Jiri Mestecky

Advances in Mucosal Immunology

The proceedings of the August 1992 congress comprise 354 papers grouped within ten sections: B and T cells of the mucosal immune system; non-lymphoid cells of the mucosal immune system; development of mucosal immunity; gnotobiology, environmental, nutritional, and intrinsic factors in mucosal immuno

Secretory immunity in the female reproductive tract

PROBLEM: Antibodies and antibody‐producing cells display a different and characteristic distribution in body fluids and tissues.

Role of aberrant glycosylation of IgA1 molecules in the pathogenesis of IgA nephropathy.

Studies of the properties of immune complexes (IC) in the circulation, urine, and mesangium of IgA nephropathy (IgAN) patients have provided data relevant to the pathogenesis of this disease. IC contain predominantly polymeric IgA1 molecules which are deficient in galactose (Gal) residues on O-linked glycan chains in the hinge region (HR) of their heavy (H) chains. As a result of this aberrancy, a novel antigenic determinant(s) involving N-acetylgalactosamine (GalNAc) and perhaps sialic acid (SA) of O-linked glycans is generated and recognized by naturally occurring GalNAc-specific antibodies. Thus, IC in IgAN consist of Gal-deficient IgA1 molecules as an antigen, and GalNAc-specific IgG and/or IgA1 as an antibody. IgG antibodies to Gal-deficient IgA1 are probably induced by cross-reactive microbial antigens; they are present at variable levels not only in humans with or without IgAN but also in many phylogenetically diverse vertebrate species. Incubation of human mesangial cells with IC from sera of IgAN patients indicated that stimulation of cellular proliferative activity was restricted to the large (>800 kDa) complexes. These findings suggest that experimental approaches that prevent the formation of large Gal-deficient IgA1-IgG IC may be applied ultimately in an immunologically mediated therapy.

Heterogeneity of IgG Glycosylation in Adult Periodontal Disease

Periodontal disease is a chronic inflammatory disease of bacterial etiology. In many other chronic inflammatory diseases, IgG glycans are galactose-deficient and thus capable of complement activation through the lectin pathway. In this study, we examined whether IgG in serum and gingival crevicular fluid, and IgG locally produced by plasma cells in gingiva of periodontal disease patients, display altered glycosylation. We developed a lectin-ELISA to measure levels of galactose-deficient IgG in the fluids and immunofluorescence staining to detect galactose-deficient IgG-producing cells in gingiva. Our results indicated higher levels of galactose-deficient IgG in sera and gingival crevicular fluid from periodontal disease patients, compared with levels in healthy controls. Furthermore, gingivae from periodontal disease patients exhibited infiltration of IgG-producing plasma cells; many of them contained galactose-deficient IgG in the cytoplasm. Analysis of our data suggests that IgG secreted by B-cells was aberrantly glycosylated, which resulted in the production of pro-inflammatory galactose-deficient IgG.

New Strategies for Oral Immunization

The potential of biocompatible and biodegradable microspheres as a controlled release oral vaccine delivery system has been examined. Orally-administered 1-10 11m microspheres composed of poly (DL-Iactide-co-glycolide) were specifically taken up into the Peyers patch lymphoid tissue of the gut, where those ~ 5 !lID remained for up to 35 days. Microspheres < 5 11m disseminated within macrophages to the mesenteric lymph nodes and spleen. In contrast to soluble staphylococcal enterotoxin B toxoid, oral immunization with enterotoxoid in microspheres induced circulating toxin-specific antibodies and a concurrent secretory IgA anti-toxin response in saliva and gut fluid.

