In article <Pine.SUN.3.91.971209120117.977D-100000 at ccsp-23.brunel.ac.uk>,
Andrew Louka <URL:mailto:bb95asl at brunel.ac.uk> wrote:
> Why one B cell, one specificity? Why not have multiple specificities per
> B cell - surely this would have been more effective (and energy efficient!).
>> I'd appreciate any comments or explanations :-)
>> Thanks,
> Andy
>Hi Andy,
I've frequently thought about this problem when discussing T and B cell
receptors with my students. Although it's always difficult to prove a
particular hypothesis with regard to an evolutionary perspective I can make
the following points which I think are relevant.
1) The process of allelic and also allotypic exclusion is very rigourously
maintained for immunoglobulin in B-cells but it seems less so for the
homologous receptor in T-cells.
2) Others in this thread have argued the case for autoimmunity being
triggered easily if you have two or more receptors but many T-cells fall
into this category and it doesn't seem to be a problem. Presumably as long
as negative selection or tolerance induction can act through all the
receptor types then the precise number of types is not important.
3) The reduction in the density of receptors on the surface is also not a
strong argument as far as I can see. A reduction in the density of an
individual receptor by two or four fold could esily be overcome by an
increase in total receptor concentration. Also evidence again from T-cells
suggests that only a small proportion of the surface recptors need to be
triggered.
4) Work by myself and many others more than 10 years ago on
hybrids made with secreting myeloma cell lines [eg Kohler and Milstein
(1975); Clark,M.R., & Milstein,C. (1981), Som. Cell Genet. 7, 657-666
Expression of spleen cell immunoglobulin phenotype in hybrids with myeloma
cell lines] and also bispecific antibodies made from hybrid-hybridomas
demonstrates that myeloma cells are quite capable of synthesising mixed
molecules of antibodies with codominant expression of the immunoglobulin
genes.
5) However the properties of the hybrid molecules I believe gives some
clues as to why bispecific antibodies are a problem.
(5a) Firstly I showed that although mixed IgG molecules could be made
between different IgG subclasses, many combinations resulted in antibodies
which could no longer trigger effector functions because they did not
interact with Fc receptors appropriately. [see Clark,M.R., & Waldmann,H.
(1987), JNCI 79, 1393-1401 T-cell killing of target cells induced by
hybrid antibodies: Comparison of two bispecific monoclonal antibodies;
Haagen,I-A., Geerars,A.J.G., Clark,M.R., & van de Winkel,J.G.J. (1995),
Journal of Immunology 154, 1852-1860 Interaction of human monocyte Fc
gamma receptors with rat IgG2b: A new indicator for the Fc gamma RIIA
(R-H131) polymorphism]
(5b) Secondly and perhaps more importantly most antibodies particularly
during a primary immune response seem to rely upon avidity for binding to
antigen. Thus if you reduce an IgM to it's subunits or you make a
monovalent IgG or Fab fragment it binds less well to the antigen.
So my main argument in favour of strong allelic exclusion in B-cells is to
do with the properties of the secreted immunoglobulin rather than the
B-cell surface receptor.
Mike Clark, <URL:http://www.path.cam.ac.uk/~mrc7/>
--
o/ \\ // || ,_ o M.R. Clark, PhD. Division of Immunology
<\__,\\ // __o || / /\, Cambridge University, Dept. Pathology
"> || _`\<,_ // \\ \> | Tennis Court Rd., Cambridge CB2 1QP
` || (_)/ (_) // \\ \_ Tel.+44 1223 333705 Fax.+44 1223 333875
