School of Biotechnology, GGS IP University held its annual Yellapragada SubbaRow Memorial Lecture on January 14th, 2013. SubbaRow, according to his biographer SPK Gupta, was a miracle man of miracle drugs. His contributions to medicine include folic acid (cures sprue and inhibits growth of cancer cells), aureomycin (first ever broad-spectrum antibiotic), hetrazan (anti-filarial drug), discovery of ATP and much more. You can know why such an amazing scientist is so less known and more about his life in this website dedicated to him. The memorial lecture was delievered by Dr. Shiv S. Pillai who is a professor at the same Harvard School of Medicine where SubbaRow did his work. His talk featured on the enzymatic regulation of lymphocyte cell fate decision and new therapies for human diseases and this post is a brief summary of his words.
The first idea of an immune system
Louis Pasteur and Robert Koch’s germ theory of disease proved that most infections were caused by microbes (many exceptions were later observed). Paul Ehrlich proposed the side-chain theory to explain the specifity of antigen-antibody interactions. He hypothesized existence of side chains on living cells which interact with particular toxins in the similar lock-and-key mechanism of enzyme-substrate interactions proposed by Emil Fischer. He suggested that interaction between an infectious agent and a cell-bound receptor would induce the cell to release more receptors with same specifity. Incidentally, all of what he proposed was proven correct with little modification. The receptor exists as both a soluble antibody and a cell-bound receptor and it is the soluble form which is secreted rather than cell-bound form released.
The diversity of B cells
Both B and T cells arise from haematopoietic stem cells. B cells develop in the bone marrow while T cells develop in the thymus. During differentiation, gene expression changes in an ordered fashion and the gene encoding antigen receptors are rearranged. Commitment to a particular lineage occurs relatively late during lymphocyte development. Quantitative differences in signal strength have a major impact in deciding the fate of the lymphocytes. The expression of genes associated with specific lineages and the survival and expansion of committed B cell types are both regulated by multiple transcription factors and growth-factor receptors. Studies have revealed that unlike linear transcriptional hierarchy, efficient B cell commitment and differentiation requires the combinatorial activity of multiple transcription factors in a complex gene regulatory network. A similar network exists for the differentiation and commitment of T cells too. Every step in B cell development is marked by activation of specific gene characteristic of the new progenitor generated. B cells can act against an infinite variety of antigens. Each particular B cell however binds to a specific antigen. On interaction of a specific antigen-antibody pair, proliferation of the particular antibody producing B cell is triggered. This ensures a sufficient quantity of B cells for appropriate response and is termed as clonal selection. But, how is this immense diversity of B cells possible? The immense B cell repertoire results due to random recombination in B cell precursors within the bone marrow. The population of B cells, hence, contains B cells with highly diverse B cell receptors (BCRs). Abundance and localization of histone methylation also play a major role in the diversity.
Autoimmune regulator gene
Autoimmune disorders have long been classified into two classes – one in which T cells drive the inflammation and another where auto-antibodies are critical (B cell based). The classification, it seems, is diminishing as recent findings suggest that T cells drive the autoimmune B cell response. Also, B cells have been found to play important roles in autoimmune disorders that have till now been considered mediated primarily by T cells. B cell tolerance has been studied extensively using BCR transgenic, knockin or mutated mice. Studies have shown the autoimmune regulator (air) gene bind with CREB binding protein and initiate transcription of diverse self-antigens in the thymus. This makes the maturing B cells to become tolerant to internal organs and their metabolites. Mutation in the gene causes lack of the autoimmune regulator (AIRE) protein due to which many autoimmune disorders develop.
Btk refers to B cell receptor associated tyrosine kinase that is required for normal function and development of B cells. PCI-32765 or Ibrutinib, an irreversible covalent Btk-inhibitor, has shown much promise with excellent disease activity and minimal toxicity to date in the treatment of relapsed refractory chronic leukemia. Other diseases that may be cured are B cell aplasia and X-linked agammaglobulinemia. Also, epigenetic lesions are promising biomarkers to improve diagnosis and predict outcomes in B cells.
Read more here:
- Kuby, Immunology
- Nutt, S. L., Kee, B. L., The Transcriptional Regulation of B Cell Lineage Commitment, Cell Immunity, 22 June 2007
- Pillai, S. S., Mattoo, H., Cariappa, A., B cells and autoimmunity, Current Opinions in Immunology, December 2011, pages 721-731
- Brown, J. R., Ibrutinib, the first Btk inhibitor in clinical trials, Current Hematologic Malignancy Reports, January 2013
- Shaknovich, R., Melnick, A., Epigenetics and B-cell Lymphoma, Current Opinions in Hematology, July 2011, pages 293-299