Correlation of the character of intramolecular melting with digestibility by pepsin in precipitating and non-precipitating pig anti-DNP antibodies

Loseva, Olga; Tlschenko, V.M.; Olsovská, Z; Franěk, František; Zav’yalov, V.P.

doi:10.1016/0161-5890(86)90085-4

Cited by 12 publications

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“…The trans-CH1±CH2 contact option is found in hinge-de®cient mutants such as protein Mcg (PDB1MCO). A suggestive analogy is found between human IgG4 and non-precipitating pig antibodies, which have been investigated in considerable detail by Franek et al 34 The structural basis for the non-precipitating behaviour of these porcine antibodies has not been elucidated to our knowledge. These non-precipitating antibodies are relatively resistant to digestion by pepsin.…”

Section: Is the Relatively Compact Structure Of Igg4 Caused By A Ch1±mentioning

confidence: 99%

IgG4 breaking the rules

2002

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SUMMARYImmunoglobulin G4 (IgG4) antibodies have been known for some time to be functionally monovalent. Recently, the structural basis for this monovalency has been elucidated: the in vivo exchange of IgG half-molecules (one H-plus one L-chain) among IgG4. This process results in bispeci®c antibodies that in most situations will behave as functionally monovalent antibodies. The structural basis for the abnormal behaviour of IgG4 seems to be largely the result of a single amino acid change relative to human IgG1: the change of a proline in core hinge of IgG1 to serine. This results in a marked shift in the equilibrium between interchain disulphide bridges and intrachain disulphide bridges, which for IgG4 results in 25±75% absence of a covalent interaction between the H-chains. Because of strong non-covalent interactions between the CH3 domains (and possibly also between the CH1 domain and the trans-CH2 domain) IgG4 is a stable four-chain molecule and does not easily exchange halfmolecules under standard physiological conditions in vitro. We postulate that the exchange is catalysed in vivo by protein disulphide isomerase (PDI) and/or FcRn (the major histocompatibility complex (MHC)-related Fc receptor) during transit of IgG4 in the endosomal pathway in endothelial cells. Because IgG4 is predominantly expressed under conditions of chronic antigen exposure, the biological relevance of this exchange of half-molecules is that it generates antibodies that are unable to form large immune complexes and therefore have a low potential for inducing immune in¯ammation. In contrast to monovalent immunoglobulin fragments, these scrambled immunoglobulins have a normal half-life. The signi®cance of the ensuing bispeci®city needs further evaluation, because this will be relevant only in situations where high IgG4 responses are found to two unrelated antigens that happen to be present in the body at the same time and place. In this context the signi®cance of IgG4 autoreactivity might have to be re-evaluated. The main function of IgG4, however, is presumably to interfere with immune in¯ammation induced by complement-®xing antibodies, or, in the case of helminth infection or allergy, by IgE antibodies.

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