Humoral Immune Response I PDF 2024-2025 Lecture Notes

Block 1.2 lectures 2024-2025 lecture Highlighter key Writer Reviewer Doc...

Block 1.2 lectures 2024-2025 lecture Highlighter key Writer Reviewer Doctor explanation Abbreviation Key information Book >> >> Enass Alkhars Abdulhamid Alabadi 221-222-223 notes References Student explaintion Deleted Humoral Immune Response I Dr. Sayed A. Quadri 1. Phases of B lymphocytes in the humoral immune response. 2. T-dependent and T-independent antigens. 3. B cells recognition, activation and response to antigens. Complement role. 4. In vivo antigen activated B lymphocytes interaction with T- lymphocytes. 5. Activated B lymphocyte development into memory lymphocyte or mature to a plasma cell. 6. Molecular changes enable the secretion of antibodies. 7. Mechanisms of the germinal center reaction; Role of Follicular Dendritic cells(FDC). 8. Immune complexes and the immune response.  Humoral Immune Response It is mediated by B lymphocytes and also require Adaptive immune response mediated by antibodies the help of T lymphocytes The antibodies are secreted in the body fluids (IgM, IgG, IgA, IgE, IgD) (isotypes). (ex.plasma) Neutralize and eliminate extracellular microbes and microbial toxins. Secreted antibodies enter the circulation and mucosal fluids Activation: (humor= fluid) T cells migrate to the site of infection B cells don’t need to migrate (just the The principal defense mechanism against microbes antibodies go to the site of infection) with capsules rich in polysaccharides and lipids as T cells cannot respond to non-protein antigens. Phases of B lymphocytes in the humoral immune response B lymphocytes mature in the bone marrow, Central = primary= generative lymphoid and T lymphocytes mature in the thymus. organs: Which is thymus and bone marrow B.M , Thymus called generative lymphoid Location of maturation- organs. Peripheral =secondary lymphoid organs: Location of the immune response Mature lymphocytes (naïve) leave the generative lymphoid organs and enter the circulation and the peripheral lymphoid organs (lymph nodes, spleen & mucosal lymphoid tissues), where they may encounter antigen for which they express specific receptors….(a naïve B cell). Phases of B lymphocytes in the humoral immune response The selection of the clones of specific B lymphocytes for a specefic Ag Clonal selection Clonal expansion Heavy-chain isotype (or class) switching These are important changes which enhance the efficiency of humoral immune response. Affinity maturation: Repeated exposure to a protein antigen results in the production of antibodies with increasing affinity for the antigen…. improved capacity to bind to and neutralize microbes and their toxins Prolifeation = Expansion  Phases of B lymphocytes in the humoral immune response** When naive B lymphocytes recognize microbial antigens (clonal selection) B cell activation proliferation (clonal expansion) & differentiation into effector cells and memory cells. The effector cells are antibody-secreting cells, called plasma cells (primary immune response) Memory cells survive for long periods, when they meet specific antigen again they respond rapidly …… (secondary immune response). Primary: First exposure of the B lymphocyte to the Ag Secondary: subsequent exposure to the same Ag  1- B lymphocytes recognize the antigen in its Memory cells Effector cells native state (without APC) Note :Naïve B lymphocytes express receptors (IgM-IgD) After activation( and class switching)B lymphocytes will have IgD and other receptors IgD = in all B lymphocytes. (Membrane bound antibody) ———— 2- Activation :some B lymphocytes will get help of helper T lymphocytes(for that we can classify antigens as T dependent and T independent) ———— 3-proliferation ———— 4-differentiation :into plasma cells (antibody secreting cells) and memory cells. _________ In differentiation there are 2 processes : remember that emory cells can survive for year isotype switching-affinity maturation some researchers show that it could be life long Phases of B lymphocytes  P.A.R: The Ag specific B lymphocyte has to interact with an Ag, then it has to get activated, proliferate and differentiate into plasma cells, these plasma cells will secrete Immunoglobulins(Mainly IgM). — once the P.A.R is produced, the plasma cells (some of them) will differentiate into memory cells. And those memory cells live for decades, therefore, if a person encountered the same Ag in the future, memory cells can quickly interact with those Ags and proliferate and differentiate into the plasma cells to produce immunoglobulins. P.A.S: primary antibody response Ag: antigen The amount of produced antibodies No IgD is produced. (It functions only as membrane bound immunoglobulin) The strength with which an antibody binds to an epitope is ‘Affinity’.  T-dependent and T-independent antigens only peptide antigen(proteins). The 4 qualitative changes of B The T helper cell’s (help) is involved The T helper cell’s (help) is not involved lymphocyte If there is help of T helper cells the respsones will be more efficient.  