Cloning and Characterization of the Bovine MHC Class I-Like Fc Receptor

Kacskovıcs, Imre; Wu, Zezhou; Simister, Neil E.; Frenyo, Laszlo V.; Hammarström, Lennart

doi:10.4049/jimmunol.164.4.1889

Cited by 87 publications

(91 citation statements)

References 61 publications

(71 reference statements)

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“…The Fc-binding FcRn is a heterodimer, which comprises ␤ 2 -microglobulin and a membrane-anchored ␣ chain that is related to the ␣ chain of major histocompatibility complex class I molecules. The corresponding sequences and overall structures are well conserved across species such as in human, mouse, rat, and cow (2,3,4,5,6,7), as well as in non-eutherian mammals (8). However, differences in their binding specificity to various IgG exist (9), indicating the presence of species-specific binding mechanisms.…”

Section: Conclusive Evidence Indicates That the Neonatal Fc Receptor mentioning

confidence: 99%

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)

Dall’Acqua¹,

Kiener²,

Wu³

2006

Journal of Biological Chemistry

544

490

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We describe here the functional implications of an increase in IgG binding to the neonatal Fc receptor. We have defined in a systematic fashion the relationship between enhanced FcRn binding of a humanized anti-respiratory sincytial virus (RSV) monoclonal antibody (MEDI-524) and the corresponding biological consequences in cynomolgus monkeys. The triple mutation M252Y/S254T/T256E (YTE) was introduced into the Fc portion of MEDI-524. Whereas these substitutions did not affect the ability of MEDI-524 to bind to its cognate antigen and inhibit RSV replication, they resulted in a 10-fold increase in its binding to both cynomolgus monkey and human FcRn at pH 6.0. MEDI-524-YTE was efficiently released from FcRn at pH 7.4 in both cases. We show that MEDI-524-YTE consistently exhibited a nearly 4-fold increase in serum half-life in cynomolgus monkeys when compared with MEDI-524. This constituted the largest half-life improvement described to date for an IgG in a primate. For the first time, we demonstrate that these sustained serum levels resulted in an up to 4-fold increase in lung bioavailability. Importantly, we also establish that our non-human primate model is relevant to human. Finally, we report that the YTE triple substitution provided a means to modulate the antibodydependent cell-mediated cytotoxicity (ADCC) activity of a humanized IgG1 directed against the human integrin ␣ v ␤ 3 . Therefore, the YTE substitutions allow the simultaneous modulation of serum half-life, tissue distribution and activity of a given human IgG1.

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Section: Conclusive Evidence Indicates That the Neonatal Fc Receptor mentioning

confidence: 99%

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)

Dall’Acqua¹,

Kiener²,

Wu³

2006

Journal of Biological Chemistry

544

490

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“…Evidence derived in ruminants is in favour of the hypothesis that FcRn selectively transports IgG from serum to milk. [14][15][16][17] Previous studies have shown that expression of the Fc receptor in the mammary gland correlates with the period of highest IgG-transfer into milk in three species: possum, sheep and pigs. 15,18,19 However, the data obtained from rodent models supports the notion either that FcRn was not involved in IgG transfer from serum to milk or that transport of IgG was in an inverse correlation with their binding affinity to FcRn.…”

Section: Introductionmentioning

confidence: 99%

Over‐expression of the bovine FcRn in the mammary gland results in increased IgG levels in both milk and serum of transgenic mice

Lü

Zhao

et al. 2007

Immunology

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SummaryThe neonatal Fc receptor (FcRn) protects immunoglobulin G (IgG) from catabolism and is also responsible for IgG absorption in the neonatal small intestine. However, whether it mediates the transfer of IgG from plasma to milk still remains speculative. In the present study, we have generated transgenic mice that over-express the bovine FcRn (bFcRn) in their lactating mammary glands. Significantly increased IgG levels were observed in the sera and milk from transgenic animals, suggesting that the over-expressed bFcRn could bind and protect endogenous mouse IgG and thus extend its lifespan. We also found that injected human IgG showed a significantly longer half-life (7-8 days) in the transgenic mice than in controls (2Á9 days). Altogether, the data suggested that bFcRn could bind both mouse and human IgG, showing a cross-species FcRnIgG binding activity. However, we found no selective accumulation of endogenous mouse IgG or injected bovine IgG in the milk of the transgenic females, supporting a previous hypothesis that IgG was transported from serum to milk in an inverse correlation to its binding affinity to FcRn.

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“…and Thompson-Crispi et al (2013) found similar results, in milk and plasma respectively. The present findings showed that NAb levels were lower in milk than in plasma, this is in agreement with earlier studies NAb isotypes IgM and IgG may both be transported from plasma to milk (Kacskovics et al, 2000; in varying degrees depending on stage of lactation, colostrogenesis, and also in response to inflammation in the mammary gland. Phenotypic correlations between NAb levels measured in plasma and milk were moderately positive (Table 2.4), which means that these correlations are not close to one and are lower than genetic correlations.…”

Section: Phenotypic Parameters Of Nab Levels In Milk and Plasmasupporting

confidence: 81%

Antibodies and longevity of dairy cattle : genetic analysis

Klerk¹

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De . Antibodies and longevity of dairy cattle: genetic analysis. PhD thesis, Wageningen University, the Netherlands In dairy cattle longevity is an important trait. Longevity is strongly related to disease resistance, since a more healthy cow is expected to realize a longer productive life (longevity). Information on longevity records, however, can only be measured after an animal has been culled. Therefore, predictors of longevity traits are needed in order to breed for improved longevity. This thesis aimed to gain more knowledge and genetic background on (natural) antibodies as predictors for longevity. Both natural antibody-and specific antibody levels were studied. Antibody binding the naive antigen KLH was assumed to be natural antibody. Antibodies binding bacteria-derived antigens LTA, LPS and PGN were assumed to be specific antibodies. It was shown that natural antibody levels measured in milk and blood are genetically high correlated (± 0.80) for the two studied isotypes (IgG and IgM). On the other hand, phenotypically, natural antibodies (from both IgG and IgM isotype) measured in milk cannot be interpreted as the same trait (phenotypic correlation = ± 0.40). Antibodies (both natural-and specific antibodies) showed a negative relation with longevity: first lactation cows with low IgM or IgG levels were found to have a longer productive life. When using estimated breeding values for longevity, only a significant relation was found between natural antibody level (IgM binding KLH) and longevity. Lastly, this thesis reports on a genome-wideassociation study (GWAS), to detect genes contributing to genetic variation in natural antibody level. For natural antibody isotype IgG, genomic regions with a significant association were found on chromosome 21 (BTA). These regions included genes that play an important role in isotype class switching (from IgM to IgG). The gained knowledge on relations between antibodies and longevity and the gained insight on genes responsible for natural antibodies level make antibodies potential predictors for longevity.

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Cloning and Characterization of the Bovine MHC Class I-Like Fc Receptor

Cited by 87 publications

References 61 publications

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)

Over‐expression of the bovine FcRn in the mammary gland results in increased IgG levels in both milk and serum of transgenic mice

Antibodies and longevity of dairy cattle : genetic analysis

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