lewis-x-antigen and Necrosis

Apoptosis is the most common form of neutrophil death under both physiological and inflammatory conditions. However, forms of nonapoptotic neutrophil death have also been observed. In the current study, we report that human neutrophils undergo necroptosis after exposure to GM-CSF followed by the ligation of adhesion receptors such as CD44, CD11b, CD18, or CD15. Using a pharmacological approach, we demonstrate the presence of a receptor-interacting protein kinase-3 (RIPK3)-a mixed lineage kinase-like (MLKL) signaling pathway in neutrophils which, following these treatments, first activates p38 MAPK and PI3K, that finally leads to the production of high levels of reactive oxygen species (ROS). All these steps are required for necroptosis to occur. Moreover, we show that MLKL undergoes phosphorylation in neutrophils in vivo under inflammatory conditions. This newly identified necrosis pathway in neutrophils would imply that targeting adhesion molecules could be beneficial for preventing exacerbation of disease in the neutrophilic inflammatory response.

Topics: CD11b Antigen; CD18 Antigens; Cell Adhesion Molecules; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hyaluronan Receptors; Inflammation; Lewis X Antigen; Necrosis; Neutrophils; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphorylation; Reactive Oxygen Species; Receptor-Interacting Protein Serine-Threonine Kinases; Respiratory Burst; Signal Transduction

Mucinous tubular and spindle cell carcinoma is a rare and newly described type of renal cell carcinoma (RCC) with a relatively indolent behavior. However, its histogenetic origin or line of differentiation remains unclear. Twelve cases of mucinous tubular and spindle cell carcinoma were identified and retrieved from the files of 3 institutions. Detailed morphological features, as well as their immunohistochemical profile established with markers of proximal renal tubules (RCC marker antigen, CD15, and alpha-methylacyl-CoA racemase) and of distal renal tubules (kidney-specific cadherin and cytokeratin 7), were studied. The age range of the patients was 35 to 73 years with a median of 56 years. The male to female ratio was 1:3. All of the patients were alive with follow-up between 4 and 38 months. All the tumors were confined to the kidney with a mean tumor size of 6.9 cm (range, 1.8-17 cm). The tumors were composed of variable proportions of tubular and spindle cell areas with focal to prominent mucinous or myxoid stroma. Foamy macrophages were seen in 10 cases and were prominent in 4 cases. A focal compressed tubulopapillary growth pattern was seen in 10 cases. The tumor cells were uniformly cuboidal with ovoid to round nuclei and inconspicuous nucleoli (Furhman nuclear grade 3 in 6 cases). Focal necrosis was seen in 3 cases. Immunostains showed that tumors were positive for RCC marker antigen (11/12), alpha-methylacyl-CoA racemase (11/12), CD15 (8/12), CD10 (2/12), kidney-specific cadherin (1/12), and cytokeratin 7 (11/12). Its morphological features as well as a strong preferential expression of proximal tubule markers suggest that this tumor is a type of RCC with proximal tubular differentiation, which appears closely related to or represents a morphological variant of papillary RCC.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Antigens, Neoplasm; Biomarkers, Tumor; Cadherins; Carcinoma; Carcinoma, Papillary; Carcinoma, Renal Cell; Female; Humans; Keratin-7; Kidney Neoplasms; Lewis X Antigen; Male; Middle Aged; Mitogen-Activated Protein Kinases; Necrosis; Neprilysin; Racemases and Epimerases

