B Cell Development and Activation PDF

B cell development and activation Learning Objectives On completion of this session you should be able to 1) Explain the stages of B cell development from hematopoietic stem cells in the bone marrow to mature B cells in peripheral lymphoid organs. 2) Describe the process of B cell activ...

B cell development and activation Learning Objectives On completion of this session you should be able to 1) Explain the stages of B cell development from hematopoietic stem cells in the bone marrow to mature B cells in peripheral lymphoid organs. 2) Describe the process of B cell activation upon encountering antigens. 3) Explain the formation of germinal centres within secondary lymphoid organs, and understand the role of germinal centres in facilitating B cell proliferation, affinity maturation, and the generation of high-affinity antibody- producing plasma cells and memory B cells. 4) Define class switching as the process by which B cells change the class of antibody they produce (e.g., switching from IgM to IgG, IgA, or IgE). B Cell Development 1) Occurs in the bone marrow 2) B cells develop from a common haemopoietic stem cell 3) 4 broad stages are recognised: 1. Pro B cell - earliest B cell progenitor. During this stage heavy chain genes rearrange (DJ then VDJ rearrangements) 2. Pre B cell - expresses surface µ chain in association with surrogate light chain. Light chain genes rearrange 3. Immature B cell - expresses surface IgM 4. Mature B cell (naïve B cell) - expresses surface IgM and IgD and B cell co-receptor B Cell Development B Cell Development 1) B Cell Selection 2) Immature B cells enter peripheral circulation (transitional B cells) 3) Mature into B1, marginal zone or follicular B cells in several days 4) If recognise self-antigen they will undergo apoptosis 5) If encounter antigen in secondary lymphoid tissue, they will differentiate into plasma cells and memory cells and undergo class switching B Cell Activation 1) Membrane bound antibody have short cytoplasmic tails 2) Too short to generate signal by associating with tyrosine kinases and G proteins 3) Membrane Ig must be associated with B-cell receptor 4) Ig-α/Ig-β have ITAMs (Immunoreceptor Tyrosine Activation Motifs) 1) ITIM (immunoreceptor tyrosine inhibitory motif) 2) Associated with CD22 3) Functions to deactivate B cells- negative regulation 4) Important in preventing autoimmunity B Cell Activation 1) Thymus-dependent (TD) antigens B cell required direct contact with TH cells 2) Thymus-independent antigens (TI) These antigens activate B cells by different means Type 1 (TI-1) - lipopolysaccharide Type 2 (TI-2) – highly repetitious molecules (bacterial flagella) Activation of B cells in TD Response 1) Naïve B cells recognise antigen in lymphatics via BCR 2) Receive co-stimulation from TFH cell in T cells zone 3) B cells proliferate in T cell zone or red pulp of spleen and produce IgM of early response 4) Other B cells migrate to B cell follicles to form a germinal centre  Events in the Germinal Centre 1) Activated B cells proliferate rapidly to give dark zone of centroblasts 2) Undergo: 1. Somatic hypermutation– point mutation in nucleotide sequence encoding V regions Alters antibody specificity and high affinity B cells rescued 2. Class/Isotype Switching – break and rejoining to express different C region DNA and antibody class Reactions monitored by follicular dendritic cells and TFH cells Events in the Germinal Centre Mediated by cytokines and chemokines B cells move to edge of germinal centre (light zone) and are called centrocytes Affinity for antigen is assessed and cells survive (high affinity) or undergo apoptosis (low affinity) B cells can undergo multiple rounds of proliferation and somatic hypermutation to generate very high affinity antibodies – AFFINITY MATURATION Germinal centre reaction can last several weeks  Events in the Germinal Centre 1) During the reaction, centrocytes become either plasma cells or memory cells 2) Plasma cells continue to produce antibody and confer long lasting protection 3) Produce 2000 antibody molecules/sec 4) On re-infection, if pathogen overwhelms existing antibody, memory B cells are reactivated 5) Memory cells divide rapidly and produce large amounts of high affinity antibody 6) Initiate a second germinal centre reaction 7) A secondary response can generate up to 10x more long-lived plasma cells than the primary response Germinal Centre https://www.nature.com/articles/nri2217  Class Switching 1) Dependent on cytokines to switch from IgM to other isotypes 2) Thymus-dependent antigens 3) Interaction of CD40 on B cell and CD40L on T cell 4) X-linked hyper-M syndrome 5) TH cells don’t express CD40L, patients only produce IgM 6) No memory cell populations Summary 1. Upon encountering antigens, B cells undergo activation, involving antigen recognition by B cell receptors (BCRs), co-stimulation, and cytokine signalling. 2. This activation leads to the formation of germinal centres within secondary lymphoid organs, where B cells undergo proliferation, affinity maturation, and differentiation into high-affinity antibody-producing plasma cells and memory B cells. 3. Class switching is a crucial process in B cell maturation, allowing B cells to change the class of antibody they produce, such as switching from IgM to IgG, IgA, or IgE, through recombination between switch regions.