B_cell_mediated_immunity the seminar finding

basic immunology knowladge

1. INSTITUTE of BIOTECHNOLOGY Course Title: Advanced Cell Biology Assignment Title: B Cell-Mediated Immunity Prepared by Name ID number Dawit Regasa GSR/2558/16 Edelawit Gebreselassie GSR/3881/16 Emnet Simalew GSR/2246/16

2. B Cell-Mediated Immunity: Basic concepts and implication in health and diseases

3. Presentation outline Introduction B-cells location B-cell development and Structure The steps occurs when your immune system needs B-cells to fight invaders Different types of B-cells Applications of B-cell mediated immunity in both medicine and biotechnology Common conditions and disorders associated with B-cells Autoimmune diseases Cancers associated with abnormal B-cell B cell-directed therapeutics Mechanisms of action of CD20 antibodies

4. Introduction B-cells are an important part of immune system type of  white blood cells  that makes infection-fighting proteins called  antibodies It is a type of white blood cell called  lymphocytes Lymphocytes fight harmful invaders and abnormal cells, like cancer cells B-cells make antibodies in response to antigens   Antigens  are markers that allow your immune system to identify substances in your body, including harmful ones like viruses and bacteria

5. B-cells location B-cells exist in different places depending on their stage of development In foetuses, the liver makes B-cells Once you’re born, B-cells develop in the spongy tissue inside your bone called  bone marrow . They start as hematopoietic stem cells and eventually become B-cells during a process called  hematopoiesis . Once they’re fully mature, your B-cells travel to important parts of your  lymphatic system , including your  spleen  and  lymph nodes .

6. B-cell development and Structure Immunoglobulins consist of two identical heavy and light chains, which are joined by disulphide bonds. During B cell development, rearrangement of the Ig heavy chain occurs first, commencing with D-J recombination, which takes place in the common lymphoid progenitors (CLPs) and pre-pro B cells. This is followed by V-DJ recombination yielding a functional heavy chain protein (Ig) in large pre-B cells. The recombined heavy chain then associates with the surrogate light chains and the Ig dimer to form the pre-B cell receptor (pre-BCR) which is expressed on the cell surface.

7. Cont’n … After production in the BM, immature surface IgM+ B cells migrate to the spleen where they differentiate through distinct transitional B cell stages termed T1 and T2, before differentiating into long-lived mature follicular (FO) or marginal zone (MZ) B cells  Thus, B cells experience both antigen-dependent and -independent phases of selection, which are tightly regulated through signalling events T3 B cells do not give rise to mature B cells, but instead represent a subset of anergic B cells which have been selected away from the B cell developmental pathway

8. Cont’n … Signalling through the pre-BCR drives intense proliferation and differentiation into the small pre-B cell stage. pre-B cells then undergo V-J rearrangement of the Ig light chain, allowing the production of a complete functional BCR with a unique specificity that is expressed as IgM on the surface of immature B cells.

9. The steps occurs when your immune system needs B-cells to fight invaders An antigen-presenting cell (APC) attaches to the antigen, breaking it down into smaller pieces The APC attaches the antigen pieces to a molecule called the major histocompatibility-II complex, or MHC-II Helper T-cells  (a type of T-cell) bind to the MHC-II complex; t his binding activates helper T-cells Activated helper T-cells are important because they shoot B-cells into action An activated T-cell attaches to a B-cell, causing it to make copies, or clones, of itself

10. Cont’n … Some of the B-cells become plasma cells capable of producing antibodies Other B-cells become memory cells that get stored in your body Plasma cells make millions of antibodies over the next several days All antibodies are customized to destroy only the specific pathogen that produced the antigen These antibodies bind to antigens or the part of the pathogen that contains the antigen marker

11. B cell responses to antigen

12. Different types of B-cells There are two main types of B-cells: plasma cells and memory cells Plasma cells : Plasma cells release antibodies in response to antigens Once a B-cell becomes a mature plasma cell, it can release up to 2,000 antibodies per second. Plasma cells are also called plasmacytes or effector cells They have a shorter lifespan than memory cells Memory cells : They "remember" the antigen that led to their formation and can mount a faster and stronger immune response upon re-exposure to the same antigen in the future For example, most  vaccines  work because they expose your immune system to antigens that your memory cells remember If an invader appears, your body can mount an attack quickly

13. Applications of B-cell mediated immunity in both medicine and biotechnology Here are some applications Vaccines : B-cells play a central role in the development of vaccines. Monoclonal Antibody Therapy : These antibodies are designed to bind to specific targets, such as antigens on the surface of cancer cells or viral proteins Diagnostic Tests : B-cell mediated immunity is also utilized in diagnostic tests to detect the presence of specific antigens or antibodies in patient samples Immunotherapy for Autoimmune Diseases : B-cell targeted therapies, such as rituximab, have been developed to selectively deplete B-cells or inhibit their function

