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The objectives were to study the effect of microbial 70 kDa heat shock protein (HSP70) on the production of tumour necrosis factor (TNF)-α and interleukin (IL)-12 by dendritic cells (DC) from patients with Crohn's disease. TNF-α concentration was increased significantly when DC from Crohn's disease were stimulated with HSP70 or CD40L and this was associated with signalling by the extracellular signal regulated kinase (ERK) 1/2 and p38 mitogen activated protein (MAP) kinase pathway. IL-12 production was also increased when DC were stimulated with HSP70. Cells eluted from inflamed intestinal mucosa from Crohn's disease, stimulated with HSP70, CD40L or lipopolysaccharide produced significantly greater TNF-α and IL-12 concentrations than cells from uninflamed mucosa. Significant inhibition of TNF-α production was demonstrated when DC from peripheral blood mononuclear cells or cells eluted from intestinal mucosa of Crohn's disease were treated with either the HSP70 inhibitory peptide (aa 457–496) or peptides derived from CD40 and CD40L. These inhibitory peptides target the CD40–CD40L and the emerging CD40–HSP70 co-stimulatory pathway. Our findings offer a novel strategy to prevent excessive production of TNF-α in Crohn's disease. [ABSTRACT FROM AUTHOR]

Passive immunization with the monoclonal antibody 61BG1.3 selectively prevents colonization by Porphyromonas gingivalis in humans (Booth V, Ashley FP. Lehner T. Infect Immun 1996; 64:422-7). The protective MoAb recognizes the β component of the R1 protease of P. gingivalis which is formed by proteolytic processing of a polyprotein precursor termed PrpR1. This subunit is both a haemagglutinin and an antigen which is recognized by sera from patients with periodontitis. In this study the relationship was investigated between a colonization epitope which is recognized by the MoAb 61BG1.3, a haemagglutinating and B cell epitope which are recognized by sera from patients with periodontitis, B cell epitopes were mapped by Western blotting with a series of truncated recombinant polypeptides spanning the adhesion domain within residues 784-1130 of PrpR1 and by ELISA using a panel of synthetic peptides spanning the same sequence. The epitope which is recognized by the protective MoAb was mapped within residues 907-931 of PrpR1, while serum responses of patients were directed predominantly to the adjacent carboxy-terminal sequence within residues 934-1042. The haemagglutinating epitope was mapped to residues 1073-1112. In view of our previous findings that the MoAb 61BG1.3 prevents colonization of P. gingivalis in vivo and inhibits haemagglutination, these two epitopes may be in proximity in the native protein. Active or passive immunization strategies which target the protective or haemagglutinating epitopes of the adhesion domain of PrpR1 may provide a means of preventing infection with P. gingivalis. [ABSTRACT FROM AUTHOR]

Rectal and cervicovaginal mucosa are common routes of transmission of HIV, although the mechanism of transmission is unknown. We have investigated human rectal and cervicovaginal epithelia for the expression of complement receptors (CR) and cell adhesion molecules which may be involved in HIV and other infections. In rectal mucosa, CR3 was detected in the surface and crypt epithelial cells by immunohistology, using MoAbs to CD18 and CD11b in 10 out of 15 specimens. RNA transcripts encoding both CD11b and CD18 were also demonstrated in surface and crypt epithelial cells by in situ hybridization. Although CD11b was detected in the epithelial cells in three out of the 14 cervicovaginal specimens, we were unable to detect CD18. We suggest that expression of the CD11b/CD18 heterodimer might facilitate transmission of HIV by enhancing binding of HIV-antibody complexes in seminal fluid to epithelial cells. Alternatively, since intercellular adhesion molecule-1 (ICAM-1) is a receptor for CD11b/CD18, this may promote adhesion between epithelial cells and HIV-infected mononuclear cells in seminal fluid. [ABSTRACT FROM AUTHOR]

The mechanism of transmission of HIV from the male to the female genital tract or in the reverse order is not clear. CD4 glycoprotein is the receptor lot HIV and Langerhans cells and the related dendritic cells could play a role in the initial transmission of HIV. For receptors (FcR) for IgG might be involved in antibody-mediated binding of HIV. We carried out an immunohistological study of normal human cervical and vaginal epithelia for the presence of CD4+ glycoprotein. Langerhans cells and FcR to IgG, CD4+ glycoprotein was not found in the vaginal or cervical epithelium with the exception of a few endocervical epithelial cells. A small number of CD4+ mononuclear cells were found in the endocervical epithelial of a third of the specimens but a large number of CD4+ cells was found in the submucosa of most of the cervical and vaginal specimens. Langerhans cells expressing CD4, HLA class IL, FcγR2 and FcγR3 were detected in most vaginal, ectocervical and transformation zone epithelia and in 9/14 endocervicul tissues. FcγR3 was detected in about two-thirds of the columnar endocervical epithelium and the transformation zone. A smaller number of specimens expressed FcγR2 in these epithelia, but FcγR1 was not detected. We then demonstrated mRNA for FcγR3 in the columnar endocervical epithelial cells and transformation zone by in situ hybridization using a CDl6-RNA probe. FcγR3 and FcγR2 gene transcripts were also found in fetal cervical tissue by applying the polymerase chain reaction to amplify portions of the FcγRl and FcγR2 coding sequences in cDNA prepared from fetal RNA. HLA-DR was found in the endocervical cells. transformation zone and in Langerhans cells of all specimens. The presence of Langerhans cells, Fey receptors and HLA class II antigen offers three potential mechanisms for cervico-vaginal HIV transmission: (i) direct HIV infection of Langerhans cells. (ii) binding of HIV antibody complexes to cervical epithelial Fcγ receptors and (iii) binding of HIV infected CD4+ cells to cervical HLA class IT antigen which may infect these or the adjacent CD4+ cells. [ABSTRACT FROM AUTHOR]