Vollrath IMM Lecture 4 2024 PDF

Summary of Lecture 3 - Immunology Specific/Adaptive Immunity APCs activate lymphocytes – with matching receptors – in the regional lymph node TH – the first cells to show specificity required to activate B and TC cells Co-reception and Checkpoint Inhibition Memory cells are formed for all l...

Summary of Lecture 3 - Immunology Specific/Adaptive Immunity APCs activate lymphocytes – with matching receptors – in the regional lymph node TH – the first cells to show specificity required to activate B and TC cells Co-reception and Checkpoint Inhibition Memory cells are formed for all lymphocyte types Antibodies – Structure, Classes and Functions Class-switching Antibodies – Structure, Function, Classes Summary of Lecture 3 - Immunology Specific/Adaptive Immunity APCs activate lymphocytes – with matching receptors – in the regional lymph node TH – the first cells to show specificity required to activate B and TC cells Co-reception and Checkpoint Inhibition Memory cells are formed for all lymphocyte types Antibodies – Structure, Classes and Functions Class-switching Active vs. Passive Immunity Natural vs. Artificial Humoral – Antibodies play many roles in fighting infection Complement Cascade and Membrane Attack Complex ComplementComplement Cascade Cascade – Membrane Attack Complex C5-C9 = Membrane Attack Complex (MAC) makes holes in microbe cell wall Antigen and Antibody binding MAC leads to C1 activation Membrane Attack Complex  APC Encounter and Recognition MHC II Antigen Antigen Antigen Antigen B Cell Helper T Cell (TH) Cytotoxic T Cell (TC) B TH CD4+ TC CD8+ Activation + Cytokines Cytokines + TH1 TH2 Ç√çç√ç√ç√ç√ Plasma Cells Antibodies TC TC Attack Humoral Cellular Guide phagocytes, Directly attack complement and NK antigen-bearing cells cells to attack antigen- bearing cells or to neutralize free antigen How do Lymphocyte Develop their Specific Receptors? Lymphocytes Must Gain Immunocompetence - Develop Antigen Receptors FAB Region FC Region HEAVY CHAIN Lymphocytes Must Gain Immunocompetence - Develop Antigen Receptors Pro-B Cell Pre-B Cell B Cell Plasma Call Mature Antibody B Cell Receptor B-Cell Receptor Expression of RAG1 and RAG2 (Recombination Activating Genes) Heavy Chain Immunoglobulin Gene Rearrangement V1-50 D1-25 J1-6 Constant          DNA TdT Rearrangement of D and J TdT Rearrangement of V Heavy-chain primary RNA transcript Heavy-chain messenger RNA Lymphocytes Must Gain Immunocompetence - Develop Antigen Receptors Pro-B Cell Pre-B Cell B Cell Plasma Call Mature Antibody B Cell Receptor B-Cell Receptor Expression of RAG1 and RAG2 (Recombination Activating Genes) Heavy Chain Immunoglobulin Gene Rearrangement V1-50 D1-25 J1-6 Constant          RAGs TdT Recombination DNA Activating Genes Rearrangement of D and J splice out gene segments TdT Rearrangement of V Heavy-chain primary RNA transcript RNA Heavy-chain messenger RNA Lymphocytes Must Gain Immunocompetence - Develop Antigen Receptors Pro-B Cell Pre-B Cell B Cell Plasma Call Mature Antibody B Cell Receptor B-Cell Receptor Expression of RAG1 and RAG2 (Recombination Activating Genes) Heavy Chain Immunoglobulin Gene Rearrangement V1-50 D1-25 J1-6 Constant          TdT DNA Rearrangement of D and J TdT TdT Terminal Rearrangement of V deoxynucleotidyl Transferase adds single bases Heavy-chain primary RNA transcript RNA Heavy-chain messenger RNA Lymphocytes Must Gain Immunocompetence - Develop Antigen Receptors Pro-B Cell Pre-B Cell B Cell Plasma Call Mature Antibody B Cell Receptor B-Cell Receptor Expression of RAG1 and RAG2 (Recombination Activating Genes) Heavy Chain Immunoglobulin Gene Rearrangement V1-50 D1-25 J1-6 Constant          TdT DNA Rearrangement of D and J TdT Rearrangement of V Heavy-chain primary RNA transcript RNA Heavy-chain messenger RNA Immature B Cell Variable Diversity Joining Constant DNA Immature B Cell Variable Diversity Joining Constant DNA RAGs Recombination Activating Genes Splices out some of the V D and J regions DNA Mature B Cell Variable Diversity Joining Constant DNA TdT - Terminal deoxynucleotidyl transferase inserts additional nucleotides at the junctions between gene segments. AT G A CC DNA Mature B Cell AT G A CC Variable Diversity Joining Constant DNA mRNA transcript Secreted IgM Antibodies Protein Mature B Cell AT G A CC Variable Diversity Joining Constant DNA Secreted IgG mRNA transcript Antibodies Protein How do Lymphocyte Develop their Specific