The clinical features among the affected patients were nearly identical, consisting of relatively mild CNS manifestations and complete recovery within 1 month.
In a mouse experimental asthma model, the administration of bacterial lipopolysaccharide (LPS), particularly at low doses, enhances the levels of ovalbumin (OVA)-induced eosinophilic airway inflammation. In an effort to clarify the cellular and molecular basis for the LPS effect, we demonstrate that the OVA-induced eosinophilic inflammation in the lung is dramatically increased by the administration of LPS in wild-type mice, whereas such increase was not observed in mast-cell-deficient mice or Toll-like receptor (TLR)4-deficient mice. Adoptive transfer of bone-marrow-derived mast cells (BMMCs) from wild-type, but not from TLR4-deficient, mice restored the increased eosinophilic inflammation in mast-celldeficient mice. Wild-type BMMCs pretreated with LPS in vitro also reconstituted the eosinophilic inflammation. Moreover, in vitro analysis revealed that the treatment of BMMCs with LPS resulted in NF-B activation, sustained up-regulation of GATA1 and -2 expression, and increased the capability to produce IL-5 and -13. Dramatic increases in the expression of IL-5 and -13 and Eotaxin 2 were detected in LPS-treated BMMCs after costimulation with LPS and IgE͞Ag. Overexpression of GATA1, but not GATA2, in MC9 mast cells resulted in increased transcriptional activity of IL-4, -5, and -13. Furthermore, the levels of transcription of Th2 cytokines in BMMCs were decreased by the introduction of small interfering RNA for GATA1. Thus, mast cells appear to control allergic airway inflammation after their activation and modulation through TLR4-mediated induction of GATA1 and subsequent increase in Th2 cytokine production.cytokine ͉ GATA1 ͉ mast cell ͉ lipopolysaccharide ͉ bone-marrow-derived mast cells
Graves disease is an autoimmune thyroid disease characterized by the presence of antibodies against the thyrotropin receptor (TSHR), which stimulate the thyroid to cause hyperthyroidism and/or goiter. By immunizing mice with fibroblasts transfected with both the human TSHR and a major histocompatibility complex class II molecule, but not by either alone, we have induced immune hyperthyroidism that has the major humoral and histological features of Graves disease: stimulating TSHR antibodies, thyrotropin binding inhibiting immunoglobulins, which are different from the stimulating TSHR antibodies, increased thyroid hormone levels, thyroid enlargement, thyrocyte hypercellularity, and thyrocyte intrusion into the follicular lumen. The results suggest that the aberrant expression of major histocompatibility complex class II molecules on cells that express a native form of the TSHR can result in the induction of functional anti-TSHR antibodies that stimulate the thyroid. They additionally suggest that the acquisition of antigen-presenting ability on a target cell containing the TSHR can activate T and B cells normally present in an animal and induce a disease with the major features of autoimmune Graves.Numerous attempts (1-10) to develop a Graves disease (GD) model by immunizing animals with the extracellular domain of the thyrotropin receptor (TSHR) have largely failed. In most cases, antibodies to the TSHR that could inhibit thyrotropin (TSH) binding and, in some cases, thyroiditis with a large lymphocytic infiltration were produced (1-10). However, in no case did the immunization produce thyroid-stimulating TSHR antibodies (TSHRAbs), which increase thyroid hormone levels, the hallmark of Graves, nor were the morphologic or histologic features of the disease induced: glandular enlargement, thyrocyte hypercellularity, and thyrocyte intrusion into the follicular lumen. Further, in most studies (1-10), the antibodies that inhibited TSH binding were not shown to inhibit TSH activity mediated specifically by the TSH receptor, a feature characteristic of TSH binding inhibitory immunoglobulins (TBIIs) in GD (11-13).These studies depended on the ability of the animal to process the TSHR as an extracellular antigen, rather than as a receptor in a functional state on a cell. They did not take into account the possibility that the TSHR might be presented to the immune system as a result of abnormal major histocompatibility complex (MHC) class I or class II expression on thyrocytes, thereby allowing normal immune tolerance to be broken. Thus, several studies have implicated class I as an important component in the development of autoimmune thyroid disease and in the action of methimazole, a drug used to treat GD (14-18). In addition, aberrant class II expression, as well as abnormal expression of class I molecules, is evident on thyrocytes in autoimmune thyroid diseases (19-21), although the cause and role of aberrant class II in disease expression remains controversial (22). The sum of these observations (1-22) raised...
Background-Increased microvascular permeability is an initial step of Kawasaki disease (KD). We reported that vascular endothelial growth factor (VEGF) might play a role in the vascular leakage of KD. In fatal KD, plasma leakage was extensively documented at VEGF-positive microvessels. Increases in vascular leakage cause hypoalbuminemia and noncardiogenic edema. However, the prognostic impact of vascular leakage in KD remains unclear. Methods and Results-We compared 76 patients who became afebrile within 5 days after starting intravenous gamma globulin (IVGG) (2 g/kg over 5 days) (IVGG-responsive) with 27 patients who did not respond (IVGG-resistant). Baseline levels of serum VEGF and albumin were similar between the groups. After IVGG, VEGF levels increased (PϽ0.0001) and albumin levels decreased (PϽ0.00001) in both groups. However, the IVGG-resistant group had higher VEGF levels (Pϭ0.029) and severe hypoalbuminemia (PϽ0.00001) compared with the IVGG-responsive group. Coronary aneurysms were documented in 12 patients from the IVGG-resistant group but not in the IVGG-responsive group. Then IVGG-resistant patients were divided into 2 subgroups according to the presence (nϭ12) or absence (nϭ15) of coronary aneurysms. There was no difference between subgroups in age, sex, laboratory data including albumin, and retreated doses of IVGG. However, body weight gain after IVGG was documented in patients who subsequently developed coronary aneurysms (Pϭ0.003) but not in those who did not (Pϭ0.967). Conclusions-These
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