lewis-x-antigen and Chronic-Disease

Helicobacter pylori is a Gram-negative bacterium that infects over 50% of the world's population. This organism causes various gastric diseases such as chronic gastritis, peptic ulcer, and gastric cancer. H. pylori possesses lipopolysaccharides that share structural similarity to Lewis blood group antigens in gastric mucosa. Such antigenic mimicry could result in immune tolerance against antigens of this pathogen. On the other hand, H. pylori colonizes gastric mucosa by utilizing adhesins that bind Lewis blood group antigen-related carbohydrates expressed on gastric epithelial cells. After colonization, H. pylori induces acute inflammatory responses mainly by neutrophils. This acute phase is gradually replaced by a chronic inflammatory response. In chronic gastritis, lymphocytes infiltrate the lamina propria, and such infiltration is facilitated by the interaction between L-selectin on lymphocytes and peripheral lymph node addressin (PNAd), which contains 6-sulfo sialyl Lewis X-capped O-glycans, on high endothelial venule (HEV)-like vessels. H. pylori barely colonizes gland mucous cell-derived mucin where alpha1,4-GlcNAc-capped O-glycans exist. In vitro experiments show that alpha1,4-GlcNAc-capped O-glycans function as a natural antibiotic to inhibit H. pylori growth. These findings show that distinct sets of carbohydrates expressed in the stomach are closely associated with pathogenesis and prevention of H. pylori-related diseases, providing therapeutic potentialities based on specific carbohydrate modulation.

Topics: Adhesins, Bacterial; Animals; Chronic Disease; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; L-Selectin; Lewis X Antigen; Lipopolysaccharides; Molecular Mimicry; Mucin-2; Neutrophils; O Antigens; Oligosaccharides; Peptic Ulcer; Polysaccharides; Sialyl Lewis X Antigen; Stomach Neoplasms

Lymphocyte homing is mediated by a cascade of adhesive interactions between circulating lymphocytes and specialized endothelial cells comprising high endothelial venules (HEVs). Sulfated O-glycans expressed on HEVs, collectively called peripheral lymph node addressin (PNAd), interact with L-selectin expressed on lymphocytes, contributing to the initial step of the lymphocyte homing. In chronic inflammatory states, PNAd is induced on HEV-like vessels but absent in non-lymphoid tissues under normal conditions. Such HEV-like vessels have been observed in various chronic inflammatory diseases including rheumatoid arthritis, lymphocytic thyroiditis, Helicobacter pylori-associated chronic gastritis, and inflammatory bowel disease (IBD), and implicated in lymphocyte recruitment in those diseases. In H. pylori-associated chronic gastritis, PNAd-expressing HEV-like vessels are induced, and the progression of chronic inflammation is highly correlated with appearance of these vessels. Furthermore, eradication of H. pylori by antibiotics resulted in disappearance of PNAd. These results indicate that inhibition of PNAd formation could have therapeutic effect by attenuating lymphocyte recruitment. In ulcerative colitis (UC), PNAd-expressing HEV-like vessels are induced, preferentially in the active phase, and T cells, particularly CD4(+) T cells, are closely associated with these vessels, suggesting that T cell recruitment via PNAd-expressing HEV-like vessels plays at least a partial role in UC pathogenesis. Additionally, N-acetylglucosamine-6-O-sulfotransferase 1 (GlcNAc6ST-1) is suggested to be a candidate to regulate PNAd induction on HEV-like vessels in UC. These results provide a potential therapeutic strategy to treat UC by blocking T cell adhesion to PNAd-expressing HEV-like vessels. Inhibition or down-regulation of GlcNAc6ST-1 may be an alternative.

Topics: Antigens, Surface; Chronic Disease; Colitis, Ulcerative; Endothelial Cells; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; L-Selectin; Lewis X Antigen; Membrane Proteins; Oligosaccharides; Polysaccharides; Receptors, Lymphocyte Homing; Sialyl Lewis X Antigen; Venules

