Alexander W. Beham

A variable immunoreceptor in a subpopulation of human neutrophils

Neutrophils are thought to rely solely on nonspecific immune mechanisms. Here we provide molecular biological, immunological, ultrastructural, and functional evidence for the presence of a T cell receptor (TCR)-based variable immunoreceptor in a 5–8% subpopulation of human neutrophils. We demonstrate that these peripheral blood neutrophils express variable and individual-specific TCRαβ repertoires and the RAG1/RAG2 recombinase complex. The proinflammatory cytokine granulocyte colony-stimulating factor regulates expression of the neutrophil immunoreceptor and RAG1/RAG2 in vivo. Specific engagement of the neutrophil TCR complex protects from apoptosis and stimulates secretion of the neutrophil-activating chemokine IL-8. Our results, which also demonstrate the presence of the TCR in murine neutrophils, suggest the coexistence of a variable and an innate host defense system in mammalian neutrophils.

Gastrointestinal stromal tumors

IntroductionThe gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the intestinal tract, known to be refractory to conventional chemotherapy or radiation. Its pathogenesis is defined by mutations within the KIT and PDGFRA gene, which constitutively activate KIT and PDGFRA oncoproteins, and serve as crucial diagnostic and therapeutic targets.DiscussionBesides surgery, therapy with imatinib mesylate, which inhibits KIT kinase activity, represents the other cornerstone for the treatment of GIST. Still, the only curative option for GIST is given after complete surgical removal even in a metastatic setting, but recurrence is common, and the risk can be defined by surgical factors like incomplete resection, intraperitoneal rupture, or bleeding and tumor associated factors like tumor size, mitotic index, or localization.ConclusionConsequently, adjuvant therapy with imatinib mesylate or other tyrosine kinase inhibitors is recommended for high-risk patients after complete resection. For unresectable and advanced GIST, a partial response or stable disease can be achieved in about 80% of patients with imatinib mesylate.

A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis

Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) αβ based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCRαβ induces the release of CCL2 and modulates phagocytosis. TNF blockade suppresses macrophage-TCRαβ expression. Infection of macrophages from healthy individuals with mycobacteria triggers formation of clusters that express restricted TCR Vβ repertoires. In vivo, TCRαβ bearing macrophages abundantly accumulate at the inner host-pathogen contact zone of caseous granulomas from patients with lung tuberculosis. In chimeric mouse models, deletion of the variable macrophage-TCRαβ or TNF is associated with structurally compromised granulomas of pulmonary tuberculosis even in the presence of intact T cells. These results uncover a TNF-regulated recombinatorial immune receptor in monocytes/macrophages and demonstrate its implication in granuloma formation in tuberculosis.

Common Genomic Aberrations in Basaloid Squamous Cell Carcinoma and Carcinosarcoma of the Esophagus Detected by CGH and Array CGH

Basaloid squamous cell carcinoma (BSCC) and carcinosarcoma of the esophagus are rare entities, making up fewer than 2% of esophageal malignancies. Comparative genomic hybridization (CGH) in 1 case of BSCC and 2 cases of carcinosarcoma and subsequent array CGH in 1 case each of BSCC and carcinosarcoma revealed common chromosomal gains at 2p25.3-2p12, 7q21.3-7q22.3, and 11q13.2-11q13.4. Chromosomal losses at 13q31qter were observed in both carcinosarcomas. In addition, progression of genomic instability from in situ to invasive carcinosarcoma could be demonstrated by using array CGH. Our observations suggest a common genetic origin of BSCC and carcinosarcoma.

The neutrophil recombinatorial TCR-like immune receptor is expressed across the entire human life span but repertoire diversity declines in old age.

Recent evidence has revealed the existence of T cell receptor (TCR) αβ-based recombinatorial immune receptors in phagocytes. Here, we performed a systematic survey of the variable β-chain repertoires of the neutrophil TCR-like αβ immunoreceptor (referred to as TCRL(n)αβ) in defined cohorts of young and old individuals. Peripheral blood CD15(+) neutrophils from young adults (age 30 ± 7 years, n=12) expressed an average number of 13 ± 6 distinct TCRL(n) Vβ-chains from the total pool of 25 human Vβ-chains. Neutrophils from aged subjects (age 76 ± 6 years, n=12) also consitutively express the TCRL(n), however, only a small number of Vβ-chains is used (4 ± 2). Consistent with this, the average number of expressed CDR3 Vβ length variants was fourfold higher in young individuals than in aged subjects (33 ± 24 vs. 8 ± 3). Young adults showed broad usage of all TCRL(n) Vβ-chains. In contrast, >70years individuals displayed a striking repertoire polarization towards the TCRL(n) Vβ1 and Vβ5b chains and a high degree of Vβ5b clonotype sharing. Our study reveals broad TCRL(n) repertoire diversity in young adults and demonstrates that the neutrophil variable immune receptor is expressed throughout the entire human life span. The marked decline in TCRL(n) repertoire diversity in old age identifies a novel mechanism of immunosenescence in neutrophils.

