete gal-8, to a concentration of 25–65 nM, well within the concentration of gal-8 required to induce apoptosis of SF cells. We further show that not all gal-8 remains freely soluble in the SF and at least part forms triple complexes with CD44 and fibrinogen that can be detected, after fibrinogen immunoprecipitation, with Abs against fibrinogen, gal-8 and CD44. These triple complexes may therefore increase the inflammatory reaction by sequestering the soluble gal-8, thereby reducing its ability to induce apoptosis in the inflammatory cells. Our findings not only shed light on the receptor-ligand relationships between CD44 and gal-8, but also underline the biological significance of these interactions, which may affect the extent of the autoimmune inflammatory response in the SF of RA patients.

H syndrome: recently defined genodermatosis with distinct histologic features. A morphological, histochemical, immunohistochemical, and ultrastructural study of 10 cases.

This study analyzes the histopathological findings in H syndrome, a recently recognized autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin in well-defined anatomical areas accompanied by various systemic manifestations. So far, descriptions of the histopathological skin changes in this disorder, as reported in a few small case series, were inconsistent, leading to diverse clinical interpretations. In an attempt to define standardized, diagnostic, morphological criteria that will distinguish this disorder from other fibrosing conditions, we studied skin biopsies from 10 patients with H syndrome. The characteristic morphology included widespread fibrosis (moderate in dermis and severe in subcutis); striking mononuclear infiltrates consisting mainly of monocyte-derived cells (small CD68+ histiocytes and CD34+ and FXIIIa+ dendrocytes) and plasma cells; and thickened, fragmented, and partially calcified elastic fibers, admixed with well-formed psammoma bodies, a previously unrecognized feature in nonneoplastic skin and subcutaneous conditions. In addition, the ultrastructure of CD68+ small histiocytes exhibited distended endoplasmic reticulum and scarcity of lysosomes, features typical for fibroblasts but unusual for histiocytes. These unusual findings in the histiocytes pose a question as to their possible role in the fibrotic cascade in this disorder. We conclude that the above findings are essential for the diagnosis of H syndrome and that incisional biopsies are mandatory for recognition of the full spectrum of histopathological findings.

Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

Metabolic syndrome, leaky guts, and infection Metabolic syndrome often accompanies obesity and hyperglycemia and is associated with a breakdown in the integrity of the intestinal barrier and increased risk of systemic infection. Thaiss et al. found that mice with systemic infection of a Salmonella analog, Citrobacter rodentium, also exhibited hyperglycemia. Deletion of the glucose transporter GLUT2 altered sensitivity to chemically induced epithelial permeability and protected mice from pathogen invasion. The authors also found a correlation in humans between glycated hemoglobin (an indicator of hyperglycemia) and serum levels of pathogen recognition receptor ligands. Science, this issue p. 1376 High blood sugar levels cause epithelial reprogramming, compromising gut barrier integrity and increasing susceptibility to pathogens. Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial–specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.

Pulmonary Hemorrhage in Antiphospholipid Antibody Syndrome

Objective. To characterize the clinical manifestations of patients with antiphospholipid antibody syndrome (APS) and pulmonary hemorrhage (PH). Methods. We performed a retrospective, single-center analysis of patients with APS who were followed up from 1980 to 2011. Of these patients, only those who fulfilled the Sydney criteria for APS were included. Patients with APS that manifested with PH were called the PHAPS group. The rest of the patients with APS served as controls. Clinical manifestations were compared between the PHAPS group and controls. Results. Sixty-three patients fulfilled the criteria for APS. Thirteen experienced PH and were included in the PHAPS group. Seventy-five percent of the patients with PHAPS and 22% of the controls had mitral valve disease (p = 0.001). Central nervous system (CNS) involvement (cerebrovascular accident, seizures) was present in 61% and 16% of the patients with PHAPS and controls, respectively (p = 0.001). Skin involvement (livedo reticularis, chronic leg ulcers) was present in 54% and 8% of the patients with PHAPS and controls (p = 0.001). Pregnancy morbidity occurred in 87.5% and 32.5% of the patients with PHAPS and controls (p = 0.005). Ninety-two percent and 83% of the patients with PHAPS had high-titer immunoglobulin γ (IgG) anticardiolipin and β2-glycoprotein I IgG antibodies compared to 43% and 30% of the controls (p = 0.002, p < 0.001, respectively). Conclusion. Patients with PHAPS were more likely than controls to have mitral valve disease, skin disease, CNS involvement, and pregnancy morbidity as well as high-titer APS. PHAPS seems to be a unique subgroup of all patients with APS.

Bilateral septic arthritis of the hip: does etanercept play a role? A case report.

The cytokines that modulate immune-mediated rheumatic diseases are rapidly being elucidated1,2. In rheumatoid arthritis, persistent inhibition of tumor necrosis factor-alpha (TNF-α) induces an appreciable reduction of disease activity. TNF-α antagonists abrogate the inflammatory reaction by several mechanisms3-5: they reduce the expression of cytokines (TNF-α, interleukin-1α, and interleukin-1β), adhesion molecules, and chemokines (interleukin-8 and monocyte chemotactic protein-1) in the inflamed synovial tissue; they diminish leukocyte chemotaxis through the endothelium; and they suppress the activation and differentiation of osteoclasts that enhance bone resorption. Several studies have demonstrated that both etanercept and infliximab are highly effective in the treatment of patients who have inadequate responses to conventional disease-modifying antirheumatic drugs such as methotrexate3-7. To date, short-term clinical trials with anti-TNF-α agents have not been associated with a higher prevalence of serious bacterial infections. In this report, we present the case of a young woman with seropositive rheumatoid arthritis in whom bilateral septic arthritis of the hip developed after four months of therapy with etanercept alone. Staphylococcus aureus infection was found unexpectedly during exposure of the hips at the beginning of an elective total hip arthroplasty. This report highlights a possible association between TNF-α blockade therapy and multifocal septic arthritis. Our patient was …

Interleukin-1 activity in injured peripheral nerve

INTERLEUKIN-1 ACTIVITY IN INJURED PERIPHERAL NERVE Rotshenker Sl, Aamar Sl, and Barak v., Dept. Anato,ny 4 P:o:qi;!tgyt and Dept. of Oncologyz, Hebrew University’ Hadassah Hospitsl2’: Mtiical Sc%o:, Jerusalem, Israel. Interleukin-1 (ILl) is involved in a wide range of inflammatory amt immune v. As such, IL1 could play a role in nerve repair mechanisms. Sp,uificaliy, by its established properties as a regulator of nerve growth factor (NGP) synthesis, and as a cuemti~tant :o macrophages. We examined, therefore. IL1 production in injured mouse pe+-_r_. zr’ve. Injured nerve segments were incubated in serum free medium to produce coi&ioned medium (CM) that was then tested for IL1 activity in a thymocyte proliferatizt qs~:y. CM indured thymocyte proliferation in a dose dependent manner. Proliferation was inb~~ted by M20 IL1 inhibitor, ILl-t-a, and antisera raised against recombinant mouse ILl-a. Inhibitions produced by these three specific inhibitors of IL1 induced tbymocyte proliferation strongly suggest that proliferation induced by CM was mediated by IL1 secreted by nonneuronal cells residing in the damaged nerve. IL1 activity was detected within hours after lesion, and one week thereafter. The rapid and prolonged production of IL1 suggests a dual role for IL1 in peripheral nerve repair mechanisms. One, the regulation of NGF synthesis. Second, the recruitment of white blood cells, macrophages in particular, from blood to the damaged nerve tissue.