Adaptive Immunity II: Clonal Selection Theory and B Cell Development PDF

Adaptive Immunity II: Clonal Selection Theory and B Cell Development- Objectives Describe the 4 major tenets of clonal selection theory Describe the general germ-line arrangements of B cell antigen receptor gene loci Explain how somatic recombination within antigen receptor gene loc...

Adaptive Immunity II: Clonal Selection Theory and B Cell Development- Objectives Describe the 4 major tenets of clonal selection theory Describe the general germ-line arrangements of B cell antigen receptor gene loci Explain how somatic recombination within antigen receptor gene loci contributes to receptor repertoire diversity Describe B cell antigen receptor assembly and form of cell surface expression Describe how negative selection shapes the B cell antigen receptor repertoire Describe and distinguish antigen-dependent and independent steps in B cell development Clonal Selection Theory Explains Most Behaviour of the Adaptive Immune System Each lymphocyte bears a single type of antigen-specific receptor with a unique specificity, while the overall repertoire includes lymphocytes capable of responding to any antigen. (Enough unique clones to leave no blind spots). Receptor binding is required for lymphocyte activation. (recognition leads to action) Effector cells derived from an activated lymphocyte (the progeny) bear receptors of identical specificity to the parent cell. (Expansion = memory) Lymphocytes bearing receptors for self molecules (antigens produced within the body) are inactivated or deleted. (T cells in thymus, B cells in bone marrow).  Clonal Selection Theory- Tenet 1 Each lymphocyte bears a single type of antigen-specific receptor with a unique specificity, while the overall repertoire includes lymphocytes capable of responding to any antigen. (enough unique clones to leave no blind spots). Individuality Each B or T lymphocyte is clonotypic and distinguished from all other cells except its immediate progenitor and progeny by the antigen specific receptor that it expresses and the genetic process that generated it. Diversity Antigen specific receptors are assembled from germ-line genes through a somatic rearrangement (shuffling) process that occurs independently in each cell. This generates far more diversity than could be encoded in the human genome through normal gene expression processes and fixes receptor-encoding genes so that progeny have identical receptors.  Genetic Basis and Structure of Antigen-specific Receptors- B cell Receptor B cell receptor (BCR) is made up of heavy (H) and light (L) chain proteins. 1 H chain locus, 2 L chain loci 1 k and 1 l, all of which contain multiple gene segments. Germ-line gene configuration B Cell Receptor Expression Heavy (H) chain made up from V, D and J gene segments that are physically moved adjacent to each other. Expressed initially with the most 5’ of C region genes (µ & d = IgM & IgD). Light (L) chain is made up of V and J segments that rearrange & are expressed together with a C gene segment. Only 1 of either k or l is expressed. H and L chain rearrange independently and then pair to create receptor. Clonal Selection Theory- Tenets 2 and 3 Receptor binding is required for lymphocyte activation. (recognition leads to action) BCR expressed on cell surface together with non-polymorphic signaling molecules. Signaling complex senses receptor binding and transduces it into intracellular activation. Antibody production, proliferation and differentiation. Clonotype of B cell and specificity of antibody is fixed by the genetic rearrangement that created the receptor. Clonal Selection Theory- Tenet 4 B cell development in bone marrow is antigen-independent except for negative selection step. Periphery Strong antigen binding at immature B cell stage leads to apoptosis (deletion). Weaker binding can make B cells anergic (unresponsive to antigen). Antigen and T cell-dependent B Cell Development Antigen binding after leaving the bone marrow can cause the B cell to release IgM based on its cell surface receptor. Isotype switching requires interaction with T cells (T cell “help”). Isotype switching occurs in parallel with somatic hypermutation in specialized structures within the lymph nodes called germinal centres.  Isotype Switching Preserves Antibody Specificity, Changes Distribution and Function Somatic Hypermutation Improves Antigen Binding Mutations within H and L chain variable regions that improve antigen binding are selected. Accumulate within “complementarity determining regions” (CDRs) or “hypervariable” regions of antibodies. Occur in parallel with isotype switching Isotype Switch and Somatic Hypermutation Occur in Germinal Centres Quiescent lymph node with resting B cells Germinal centre within lymph node. Proliferating organized into follicles. B cells compete to present limiting amounts of antigen to T cells and receive “help” in the form of survival signal. Survival of the fittest.  Summary Somatic rearrangement key to B cell repertoire diversity. Antigen-independent and antigen-dependent steps in B cell development. Some autoreactive B cells deleted at immature stage in bone marrow. Antigen binding signals activation of B cells. Antibody specialization through isotype switching and somatic hypermutation occurs in germinal centres with T cell help.