Background: Paraneoplastic neurological syndromes (PNS) are indirect remote effects of cancer on the nervous system, often associated with the presence of specific serum antibodies. The most recently described PNS defining reactivity is anti-Ma/anti-Ta. Here we present 22 newly diagnosed patients with anti-Ma or antiTa reactivity, refine the associated clinical picture and review all published patients to date. Patients and methods: Patients were identified by testing for PNMA1 and PNMA2 antibodies by western blotting and indirect immunofluorescence. Clinical data were obtained either by referral of the patient or from the referring physicians. Results: Analysis of 22 new patients (14 anti-Ma, eight anti-Ta) confirmed that anti-Ta are usually found in young men with limbic encephalitis and testicular germ cell tumours who stabilise neurologically with long term survival after tumour treatment. Patients with anti-Ma were of either sex, middle-aged, presented with a range of tumours and neurological symptoms and had a limited response to treatment. Furthermore, we expanded the range of associated clinical features: (1) the peripheral nervous system may be involved; (2) an overlap with antiHu is possible; and (3) testicular tumour manifestation can be extragonadal or detectable only at orchiectomy. Conclusion: Refining and expanding the range of antiMa/anti-Ta associated neurological presentations and tumours clearly demonstrated that the distinction between anti-Ma and anti-Ta associated PNS is of high clinical relevance.Paraneoplastic neurological syndromes (PNS) are indirect remote effects of cancer on the nervous system.
T-cell ubiquitin ligand-2 (TULA-2) is a recently discovered histidine tyrosine phosphatase thought to be ubiquitously expressed. In this work, we have investigated whether TULA-2 has a key role in platelet glycoprotein VI (GPVI) signaling. This study indicates that TULA-2 is expressed in human and murine platelets and is able to associate with Syk and dephosphorylate it. Ablation of TULA-2 resulted in hyperphosphorylation of Syk and its downstream effector phospholipase C-␥2 as well as enhanced GPVI-mediated platelet functional responses. In addition, shorter bleeding times and a prothrombotic phenotype were observed in mice lacking TULA-2. We therefore propose that TULA-2 is the primary tyrosine phosphatase mediating the dephosphorylation of Syk and thus functions as a negative regulator of GPVI signaling in platelets. (Blood. 2010;116(14):2570-2578) IntroductionThe platelet is the primary hemostatic cell that circulates in the bloodstream in a quiescent, discoid state. After damage to the vascular wall, collagen, as part of the extracellular matrix, becomes exposed. Platelets interact with the exposed collagen. This serves as a trigger that causes platelet activation and the development of a hemostatic plug to arrest bleeding. 1 Of all the receptors expressed on the platelet surface, it is thought that the glycoprotein VI (GPVI)/Fc receptor-␥ chain (FcR-␥ chain) complex is the primary collagen receptor to elicit the activation of platelets. 2 After the interaction with collagen, a signaling cascade is initiated downstream of the GPVI receptor involving numerous proteins. 2 On binding of collagen to GPVI, it is thought that clustering of the receptor occurs and phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of the FcR-␥ chain follows. 3 This event is thought to be mediated by the Src-family tyrosine kinases Fyn and Lyn, which are constitutively associated with GPVI. 4 After phosphorylation of the ITAM, the tyrosine kinase, spleen tyrosine kinase (Syk), is recruited to the phosphorylated ITAM. 5 Once bound, Syk undergoes tyrosine phosphorylation at multiple sites, including Y525 and Y526 (Y519/20 in murine Syk) to increase its kinase activity. 6 The activation of Syk leads to the formation of a protein complex containing several adapter proteins, such as linker-for-activation of T cells, and kinases, such as phosphatidylinositol-3-kinase that leads to the eventual phosphorylation and activation of phospholipase C-␥2 (PLC-␥2) and release of Ca 2ϩ from intracellular stores. 7 As a result, the secretion of several autocoids occurs that in turn activate nearby circulating platelets to recruit them to the site of injury to form a stable platelet plug. The central role of Syk in GPVI signaling is undisputed, as Syk-deficient platelets fail to aggregate, secrete stored granules, form arachidonic acid, and exhibit no PLC-␥2 phosphorylation in response to GPVI agonists. 8 Although a lot of work has been undertaken to reveal the molecular mechanisms of GPVI-mediated platelet activation, less ...
