B Cell Signaling and Bioinformatics: Revealing Components of the MHC Class II Antigen Processing and Presentation Pathway




Lee, Jamie Ann

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Stimulation of mature B lymphocytes by extracellular ligands induces phenotypic changes through complex signal transduction pathways. Gene expression is altered as a result of these changes and re-programs the cell to undergo differentiation, activation, effecter function, anergy, and/or apoptosis. Gene expression microarrays are used to determine expression levels of a large number (tens of thousands) of genes simultaneously, resulting in a gene expression profile of the experimental sample. Microarray data must be appended with biological information in order to be interesting, and this field of microarray bioinformatics is rapidly expanding. These studies prompted the development of a bioinformatics tool termed CLASSIFI (Cluster Assignment for Biological Inference), which identifies statistically significant co-clustering of genes with similar Gene Ontology annotation within microarray gene clusters. CLASSIFI was used to analyze microarray results from two B cell projects from the Alliance for Cellular Signaling (AfCS): 1) the BAFF/CD40L project, which evaluates the effects of BAFF and CD40L on primary mouse B cells in long-term cultures, and 2) the B cell single ligand screen project, which evaluates the effects of 32 single ligands on primary mouse B cells in short-term cultures. CLASSIFI was able to identify significant overrepresentation of related genes within gene clusters for both of these data sets and facilitates hypothesis generation as to the biological process affected by a specific ligand. As CLASSIFI is strictly a statistical tool that aids in hypothesis generation, experimental validation of hypotheses was performed. The B cell single ligand screen microarray and CLASSIFI analysis followed by experimental validation revealed a biological process specific to B cell antigen receptor stimulation but not LPS or CD40L stimulation - antigen processing and presentation - and provides the groundwork for new discoveries in this field. As a result, several putative components were identified that are not currently known to play a role in antigen processing and presentation in B cells.

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