14. Common conditions and disorders associated with B-cells Abnormal B-cells can cause autoimmune diseases and various types of cancers Autoimmune diseases Sometimes, B-cells make antibodies in response to antigens associated with your body’s healthy cells When this happens, the antibodies attack your healthy cells like a dangerous pathogen This is what happens with  autoimmune diseases , including: Lupus : the immune system mistakenly attacks healthy tissues, leading to inflammation and damage in multiple organs and systems of the body Multiple sclerosis : the immune system mistakenly attacks the protective covering of nerve Fibers (myelin) in the brain and spinal cord Rheumatoid arthritis : the immune system mistakenly attacks the lining of the joints, leading to inflammation and damage Type 1 diabetes : the immune system mistakenly attacks and destroys the insulin-producing cells in the pancreas

15. Cont’n … B cells in autoimmune diseases B cells have antibody-dependent and antibody-independent pathogenic functions Secreted autoantibodies specific to receptors or receptor ligands can activate or inhibit receptor functions deposited immune complexes can activate complement and effector cells Autoantibodies can bind to basic structural molecules and interfere with the synthesis of structural elements and facilitate the uptake of antigen independent of antibody secretion B cells secrete proinflammatory cytokines, support the formation of ectopic GCs, and serve as antigen presenting cells

16. Cont’n Both secreted autoantibodies and BCR on B cells can modulate the processing and presentation of antigen and thereby affect the nature of presented T-cell determinants Pathogenic effects of deposited immune complexes The Fc portion of antibodies in immune complexes can be bound by C1q of the classical complement pathway, which eventually leads to the release of C5a and C3a These anaphylatoxins promote release of proinflammatory cytokines and serve as chemo attractants for effector cells

17. Cont’n … Moreover, they induce the upregulation of activating FcR on effector cells Binding of the Fc portion of the antibodies to FcR leads to activation of effector cells and further release of proinflammatory cytokines and proteolytic enzymes, mediators of antibody-dependent cell-mediated cytotoxicity (ADCC)

18. Cont’n

19. Cont’n Effect of antibodies and antigen specific B cells on antigen uptake Antigen bound by antibody is taken up via FcR on APCs such as dendritic cells or macrophages After processing, antigen is presented on MHC molecules This FcR -mediated antigen uptake is more efficient than antigen uptake by pinocytosis Antigen binds to the BCR of antigen-specific B cells and is internalized B cells are highly efficient APCs in situations of low antigen concentrations

20. Cont’n Effect of antibodies and antigen-specific B cells on antigen processing and presentation BCR-mediated antigen uptake can influence antigen processing and the nature of MHC-displayed T-cell determinants Likewise, antigen/antibody complexes are bound by the FcR of APCs and processed in a unique fashion dependent on the epitope specificity of the bound antibody The BCR or antibody can shield certain protein determinants from the proteolytic attack in endocytic compartments Presentation of some determinants may thereby be suppressed, while others are boosted Thereby cryptic pathogenic peptides may be presented and stimulate autoreactive T cells

21. Cont’n

22. Cancers associated with abnormal B-cell Several  cancers  are associated with abnormal B-cell development, some of them are: Acute lymphocytic leukemia a type of cancer that affects the blood and bone marrow Chronic lymphocytic leukemia a type of cancer that affects a specific type of white blood cell called lymphocytes Hodgkin lymphoma a type of cancer that originates in the lymphocytes and can affect various organs and tissues. Reed-Sternberg cells represent a minority of cells within the tumor microenvironment. Orchestrate an inflammatory and immunosuppressive milieu that supports tumor growth and survival. Non Hodgkin lymphoma is same as HL but it doesn’t have is Reed-Sternberg cells Multiple myeloma a type of blood cancer that develops in plasma cells in the bone marrow.

23. Mechanisms of B cell recruitment into the CNS Immune cells are recruited into the central nervous system (CNS) by first rolling along the lumen of the blood vessel and being activated by locally produced cytokines. Activation of B cells, including by chemokines found on endothelial cells, then induces conformational changes in integrins, allowing high affinity interactions and firm tethering to the vessel; this enables cells to migrate across the endothelial cell layer into CNS barriers such as the perivascular space

24. Direct Mechanisms of B Cells in MS Pathology : Antibody Production : contributing to demyelination and tissue damage. Antigen Presentation : B cells act as antigen-presenting cells (APCs) within the CNS, presenting myelin antigens to T cells and amplifying the immune response. Cytokine Production : B cells produce pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), which can exacerbate inflammation and tissue damage in the CNS.