Chapter 95 – Mucosal Immunity in the Human Female Reproductive Tract

The mucosal immune system of the female genital tract is under a strong hormonal control that regulates the transport of immunoglobulins, the levels of cytokines, the distribution of various cell populations, and the antigen presentation in the genital tissues during the reproductive cycle. Unique to the genital tract and unlike other mucosal secretions in which S-IgA is the dominant isotype, IgG levels in the lower genital tract secretions equal or exceed the levels of S-IgA. The presence of the mucosal effector sites and a significant contribution of the systemic immune compartment are of considerable functional importance in the stimulation of protective immune responses. Comparison of—the levels and molecular properties of Ig of the major isotypes in blood, external secretions such as saliva, milk, and intestinal fluid, and female genital tract secretions—indicate that in humans the systemic and mucosal compartments of the immune system display a considerable degree of independence. In contrast to the mucosal system of, for example, the alimentary tract—the mucosal system of the genital tract is characterized by a significant contribution of the systemic compartment with respect to—the Ig isotype distribution, unique distribution and phenotypes of B and T cells, strong hormonal dependency, lack of typical lymphoepithelial inductive sites, and relative weakness of immune responses to local infections or immunizations with certain antigens.

HIV- 1(MN) recombinant glycoprotein 160 vaccine-induced cellular and humoral immunity boosted by HIV-1(MN) recombinant glycoprotein 120 vaccine

We evaluated prime-boost immunization with two recombinant envelope glycoprotein subunit vaccines (HIV-1MN recombinant gp160 vaccine in alum adjuvant [MN rgp160] and HIV-1MN recombinant gp120 vaccine in alum adjuvant [MN rgp120]) for safety and immunogenicity in healthy, HIV-1-uninfected adults. The rationale was to combine the helper T cell memory and binding antibody responses typically induced by rgp160 vaccines with the superior neutralizing antibody responses induced by rgp120 vaccines. In a double-blinded, controlled trial, volunteers were randomly assigned to receive MN rgp160 or adjuvant placebo, and a subset later received MN rgp120. The two vaccines were safe, but reactions to MN rgp160 and its adjuvant placebo exceeded those to MN rgp120. MN rgp160 induced IgG binding antibodies, including all IgG subclasses, to MN rgp160 in all vaccine recipients. HIV-1MN-neutralizing and anti-V3 MN peptide-binding antibodies were observed in a majority of volunteers after the fourth MN rgp160 immunization, but at lower levels compared with immunization with MN rgp120 in historical controls. HIV-1-binding, neutralizing, and fusion inhibition antibodies were boosted to the highest levels among MN rgp160 recipients after MN rgp120 booster injections. MN rgp120 boosting appeared to alter the distribution of MN rgp160 vaccine-induced, anti-MN rgp160 IgG subclass antibodies. MN rgp160 induced helper T cell memory, measured by lymphocyte proliferation, Thl and Th2 cytokine production, and skin testing. Strategies including both subunit vaccines may help maximize antibody and helper T cell memory responses to HIV-1 envelope glycoprotein.

Immunoinhibitory elements in human colostrum

ConclusionBirth thrusts the mammalian neonate into an environment rich in antigenic stimulation. Because of the lack of exposure of the infant’s immune system to environmental antigens, the possibility exists that untoward responses to food and microbial antigens results in the development of hypersensitivity reactions. It is also possible that the ingestion of maternal lymphocytes could result in graft-versus-host reactivity. The presence of immunoregulatory factors in colostrum would modulate such unfavorable reactions. Further clarification of the nature of humoral factors, colostral cells, their immune reactivity and their effect on the immune response of other lymphocytes would give insight into the immunological consequences associated with breast feeding.

Characterization of IgA1, IgA2 and secretory IgA carbohydrate chains using plant lectins.

The glycosylation pattern of immunoglobulins varies according to class and subclass. IgA1 and IgD, but not the other Ig isotypes, are substituted with O-linked oligosaccharide chains, which are linked to serine or threonine in the polypeptide chain. N-linked oligosaccharide chains are, in contrast, found in all isotypes, but their number varies, from one per heavy chain in IgG to six per heavy chain in IgE.1 N-linked oligosaccharide chains can be either of the “complex” type (Fig. la), or of the “oligomannose” type (Fig. lb). The N-linked oligosaccharide chains are attached to asparagine residues in the polypeptide backbone of the protein.