International Glycoconjugate Organization Award 1999
Glyco-Forum section
mannose binding components within the human immune system.
High mannose type glycan sequences are usually poorly expressed on the surface of mammalian cells. Yeast and bacterial
pathogens expressing such glycan sequences can therefore be
easily targeted by serum mannose binding protein (MBP; Stahl et
al., 1978; Kawasaki et al., 1983) and specific mannose receptors
expressed on activated macrophages (Stahl et al., 1980). Children
deficient in MBP develop recurrent yeast and bacterial infections
(Sumiya et al., 1991), suggesting a crucial role for such proteins
in manifesting the innate immune response against such
pathogens. In addition, intravascular injection of Candida
albicans into transgenic mice expressing human MBP results in
rapid clearance of such yeast that correlates with a decrease in the
serum levels of both human and murine MBP (Tabona et al.,
1995). Collectively, such studies indicate that humans and other
mammals are protected from opportunistic yeast infections by
specific mannose binding components of the innate immune
response.
As noted by Zanetta and colleagues, patients with α-mannosidase deficiency develop greatly elevated levels of high mannose
glycans and derivatives in their serum and tissues that could
certainly interfere with IL-2 mediated activation (Zanetta et al.,
1998a). However, extrapolation of the immunodeficiency caused by
this rare genetic defect to the immunosuppression induced by HIV
may not be appropriate, especially if innate immunity is operational.
Whether gp120 can block IL-2 mediated activation at physiological
concentrations needs to be determined. Other investigators have
suggested that the expression of high mannose type glycans on
gp120 may be involved in HIV clearance or infectivity. MBP has
been shown to block HIV infection in vitro presumably by binding
to the high mannose type glycans associated with gp120 (Ezekowitz
et al., 1989), suggesting a role for this lectin-like protein in viral
inactivation. Other investigators have proposed that MBP interaction
with HIV may be responsible for CD4 independent infection of
immune effector cells (Mizuochi, 1992).
We have presented an alternative hypothetical model suggesting
that glycoconjugate recognition plays a crucial role in persistent
infections and related pathological conditions (e.g., HIV, helminthic
parasites, Helicobacter pylori, aggressive tumors; Clark et al.,
1996, 1997). In this paradigm, certain pathogens mimic or acquire
carbohydrate sequences associated with glycoconjugates that
protect gametes or induce fetomaternal tolerance. The presentation
of such functional sequences on pathogenic proteins or lipids in
the right context invokes the same response utilized by the
gametes and the developing human to protect them from potential
maternal immune responses. The pathogen is thus allowed to
persist to the detriment of the host. We have designated this model
as the human fetoembryonic defense system (hu-FEDS) hypothesis
(Clark et al., 1996; 1997).
We believe that our model more adequately explains how HIV
and other persistent pathogens are able to compromise the human
immune response. Intravascular pathogens must be able to
circumvent both cellular and humoral defense mechanisms to
persist. Eutherian mammals must accommodate an allogeneic
fetus for an extended period of time to support sexual reproduction.
Therefore, it is logical that persistent pathogens would be selected
to employ an existing system used to protect the gametes and the
developing human. In our opinion, this essential reproductive
imperative provides pathogens with an accessible “Achilles heel
that they can exploit to survive and propagate in humans and other
eutherian mammals.
iv
References
Clark,G.F., Dell,A., Morris,H.R., Patankar,M., Oehninger,S. and Seppala,M.
(1997) Viewing AIDS from a glycobiological perspective: potential linkages
to the human fetoembryonic defence system hypothesis. Mol. Hum. Reprod.,
3, 5–13.
Clark,G.F., Oehninger,S., Patankar,M.S., Koistinen,R., Dell,A., Morris,H.R.,
Koistinen,H. and Seppala,M. (1996) A role for glycoconjugates in human
development: the human feto-embryonic defence system hypothesis.
Hum. Reprod., 11, 467–473.
Ezekowitz,R.A., Kuhlman,M., Groopman,J.E. and Byrn,R.A. (1989) A human
serum mannose-binding protein inhibits in vitro infection by the human
immunodeficiency virus. J. Exp. Med., 169, 185–196.
Kawasaki,N., Kawasaki,T. and Yamashina,I. (1983) Isolation and characterization of
a mannan-binding protein from human serum. J. Biochem. Tokyo, 94, 937–947.
Mizuochi,T. (1992) Structure and function of oligosaccharide chains of the
envelope glycoprotein gp120 of human immunodeficiency virus type 1.
Nippon Rinsho, 50, 1419–1429.
Stahl,P., Schlesinger,P.H., Sigardson,E., Rodman,J.S. and Lee,Y.C. (1980)
Receptor-mediated pinocytosis of mannose glycoconjugates by macrophages:
characterization and evidence for receptor recycling. Cell, 19, 207–215.
Stahl,P.D., Rodman,J.S., Miller,M.J. and Schlesinger,P.H. (1978) Evidence for
receptor-mediated binding of glycoproteins, glycoconjugates, and lysosomal
glycosidases by alveolar macrophages. Proc. Natl. Acad. Sci. USA, 75,
1399–1403.
Sumiya,M., Super,M., Tabona,P., Levinsky,R.J., Arai,T., Turner,M.W. and
Summerfield,J.A. (1991) Molecular basis of opsonic defect in immunodeficient
children. Lancet, 337, 1569–1570.
Tabona,P., Mellor,A. and Summerfield,J.A. (1995) Mannose binding protein is
involved in first-line host defence: evidence from transgenic mice. Immunology,
85, 153–1539.
Zanetta,J.P., Alonso,C. and Michalski,J.C. (1996) Interleukin 2 is a lectin that
associates its receptor with the T-cell receptor complex. Biochem. J., 318, 49–53.
Zanetta,J.P., Bonaly,R., Maschke,S., Strecker,G. and Michalski,J.-C. (1998a)
Hypothesis: immunodeficiencies in α-mannosidase, mycosis, AIDS and
cancer a common mechanism of inhibition of function of the lectin interleukin
2 by oligomannosides. Glycobiology, 8, vi–ix.
Zanetta,J.P., Bonaly,R., Maschke,S., Strecker,G. and Michalski,J.-C. (1998b)
Differential binding of lectins IL-2 and CSL to Candida albicans and cancer
cells. Glycobiology, 8, 221–225.
Announcement
International Glycoconjugate Organization
Award 1999
The International Glycoconjugate Organization (IGO) is accepting
nominations of glycoscientists who have clearly advanced the field
of glycoscience and show promise of continuing advancements.
The award (US$4,000) will be given at the XVth International
Symposium on Glycoconjugates (Glyco XV) in Tokyo, Japan,
August 22–27, 1999. The awardee will present his/her accomplishments at Glyco XV. Travel expenses up to US$1,500 will be
provided. Notification of the award will be made by April 15, 1999.
Nominations must be submitted in 6 copies and should be in the
form of a curriculum vitae with bibliography and supporting letter
summarizing in detail the accomplishments of the nominee.
Institutional or self-nominations will not be accepted. Nomination (...truncated)
