Anti-a-galactosyl immunoglobulin G (anti-Gal) is a natural antibody present in unusually high amounts in human sera. It constitutes as much as 1% of circulating immunoglobulin G in humans and displays a distinct specificity for the carbohydrate epitope galactosyl a(1-3) galactosyl (Gala1-3Gal). Recently, it has been suggested by various investigators that anti-Gal may be related to some autoimmune phenomena, since marked elevation of its titer was found in sera of patients with autoimmune thyroid disorders, rheumatoid arthritis, glomerulonephritis, and Chagas' disease. In view of the ubiquitous presence of anti-Gal in high titers in humans, throughout life, we hypothesized that, analogous with synthesis of anti-blood group antibodies against bacterial antigens, bacteria within normal intestinal flora may provide constant antigenic stimulation for the synthesis of anti-Gal. This hypothesis would imply that anti-Gal may bind to a variety of bacterial strains of human flora. In the present study, the interaction between affinity chromatography-purified anti-Gal and various bacterial strains was studied. By the use of a direct immunostaining assay and an enzyme-linked immunosorbent assay, anti-Gal was found to interact with a variety of Escherichia coli, Klebsiella, and Salmonella strains, some of which were isolates from normal stool. Furthermore, the anti-Gal-binding sites in some strains were found to be present on the carbohydrate portion of bacterial lipopolysaccharides. It is thus suggested that Gald-*>3Gal epitopes in the outer membranes of normal flora enterobacteria may provide a continuous source for antigenic stimulation. Since there is no immune tolerance to the Galal->3Gal carbohydrate structure in humans, anti-Gal seems to be constantly produced in response to these enterobacteria. In addition, bacteria which express Gala-*3Gal epitopes and which may adhere to various cells mediated binding of anti-Gal to human cell lines. These findings raise the possibility that anti-Gal may damage normal human tissues via inflammatory processes facilitated by bacterial Galo+l-*3Gal epitopes.
SummaryGspB and Hsa are homologous serine-rich surface glycoproteins of Streptococcus gordonii strains M99 and Challis, respectively, that mediate the binding of these organisms to platelet membrane glycoprotein (GP) Ib α α α α . Both GspB and Hsa consist of an N-terminal putative signal peptide, a short serine-rich region, a region (BR) that is rich in basic amino acids, a longer serine-rich region and a C-terminal cell wall anchoring domain. To further assess the mechanisms for GspB and Hsa binding, we investigated the binding of the BRs of GspB and Hsa (expressed as glutathione Stranferase fusion proteins) to sialylated glycoproteins in vitro . Both fusion proteins showed significant levels of binding to sialylated moieties on fetuin and GPIb α α α α . In contrast, the corresponding region of a GspB homologue of Streptococcus agalactiae , which is acidic rather than basic, showed no binding to either fetuin or GPIb α α α α . As measured by surface plasmon resonance kinetic analysis, GspB-and Hsaderived fusion proteins had high affinity for GPIb α α α α , but with somewhat different dissociation constants. Dot blot analysis using a panel of synthesized oligosaccharides revealed that the BR of Hsa can bind both α α α α (2-3) sialyllactosamine [NeuAc α α α α (2-3)Gal β β β β (1-4)GlcNAc] and sialyl-T antigen [NeuAc α α α α (2-3)Gal β β β β (1-3)GalNAc], whereas the BR of GspB only bound sialyl-T antigen. Moreover, far Western blotting using platelet membrane proteins revealed that GPIb α α α α is the principal receptor for GspB and Hsa on human platelets. The combined results indicate that the BRs of GspB and Hsa are the binding domains of these adhesins. However, the subsets of carbohydrate structures on GPIb α α α α recognized by the binding domains appear to be different between the two proteins.
Summal~To learn how lipooligosaccharide (LOS) phase variations affect pathogenesis, we studied two male volunteers who were challenged intraurethrally with Neisseria gonorrhoeae that make a single LOS of 3,600 daltons and sequentially followed LOS expression by gonococci as urethritis developed. LOS variation occurred in vivo. Signs and symptoms of gonorrhea began with the appearance of variants making 4,700-dalton LOS that are immunochemically similar to glycosphingolipids of human hematopoietic cells (Man&ell, R. E., J. M. Griffiss, and B. A. Macher. 1989. J. Exp. Med. 168:107) and that have acceptors for sialic acid. A variant that appeared at the onset of leukorrhoea was shed by 34/36 men with naturally acquired gonorrhea at the time they sought medical attention; the other two shed the variant associated with dysuria. None shed the challenge variant. These data show that in vivo phase shifts to higher molecular mass LOS that mimic human cell membrane glycolipids are associated with the development of gonococcal leukorrhea. Outer membrane glycolipids of Gram-negative bacteria that cause disease along the respiratory or genital mucosae are relatively small (<7,000-dalton) lipooligosaccharides (LOS) 1 whose multiantennary oligosaccharide structures mimic those of human cell membrane glycosphingolipids (GSL) (1-4). During a study of the effect of piliation on infectivity, human volunteers developed gonorrhea after intraurethral challenge with a piliated Ndsseria gonorrhoeae strfm (5) that made a single LOS of 3,600 daltons. We made serial analyses of the LOS made by the organisms infecting two of the volunteers to learn whether LOS phase variations occurred during infection. We then confirmed the results by studying men with naturally acquired gonorrhea.
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