Adaptive Immune System Pre-recorded PDF

Adaptive Immune System and hypersensitivity Sandra Ramos [email protected] Much more time to develop [email protected]; School of Medicine and Dentistry, GU Adaptive immune response Specificity – Ability to discriminate between different molecular entities and respond uniquely Discrimina...

Adaptive Immune System and hypersensitivity Sandra Ramos [email protected] Much more time to develop [email protected]; School of Medicine and Dentistry, GU Adaptive immune response Specificity – Ability to discriminate between different molecular entities and respond uniquely Discrimination between self and non-self – Ability to recognise foreign molecules and to avoid responding to self Memory – Ability to recall previous contact and respond with a larger and more rapid response faster and larger response Cells involved in adaptive response Antigen presenting cells (APCs) macrophages, dendritic cells and B cells Humoral B lymphocytes (B cells) - become plasma cells (antibody factories) antibodies Cell mediated immunity T lymphocytes (T cells) Three types of effector cells: TH1 cells, TH2 cells, TC cells and Treg Adaptive immune response from primary lymphoid organs Non-reactive T and B cells leave bone marrow (B cells) and thymus (T cells) have tolerance Known as Naïve Move to secondary lymphoid tissue- spleen, lymph nodes from primary lymphoid tissue Encounter antigen via APC Activation of lymphocytes Specific lymphocyte selected for clonal expansion specific for antigen large response Activation and Memory cells T cell Tolerance - thymus Cell type Developmental steps Surface proteins Associations T cell precursor Double negative Commitment to T cell lineage None Rearrangement of β TCR chain Proliferation Pro TCR Double positive Rearrangement of α TCR Cells express both CD4 and CD8 Positive selection against class I and II MHC CD4+, CD8+, TCR Key steps in determining type of T cell MHC I binds to CD8+ cells MHCII binding to CD4+ cells Single positive Migration to medulla of thymus Negative selection against selfantigens Mature T cell Exit into blood stream, awaits peripheral activation TCR/CD3 complex and either CD4+ or CD8+ TCR and either CD4+ or CD8+ Transcript factor AIRE allows thymic cells to express proteins from all areas of body - tolerance to vast majority of self-antigens Circulates and awaits activation by antigen Lack of thymic development leads to DiGeorge syndrome Occurs in the thymic cortex Activation and differentiation of T cells 1. Antigen binding - APC expresses antigen in association with MHC I or II 2. Co-stimulation- binding of accessory proteins (B7 protein) Clonal selection Proliferation of specific T cells and memory cell for antigen All T cells are CD3+ All T cells also express either CD4+ or CD8+ coreceptor molecules (never both) 3. Cytokines - differentiation Helper T cell – CD4+ T-cell proliferation and macrophage differentiation TH1 induces T-cell proliferation. Induces macrophage differentiation in bone marrow, help with engulphed bacteria and viruses (macrophages). Produce IFN and IL2. promote inflammation and immune resp. TH2 binds to peptide:MHCII complex on B cell. TH2 cell produce IL-4, IL-5,IL-6, which stimulate the proliferation & differentiation of B cells cytokines ro differentiate B-cells to plasma cells Tfh most important one to help B cell switching. Cytokines characteristic of either TH1 or TH2 TH17 promotes inflammation indirectly, Promotes local innate defense to pathogen co-stimulation CD40 CD40L Cytotoxic T cell – CD8+ T cells that can directly attack and kill other cells Circulate throughout the body in search of body cells that display the antigen to which they have been sensitized Recognise antigen by Class I MHC expressed on all nucleated cells Their targets include: compare with NK cells - penetrate and cause lysis of cells failing to express MHC – Virus-infected cells – Cells with intracellular bacteria or parasites – Cancer cells – Foreign cells from blood transfusions or transplants destruction, but may cause fibrosis/scarring DESTRUCTION punch a whole in the membrane leak https://youtu.be/ntk8XsxVDi0 B cells B lymphocytes have ~ 100,000 antibody molecules highly specific to one type of antigen Before exposure to a specific antigen, the clones of B lymphocytes remain dormant in the lymphoid tissue Foreign antigen, presented by macrophage and Th to B lymphocytes B lymphocytes specific for the antigen enlarge and become plasma cells (4 days ~500 cells and 2000 antibodies per second) Some become Memory cells RESPOND QUICKLY LATER B cell development lymph nodes - filter Isotype switching is T-dependent role in B-cell activation non-specific release specific antibodies as plasma cells Active and passive immunity Active immunity – Antibodies or T cells produced after either a natural or artificial exposure to an antigen – Long-lasting protection (memory), multiple effector mechanisms activated, lag time Passive immunity – Preformed antibodies or T lymphocytes are transferred from a donor to a recipient from mother – Maternal immunity – Rapid protection, short duration e.g. vaccine [email protected]; School of Medicine and Dentistry, GU Immunological memory Primary immune response Lag period: 3 to 6 days after antigen challenge​, peak in 10 days​ Antibody levels then decline Secondary immune response Sensitized memory cells respond within hours​ Antibody levels peak in 2 to 3 days at much higher levels, much faster remain high for weeks to months Subsequent encounters stronger and faster Purpose of vaccination is to induce a primary response so subsequent exposure to pathogen induces secondary response Putting it all together Antibodies Specific for a particular antigen 2 Identical heavy chains & 2 identical light chains Variable and constant region - The antigen binds at two different sites on the variable portions of the chains Each of the immunoglobulin heavy chain genes is assembled from V, D, J, and C gene segments. Five main classes of antibodies Direct attack the invader or activate complement system Effector functions of antibody help with complement enhances Antibody classes IgM First immunoglobulin class secreted by plasma cells non-specific Monomer or pentamer forms – numerous binding sites (potent agglutinating agent) Monomer antigen receptor on B cell surface Pentamer circulates in blood plasma Readily fixes and activates complement Usually indicates current infection IgG Monomer Most abundant 75-85% of circulating Secondary or late primary responses Fixes and activates complement Protects against viruses, bacteria, and toxins Crosses placenta – passive immunity IgA Dimer – secretions secretion antibody Monomer - serum Found in body secretions (saliva, sweat, intestinal juice and milk) Mucous membrane and epidermis (stops pathogens from attaching) IgE Stem end binds to mast cells or basophilstriggers these cells to release histamine and other chemicals that mediate inflammation and allergic reaction bradykinin? Secreted by plasma cells in skin, mucosa of the gastrointestinal and respiratory tracts, and tonsils, only traces found in plasma Levels rise during severe allergic attacks or chronic parasitic infections of the gastrointestinal tract IgD cell-bound, uncommon Antigen receptor on B cells co-expressed with IgM – naïve B cells Activates basophil and mast cells Immune surveillance 1.Organ/tissue transplant 2.Primary immunodeficiency 3.Secondary immunodeficiency 4.Cancer 5.Hypersensitivity 6.Autoimmunity Organ/tissue transplant Non-self MHC molecules is a major determinant of graft rejection Immunosuppressive drugs are necessary Autografts- donor is the recipient to self Isografts – identical twins Allograft – not identical twins, same species Xenografts – another animal Primary immunodeficiency genetic related X-linked agammaglobulinemia (XLA) Selective IgA deficiency Hyper IgM syndrome Di George syndrome Severe combined immunodeficiency deletion of long arm of Chromosome 22 (SCID) Leukocyte adhesion deficiency lose precursors Secondary Immunodeficiency from environment or infection HIV - CD4+ helper T cells and macrophages Immunosuppression (chemotherapy) Malnutrition Burns Drugs Splenectomy Prematurity, ageing, pregnancy toxicity of drug Cancer immunoediting adapt immune system BioLegend https://www.biolegend.com/en-us/cancer-immunoediting Hypersensitivity ccell-associated antigen only immune complex activate macrophages IgE production cytotoxic delayed antibody and complement Allergies or urticaria Type I – IgE mediated Triggered by antigen with antigen-specific IgE bound to FcεRs on mast cells Histamine, chemokines, cytokines, and leukotrienes Increase vascular permeability, break down tissue matrix proteins, platelet-activating factor, constriction of smooth muscle, stimulation of mucus secretion Late phase response (production and activation eosinophil, basophil and TH2 cell) Anaphylaxis Life-threatening systemic or hypersensitivity reaction with sudden onset Symptoms can be cutaneous, respiratory, cardiovascular, gastrointestinal, CNS and other Immunologic – IgE, mast cells, basophils Non-immunologic (anaphylactoid reaction) - mast cells and basophils Idiopathic Epinephrine or adrenaline to treat Type II Caused by chemical modification of cell surface or matrix-associated antigens that generates “foreign” epitopes to which the immune system is not tolerant. B cells respond to this antigenic challenge by producing IgG IgG binds to these modified cells and renders them susceptible to destruction through complement activation, phagocytosis, and antibody-dependent cytotoxicity Type III Deposition of immune complexes Activation of mast cells, monocytes, neutrophils, and platelets bearing the Fc receptor for IgG (FcγR), Initiates the complement cascade Tissue damage Generation of complement components C3a and C5a recruits and stimulates inflammatory cells and amplifies effector functions Type IV – Delayed type (1-3 days) Mediated by T cells through three different pathways: TH1 cells recognize soluble antigens and release IFNγ to activate macrophages and cause tissue injury TH2 cells produce cytokines to recruit and activate eosinophils, leading to their degranulation and tissue injury. CD8+ T cell direct toxicity