Histologic features of recurrent Hodgkin's disease (HD) after conventional therapy are well known, but few studies describe HD after bone marrow transplantation (BMT). Histologic material from 63 patients who underwent BMT performed to treat recurrent nodular sclerosing HD (NSHD) between 1985 and 1994 was examined; 13 of the 63 patients had histologically proved recurrent disease after BMT. Histologic material and clinical findings from the original diagnostic biopsy specimen and pre-BMT and post-BMT specimens were available from our study population of eight patients (five male, three female; age range, 16 to 38 years; median age, 27.5 years). Seven patients had recurrent NSHD after BMT; sites of recurrence included lymph nodes only (four patients), and lymph nodes and lung, lung and liver, and lung only (one patient each). In one patient, a high-grade non-Hodgkin's B-cell lymphoma developed in the large intestine 5 years after BMT. In another, disease progressed from grade 1 in the original biopsy specimen to grade 2 in both the pre-BMT and post-BMT recurrent HD biopsy specimens. Post-BMT biopsy specimens of recurrent HD with lung involvement revealed a substantial increase in sclerosis and fibroblastic features. Paraffin immunoperoxidase studies in seven patients demonstrated substantial change in phenotype of Reed-Stemberg cell variants in only one post-BMT recurrent HD specimen, which showed a +2 reaction with CD30 (Ki-1). No substantial differences in the reactive component were noted between the original biopsy specimen and pre-BMT and post-BMT specimens of recurrent disease. In summary, histologic findings of post-BMT recurrent NSHD do not differ significantly from those of the original diagnostic biopsy or pre-BMT recurrent HD specimens. The lung is the most common site of extranodal post-BMT recurrence. In one patient, high-grade non-Hodgkin's B-cell lymphoma developed after BMT performed to treat recurrent HD.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Female; Hodgkin Disease; Humans; Immunoenzyme Techniques; Ki-1 Antigen; Lewis X Antigen; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Male; Mediastinal Neoplasms; Mucin-1; Necrosis; Recurrence; Sclerosis

We describe a case of recurrent histiocytic necrotizing lymphadenitis (HNL) with aseptic meningitis. The patient was a 46-year-old male and a carrier of human T lymphotropic virus type I (HTLV-I). The patient had a past medical history of at least three relapses of HNL. In addition, his sister, who was also an HTLV-I carrier, had recurrent clinical episodes consistent with those of HNL, suggesting familial HNL occurrence. This observation suggests the possibility that HTLV-I infection is relevant to the pathogenesis of HNL.

Topics: Antibodies, Viral; Carrier State; CD8 Antigens; Cell Division; Fatal Outcome; Herpesviridae Infections; Herpesvirus 6, Human; Histiocytes; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Immunohistochemistry; Lewis X Antigen; Lymphadenitis; Male; Meningitis, Aseptic; Middle Aged; Necrosis; Pedigree; Recurrence

Polymorphonuclear leukocytes (PMNs) have been shown to mediate coronary vascular and myocardial tissue injury after coronary artery ischemia and reperfusion. Previous studies using specific monoclonal antibodies directed against P-selectin and L-selectin have demonstrated the involvement of the selectin family of glycoproteins in the early phase of PMN-induced myocardial ischemia-reperfusion injury. We examined the effects of a novel oligosaccharide analog of sialyl LewisX (SLeX), which blocks both P-selectin and E-selectin in an acute canine model of myocardial ischemia and reperfusion.. Anesthetized, open-chest dogs were subjected to 1.5 hours of left circumflex coronary artery (LCx) occlusion followed by 4.5 hours of reperfusion and randomly received the SLeX analog CY-1503 (5 mg/kg IV), the nonfucosylated analog of CY-1503, SLN (5 mg/kg IV), or saline 5 minutes before reperfusion. The investigators were blinded to the treatment until all the data analysis was completed. All three groups of dogs exhibited similar and severe reductions in transmural myocardial blood flow in the LCx region as well as pronounced myocardial contractile dysfunction during occlusion, suggesting comparable degrees of myocardial ischemia. After reperfusion, dogs receiving saline (n = 6) displayed an enhanced degree of myocardial injury that was evidenced by a dramatic elevation in plasma creatine kinase (CK) activity, PMN accumulation, and myocardial necrosis. Plasma CK activity increased from 1.9 +/- 0.5 IU/microgram protein at baseline to 73.0 +/- 11.0 IU/micrograms protein (P < .001) at 4.5 hours of reperfusion and myocardial PMN accumulation, as measured by cardiac myeloperoxidase (MPO) activity, and was significantly enhanced (P < .01) within the necrotic zone compared with the nonischemic zone (4.3 +/- 0.6 versus 0.7 +/- 0.1 U/100 mg tissue). After 4.5 hours of reperfusion, 36% of the myocardium within the ischemic zone and 17% of the left ventricle became necrotic in the dogs receiving saline. Treatment with CY-1503 (n = 6) significantly (P < .05) blunted plasma CK activity by more than 50% throughout the reperfusion period, reduced necrotic zone PMN accumulation by 63% (P < .05), and reduced myocardial necrosis in the area at risk by 65% (P < .01) and by 72% within the left ventricle (P < .01). In contrast, administration of the nonfucosylated analog of CY-1503, SLN (n = 6), failed to exert any detectable cardioprotective effects after myocardial ischemia and reperfusion.. Our results provide strong evidence that treatment with a unique carbohydrate analog of SLeX, CY-1503, significantly reduces the degree of myocardial injury associated with coronary artery ischemia and reperfusion. The profound cardioprotection appears to be related to a reduction in PMN accumulation within the ischemic-reperfused myocardium. Additional studies investigating more-prolonged periods of reperfusion are required to determine whether CY-1503 treatment merely delays the onset or actually reduces the full extent of myocardial necrosis after ischemia and reperfusion.

