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Current Trends in Immunology   Volumes    Volume 2 
Abstract
Evidence and hypothesis to explain the structural basis of polyreactivity
Minou Adib-Conquy
Pages: 145 - 151
Number of pages: 7
Current Trends in Immunology
Volume 2 

Copyright © 1999 Research Trends. All rights reserved

ABSTRACT

Natural antibodies that bind to various self and non-self antigens have been shown to be present in normal sera without any autoimmune manifestation. These antibodies are mainly polyreactive and of the IgM isotype, but polyreactive IgG and IgA are also found. Many investigators have tried to define the structural basis of their reactivity. Sequencing of the variable regions of the heavy and light chains of polyreactive mAb, did not show a special usage of VH or VL gene families. Several hypothesis have been proposed to explain their capacity to react with various antigens. It has been proposed that the same epitope could be present on different antigens or that polyreactivity could be due to the same distribution of charged residues. Experiments of CDR shuffling and mutagenesis performed by several groups have pointed out the important role of CDR regions of antibodies for polyreactivity, especially the CDR3 of the heavy chain (HCDR3). The amino acid composition of this region is important, HCDR3 of polyreactives antibodies are more heteregenous by their length and contain frequently charged amino acids, especially arginine and lysine. However, charged residues cannot explain by themselves polyreactivity, because monospecific anti-DNA IgG in lupus also often contain positively charged residues. The importance of non-charged residues for polyreactivity has also been studied by site-directed mutagenesis. From the results of these experiments, it appears that a certain flexibility and hydrophilicity of the HCDR3 are important in order to have polyreactivity. Similarly, by mesuring the effect of environmental parameters (pH, ionic strength, temperature) on the global reactivity of several poly-and monospecific monoclonal IgG it was observed that the reactivity of polyspecific IgG was modified to a greater extent by pH and temperature extremes, while monospecific antibodies showed minor modifications of their reactivity in the same conditions. On the whole, the data accumulated suggest that electrostatic interactions and charged residues seem to be very important for polyreactive antibodies. However, beside the presence of charged amino acids in their CDR, polyreactive antibodies seem to possess a more plastic structure, that would enable them to adapt their binding site to several antigens. Analysis of more antibodies in junction with other technologies (such as Nuclear Magnetic Resonance) may help to more clearly define the true structure-function differences between mono- and polyreactive antibodies.

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