The Toll-like receptor 2 (TLR2)/TLR1 receptor complex responds to amyloid fibrils, a common component of biofilm material produced by members of the phyla Firmicutes, Bacteroidetes, and Proteobacteria. To determine whether this TLR2/TLR1 ligand stimulates inflammatory responses when bacteria enter intestinal tissue, we investigated whether expression of curli amyloid fibrils by the invasive enteric pathogen Salmonella enterica serotype Typhimurium contributes to T helper 1 and T helper 17 responses by measuring cytokine production in the mouse colitis model. A csgBA mutant, deficient in curli production, elicited decreased expression of interleukin 17A (IL-17A) and IL-22 in the cecal mucosa compared to the S. Typhimurium wild type. In TLR2-deficient mice, IL-17A and IL-22 expression was blunted during S. Typhimurium infection, suggesting that activation of the TLR2 signaling pathway contributes to the expression of these cytokines. T cells incubated with supernatants from bone marrow-derived dendritic cells (BMDCs) treated with curli fibrils released IL-17A in a TLR2-dependent manner in vitro. Lower levels of IL-6 and IL-23 production were detected in the supernatants of the TLR2-deficient BMDCs treated with curli fibrils. Consistent with this, three distinct T-cell populations-CD4؉ T helper cells, cytotoxic CD8 ؉ T cells, and ␥␦ T cells-produced IL-17A in response to curli fibrils in the intestinal mucosa during S. Typhimurium infection. Notably, decreased IL-6 expression by the dendritic cells and decreased IL-23 expression by the dendritic cells and macrophages were observed in the cecal mucosa of mice infected with the curli mutant. We conclude that TLR2 recognition of bacterial amyloid fibrils in the intestinal mucosa represents a novel mechanism of immunoregulation, which contributes to the generation of inflammatory responses, including production of IL-17A and IL-22, in response to bacterial entry into the intestinal mucosa.
Curli fibrils, the best-characterized functional bacterial amyloids, are an important component of enterobacterial biofilms. We have previously shown that curli fibrils are recognized by the Toll-like receptor 2 (TLR2)/TLR1 heterodimer complex. Utilizing polarized T-84 cells, an intestinal epithelial cell line derived from colon carcinoma grown on semipermeable tissue culture inserts, we determined that infection with a Salmonella enterica serovar Typhimurium csgBA mutant, which does not express curli, resulted in an increase in intestinal barrier permeability and an increase in bacterial translocation compared to infection with curliated wild-type S. Typhimurium. When the TLR2 downstream signaling molecule phosphatidylinositol 3-kinase (PI3K) was blocked using wortmannin or LY294002, the difference in disruption of the intestinal epithelium and bacterial translocation was no longer observed. Additionally, disruption of polarized T-84 cells treated basolaterally with the TLR5 ligand flagellin was prevented when the polarized cells were simultaneously treated with the synthetic TLR2/TLR1 ligand Pam 3 CSK 4 or with purified curli fibrils in the apical compartment. Similar to in vitro observations, C57BL/6 mice infected with the csgBA mutant suffered increased disruption of the intestinal epithelium and therefore greater dissemination of the bacteria to the mesenteric lymph nodes than mice infected with wild-type S. Typhimurium. The differences in disruption of the intestinal epithelium and bacterial dissemination in the mice infected with csgBA mutant or wild-type S. Typhimurium were not apparent in TLR2-deficient mice. Overall, these studies report for the first time that activation of the TLR2/PI3K pathway by microbial amyloids plays a critical role in regulating the intestinal epithelial barrier as well as monitoring bacterial translocation during infection.
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