The T cell - B cell interaction will produce some of the 4 qualitative changes Only peptide antigens The B lymphocyte is an APC, it can capture, process, display the Ag (peptide Ag in this case) on its surface with MHC II and present the Ag to the T helper cell Non-protein antigens in general Always remember, with T-independent antigen response the 4 qualitative changes are not really seen, even so, they are not going to be as effective as the T-dependent antigen response  Subsets of B cells respond preferentially to protein and non-protein antigens large number It is mainly involved in T-dependent 1. Follicular B cells: reside in and circulate through the follicles of lymphoid organs, make the bulk of T-dependent, class-switched, and high- affinity antibody responses to protein antigens and give rise to long-lived plasma cells. against 2. Marginal-zone B cells: located in the peripheral region of the splenic white pulp, respond largely to blood-borne polysaccharide are mainly involved in T-independent and lipid antigens.Especially antigens from capsulated organisms, e.g. capsulated bacteria (Streptococcus pneumonia) The capsules are USUALLY made of polysaccharide 3. B-1 cells respond to non-protein antigens in the mucosal tissues MALT and peritoneum. B cells recognition, activation and response to antigens Antigen recognition and the immune response are located in the secondary lymphoid organs. Humoral immune responses are initiated when antigen-specific B lymphocytes in the spleen, lymph nodes, and mucosal lymphoid tissues recognize antigens using their membrane-bound immunoglobulin as receptors. Membrane bound IgM and IgD, the antigen receptors of naive B lymphocytes, have highly variable antigen- binding regions. B cell receptor (BCR) complex: Membrane bound immunoglobulin + two proteins, called Igα and Igβ. Signal transduction molecules B cells recognition, activation and response to antigens Antigen-Induced Signaling in B Cells: Polysaccharides, lipids, and other non-protein antigens often contain multiple identical epitopes in each molecule and are therefore able to bind to numerous Ig receptors on a B cell at the same time….cross linking. Even protein antigens may be expressed in an array on the surface of microbes and are thus able to cross-link multiple antigen receptors of a B cell. A polysaccharide Ag Role of Innate Immune Signals in B Cell Activation B lymphocytes express a receptor for C3d called complement receptor type 2. One of these fragments is called C3d (proteolytic fragments of the most abundant complement protein, C3). Complement activation represents one way in which innate immunity facilitates B lymphocyte activation. Microbial products also directly activate B cells B cells express Toll-like receptor on its surface. TLR engagement on the B-cells by microbial products triggers activating signals which stimulate B-cell proliferation, differentiation, and Ig secretion. B-cell activation by antigen (and other signals) initiates the proliferation and differentiation of the cells and prepares them to interact with helper T lymphocytes if the antigen is a protein  Another molecule involved in innate immunity is the TLR. Which is a receptor for the PAMP simultaneous engagment will Enhance B C3D: is a by-product of the complement cell activation system activation and it is deposited on the TLR: Toll like receptor microbe. PAMP: Pathogen-associated molecular patterns The B lymphocyte has a receptor for C3D called CR2. simultaneous engagement of CR2 and B lymphocyte with C3D, and an Ag with Ag receptor of B lymphocyte will Enhance B cell activation  Functional sequences of B cells activation by antigen The basic idea of B cell activation, is that they will start expressing genes for certain proteins. What are these proteins? 1- proteins that are involved in the cell survival and life cycle (proliferation). ——————— 2- Antigen presentation proteins, mainly MHC molecules. ——————— 3- cytokines receptors. ——————— 4- CCR7. ——————— 5- Immunoglobulin genes, for antibody secretion. All the functional sequences are happening at the same time. They are not even (sequential events). As soon as an Ag binds, all of these changes happen simultaneously during the clonal expansion. Activated B lymphocytes interaction with T- lymphocytes 1. Naive CD4+ T cells are activated in the T cell zone of a secondary lymphoid organ by antigen presented by dendritic cells, and differentiate into functional helper T cells. 2. Naive B cells are activated in the follicles of the same lymphoid organ by the same protein antigen that is transported to the follicle. 3. The antigen-activated helper T cells and B cells migrate toward one another and interact at the edges of the follicles, where the initial antibody response develops. Helper T-cells activated by dendritic cells. 