Immune System_The Immune Response (3).pdf

IMMUNE SYSTEM – THE IMMUNE RESPONSE Date: 09/12/2023 PHM 310 Avinash Kumar, Ph.D. Announcements Office Hours: By Appointment (Email) Office: WL 203 Email: [email protected] Objectives ü Describe the innate immune response and its role in patient health ü Describe the humoral acquired immune...

IMMUNE SYSTEM – THE IMMUNE RESPONSE Date: 09/12/2023 PHM 310 Avinash Kumar, Ph.D. Announcements Office Hours: By Appointment (Email) Office: WL 203 Email: [email protected] Objectives ü Describe the innate immune response and its role in patient health ü Describe the humoral acquired immune response and its role in patient health ü Describe the cell-mediated acquired immune response and its role in patient health Recap Ø Physical/Chemical barriers – Skin etc. – 1st line of defense Ø Immune System – Innate Immune System – Acquired Immune System Ø Cells of the Innate immune system – 2nd line of defense • Neutrophils - Bacteria • Eosinophils - Parasites • Basophils Mast cells – Allergy /Hypersensitivity • Monocytes Macrophages – Antigen presentation Ø Cells of the Acquired immune system – 3rd line of defense • B and T Lymphocytes • Natural Killer (NK) cells Ø Organs of the Immune System • Primary organs ü Bone marrow and Thymus – Immune Cells are produced here • Secondary organs ü Lymph nodes, Lymphoid tissue and Spleen – Immune Response occurs here How does immune system protect or keep an organism safe? WHO? The players; security guards; cells/organs HOW? WHAT? Means/ways; immune response The Immune Response ü KILL THE PATHOGEN AND DON’T HARM THE HOST • Identification - is this thing self or non-self? • Designation - amplify the foreign nature of the invader, help the other parts of the immune system recognize it - Opsonization • Recruitment - activate other components of the immune system • Elimination - get rid of the pathogen • Prevent recurrence - prepare for the future Innate Immune Response Acquired Immune Response INFECTION!!! Innate Immune Response (0-96 hours) Acquired Immune Response (After 96 hours) Recognition of (non-specific) microbialassociated patterns Monocytes Neutrophils Basophils Eosinophils Removal of infectious agent Memory Inflammation Recruitment and activation of effector cells RAPID SHORT NON-SPECIFIC (GENERIC) Clonal expansion and differentiation to effector cells DELAYED SPECIFIC MEMORY Removal of infectious agent + Triggering of Acquired Immune System Recognition of specific antigen B lymphocytes T lymphocytes NK cells Innate Immune Response - Identification Pattern recognition receptor (PRR) Pathogen associated molecular pattern (PAMP) Pathogen Phagocyte PAMP: Mannose, Lipopolysaccharide (LPS), Phosphatidylcholine, Zymosan, Flagellin PRR: Mannose-binding lectin (MBL), LPS-binding protein (LBP), Toll-like receptor 4 (TLR4), c-reactive protein (CRP), TLR2, TLR5 Innate Immune Response – Designation (Opsonization) ü Activation of B lymphocytes – Antibody production ü Activation of Complement system ü Activation of phagocytes (Monocytes (macrophages), Neutrophils etc.) Receptor for antibody Receptor for C3b C3b Pathogen Y C3b C3b Phagocyte Innate Immune Response - Recruitment ü Activation of phagocytes (Monocytes (macrophages), Neutrophils etc.) – Release of Cytokines ü Infected tissue – release Cytokines Cytokines Pro-inflammatory Anti-inflammatory Chemokines cause inflammation stop inflammation recruit neutrophils and macrophages to infection site Adhesion molecules allow neutrophils and macrophages to stick to vessel walls so they can migrate out and get to the infection site Innate Immune Response - Recruitment Activated phagocyte expresses LFA-1 Releases IL-8 Infected tissue LFA-1 Endothelial cells around Infected tissue expresses ICAM-1 Phagocyte binds to infected tissue Activated phagocyte Infected tissue Infected tissue ICAM-1 LFA-1 ICAM-1 Innate Immune Response – Elimination (Phagocytosis) Innate Immune Response and patient health BUT . . . in