B Cell Development Pt 2 PDF

WELCOME! BMS 545 IMMUNOLOGY OCTOBER 28, 2024 ANNOUNCEMENTS  Any shift in exam material/course structure will be posted to Canvas!  OBJECTIVES  Compare and contrast B1 & B2 lineages, their roles, functions, locations, etc.  Compare and contrast subtypes o...

WELCOME! BMS 545 IMMUNOLOGY OCTOBER 28, 2024 ANNOUNCEMENTS  Any shift in exam material/course structure will be posted to Canvas!  OBJECTIVES  Compare and contrast B1 & B2 lineages, their roles, functions, locations, etc.  Compare and contrast subtypes of T and B cells in terms of development, roles, activation, etc.  Describe what happens with B cell negative & positive selection & the consequences of “passing” or “failing” each  Compare and contrast T & B cell positive and negative selection  What is the significance of a B cell binding a multivalent vs. monovalent self antigen? Are there any corrective measures?  What is receptor editing?  Describe the movement of B cells to secondary lymphoid tissue  Outline the parts of secondary lymphoid tissue where B cells travel. What is the role of these areas?  What happens to B cells that encounter their antigen? What happens to B cells that DON’T encounter their antigen?  The development of B cells in the bone marrow 6-9 B cells expressing the cell-surface protein CD5 have a distinctive repertoire of receptors- These cells are known as B1 cells Figure 6.14 Comparison of the properties of B-1 cells and B-2 cells  A pool of self-renewing B-1 cells is established & does not require the microenvironment of BM for its survival  B-1 cells make antibodies that have low diversity, weak binding, & polyspecificity, properties suggesting that B-1 cells produce simpler, less adaptive immune responses than those of B-2 cells PARALLELS & DIFFERENCES OF TRANSITIONAL & ADAPTIVE B-CELL & T-CELL LINEAGES  B1 B-CELLS  B-1 B cells- arise from fetal liver by 8th gestational week (early in embryogenesis)  Described ~20 years ago, important in innate-related immunity & autoimmune dis.  Possibly a transitional lymphocyte that bridges innate & adaptive immune systems?  Slight immunologic memory, limited isotype switching, & limited repertoire  B-1 cell repertoire < B-2 cell repertoire  BCRs & antibodies often directed against conserved microbial antigens (e.g. LPS)  Found predominantly in tissues that are potential portals of microbial entry (e.g., the peritoneal cavity & respiratory tract) & are self-renewing  Most (maybe all???) natural antibodies (e.g. IgMs directed against A & B blood groups that exist in the absence of known immunization) are B-1 origin  B2 CELLS  B-2 cells (Conventional B cells) arise during & after the neonatal period, & are widely distributed throughout lymphoid organs & tissues  Continually replaced from the bone marrow throughout adult life  Require interaction with T cells for activation & proliferation  Range of epitopes that can be recognized by B-2 B cells is vast  Upon repeated antigen exposure, B-2 B cells respond quickly with increased antibody quantity & quality often by “fine-tuning” affinity of antibody produced (aka affinity maturation)  Responses are often accompanied by a change in immunoglobulin isotype (aka isotype switching)  All of these properties are hallmarks of immunologic memory REVIEW OF LAST CLASS  List the 6 phases of functional B cell development and what occurs during each phase  Selection and further development of the B-cell repertoire 6-10 The immature B-cell population is purged of cells bearing self- reactive B-cell receptors T cell vs B cell Positive & Negative selection T cells undergo positive selection, THEN negative selection, B cells undergo negative selection, THEN positive T cells are positively selected based on their ability to bind to self MHC molecules, while B cells are positively selected based on their ability to bind antigen directly T cells are negatively selected to remove those T cells that bind self MHC TOO strongly, while B cells undergo negative selection to eliminate self-reactive cells Figure 6.16 Immature B cells with specificity for multivalent self antigens are retained in the bone marrow  Immature B cells that are not specific for a self antigen in bone marrow are permitted to continue their maturation  They have IgM AND IgD on their surface & leave the bone marrow  Immature B cells that recognize a self antigen on bone marrow cells are retained in the bone marrow Selection and further development of the B-cell repertoire 6-11 The antigen receptors of autoreactive immature B cells can be modified by receptor editing Figure 6.17 Receptor editing rescues many self-reactive B cells by changing their antigen specificities (Part 1)  Binding to a multivalent self antigen in bone marrow causes immature B cell