High Affinity Serum‐Derived Fab Fragments as Another Source of Antibodies in the Gut Lumen of both Neonates and Adults

Quan, Canh P.; Ruffet, Emmanuel; Arihiro, K.; Pirès, René; Bouvet, Jean‐Pierre

doi:10.1046/j.1365-3083.1996.d01-288.x

Cited by 22 publications

(16 citation statements)

References 16 publications

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“…First, IgG is present in secretions of the human oral mucosa, small and large intestine, lung, and genitourinary tract (50)(51)(52)(53). The mechanism by which IgG is transported onto these mucosal surfaces is unknown.…”

Section: Discussionmentioning

confidence: 99%

Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line

Dickinson¹,

Badizadegan²,

Wu³

et al. 1999

J. Clin. Invest.

393

361

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IntroductionSteady-state levels of IgG in the blood of adult mice, and likely all mammals, depend on IgG catabolism mediated in part by the MHC class I-related Fc receptor, FcRn (1). FcRn also mediates vectorial transport of IgG across certain epithelial barriers. In suckling mice and rats, intestinal absorption of maternal IgG from breast milk into the systemic circulation depends on FcRn (2). In humans, maternofetal transfer of IgG across the placenta also likely depends on FcRn (3). Thus, FcRn plays critical and well-documented roles in the regulation of IgG metabolism in adults and in the acquisition of humoral immunity in early life. These effects on the physiology of IgG in vivo result from the action of FcRn as an intracellular trafficking receptor (4).FcRn has been cloned from the rat, mouse, and human. The molecule is expressed as a heterodimer composed of a glycosylated heavy (α) chain (51 kDa in rodents and 40-45 kDa in humans) associated noncovalently with β2-microglobulin (β2M) (5). Binding of IgG to FcRn requires contact between solvent-exposed peptide sequences in the CH2 and CH3 domains of IgG and the α1 and α2 domains of FcRn, together with a single contact site in β2M (6-11). A hallmark of FcRn interaction with IgG is its pH dependence, showing high-affinity binding at acidic pH (pH ≤ 6.5) and weak or no binding at neutral pH (pH ≥ 7.0) (12, 13). FcRn is the only Fcγ receptor that exhibits MHC class I structure, and the only Fcγ receptor to exhibit pH dependency in ligand binding.The function of FcRn in the intestine of suckling mice and rats has been well documented (14). In neonatal mice and rats, FcRn is expressed at high levels by intestinal epithelial cells and mediates absorption of IgG by receptor-mediated transcytosis. FcRn expression in the neonatal rodent is developmentally downregulated, resulting in nearly complete loss of intestinal FcRn at the time of weaning (15)(16)(17) The MHC class I-related Fc receptor, FcRn, mediates the intestinal absorption of maternal IgG in neonatal rodents and the transplacental transport of maternal IgG in humans by receptor-mediated transcytosis. In mice and rats, expression of FcRn in intestinal epithelial cells is limited to the suckling period. We have recently observed, however, clear expression of FcRn in the adult human intestine, suggesting a function for FcRn in intestinal IgG transport beyond neonatal life in humans. We tested this hypothesis using the polarized human intestinal T84 cell line as a model epithelium. Immunocytochemical data show that FcRn is present in T84 cells in a punctate apical pattern similar to that found in human small intestinal enterocytes. Solute flux studies show that FcRn transports IgG across T84 monolayers by receptor-mediated transcytosis. Transport is bidirectional, specific for FcRn, and dependent upon endosomal acidification. These data define a novel bidirectional mechanism of IgG transport across epithelial barriers that predicts an important effect of FcRn on IgG function in immune surveillance and host de...

