ABSTRACT
BACKGROUND AND OBJECTIVE: Understanding the regulation of efferocytosis by myeloid phagocytes is important in identifying novel targets in systemic lupus erythematosus (SLE). Cadherin-11 (CDH11), a cell adhesion molecule, is implicated in inflammatory arthritis and fibrosis and recently been shown to regulate macrophage phagocytosis. The extent and mechanism of this regulation is unknown. Our objective was to examine the extent to which CDH11 regulates myeloid phagocytes and contributes to autoimmunity and tissue inflammation. METHODS: We analyzed efferocytosis in macrophages and dendritic cells (DCs) from WT and Cdh11-/- mice and investigated the mechanisms in vitro. We investigated the role of CDH11 in disease development in vivo using the pristane induced lupus model. To translate the clinical relevance of CDH11 in human disease, we measured serum CDH11 levels in two independent pediatric SLE (pSLE) cohorts and healthy controls. RESULTS: Using bone marrow derived macrophages (BMDMs) and DCs (BMDCs), we found impaired efferocytosis in phagocytes from Cdh11-/- mice, mediated by downregulated efferocytosis receptor expression and RhoGTPase activation. Specifically, loss of CDH11 downregulated Mertk expression and Rac1 activation in BMDMs, and integrin αVß3 expression and Cdc42 activation in BMDCs, highlighting distinct pathways. In vivo, Cdh11-/- mice displayed defective efferocytosis and increased accumulation of apoptotic debris in pristane-induced lupus. Further, Cdh11-/- mice had enhanced systemic inflammation and autoimmune inflammation with increased anti-dsDNA autoantibodies, splenomegaly, type I interferons, and inflammatory cytokines. Paradoxically, at the tissue level, Cdh11-/- mice were protected against glomerulonephritis, indicating a dual role in murine lupus. Finally, SLE patients had increased serum CDH11 compared to controls. CONCLUSION: This study highlights a novel role of CDH11 in regulating myeloid cells and efferocytosis and its potential as a contributor to development in autoimmunity murine lupus. Despite the increase in autoimmunity, Cdh11-/- mice developed decreased tissue inflammation and damage.
Subject(s)
Cadherins , Dendritic Cells , Disease Models, Animal , Lupus Erythematosus, Systemic , Macrophages , Phagocytosis , Animals , Child , Female , Humans , Mice , Autoimmunity , c-Mer Tyrosine Kinase/genetics , c-Mer Tyrosine Kinase/metabolism , Cadherins/metabolism , Cadherins/genetics , Dendritic Cells/immunology , Dendritic Cells/metabolism , Inflammation/immunology , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/genetics , Macrophages/immunology , Macrophages/metabolism , Mice, Knockout , Myeloid Cells/immunology , Myeloid Cells/metabolism , Phagocytes/immunology , Phagocytes/metabolism , Phagocytosis/immunology , TerpenesABSTRACT
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe drug-induced hypersensitivity reaction carrying a mortality rate of up to 10%. We present a rare case of DRESS syndrome induced by amoxicillin-clavulanate, initially masquerading as red man syndrome. A 32-year-old male was admitted with flu-like symptoms and a maculopapular rash on the trunk and face that was exacerbated with vancomycin infusion, concerning for red man syndrome. He was receiving systemic antibiotics (vancomycin, ceftriaxone, and metronidazole) for infective endocarditis and previously took amoxicillin-clavulanate for a dental abscess. Despite the discontinuation of vancomycin, the exanthem continued to worsen, extending to involve >50% of his body surface area. Eosinophilia, hepatosplenomegaly, and acute kidney and liver injuries prompted consideration of DRESS syndrome. All antibiotics were discontinued, and systemic glucocorticoids were initiated. Punch biopsy revealed interface dermatitis with eosinophilic infiltrates; a high RegiSCAR score confirmed the diagnosis of DRESS. Amoxicillin-clavulanate was flagged as a severe allergy and deemed the culprit owing to the timing of exposure and personal/family history of hypersensitivity.
ABSTRACT
BACKGROUND: Cancer is a major health problem facing the entire world, and Jordan is no exception. However, patterns of cancer incidence and cancer burden in Jordan have never been explored thoroughly, and the aim of this study was to close this knowledge gap. MATERIALS AND METHODS: The study was based on data obtained from the Jordan cancer registry from 1996 to 2009. All cancer cases that were diagnosed during the study period were registered and included in this study. RESULTS: A total of 51,626 cases were registered in Jordan during the 14- year period. The incidence rate showed no significant increase in males (percent change PC 6.8%), while in females a marked increase was observed (PC 14.8%). The major cancer sites for males were bronchus and lung, colorectal, bladder, leukemia and prostate. In females, the leading cancer sites were breast, colorectal, leukemia, thyroid and NHL. CONCLUSIONS: Compared to other countries in the region, Jordan has comparable rates. On the other hand the rates of cancer are markedly lower in Jordan compared to more industrialized countries such as the US and Europe. There was an overall increase in the incidence of cancer in Jordan, especially among females, which stresses the need for programs to raise awareness on the importance of early diagnosis and preventive life style measures.