4. Some of the B-cells migrate back into follicles to form germinal centers,. This is the diagram of the lymph node B cells are located in the cortex. Aggregation of B lymphocyte are called follicles. T cells are located in the paracortex we are here talking about the same specific Ags CCR5 for both T, B cell, but are in different locations CCR7 in the lymph node.  2 1 For the B lymphocyte to recognize an Ag, the antigen is For the T lymphocyte to recognize an Ag, the dendritic brought through the lymph by the afferent lymphatics cell (which is found in the epithelial surfaces) will to the B cell zone. The B lymphocyte will capture, capture, process, migrate and present the Ag in the process and display the Ag with MHC II on its surface paracortex to the T lymphocyte and get it activated. and get activated. 3 The Ag specific B lymphocyte has to interact with the T lymphocyte. For this interaction to be possible, the B cell migrates out of the follicle towards the paracortex. —— The Ag specific T helper cell migrates out of the paracortex towards the follicle. = they will interact at the edge of the follicle. The migration processes are only possible because of the For B lymphocyte: expression of the chemokine receptors. CCR5 For T lymphocyte: It enables the B lymphocyte to stay at the B zone CCR7 (follicles). It enables the T lymphocyte to stay at the T zone CCR7 (paracortex). It drives the migration of B lymphocyte towards the It is also disposable for the dendritic cell to come to the paracortex T cell. CCR5 = After B cell activation, it will decrease the expression It is secreted by the stormal cells of the follicles of CCR5, and increase the expression of CCR7 It drives the migration of T lymphocyte towards the follicle This T cell - B cell interaction (again) is important for the 4 qualitative changes. = After T cell activation, it will decrease the expression The B lymphocyte migrates back into the follicle and start to of CCR7, and increase the expression of CCR5 proliferate which produces the germinal center reaction. CCR = C-C Chemokine Receptor (number of the type)  Signals for T cell activation: 1- MHC displaying a peptide Ag binding with a TCR. 2- Co-stimulatory molecules, (B7-CD28), (CD40-CD40L). 3- cytokines released by the APC binding with the cytokine receptor on the T cell. If you have a deficiency in CD40 molecule or CD40 ligand this will affect the activation of B cell. If B cell is not activated, The interaction between CD40 and CD40 ligand will not happen so there will not be an isotype switching, with out this interaction(isotype switching) the B cell will keep produce IgM and will not produce IgG. This known as hyper IgM syndrome. Follicular Dendritic cells (FDC). Reside in the light zone of the germinal center of lymphoid follicles in the peripheral lymphoid organs. Displays antigens that stimulate the differentiation of B cells in the follicles. FDCs do not present antigens to T cells and differ from the dendritic cells that function as APCs for T lymphocytes. Activated B lymphocyte development & germinal center reaction  The FDC is binding to the Ag and displaying the Ag (but not through Ag presentation process) The FDC has a receptor called FC receptor This receptor is for the FC region of the immunoglobulin. The B lymphocytes when they produce antibodies, they will bind to the antigen. This Antigen-Antibody complex can be attached to the FC receptor of the FDC. Therefore, it is now displaying the antigen. Class Switching Helper T cells stimulate the progeny of IgM and IgD expressing B lymphocytes to produce antibodies of different heavy-chain isotypes (classes). Heavy-chain isotype switching is induced by a combination of CD40L- mediated signals and cytokines. Cytokines produced by follicular helper T cells determine which heavy- chain isotype is produced  How isotype switching will take place? 1- CD40-CD40L interaction between the B\T cells 2- The type of cytokines -types of cytokines will influence to which class immunoglobulin switching will take place) IL10 Q: IgA is produced by which subset of B lymphocyte? B1 (MALT)  Heavy chain Class switching The cytokines that produced by TFH cell will make some genetic changes at constant region. gamma gene for IgG. Alpha gene for IgA. VDJ changes happen for T cell during maturation in thymus gland. for example, the recombination between S meu with S gamma with deletion of C region will give us an IgG. Why class switching happen after singling ? That’s because activation induced aminase (AID) The molecular mechanism of isotype switching, called switch recombination, takes the previously formed VDJ exon encoding the V domain of an Ig μ heavy chain and moves it adjacent to a downstream C region Affinity Maturation Affinity maturation is the process by which the affinity of antibodies produced in response to a protein antigen increases with prolonged or repeated exposure to that antigen. Occurs in the germinal centers of lymphoid follicles. Affinity Maturation Selection of high-affinity B cells in germinal centers. Memory cells High affinity isotype switched B cell. Do not secrete antibodies, but they circulate in the blood and reside in mucosal and other tissues. They survive for months or years. Respond rapidly if the antigen is reintroduced.  team Wishes you the best