Antibody Variable (V) region sequence comparison is a powerful aproach toward determining the structural and genetic basis of antibody specificity. (Recent advances in direct mRNA sequencing provide a rapid and reliable way of determining the primary structure of the V regions of monoclonla antibodies produced by hybridomas and B cell lines or lymphomas.) Comparisons of antibodies with similar specificities can reveal regions of homology that predict which domains, complementarity determining regions are specific residues are important for binding (the current technology for introducing base substitutions into specific cloned DNA sequences provides a powerful way to test these predictions). Knowing the structural basis for a given antibody specificity allows one to assess how this specificity is controlled at the genetic level as comparison of expressed V region nucleic acid sequences to their germline counterparts can disttinguish whether a specificity is derived by somatic mutation or encoded in the germline. These approaches will be used to study antibodies directed to determinants on proteins such as influenza hemagglutinin (HA), the I-E histocompatability antigen (Ia.7), rebonucleoprotein (Sm), and immunoglobuin (IgG). Anti-HA and anti-Ia.7 antibodies will be analysized at different intervals during the response to these proteins to determine the relative contribution of germline encoded specificities and mutationally derived specificities to primary and secondary response, how mutations accumulate during the response, and how mutations influence specificity. The autoantibodies, anti-Sm and anti-IgG (Rheumatoid Factor, RF), derived from autoimmune mice (the inbred strain MRL/rpr,) will be studied to determine the structural basis for these specificities. To fully understand these antibodies, however, they will be compared to the RF and anti-Sm antibodies that are produced by normal mice and comparisons between autoantibodies from autoimmune and normal mice will be made between sets with equivalent fine specificities. Knowing how normal and disease autoantibodies differ in their structure and genetic control will lead to an understanding of the process by which they arise in these different settings. The principles derived from the mouse model for autoimmunue disease will be applied to the human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM020964-20
Application #
3484380
Study Section
Special Emphasis Panel (NSS)
Project Start
1977-01-01
Project End
1993-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
20
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Institute for Cancer Research
Department
Type
DUNS #
872612445
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Schoettler, Nathan; Ni, Dongyao; Weigert, Martin (2012) B cell receptor light chain repertoires show signs of selection with differences between groups of healthy individuals and SLE patients. Mol Immunol 51:273-82
Calcagno, Claudia; Puzone, Roberto; Pearson, Yanthe E et al. (2011) Computer simulations of heterologous immunity: highlights of an interdisciplinary cooperation. Autoimmunity 44:304-14
Louzoun, Yoram; Vider, Tal; Weigert, Martin (2006) T-cell epitope repertoire as predicted from human and viral genomes. Mol Immunol 43:559-69
Chen, Ching; Li, Hui; Tian, Qi et al. (2006) Selection of anti-double-stranded DNA B cells in autoimmune MRL-lpr/lpr mice. J Immunol 176:5183-90
Li, Yijin; Louzoun, Yoram; Weigert, Martin (2004) Editing anti-DNA B cells by Vlambdax. J Exp Med 199:337-46
Li, Yijin; Li, Hui; Ni, Dongyao et al. (2002) Anti-DNA B cells in MRL/lpr mice show altered differentiation and editing pattern. J Exp Med 196:1543-52
Detours, V; Mehr, R; Perelson, A S (2000) Deriving quantitative constraints on T cell selection from data on the mature T cell repertoire. J Immunol 164:121-8
Mehr, R; Shannon, M; Litwin, S (1999) Models for antigen receptor gene rearrangement. I. Biased receptor editing in B cells: implications for allelic exclusion. J Immunol 163:1793-8
Shannon, M; Mehr, R (1999) Reconciling repertoire shift with affinity maturation: the role of deleterious mutations. J Immunol 162:3950-6
Detours, V; Mehr, R; Perelson, A S (1999) A quantitative theory of affinity-driven T cell repertoire selection. J Theor Biol 200:389-403

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