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Principal Investigator: Harry William Schroeder
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2024
Award: $185,625
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary:
Millions of antibody sequences from both healthy individuals and patients with a variety of immune-mediated
disorders are now freely available to the research community. This has been made possible by support primarily
provided by NIAID for the research projects themselves and for the databases that curate the data. To maximize
the benefits of this financial support, the Institute now funds efforts to use the curated data to explore new
initiatives which are beyond the scope of the original research projects. We propose to use approximately one
million of these antibody sequences to test a hypothesis concerning rare antibody sequences that was first
proposed over 35 years ago but which now can be examined on a large scale by means of these NIAID supported
databases. The expansion of the antibody repertoire by V(D)J gene rearrangement, N-nucleotide addition, and
somatic hypermutation (SHM) introduces non-germline encoded sequence changes throughout the antibody
variable domain. Many of these sequences are either totally absent from, or very rare in, the human proteome.
It is already clear that these “foreign” sequences are common in V regions of antibodies even from healthy human
controls, so it is unlikely that the majority are immuno-pathogenic. However, there is reason to test the
hypothesis that a small subset of these forbidden/rare pentapeptides will be clinically immunogenic, i.e., will
be able to induce immune responses that should be absent from normal antibodies. If this can be confirmed, it
will help us address at least two major challenges now facing medical immunology. First is the persistent problem
of immunogenicity in new therapeutic antibodies which substantially raises the cost of development of these
agents and limits their efficacy in patients. If the proposed work is successful and the immunogenic
pentapeptides are identified, it could lead to the development of new algorithms that more accurately predict the
immunogenicity of therapeutic antibodies prior to expensive clinical trials. Second is the need for more specific
and effective therapies for autoimmune diseases such as SLE, MS, and type 1 diabetes. A large body of evidence
indicates that many of the self-reactive, pathogenic autoantibodies contain idiotopes in their structures which
are recognized by anti-idiotypic antibodies. Further, it appears that the presence or absence of these anti-
idiotypic antibodies may in part be responsible for periods of remission or active disease. Few idiotope structures
are known, but it seems reasonable that these immunogenic segments in antibody variable regions may also
contain the foreign pentapeptides; this could serve as a tool for identifying idiotopes in the sequences of
pathogenic self-reactive antibodies. A major outcome of the proposed studies is a bioinformatics research tool,
the Penta-Scope, which will take as input the sequences of large numbers of antibodies and return the frequencies
of their component pentapeptides in human and murine proteomes. This tool will be made freely available online
for other investigators to use in studies of antibody structure and/or immunogenicity.
Terms: <Address><Algorithms><Allergy><Amino Acids><Animal Model><Animal Models and Related Studies><Animals><Anti-Anti-Idiotype><Anti-DNA Antibodies><Anti-Idiotype Antibodies><Anti-Idiotypic Antibodies><Antibodies><Antibody Binding Sites><Antibody Repertoire><Antigamma Globulin Antibodies><Antigenic Determinants><Antiglobulins><Atrophic Arthritis><Autoantibodies><Autoimmune><Autoimmune Diseases><Binding><Binding Determinants><Binding Sites><Bio-Informatics><Bioinformatics><Brittle Diabetes Mellitus><Cancers><Cardiovascular Diseases><Charge><Clinical><Clinical Treatment Moab><Clinical Trials><Code><Coding System><Combining Site><Communities><Complementarity Determining Regions><Complimentarity Determining Region><DNA Rearrangement><DNA analysis><Data><Data Bases><Databases><Development><Disease><Disease remission><Disorder><Disseminated Sclerosis><Doctor of Medicine><Doctor of Philosophy><Drugs><Epitopes><Financial Support><Frequencies><Funding><Funding Mechanisms><Future><Gene Rearrangement><Genome><Goals><Hereditary><Human><Hydrophobicity><Hypersensitivity><Hypervariable Loop><Hypervariable Regions><IDDM><Ig Somatic Hypermutation><Immune><Immune Globulins><Immune response><Immunes><Immunoglobulin Hypervariable Region><Immunoglobulin Somatic Hypermutation><Immunoglobulins><Immunological response><Immunology><In Vitro><Individual><Infection><Inherited><Insulin-Dependent Diabetes Mellitus><Investigators><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Literature><Lupus><Lupus Erythematosus Disseminatus><M.D.><MAb cA2><Machine Learning><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Medical><Medication><Mice><Mice Mammals><Modern Man><Molecular Interaction><Monoclonal Antibodies><Multiple Sclerosis><Murine><Mus><NIAID><National Institute of Allergy and Infectious Disease><Nucleotides><Operative Procedures><Operative Surgical Procedures><Outcome><Paratopes><Pathogenicity><Pathologic><Patients><Pentas><Ph.D.><PhD><Pharmaceutical Preparations><Play><Population><Proteins><Proteome><R-Series Research Projects><R01 Mechanism><R01 Program><Reaction><Reactive Site><Remicade><Remission><Reporting><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Research Support><Researchers><Rheumatoid Arthritis><Role><SLE><Scientist><Structure><Sudden-Onset Diabetes Mellitus><Surgical><Surgical Interventions><Surgical Procedure><System><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><T-Cells><T-Lymphocyte><T1 DM><T1 diabetes><T1D><T1DM><Testing><Therapeutic antibodies><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Vaccines><Work><aminoacid><analyze DNA><antibody combining site><antigen binding><antigen bound><antiidiotype antibody><autoimmune antibody><autoimmune condition><autoimmune disorder><autoimmunity disease><autoreactive antibody><cardiovascular disorder><clinical significance><clinically significant><cost><data base><design><designing><developmental><disseminated lupus erythematosus><drug/agent><effective therapy><effective treatment><financial assistance><host response><immune system response><immunogenic><immunogenicity><immunoresponse><improved><in silico><in vivo><infliximab><insular sclerosis><insulin dependent diabetes><insulin dependent type 1><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><mAbs><machine based learning><malignancy><medical college><medical schools><member><model of animal><monoclonal Abs><monoclonal antibody cA2><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathogenic autoantibodies><peptide aminoacid sequence><peptide sequence><physical property><prediction algorithm><protein aminoacid sequence><public data base><public database><publicly accessible data base><publicly accessible database><publicly available data base><publicly available database><restraint><rheumatic arthritis><school of medicine><secondary analysis><self reactive antibody><social role><somatic hypermutation><success><surgery><systemic lupus erythematosis><thymus derived lymphocyte><tool><type I diabetes><type one diabetes>