An autoimmune double attack

Institute for Clinical Chemistry (T Fuchs PhD, S Schneider MD, M Neumaier MD, Prof W E Kaminski MD), Department of Medicine (J Kruth MD), and Institute for Transfusion Medicine and Immunology (T J Schulze MD); University of Heidelberg Medical Faculty Mannheim, Mannheim, Germany; Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany (K Puellmann MD); and Department of Surgery, University of Gottingen, Gottingen, Germany (A W Beham MD)

Posterior cavoplasty: a new approach to avoid venous outflow obstruction and symptoms for small-for-size syndrome in right lobe living donor liver transplantation

PurposeA common and serious problem after living donor liver transplantation (LDLT) of small grafts is small-for-size syndrome (SFSS). Although hyperdynamic portal inflow and portal hypertension are cornerstones in the development of SFSS, inadequate outflow may aggravate SFSS. Therefore, enlargement of the portal outflow tract by incision of the anterior rim of the orifice of the right hepatic vein (RHV) has been advocated for right lobe LDLT. But backwards tilt of a small graft into a large abdominal cavity may lead to a choking of the otherwise large anastomosis and thus we propose posterior enlargement of the orifice of the RHV.MethodIn this test-of-concept study, we evaluated portal vein pressure (PVP), clinical parameters, and laboratory measurements in 22 patients that underwent right lobe LDLT and either received standard end-to-end anastomosis of the RHV or posterior cavoplasty.ResultsIn patients that underwent posterior cavoplasty, we observed significantly lower PVP and less hyperbilirubinemia. There was a non-significant trend to lower incidence of SFSS. Other laboratory measurements and clinical parameters were not significantly different.ConclusionWe recommend posterior cavoplasty for enlargement of the hepatic venous outflow tract in right lobe LDLT as a method to avoid portal hypertension, hyperbilirubinemia, and possibly SFSS, especially in patients that receive small grafts.

Diagnosis of Gastroesophageal Reflux Disease Using Real-time Magnetic Resonance Imaging

A small angle (His angle) between the oesophagus and the fundus of the stomach is considered to act as flap valve and anti-reflux barrier. A wide angle results in dysfunction of the oesophagogastric junction and subsequently in gastroesophageal reflux disease (GERD). Here, we used real-time magnetic resonance imaging (MRI) at 50 ms resolution (20 frames per second) in 12 volunteers and 12 patients with GERD to assess transport of pineapple juice through the oesophagogastric junction and reflux during Valsalva. We found that the intra-abdominal part of the oesophagus was bended towards the left side resulting in an angle of 75.3 ± 17.4, which was significantly larger during Valsava (P = 0.017). Reflux and several underlying pathologies were detected in 11 out of 12 patients. Our data visualize oesophagogastric junction physiology and disprove the flap valve hypothesis. Further, non-invasive real-time MRI has considerable potential for the diagnosis of causative pathologies leading to GERD.

The macrophage-TCRαβ is a cholesterol-responsive combinatorial immune receptor and implicated in atherosclerosis.

Recent evidence indicates constitutive expression of a recombinatorial TCRαβ immune receptor in mammalian monocytes and macrophages. Here, we demonstrate in vitro that macrophage-TCRβ repertoires are modulated by atherogenic low density cholesterol (LDL) and high-density cholesterol (HDL). In vivo, analysis of freshly obtained artery specimens from patients with severe carotid atherosclerosis reveals massive abundance of TCRαβ(+) macrophages within the atherosclerotic lesions. Experimental atherosclerosis in mouse carotids induces accumulation of TCR bearing macrophages in the vascular wall and TCR deficient rag(-/-) mice have an altered macrophage-dependent inflammatory response. We find that the majority of TCRαβ bearing macrophages are localized in the hot spot regions of the atherosclerotic lesions. Advanced carotid artery lesions express highly restricted TCRαβ repertoires that are characterized by a striking usage of the Vβ22 and Vβ16 chains. This together with a significant degree of interindividual lesion repertoire sharing suggests the existence of atherosclerosis-associated TCRαβ signatures. Our results implicate the macrophage-TCRαβ combinatorial immunoreceptor in atherosclerosis and thus identify an as yet unknown adaptive component in the innate response-to-injury process that underlies this macrophage-driven disease.

Rhabdoid morphology in gastrointestinal stromal tumours (GISTs) is associated with PDGFRA mutations but does not imply aggressive behaviour.

Rhabdoid morphology resembling that of the aggressive paediatric rhabdoid tumours occurs in various malignancies usually lacking characteristic SMARCB1 (INI1) loss. Little is known about the clinicopathological and molecular characteristics of the rhabdoid phenotype in gastrointestinal stromal tumours (GISTs).