Adaptive Immunity_2_2023 (1).pptx

The Adaptive Immune system (2) Aims: This lecture will explain the mechanics of generating immune cell diversity: • V(D)J recombination • Somatic hypermutation • Affinity maturation • Antibody class switching Learning outcomes: To understand the mechanistic principles that contribute to diversity o...

The Adaptive Immune system (2) Aims: This lecture will explain the mechanics of generating immune cell diversity: • V(D)J recombination • Somatic hypermutation • Affinity maturation • Antibody class switching Learning outcomes: To understand the mechanistic principles that contribute to diversity of antigen recognition and response Chris Pepper : [email protected] ITAM = Immunoreceptor tyrosine-based activation motif How do we ensure that there is a BCR and/or TCR that can recognise every antigen? B cell BCR germline sequences Heavy chain light chain Variable segments 65 70 Diversity segments 27 0 Joining segments 6 9 ~1014 possible combinations 100 trillion combinations TCR germline sequences T cell Chromosome 14 Chromosome 7 alpha chain beta chain Variable segments 70 52 Diversity segments 0 2 Joining segments 61 13 ~1018 possible combinations A million trillion combinations!! New gene sequences are produced through V(D)J recombination • Light chain rearrangement is a single step VJ recombination • Heavy chain rearrangement involves a DJ recombination event followed by a VDJ rearrangement How Does Rearrangement Occur? Rearrangement occurs between specific sites on the DNA called Recombination Signal Sequences (RSSs) These sequences contain conserved segments of DNA composed of a heptamer, a spacer and a nonomer They are found on the 3’ side of V segments, the 5’ side of J segments and both the 3’ and 5’ side of D segments Rearrangement is catalysed by two Recombination Activating Genes: RAG-1 and RAG-2 Steps in V(D)J joining 1. Cleavage -Rag1/Rag-2 endonucleases -critical to recombination of Ig, TCR 2. Repair/diversity -Tdt=terminal deoxynucleotidyl transferase 3. Joining -DNA-PK (defective in SCID mice) -DNA ligase V(D)J recombination - summary Suggested reading • Parham The Immune System Chapters 4-7 • Janeway Immunobiology Chapters 7, 8 and 10 (Ed. 8) Coming next… Adaptive immunity 2.2 – Somatic hypermutation and affinity maturation Any questions send me an email: [email protected] V(D)J recombination https://www.youtube.com/watch?v=QTOBSFJWogE The Adaptive Immune system (2.2) Aims: This lecture will explain how B cells are fine tuned to recognise and respond to antigens through the process of somatic hypermutation and affinity maturation Learning outcomes: To understand how B cells introduce (random) genetic alterations in their B cell receptor following antigenic challenge and how they are then subject to Darwinian selection resulting in a “better” B cell for specific antigen recognition and response Chris Pepper : [email protected] Somatic hypermutation and affinity maturation What is Somatic hypermutation? Somatic hypermutation or SHM is a diversitygenerating process It adds further diversity to already rearranged (V(D)J recombined) segments through the introduction of point mutations The mutation rate is ~1 base per 1000 – this is ~ 1 million times higher mutation rate than is observed during normal cell division Million-fold increase Somatic hypermutation Affinity maturation This is the process by which B cells produce antibodies with increased affinity for antigen during an immune response. Follicular dendritic cells found in the germinal centres, present antigen to the B cells that have undergone SHM. Only those with high affinity for antigen will be selected to survive. B cells that have undergone SHM but bind antigen with lower affinity are out competed and die by a process called apoptosis. Suggested reading • Parham The Immune System Chapters 4-7 • Janeway Immunobiology Chapters 7, 8 and 10 (Ed. 8) Coming next… Adaptive immunity 2.3 – class switch recombination Any questions come and see me or send me an email: [email protected] Affinity maturation https://www.youtube.com/watch?v=qGsyBwDVnTU The Adaptive Immune system (2.3) Aims: This lecture will explain how B cells undergo a further adaptation, called class switch recombination, in order to mount the most appropriate immunological response to antigen Learning outcomes: To understand how and why class switch recombination takes place Chris Pepper : [email protected] Class switch recombination Same receptor, different constant region allowing the cell to perform a range of different effector functions Alternative splicing results in IgM and IgD in naïve B-cells How is CSR achieved? The first targeted switch region is always the Sµ switch region. The other, partner, switch region is determined by the cytokines present Activation induced cytidine deaminase (AID) is the critical enzyme in this process Class switch recombination Constant regions IgM • • • IgD IgG Constant regions are spliced out using switch regions located upstream of each constant region First cut is always just before the Cµ region The second cut is determined by the cytokines secreted by follicular T helper cells IgE IgA Why does CSR matter? Suggested reading • Parham The Immune System Chapters 4-7 • Janeway Immunobiology Chapters 7, 8 and 10 (Ed. 8) Coming next… Adaptive immunity 3 - Antigen processing, presentation and recognition Any questions send me an email: [email protected] Class switch recombination https://www.youtube.com/watch?v=gyTHXjVUPWw Suggested reading • Parham The Immune System Chapters 4-7 • Janeway Immunobiology Chapters 7, 8 and 10 (Ed. 8) Coming next… Adaptive immunity 3 - Antigen processing, presentation and recognition Monday 29th 11am-12 noon Any questions come and see me or send me an email: [email protected]