BMS1062:Molecular Biology: DNA and the immune system

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Monash University
Biomedical Sciences
Peter Boag

DNA AND THE IMMUNE SYSTEM Recombination: The process in which DNA molecules are broken and the fragments are re- joined in new combinations.  This can occur in living cells o Crossing over during meiosis  In vitro by use of DNA and enzymes that can break (restriction enzymes) and join (ligases) the DNA fragments Innate immunity  Physical barriers  Fast + no memory  Based on inherited traits passed on from parents  Specific receptors on surface of phagocytic cells which can recognise pathogen structures Adaptive immunity  Cellular and humoral mechanisms (T/B cells)  Remembers antigens nd  A 2 encounter with an antigen leads to a greater and more rapid immune response  Involves white blood cells called “lymphocytes” o T lymphocytes or “T cells”  Develop in thymus  Cellular immunity o B lymphocytes or “B cells”  Develop in bone marrow  Humoral immunity –produce antibodies  T cells are on the membrane and never secreted from the cell whereas b cells are secreted The clonal selection theory:  Each lymphocyte bears a single type of antigen receptor with a unique specificity  Generated during development PRIOR to antigen exposure  Upon infection, a lymphocyte clone will display a receptor with the appropriate specificity to recognise the antigen  That clone is selected, and multiplies. The cells differentiate to become effector cells which eliminate the antigen Antigen receptors:   Each T/B cell have its own specific binding site and thus specificity Diversity:  During Lymphocyte development, there is somatic recombination of the genes associated with the generation of immunoglobulins or B cell receptors  This was subsequently also shown for the T cell receptor on T cells The T-cell receptor (TCR): V regions of α and β chains contain short stretches (approx. 10 aa) where most of the variability between different TCRs is concentrated  Called hypervariable regions or Complementarity-Determining Regions (CDRs) o Each α chain has 3 CDRs o Each β chain has 3 CDRs  B cell receptor and antibodies:  Combinatorial diversity: the generation of immunoglobulins (B cells) through gene recombination  Junctional diversity: addition and deletion of nucleotides during recombination – at the joint or junction   3 hypervariable regions or “CDR’s” in each chain  For T cells an entire T cell receptor has 6 CDRs - 3 on the alpha chain and 3 on the beta chain.  For B cells, because the B cell receptor has 2 arms, there are 2 antigen binding sites. So there are a total of 12 CDR regions on an entire B cell receptor - 6 on each arm  The actual binding site of the immunoglobulin molecule is formed by the coming together of the hypervariable regions of the heavy and light chains   During development, both T and B cells use a process of gene rearrangement to generate diversity. This is a process of random recombinations of specific gene segments (fragments) to generate a rearranged gene that encodes a functional peptide Combinatorial diversity: diversity by recombination - the generation of antigen receptors  Recombination occurs as ‘crossing over’ during meiosis  Or in-vitro by use of DNA and enzymes that break (restriction enzymes) and join (ligases) the DNA fragments  Recombination occurs in the lymph nodes in T cells   CDR 1 and 2 are encoded only by the V gene segment  CDR 3 is encoded by the V (D) and J encoded gene segments  Therefore CDR 3 is the most variable segment Recombination  Occurs in developing B cells in the bone marrow  RAG 1 and 2 enzymes o Recombination-activating genes 1 and 2 o Expressed only in developing T and B cells  DNA repair enzymes o Found in all cells and involved in DNA damage repair     Nucleotide deletion at junctions:  Catalysed by DNA exonucleases  Removes nucleotides before the V (D) and J segments are joined   RAG1 and 2 generate breaks  DNA pol fills in overhangs  Exonuclease, and TdT - Terminal deoxyribonucleotidyl transferase o directs subtraction or addition of nucleotides to ends o introduces novel amino acids I Further diversity in antibodies – isotypes II The T cell receptor During B cell development (in the bone marrow) heavy and light chain genes rearrange by somatic recombination.  Heavy chain: D-J joining and then V-D-J joining  Light Chain: V-J joining  CDR 1 and 2 encoded by V segments.  CDR3 encoded by V, (D) And J segments, and ALSO junctional diversity  Antibody is secreted from mature B cells (plasma cells) after they have been activated  The different constant regions define the isotype  The structure of the constant region defines the ISOTYPE or CLASS of antibody  Different isotypes can have same antigen binding site (red)  This process is called class or isotype switching  It occurs separately and after the recombination process that produced antigen receptor  It occurs after B cells encounter and are activated by antigen  Isotype switching can change the overall structure of the antibody, causing the Ig to be secreted as a monomer, dimer, pentamer etc…  B cells can class switch and release from surface while t cells cannot do either T cell receptor structure:  T cell receptor made up of 1 alpha chain and 1 beta chain  Each α and β chain comprises o Variable region o Constant region o Transmembrane and short cytoplasmic region o Each α chain has 3 CDRs o Each β chain has 3 CDRs  The TCR is not secreted (unlike the BCR/ antibody)  A fundamental feature of the T cell receptor is that it recognises antigen only in the form of peptides presented by Major Histocompatibility Complex (MHC) on other cells o CD4 T cells recognise MHC class II and peptide o CD8 T cells recognise MHC class I and peptide
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