to continue light-chain gene rearrangements  This deletes the gene encoding self-reactive light chain- creates possibility of gaining a new light-chain rearrangement & a B-cell receptor that does not react with a self antigen  Successive rearrangements occur until either a new non-self-reactive receptor is made OR the B cell exhausts its supply of light-chain V or J gene segments Figure 6.17 Receptor editing rescues many self-reactive B cells by changing their antigen specificities (Part 2)  IF a light chain is made that does not confer self-reactivity, the B cell is rescued & continues its development (lower right panels), but IF a B cell runs out of rearrangements & is still self-reactive, it dies by apoptosis (lower left panels)  Receptor editing is unique to B cells Selection and further development of the B-cell repertoire 6-12 Immature B cells that recognize monovalent self antigens are made nonresponsive Univalent = monovalent REVIEW OF LAST CLASS  List the 6 phases of functional B cell development and what occurs during each phase Figure 6.23 Summary of the main stages in B-cell development (Part 2) Selection and further development of the B-cell repertoire 6-13 Maturation and survival of B cells occurs in lymphoid follicles Figure 6.19 The general route of B-cell circulation through a secondary lymphoid tissue  B cells circulating in the blood enter the lymph-node T-cell areas via a high endothelial venule (HEV)  Then they pass into a primary lymphoid follicle  IF the B cells do not encounter their specific antigens, they leave the follicle & exit from the lymph node in the efferent lymph  The circulation route is the same for immature and mature B cells, which all compete with each other to enter primary follicles Figure 6.20 Immature B cells must pass through a primary follicle in a secondary lymphoid tissue to become mature B cells  Immature B cells enter the secondary lymphoid tissue through the walls of high endothelial venules (HEVs), attracted by chemokines CCL21 & CCL19, & compete with other immature & mature B cells to enter a primary follicle (PF)  Follicular dendritic cells (FDCs; turquoise) secrete chemokine CXCL13, which attracts B cells into the follicle  Immature B cells that enter a follicle interact with cell-surface components of FDCs that can signal B cells’ final development into mature B cells  Immature B cells that fail to enter a follicle also continue in recirculation but soon die  Mature B cells that do not encounter their specific antigens in follicle leave the lymph node & continue recirculating through secondary lymphoid tissues via lymph & blood  BAFF, B cell–activating factor in the TNF family; LT, lymphotoxin Selection and further development of the B-cell repertoire 6-14 Encounter with antigen leads to the differentiation of activated B cells into plasma cells and memory B cells Figure 6.21 Antigen-mediated B-cell activation and differentiation in secondary lymphoid tissue  A mature naive B cell enters the lymph node through an HEV  In the T-cell area of the lymph node, the B cell encounters antigen delivered in the afferent lymph draining from infected tissue  At the boundary between a lymphoid follicle & T-cell area, the B cell is activated by a CD4 helper T cell (blue) to form a primary focus of dividing cells  Some of these B cells migrate to the medullary cords & differentiate into antibody-secreting plasma cells; others migrate to a primary follicle & form a germinal center where they further divide & differentiate  B cells from germinal center migrate either to the medullary cords OR to bone marrow to complete maturation into plasma cells  ALSO SCIENTIST Deborah Doniach, MD FRCP This Photo by 1912-2004, Professor of Clinical Immunology Unknow n Born in Geneva, Switzerland, on April 6th, 1912 to Russian Parents. After Author is having two children with her husband, she resumed her studies at the license d under Royal Free Hospital Medical School in London, graduating in 1945. CC BY- NC-ND Dr. Doniach received additional training in Immunopathology and Endocrinology, and joined the Department of Immunology at Middlesex Hospital in the 1960s and eventually became Honorary Consultant Immunopathologist. In 1974 she became Professor of Clinical Immunology. She partnered with chemist and immunologist Ivan Roitt and they discovered that Hashimoto’s thyroiditis is an autoimmune disease in which antibodies target thyroglobulin. They also found a separate antibody cytotoxic to thyrocytes, which targets thyroid peroxidase. Their new findings contradicted the current scientific belief at the time, that antibodies targeted only nonself antigens. Thus, their work and findings pioneered the field of research into thyroid autoimmunity and autoimmune diseases.