Hello,
what would be characteristical structural/chemical/modificational differences between human and mice antibodies for all or specifif Ig classes?
Best,
Dennis
The largest sequence differences are, of course, seen in the antibody variable domains. However, the average evolutionary distance between two V-gene germline families within either the human or murine germlines repertoire are larger than the evolutionary distance between a germline family in man and its closest relative in the mouse.
A very striking difference can be found in lambda light chains, which are quite diverse in humans, while in (lab) mouse strains, only one single lambda chain V-domain is in use.
Of course, the CDR3 regions show the largest sequence variability, as they are generated for each antibody variable domain by genetic recombination of V, (D), J and C segments generating a unique combination for each precursor cell developing into a mature B-cell.
You can find a comprehensive listing of germline amino acid sequence alignments for different species and antibody domains in the IMGT repertoire pages: http://www.imgt.org/IMGTrepertoire/Proteins/. You may find some useful information on how the sequence variability translates into structural variability in the (rather old) AAAAA webpage: https://www.bioc.uzh.ch/plueckthun/antibody/Numbering/index.html
Differences between the antibody classes depend on the heavy chain C-genes used - as B-cells mature, genetic recombination leads to class switch from
IgM, in which with the help of a J-segment and disulfide bonds connecting a C-terminal extension of most c-terminal immunoglobulin domain, five to six bivalent antibody units are connected into decavalent or larger complex, to IgGs and other subclasses. IgM and IgE constant regions consist of four Immunoglobulin domains, compared to three for IgA, IgD, and IgG. In IgA, two bivalent antibody units are connected, again through a disulfide bond in a C-terminal extension, and can be associated with a secretory component that enables trans-epithelial transport to secrete thes antibodies e.g. into milk. Differential splicing leaves a fraction of the antibody heavy chains produced in the cell with a transmembrane domain, allowing these molecules to serve as antigen recognition modules in the B-cell receptor.
The sequence differences in the hinge region between the first and second constant domain determines how many (if any) disulfide bonds connect the two heavy chains in an antibody (see http://www.imgt.org/IMGTrepertoire/Proteins/protein/human/IGH/IGHC/Hu_IGHCallgenes.html and http://www.imgt.org/IMGTrepertoire/Proteins/protein/mouse/IGH/IGHC/Mu_IGHCallgenes.html to compare the sequences of human and murine constant sequences. Glycosylation sites are indicated by underscores in the alignments.
Again, the difference between two classes of antibodies within one species are larger than the differences between the species.
Of course, the biological functions of antibodies are mediated by interactions with their cognate FC receptors, and therefore the interspecies crossreactivity in these interactions determine whether or not a given antibody can elicit a particular effector function in a different species.
The largest sequence differences are, of course, seen in the antibody variable domains. However, the average evolutionary distance between two V-gene germline families within either the human or murine germlines repertoire are larger than the evolutionary distance between a germline family in man and its closest relative in the mouse.
A very striking difference can be found in lambda light chains, which are quite diverse in humans, while in (lab) mouse strains, only one single lambda chain V-domain is in use.
Of course, the CDR3 regions show the largest sequence variability, as they are generated for each antibody variable domain by genetic recombination of V, (D), J and C segments generating a unique combination for each precursor cell developing into a mature B-cell.
You can find a comprehensive listing of germline amino acid sequence alignments for different species and antibody domains in the IMGT repertoire pages: http://www.imgt.org/IMGTrepertoire/Proteins/. You may find some useful information on how the sequence variability translates into structural variability in the (rather old) AAAAA webpage: https://www.bioc.uzh.ch/plueckthun/antibody/Numbering/index.html
Differences between the antibody classes depend on the heavy chain C-genes used - as B-cells mature, genetic recombination leads to class switch from
IgM, in which with the help of a J-segment and disulfide bonds connecting a C-terminal extension of most c-terminal immunoglobulin domain, five to six bivalent antibody units are connected into decavalent or larger complex, to IgGs and other subclasses. IgM and IgE constant regions consist of four Immunoglobulin domains, compared to three for IgA, IgD, and IgG. In IgA, two bivalent antibody units are connected, again through a disulfide bond in a C-terminal extension, and can be associated with a secretory component that enables trans-epithelial transport to secrete thes antibodies e.g. into milk. Differential splicing leaves a fraction of the antibody heavy chains produced in the cell with a transmembrane domain, allowing these molecules to serve as antigen recognition modules in the B-cell receptor.
The sequence differences in the hinge region between the first and second constant domain determines how many (if any) disulfide bonds connect the two heavy chains in an antibody (see http://www.imgt.org/IMGTrepertoire/Proteins/protein/human/IGH/IGHC/Hu_IGHCallgenes.html and http://www.imgt.org/IMGTrepertoire/Proteins/protein/mouse/IGH/IGHC/Mu_IGHCallgenes.html to compare the sequences of human and murine constant sequences. Glycosylation sites are indicated by underscores in the alignments.
Again, the difference between two classes of antibodies within one species are larger than the differences between the species.
Of course, the biological functions of antibodies are mediated by interactions with their cognate FC receptors, and therefore the interspecies crossreactivity in these interactions determine whether or not a given antibody can elicit a particular effector function in a different species.
Thank you very much for this very thorough reply. I highly appreciate it.