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Section: Discussionmentioning

confidence: 99%

Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line

Dickinson¹,

Badizadegan²,

Wu³

et al. 1999

J. Clin. Invest.

393

361

View full text Add to dashboard Cite

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“…Such a compensatory role of secreted IgM could explain why IgA KO mice have a greater residual capacity to control Giardia infection than B-cell KO mice. However, the latter finding could also be explained by a role of IgG antibodies, since IgG can be transported from the basolateral to the apical side of polarized intestinal epithelial cells in vitro (12) and can be detected in the intestinal lumen in vivo (18,29,31).…”

Section: Discussionmentioning

confidence: 99%

Central Importance of Immunoglobulin A in Host Defense againstGiardiaspp

Housley²,

et al. 2002

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The protozoan pathogen Giardia is an important cause of parasitic diarrheal disease worldwide. It colonizes the lumen of the small intestine, suggesting that effective host defenses must act luminally. Immunoglobulin A (IgA) antibodies are presumed to be important for controlling Giardia infection, but direct evidence for this function is lacking. B-cell-independent effector mechanisms also exist and may be equally important for antigiardial host defense. To determine the importance of the immunoglobulin isotypes that are transported into the intestinal lumen, IgA and IgM, for antigiardial host defense, we infected gene-targeted mice lacking IgA-expressing B-cells, IgM-secreting B-cells, or all B-cells as controls with Giardia muris or Giardia lamblia GS/M-83-H7. We found that IgA-deficient mice could not eradicate either G. muris or G. lamblia infection, demonstrating that IgA is required for their clearance. Furthermore, although neither B-cell-deficient nor IgA-deficient mice could clear G. muris infections, IgA-deficient mice controlled infection significantly better than B-cell-deficient mice, suggesting the existence of B-cell-dependent but IgA-independent antigiardial defenses. In contrast, mice deficient for secreted IgM antibodies cleared G. muris infection normally, indicating that they have no unique functions in antigiardial host defense. These data, together with the finding that B-cell-deficient mice have some, albeit limited, residual capacity to control G. muris infection, show that IgA-dependent host defenses are central for eradicating Giardia spp. Moreover, B-cell-dependent but IgAindependent and B-cell-independent antigiardial host defenses exist but are less important for controlling infection.

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“…In human neonates, rotavirus infections are often asymptomatic (Vial et al, 1988 ;Flores et al, 1994) and high titres of circulating IgG antibodies acquired transplacentally may play a role in the passive protection of newborn infants (Flores et al, 1994). It is unclear whether a mechanism of IgG transport from the serum to the intestine, comparable to that demonstrated in calves, exists in humans but high titres of immunologically active Fab fragments have been noted in the stools of 1-week-old, formula-fed infants (Quan et al, 1996). These fragments were derived from serum IgG of the mother and had high affinity for their corresponding antigen (tetanus toxoid).…”

Section: Discussionmentioning

confidence: 99%

Serum and intestinal isotype antibody responses to Wa human rotavirus in gnotobiotic pigs are modulated by maternal antibodies.

Parre√±o

Hodgins

Arriba

et al. 1999

Journal of General Virology

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The effects of passive antibodies on protection and active immune responses to human rotavirus were studied in gnotobiotic pigs. Pigs were injected at birth with saline or sow serum of high (immunized) or low (control) antibody titre and subsets of pigs were fed colostrum and milk from immunized or control sows. Pigs were inoculated at 3-5 days of age and challenged at 21 days post-inoculation (p.i.) with virulent Wa human rotavirus. Pigs receiving immune serum with or without immune colostrum/milk were partially protected against diarrhoea and virus shedding after inoculation, but had significantly lower IgA antibody titres in serum and small intestinal contents at 21 days p.i. and lower protection rates after challenge compared with pigs given control or no maternal antibodies. IgG antibody titres were consistently higher in small than in large intestinal contents. Pigs given control serum with control colostrum/milk had lower rates of virus shedding after inoculation than those given control serum alone. In summary, high titres of circulating maternal antibodies with or without local (milk) antibodies provided passive protection after inoculation but suppressed active mucosal antibody responses. These findings may have implications for the use of live, oral rotavirus vaccines in breast-fed infants.

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High Affinity Serum‐Derived Fab Fragments as Another Source of Antibodies in the Gut Lumen of both Neonates and Adults

Cited by 22 publications

References 16 publications

Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line

Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line

Central Importance of Immunoglobulin A in Host Defense againstGiardiaspp

Serum and intestinal isotype antibody responses to Wa human rotavirus in gnotobiotic pigs are modulated by maternal antibodies.

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