To characterize histologic alterations and inflammatory infiltrates in the synovium of patients with chronic septic arthritis (SeA).. Synovial membranes from patients with SeA (9 specimens; disease duration >4 weeks) were compared with specimens from patients with septic joint prosthesis loosening (septic total arthroplasty [SeTA]; 9 specimens), rheumatoid arthritis (RA; 25 specimens), osteoarthritis (25 specimens), and normal histology (10 specimens). Sections were stained with hematoxylin and eosin, tissue gram stain, and immunostains for von Willebrand factor (vWF; blood vessels), Ki-67 (dividing cells), CD15 (neutrophils), CD3 (T cells), CD20 (B cells), CD38 (plasma cells), and CD68 (macrophages).. Gram stains were positive in all SeA and SeTA specimens. Mixed polymorphonuclear and mononuclear infiltrates predominated in SeA and SeTA. SeA could be differentiated from RA by higher densities of CD15+ cells (SeA:RA ratio 6.5:1; P < 0.001) or Ki-67+ cells (ratio 2.1:1; P = 0.012). The inflammatory infiltrate of SeTA was similar to SeA but contained fewer CD3+ cells (SeTA versus SeA 0.26:1; P = 0.009) and a tendency toward fewer CD20+ cells. Mean vascular density was strikingly increased in SeA (SeA:normal ratio 3.0:1; P < 0.001) and, to a lesser extent, in the vascularized areas of the SeTA specimens (SeTA:normal ratio 1.9:1). Ki-67/CD31 double immunostains demonstrated proliferating endothelial cells in small subintimal blood vessels, suggesting angiogenesis. Receiver operating characteristic curve analysis identified higher densities of CD15+ and Ki-67+ cells and vWF-positive vessels as histologic markers that differentiated SeA from RA.. This first analysis of the synovium in patients with chronic pyogenic arthritis identified dramatic neovascularization and cell proliferation, accompanied by persistent bacterial colonization and heterogeneous inflammatory infiltrates rich in CD15+ neutrophils, as histopathologic hallmarks.

Topics: ADP-ribosyl Cyclase 1; Adult; Aged; Antigens, CD; Antigens, CD20; Antigens, Differentiation, Myelomonocytic; Arthritis, Infectious; B-Lymphocytes; CD3 Complex; Cell Division; Child; Chronic Disease; Female; Humans; Ki-67 Antigen; Lewis X Antigen; Macrophages; Male; Middle Aged; Neovascularization, Pathologic; Neutrophils; Plasma Cells; Synovial Membrane

Lewis (Le) antigens have been implicated in the pathogenesis of atrophic gastritis and gastric cancer in the setting of Helicobacter pylori infection, and H. pylori-induced anti-Le antibodies have been described that cross-react with the gastric mucosa of both mice and humans. The aim of this study was to examine the presence of anti-Le antibodies in patients with H. pylori infection and gastric cancer and to examine the relationships between anti-Le antibody production, bacterial Le expression, gastric histopathology, and host Le erythrocyte phenotype. Anti-Le antibody production and H. pylori Le expression were determined by enzyme-linked immunosorbent assay, erythrocyte Le phenotype was examined by agglutination assays, and histology was scored blindly. Significant levels of anti-Le(x) antibody (P < 0.0001, T = 76.4, DF = 5) and anti-Le(y) antibody (P < 0.0001, T = 73.05, DF = 5) were found in the sera of patients with gastric cancer and other H. pylori-associated pathology compared with H. pylori-negative controls. Following incubation of patient sera with synthetic Le glycoconjugates, anti-Le(x) and -Le(y) autoantibody binding was abolished. The degree of the anti-Le(x) and -Le(y) antibody response was unrelated to the host Le phenotype but was significantly associated with the bacterial expression of Le(x) (r = 0.863, r(2) = 0.745, P < 0.0001) and Le(y) (r = 0.796, r(2) = 0.634, P < 0.0001), respectively. Collectively, these data suggest that anti-Le antibodies are present in most patients with H. pylori infection, including those with gastric cancer, that variability exists in the strength of the anti-Le response, and that this response is independent of the host Le phenotype but related to the bacterial Le phenotype.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Autoimmunity; Chronic Disease; Female; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Immunophenotyping; Lewis Blood Group Antigens; Lewis X Antigen; Male; Middle Aged; Stomach Neoplasms

Autoantibodies against gastric epithelial cells are detectable in up to 50% of patients with chronic, active Helicobacter pylori gastritis. Presence of autoantibodies against canalicular structures within human parietal cells (anticanalicular autoantibodies) correlate with gastric mucosa atrophy. It has been suggested, that molecular mimicry between H pylori and the host on the level of Lewis X and Lewis Y blood group antigens leads to these autoantibodies. This study aimed at analysing whether antigastric antibodies can be absorbed to Lewis X or Y positive H pylori strains. Sera from 14 H pylori infected patients with anticanalicular autoantibodies were effectively absorbed to H pylori. Immunohistochemical studies of the absorbed sera showed no decrease of antigastric autoreactivity. Pathogenic mechanisms other than molecular mimicry lead to the formation of antigastric autoantibodies, and epitopes other than Lewis antigens are the autoimmune targets.

