Human immune response to Clostridium difficile toxins: role of specific antibodies and mechanisms of monocyte activation

(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL

Clostridium-difficile Colitis - Recent Therapeutic and Immunological Considerations

Clostridium difficile is the main etiological agent of antibiotic associated diarrhoea and pseudomembranous colitis (PMC), It is considered as the most frequent agent of infectious diarrhoea occuring in hospitalized patients, in whom it is responsible for a high morbidity and occasional mortality even when the diagnosis and the treatment are pursued aggressively (1), The pathology is due to the production of at least two toxins: toxin A is an enterotoxin which induces intestinal tissue damage and a fluid response and toxin a Is a cytotoxin which lacks any enterotoxic activity but is believed to exert an additive effect in vivo (2) (Acta gastroenterol. belg., 1995, 58, 313-317)

Effect of Clostridium difficile toxin A on CD11/CD18 expression in vitro

Clostridium difficile toxin A is chemotactic for neutrophils and induces their emigration into the colonic mucosae of rodents. We found that toxin A did not upregulate neutrophil beta 2 integrins on isolated human neutrophils. These data support the hypothesis that in C. difficile colitis, these adhesion molecules are upregulated by endogenous mediators

Gamma globulin administration in relapsing Clostridium difficile-induced pseudomembranous colitis with a defective antibody response to toxin A.

A 53-year-old woman suffered six episodes of Clostridium difficile-pseudomembranous colitis. The serological follow-up demonstrated the absence of a rise in IgG and IgA to toxin A. Human pooled gamma globulin was administered during the fifth relapse and raised IgG levels to toxin A. Normal stools reappeared a week later. The role of the antibodies to toxin A and gamma globulin in C. difficile colitis are discussed

Detection of inner ear disease autoantibodies by immunoblotting

To define further the character of autoantibodies against the inner ear in patients with inner ear disease, Autoantibodies in sera from 82 patients with inner ear disease were investigated by immunoblotting. The inner ear antigens were extracted from Hartley guinea pigs. Brain, kidney, lung, heart and liver extracts were also prepared. Antibodies against the inner ear were found in 32 of 82 (39%) patients with inner ear disease. These sera reacted with the 30 and 58 kDa bands of the inner ear extracts. The 30 kDa band was detected in sera from patients with various inner ear diseases, while the 58 kDa band reacted with sera of patients with idiopathic progressive sensorineural hearing loss. Only two of the 52 normal control sera had a very faint band at 30 kDa. Sixteen of 32 positive sera were then used to probe Western blots of the brain, kidney, lung heart and liver extracts. The 58 kDa band was also found in the protein extracts of the brain, the lung, and the liver. On the other hand, preliminary purification of the 30 and 58 kDa proteins from the inner ear extracts were achieved by anion exchange chromatography. These results show that antibodies in sera from patients with inner ear disease reacted with at least two polypeptide bands (30 and 58 kDa) of guinea pig inner ear extracts, and the 58 kDa antigenic epitope was not cochlea specific

Differential activation of mitogen-activated protein kinases in AGS gastric epithelial cells by cag+ and cag- Helicobacter pylori.

The aim of this study was to determine whether Helicobacter pylori activates mitogen-activated protein (MAP) kinases in gastric epithelial cells. Infection of AGS cells with an H. pylori cag+ strain rapidly (5 min) induced a dose-dependent activation of extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK) MAP kinases, as determined by Western blot analysis and in vitro kinase assay. Compared with cag+ strains, cag- clinical isolates were less potent in inducing MAP kinase, particularly JNK and p38, activation. Isogenic inactivation of the picB region of the cag pathogenicity island resulted in a similar loss of JNK and p38 MAP kinase activation. The specific MAP kinase inhibitors, PD98059 (25 microM; MAP kinase kinase (MEK-1) inhibitor) and SB203580 (10 microM; p38 inhibitor), reduced H. pylori-induced IL-8 production in AGS cells by 78 and 82%, respectively (p < 0.01 for each). Both inhibitors together completely blocked IL-8 production (p < 0.001). However, the MAP kinase inhibitors did not prevent H. pylori-induced IkappaBalpha degradation or NF-kappaB activation. Thus, H. pylori rapidly activates ERK, p38, and JNK MAP kinases in gastric epithelial cells; cag+ isolates are more potent than cag- strains in inducing MAP kinase phosphorylation and gene products of the cag pathogenicity island are required for maximal MAP kinase activation. p38 and MEK-1 activity are required for H. pylori-induced IL-8 production, but do not appear to be essential for H. pylori-induced NF-kappaB activation. Since MAP kinases regulate cell proliferation, differentiation, programmed death, stress, and inflammatory responses, activation of gastric epithelial cell MAP kinases by H. pylori cag+ strains may be instrumental in inducing gastroduodenal inflammation, ulceration, and neoplasia