septic shock (sepsis): Activated macrophages release cytokines: Local release of TNFα at site of infection • recruits phagocyte and lymphocyte to infected tissue • increase platelet adhesion to blood vessel wall • phagocytosis of bacteria • local vessel occlusion • plasma and cells drain to local lymph node Goal – prevent spread of infection * Activated macrophages in liver and spleen TNFα into blood stream • systemic edema (swelling from fluid accumulation) • decreased blood volume, -> • vessel collapse, disseminated intravascular coagulation • wasting and multiple organ failure • death Acquired Immune Response Acquired Immune Response Humoral Immune Response (Humoral Immunity) B-lymphocytes Cell-mediated Immune Response (Cell-mediated Immunity) T-lymphocytes Humoral Immune Response – Identification and Designation B cell B-cell receptor (BCR) Humoral Immune Response – Recruitment and Memory Antibodies (Immunoglobulins) Recognizes a specific antigen by its 3D structure • Distinguishes different isotypes of antibody (IgA, IgD, IgE, IgG, IgM) • Binds to antibody (Fc) receptors on phagocytes during opsonization • Activates complement system Antibody isotypes Antibodies (Immunoglobulins) IgM ü Found on surface of lymphocytes. IgG the B ü First antibody produced upon exposure to antigen. ü Pentamer. ü No Fc exposed (cannot bind phagocytes – but can activate complement). ü After first producing IgM in response to antigen, plasma cells switch to producing IgG. ü Upon 2nd exposure to same antigen, memory B cells produce IgG immediately for a more rapid response. ü Only antibody class that crosses the placenta (provides passive immunity to newborn). IgA ü Found in tears, saliva, nasal fluids, and GI, genitourinary, and respiratory tracts. ü Dimer ü Secreted in breastmilk. IgD IgE on ü Found on Fc ü Found surface of B receptors on mast cells. lymphocytes. ü Function still ü Causes release of when unknown. histamine bound to antigen be ü May involved in (inflammation). ü Main function is to autoimmune diseases. eliminate parasites. ü When no parasites, IgE contributes to allergies. Antibody response First exposure, response is slow and small. Second exposure, response is immediate and strong. Memory B cells make IgG immediately! Antibody functions • Enhanced phagocytosis - Opsonization • Virus neutralization – physically prevent virus from binding to host cell Binds to receptor Y Y Tumor/ Infected cell/ Pathogen Virus Y Cannot bind Antibody (Fc) Receptor Y Y • Antibody dependent cell cytotoxicity (ADCC) – neutrophils, eosinophils, macrophages, or NK cells lyse tumor cells or infected cells or pathogen coated with antibody Y • Activates complement – leads to lysis of tumor cells or infected cells or pathogen coated with antibody Virus Y Y • Neutralize toxins – binds toxins from microorganisms (botulism, tetanus) and inactivates them Phagocyte/ NK cells Humoral Immune Response – Elimination Ø Complement System C1 Ø Antibody dependent cell cytotoxicity (ADCC) • Phagocytes (neutrophils, eosinophils, macrophages), or NK cells express antibody (Fc) receptor. • Fc receptor binds to Fc region of antibody. • Activated phagocytes or NK cells release cytotoxic factors and perforins to lyse tumor cells or infected cells or pathogen coated with antibody Tumor/ Infected cell/ Pathogen Y C1 Y C1 Y • ~35 proteins derived from blood plasma proteins involved in opsonizing pathogens and lysing pathogens or tumor/infected cell. • Serve as chemotaxis factors (recruit other immune system components). • Classic pathway is activated by C1 binding to Fc portion of antibodies. C1 Acquired Immune Response Acquired Immune Response Humoral Immune Response (Humoral Immunity) B-lymphocytes Cell-mediated Immune Response (Cell-mediated Immunity) T-lymphocytes Phagocytosis Neutrophils, eosinophils, and basophils die in the course of destroying pathogens - pus https://www.pinterest.com/pin/158259374383186758/ Cell-mediated Immune Response – Identification and Designation Antigen presentation Antigen: a molecule that immune system identifies as foreign (non-self). Antigen presenting cells (APCs): cells that present the antigen to B and T lymphocytes. APCs Professional •Macrophages •Dendritic cells •B-lymphocytes •Exogenous antigen (extracellular pathogen) Atypical •Almost any cell •Infected cell •Endogenous antigen (intracellular pathogen) Present antigen with Major Histocompatibility Complex Class II (MHC Class II) Present antigen with Major Histocompatibility Complex Class I (MHC Class I) Cell-mediated Immune Response – Recruitment APC Binds and activates cytotoxic CD8 T cells Binds and activates helper CD4 T cells Cell-mediated Immune Response – Recruitment T-cell activation co-stimulatory signal B7 = CD80/CD86 Cell-mediated Immune Response – Recruitment Helper T cells (CD4) Activated macrophages Activated B cells produce IgG Activated mast cells and eosinophils Activated B cells produce IgE Recruit neutrophils and macrophages to site of injury Suppresses immune responses Activated cytotoxic T cells Cell-mediated Immune Response – Elimination Cytotoxic T cells (CD8) Infected cell = APC Antigen + MHC Class I on APC Antigen + MHC class I binds TCR B7 (APC) binds CD28 (T) Active CTLs kill target cells 2 ways: Activated cytotoxic CD8 T cells (CTL) HIV Tat protein inhibits production of MHC Class I Herpesvirus prevents viral peptides from binding to MHC Class I 1) CTLs secrete perforin -> forms pores in target cell -> apoptosis 2) CTLs express Fas ligand (FasL) which binds to Fas receptor on target cell -> apoptosis Infected cells are not recognized or destroyed!!!! Cell-mediated Immune Response – Elimination Helper T cells (CD4) Phagocytosis Complement-mediated lysis ADCC CTL-mediated apoptosis Phagocytosis Complement-mediated lysis ADCC Phagocytosis TH1 response IgG antibodies Macrophages CTLs Can kill intracellular bacteria! TH2 response IgE antibodies Mast cells Eosinophils Not helpful for an intracellular bacteria! Vaccination http://www.jisponline.com/articles/2011/15/2/images/JIndianSocPeriodontol_2011_15_2_115_84378_f6.jpg Conclusions Ø Innate Immune Response • 0-96 hours • Identification – PAMP (mannose, LPS etc.) – PRR (MBL, LBP, TLR4 etc.) • Designation (Opsonization) – Activation of complement system – Activation of B lymphocytes – Activation of phagocytes • Recruitment – Activated phagocytes and infected tissue release cytokines – pro-inflammatory – anti-inflammatory – chemokines – adhesion molecules • Elimination – Phagocytosis Ø Acquired Immune Response • After 96 hours Conclusions Ø Acquired immune response • Humoral – B lymphocytes • Cell-mediated – T lymphocyte Ø Humoral immune response • Identification and Designation – B cell receptor – Antibodies • Recruitment and Memory – Clonal selection – Clonal expansion – Differentiation – Antibodies • Elimination – Antibodies – Complement System – ADCC – NK cells – Phagocytes (Neutrophils, Eosinophils, Macrophages) Ø Antibodies • Five isotypes – IgM, IgG, IgA, IgD, IgE • Functions – Opsonization – Virus neutralization – Toxin neutralization – Complement system activation – ADCC Conclusions Ø Cell-mediated immune response • Identification and Designation – Antigen presentation – APC – Infected host cell – MHC Class I – Professional – MHC Class II – T-cell receptor (TCR) • Recruitment and Memory – Clonal selection – Activation – MHC Class I +TCR – CD8 cytotoxic T cell (CTL) – MHC Class II + TCR – CD4 Helper T cell – Co-stimulatory signal – B7 (APC) + CD28 (T cell) – Clonal expansion – APC secreting IL12 – Th1 – Phagocytes, B cells, CTL – APC secreting IL4 – Th2 – Phagocytes, B cells – APC secreting TGFβ + IL6 – Th17 - Phagocytes – APC secreting TGFβ – Treg • Elimination – CTL – Perforin – Apoptosis – FasL – Apoptosis – Helper T-cell – Th1 – Phagocytosis, complement/CTL-mediated lysis, ADCC – Th2 – Phagocytosis, complement-mediated lysis, ADCC – Th17 – Phagocytosis – Treg – Immunosuppression