Topics: Autoantibodies; Chronic Disease; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Lewis Blood Group Antigens; Lewis X Antigen; Molecular Mimicry

Schistosoma mansoni is a blood fluke that produces glycoconjugates containing the Lewis x antigen (Le(x)) Gal beta 1-->4(Fuc alpha 1-->3) GlcNAc beta 1-->R. However, Le(x) antigen is also normally expressed in many tissues of adult rodents. We now report that mice and hamsters chronically infected with S.mansoni generate high titers of both IgM and IgG antibodies reactive with Le(x) and that no reactivity is present in sera from uninfected animals. Anti-Le(x) antibodies were detected by ELISA using the Le(x)-containing neoglycoprotein lacto-N-fucopentaoseIII-BSA. The IgG in infected animals consists of IgG1, IgG2a, and IgG2b subclasses and binds to Protein A-Sepharose. The sera of infected animals reacts only with Le(x) antigen and has no reactivity toward either Le(a) or sialyl Le(x). The IgM response to Le(x) is detectable at week 2, whereas the IgG response is detectable at weeks 5-6 following infection of mice. The sera of infected mice and hamsters can mediate the complement-dependent cytolysis (CDC) of cells expressing surface Le(x). This cytolytic activity is exclusively effected by the anti-Le(x) antibodies, since their removal from sera by adsorption depletes the sera of CDC activity. Thus, the abundant expression of the Le(x) antigens by the parasite elicits cytolytic antibodies reactive with a host antigen.

Topics: Animals; Antibodies, Helminth; Carbohydrate Sequence; Chronic Disease; Complement System Proteins; COS Cells; Cricetinae; HL-60 Cells; Humans; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Lewis X Antigen; Mice; Molecular Sequence Data; Schistosomatidae; Schistosomiasis mansoni

The serum levels of the carbohydrate antigen sialyl Lewis X (SLEX) increase in liver diseases (Sunayama T, Okada Y, Tsuji T., J Hepatol 1994; 19: 451-458). However, it is not known whether the increased serum SLEX levels are associated with the increased levels of its carrier molecules and/or the increased density of SLEX per carrier molecule. By using of rabbit antibody against an SLEX-positive fraction from HepG2 culture supernatant, we developed an enzyme-linked immunosorbent assay to determine the serum levels of the carrier molecules of SLEX (CMSLEX). The CMSLEX-levels in patients with hepatocellular carcinoma were significantly higher than those of normal controls (P < 0.001) and benign chronic liver diseases, i.e., chronic active hepatitis, mild and severe form, and liver cirrhosis (P < 0.05). Patients with chronic persistent hepatitis and chronic active hepatitis, mild form, had higher CMSLEX-levels than normal controls (P < 0.05). The serum CMSLEX-levels did not differ significantly among benign liver diseases. We concluded that serum CMSLEX-levels increase nonspecifically in liver diseases. This is a possible molecular mechanism for the increased serum SLEX levels in liver diseases.

Topics: Adult; Aged; Case-Control Studies; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Humans; Lewis X Antigen; Liver Diseases; Male; Middle Aged; Molecular Weight

The diagnostic significance of measuring sialylated stage-specific embryonic antigen-1 (SLX) in pure pancreatic juice was evaluated in 20 patients with pancreatic cancer, 43 with chronic pancreatitis, 13 with cholecystolithiasis, and 15 control individuals. Four fractions of pure pancreatic juice were collected sequentially from the pancreatic duct by endoscopic cannulation. The SLX levels in all four fractions of pure pancreatic juice were significantly higher in patients with pancreatic cancer than in controls. On the other hand, patients with chronic pancreatitis or cholecystolithiasis did not have SLX levels that significantly differed from those of controls in any fraction. When the cut-off value was set as the mean concentration +2 times the standard deviation of the control values, the positive rates of SLX in the first fraction (washout phase) and the third fraction (secretory phase) of pure pancreatic juice from pancreatic cancer were 55% (11/20) and 40% (8/20), respectively. Although the false positive rates in the first fraction were high in chronic pancreatitis (30%) and cholecystolithiasis (31%), such high SLX levels in the third fraction were found only in one (2%) patient with chronic pancreatitis and in one (8%) with cholecystolithiasis. The specificities of the test for pancreatic cancer in the first fraction and the third fraction were 70% (39/56) and 96% (54/56), respectively. These results indicate that the measurement of SLX in the third fraction of pure pancreatic juice is useful as a specific marker for pancreatic cancer.