Topics: Animals; Coronary Circulation; Coronary Vessels; Creatine Kinase; Dogs; Female; Leukocyte Count; Lewis X Antigen; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Necrosis; Neutrophils; Oligosaccharides; P-Selectin; Platelet Membrane Glycoproteins

Apoptosis (programmed cell death) is a basic physiological process which determines specific patterns of tissue size and shape, and balance of cell number, during morphogenesis, and seems to play an integral role in oncogenic progression. Since dramatic changes of cellular glycosylation pattern are well known to be closely correlated with differentiation, development and oncogenesis, it is likely that similar specific changes are associated with apoptosis. However, this possibility has not been systematically investigated. We therefore carried out histological studies of many tumours and normal tissues for which a high incidence of apoptosis is believed to occur. Sections were stained with monoclonal antibodies (MoAbs) directed to carbohydrate antigens Le(y) and Le(x), proliferating cellular nuclear antigen (PCNA) and Fas (previously claimed to be an apoptosis-inducing antigen). Antibody staining patterns were compared with morphological cell characteristics as revealed by haematoxylin/eosin staining, and DNA fragmentation patterns (a marker of apoptosis) as revealed by 3'-OH nick-end labelling technique. We found that expression of Le(y) (defined by MoAb BM1) is closely correlated with the process of apoptosis, but not with cell proliferation or necrosis. Within Le(y)-positive areas of tissue sections, typical apoptotic morphological changes and DNA fragmentation (as revealed by positive nick-end labelling) were frequently observed in certain loci, although not all Le(y)-positive cells showed such signs of apoptosis. Le(y)-positive areas showed consistent negative staining by MoAb directed to PCNA and negative or weak staining by MoAb directed to Fas antigen, regardless of tissue source. No such trends were observed for Le(x) glycosylation. We conclude that Le(y) expression is a useful phenotypic marker predictive of apoptosis, i.e. some (although not all) Le(y)-positive cells subsequently become apoptotic.

Topics: Antibodies, Monoclonal; Apoptosis; Carbohydrate Sequence; Carcinoma, Squamous Cell; Cell Division; Esophageal Neoplasms; Humans; Immunohistochemistry; Kidney Neoplasms; Lewis X Antigen; Molecular Sequence Data; Mucous Membrane; Necrosis; Nephrons; Stomach Neoplasms

The hepatocellular expression of the carbohydrate antigen sialyl monomeric Lewis X (SMLex) and sialyl oligomeric Lewis X(SOLex) in chronic hepatitis was examined using specific monoclonal antibodies. Both of these sialyl Lewis X (SLex) antigens were membranously expressed in chronic hepatitis in spite of their absence in normal liver. Although SMLex was detected in mild hepatic inflammation, the expression of SOLex was associated only with moderate to severe necroinflammation. Hepatocellular expression of these antigens increased significantly as histological diagnosis advanced. Chronological observation also showed the change of SLex expression according to the histological change. The present observations suggest that hepatocellular SLex is a novel histological marker with a close correlation to the severity of necroinflammation in chronic hepatitis.

Topics: Biomarkers; Chronic Disease; Glycolipids; Hepatitis; Hepatitis, Chronic; Humans; Lewis X Antigen; Liver; Necrosis; Reference Values