25. Direct mechanisms that B cells use to affect multiple sclerosis pathology B cells can directly damage the central nervous system (CNS) using secreted molecules, including exosomes that induce death in oligodendrocytes and neurons, through unknown mechanisms Antibodies directly contribute to multiple sclerosis pathology by facilitating T cell reactivation in CNS barriers, promoting their migration into the parenchyma, and by promoting the deposition of complement on myelin to enhance myelin phagocytosis, membrane attack complex formation on myelin, and the enhanced activation of B cell immune responses

26. Indirect Mechanisms of B Cells in MS Pathology : T Cell Activation : B cells interact with T cells within the CNS, providing co-stimulatory signals and cytokines that activate T cells and perpetuate the inflammatory cascade. Formation of B Cell Follicle-like Structures : In some cases of MS, B cell aggregates resembling lymphoid follicles form within the meninges and CNS parenchyma, serving as sites of ongoing immune activation and exacerbation of inflammation. Regulatory Functions : B cells with regulatory properties, such as regulatory B cells ( Bregs ), may play a role in modulating immune responses and controlling inflammation in MS. However, dysregulation of Breg function could contribute to disease exacerbation.

27. Indirect mechanisms that B cells use to affect multiple sclerosis pathology B cells can indirectly affect CNS pathology by inducing the differentiation of autoreactive T helper 1 (TH1) cell and TH17 cell responses in the periphery and within the CNS, in part through CD80 and CD86 upregulation

28. B cell-directed therapeutics B Cell Depletion : Therapies targeting B cells aim to deplete circulating B cells or inhibit their function. Monoclonal antibodies, such as rituximab , ocrelizumab , and ofatumumab , target the CD20 surface antigen on B cells, leading to B cell depletion and suppression of MS disease activity. B Cell Modulation : Other therapies aim to modulate B cell function rather than deplete B cells entirely. Reduce B cell activation and antibody production. For example, the monoclonal antibody, eculizumab , Plasma Cell Targeting : Strategies targeting plasma cells, the antibody-producing descendants of B cells, are also being explored. For example, agents targeting the proliferation and survival of plasma cells, such as proteasome inhibitors (e.g., bortezomib ), may have potential therapeutic benefit in MS.

29. Cont’n … B-cell-directed therapeutics refer to treatments or therapies that specifically target B cells These therapeutics aim to modulate B-cell activity and function to treat various diseases and conditions CD20 has been a target for B-cell-directed therapeutics, particularly in the treatment of B-cell malignancies and autoimmune diseases CD20 is a general B cell marker that is expressed during B cell differentiation from the pro-B cell phase until the plasma cell stadium

30. CD20 antibodies can induce tumor killing through various mechanisms  These include: 1. Direct binding and crosslinking of CD20 molecules on B cells, resulting in cell death via non-classical apoptosis 2. They can also activate complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) by engaging immune effector cells

31. Mechanisms of action of CD20 antibodies Direct binding and crosslinking of CD20 molecules on B cells This direct binding can initiate the crosslinking of multiple CD20 molecules, resulting in cell death through the induction of non-classical apoptosis The specific mechanisms of cell death may vary depending on the type of CD20 mAb used Complement-dependent cytotoxicity (CDC): CD20 mAbs , such as rituximab, can activate the classical complement pathway when they bind to CD20 antigens on B cells This triggers the formation of a membrane attack complex (MAC), leading to the lysis of the target B cell

32. Cont’n Antibody-dependent cell-mediated cytotoxicity (ADCC): CD20 mAbs can also engage immune effector cells, such as natural killer (NK) cells, macrophages, neutrophils, and eosinophils, through their Fc region. The Fc region of CD20 mAbs binds to Fc receptors ( FcRs ) on these effector cells, triggering the release of cytotoxic factors that can kill the CD20-expressing B cells.

33. Mechanisms of action of CD20 antibodies

34. The normal range of B-cells The normal range of lymphocytes in adults is between 1,000 and 4,800 lymphocytes in every microliter of blood. Approximately 10% to 20% of lymphocytes are B-cells. Having consistently high or low B-cells may mean you have a disease or condition

35. The difference between T-cells and B-cells Both T-cells and B-cells protect us from infection-causing pathogens and diseases, but they play different roles in your immune system T-cells send signals that control your immune response (helper T-cells) or kill pathogens or infected cells directly (cytotoxic T-cells) B-cells make proteins called antibodies in response to antigens, the markers that let your body know there’s an invader It’s the antibodies and not the B-cell directly that stops the invader