Topics: Chronic Disease; Humans; Lewis X Antigen; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis

A carbohydrate antigen, sialyl Lewis X (SLEX), is an inflammation-associated liver cell antigen, which is increasingly expressed as histological diagnosis progresses. A solid phase radioimmunoassay was developed to determine the plasma levels of this substance which were found to be elevated in about 70% of patients with liver disease, with no significant differences among disease groups. Although the plasma levels of SLEX were not directly correlated with the degree of hepatic SLEX expression, the abnormal values were only found in cases with hepatic SLEX expression. Cirrhotic patients with and without hepatocellular carcinoma had comparable values. Plasma levels of SLEX decreased significantly in chronic hepatitis patients successfully treated with IFN, but not in those without a favourable clinical response. Plasma SLEX was carried by some macromolecules with chromatographic and buoyant properties of mucin-type glycoproteins, and others of non-mucin type. These observations suggested that (i) the plasma levels of SLEX increase significantly but non-specifically in liver diseases, (ii) liver cells in the inflammatory lesion are probably the origin of the SLEX-active glycoproteins in the peripheral circulation, (iii) both the increased hepatic synthesis and impaired secretion of the SLEX-positive glycoproteins might be related to the tissue expression and plasma levels of SLEX, and (iv) plasma SLEX might be a useful marker to evaluate the activity of inflammatory liver disease in individual patients and to monitor their treatment.

Topics: Adult; Chronic Disease; Female; Glycoproteins; Hepatitis; Humans; Interferons; Lewis X Antigen; Liver Diseases; Liver Function Tests; Male; Middle Aged

Phenotypic expression of sialylated Lewis(x) antigen by means of the monoclonal antiserum SNH3 was studied in 87 livers, which included normal and steatotic livers and livers with chronic persistent and chronic active hepatitis, alcoholic hepatitis, allograft rejection, focal nodular hyperplasia, hepatocellular carcinoma, cholangiocarcinoma, metastatic carcinoma, cirrhosis of various causes (autoimmune, alcoholic, viral, drug induced, Wilson's disease, and primary biliary cirrhosis). The biotin-streptavidin-peroxidase method was used on formaldehyde-fixed, paraffin-embedded sections. Sialylated Lewis(x) antigen was not demonstrated in normal livers. Hepatocellular expression in a diffuse or perinodular honeycomb pattern was seen in cirrhosis, irrespective of cause. Sialylated Lewis(x) antigen was also observed in hepatocytes around metastatic carcinoma in the absence of inflammation, cirrhosis, or regeneration. Some bile ductules, most likely ductular hepatocytes, but not bile ducts, expressed sialylated Lewis(x) antigen. Sialylated Lewis(x) antigen was seen diffusely in fibrolamellar hepatocellular carcinoma, focally in other hepatocellular carcinomas, and either focally or diffusely in cholangiocarcinomas.

Topics: Chronic Disease; Fatty Liver; Humans; Hyperplasia; Lewis X Antigen; Liver; Liver Cirrhosis; Liver Diseases; Liver 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

The expression of a carbohydrate antigen, sialyl oligomeric Lewis X (SOLex), by Kupffer cells was examined in liver biopsy specimens from patients with chronic hepatitis. The antigen was expressed by Kupffer cells from these patients but not by those from normal controls. Expression of the antigen did not correlate with the histological type of chronic hepatitis, nor with SOLex expression in liver cells, which did correlate with severity of hepatic necrosis and inflammation. Treatment of patients with interferon-alpha increased SOLex expression by Kupffer cells, but not by liver cells, which suggests different means of regulation of SOLex expression in these two cell types. SOLex and HLA class II antigens were expressed simultaneously by Kupffer cells. Expression of SOLex by Kupffer cells (HLA class II antigen-positive) and liver cells (HLA class I antigen-positive) suggests a possible autoimmune response against this carbohydrate antigen in chronic hepatitis.

Topics: Adult; Chronic Disease; Glycolipids; Hepatitis; Hepatitis, Chronic; HLA Antigens; Humans; Immunoenzyme Techniques; Kupffer Cells; Lewis X Antigen; Liver; Male; Middle Aged