Receptors? Under normal circumstances the body will NOT create antibodies to self antigens Major histocompatibility complex (MHC I and II) Unique to each person Except identical twins Important in tissue/organ transplant rejection Immune tolerance develops during fetal and early postnatal life due to clonal deletion or clonal inactivation of cells that match body antigens Development of T cell Tolerance in utero, in the thymus T Cells must recognize MHC Class II molecules Any T cells that cannot will be negatively selected (destroyed) T Cells should NOT recognize self-proteins, cells expressing MHC Class-I If they do, they will be negatively selected 95% of T cells produced will be destroyed Yet, we have billions of T-cells in the Secondary Lymphoid Organs with different TCRs that can recognize virtually any foreign material that may enter the body Activation of the Cytotoxic T Cell B Cell Helper T Cell (T H) Cytotoxic T Cell (TC) CD4+ CD8+ TH2 TH1 TC Cells Recognize Endogenous Antigen – produced by body cell Infected Body Cells (virally infected) Synthesize MHC I molecules Bind virus peptide fragments (antigen) to MHC I Package antigen–MHC I complexes Insert antigen–MHC I complexes into the plasma membrane Recall… TH Cells Recognize Exogenous Antigen – foreign material from outside the body Antigen Presenting Cells Synthesize MHC II molecules Bind antigen fragments to MHC II molecules Package antigen–MHC-II complexes Insert antigen–MHC II complexes into the plasma membrane Infected Body Cells Present Antigens to TC with MHC-I Virus Killing of Virus-Infected Cells by Cytotoxic T Cells *Memory TC Cells are also formed Checkpoint Inhibition All biological processes need “shut-off” controls In immune response this involves displacement of CD28 from B7 by CTLA4 or PD-1 Checkpoint Inhibition All biological processes need “shut-off” controls In immune response this involves displacement of CD28 from B7 by CTLA4 or PD-1 Factors that Alter Resistance to Infection Protein–calorie malnutrition greatest contributor to decreased resistance to infection worldwide Preexisting disease infectious or noninfectious, can predispose the body to infection Stress and state of mind can enhance or reduce resistance to infection (and cancer) Sleep deprivation associated with decreased immune function Modest exercise and physical conditioning net beneficial effects on the immune system and host resistance Immunodeficiency Diseases Result from weak, underactive, or impaired immune systems Examples: 𝑺𝑪𝑰𝑫 = 𝑺𝒆𝒗𝒆𝒓𝒆 𝑪𝒐𝒎𝒃𝒊𝒏𝒆𝒅 𝑰𝒎𝒎𝒖𝒏𝒐𝒅𝒆𝒇𝒊𝒄𝒊𝒆𝒏𝒄𝒚 𝑫𝒊𝒔𝒆𝒂𝒔𝒆 a group of related diseases that arise from an absence of both B and T cells and, in some cases, NK cells 𝑨𝑰𝑫𝑺 = 𝑨𝒄𝒒𝒖𝒊𝒓𝒆𝒅 𝑰𝒎𝒎𝒖𝒏𝒐𝑫𝒆𝒇𝒊𝒄𝒊𝒆𝒏𝒄𝒚 𝑺𝒚𝒏𝒅𝒓𝒐𝒎𝒆 infects and kills helper T cells resulting in impaired immune responses to infectious organisms and cancers Harmful Immune Responses Tissue/Graft Rejection Transfusion Reactions Allergy (Hypersensitivity) Autoimmune Disease Excessive Inflammatory Responses Tissue Grafts and Organ Transplantation MHC I proteins on the graft cells & MHC II proteins on the macrophages differ from the recipient The recipient’s cells recognize these MHC proteins as foreign The recipient’s TC cells with the aid of TH cells kill cells bearing the foreign MHCs Avoid Rejection with… Drugs that kill actively dividing lymphocytes to decrease the recipient’s T cell population cyclosporine blocks cytokine production from helper T cells Eliminates signals for proliferation of helper- and cytotoxic T cells Transfusion Reactions Hemolysis when erythrocytes are destroyed during blood transfusion Erythrocytes lack MHC proteins, but have membrane proteins and carbohydrates on their surfaces that function as antigens The ABO system of carbohydrates is key for transfusion reactions Rh erythrocyte-membrane antigens are also of medical importance Human ABO Blood Groups Blood Group Percentage Antigen on RBC Antibody in Blood In the United States A 42 A Anti-B B 10 B Anti-A Neither anti-A AB 3 A and B nor anti-B Neither A O 45 Both anti-A and anti-B nor B Rh factor: negative or positive Universal donor: O Universal recipient: AB Allergic Reaction Reactive to a substance that most others tolerate well Two types of reactions Immediate Hypersensitivity Delayed Hypersensitivity - Appears 12-72 hours after allergen exposure Usually restricted to the site of injury Mast Cell Colorized Electron Micrograph of a Mast Cell, Showing Numerous Secretory Vesicles © MedImage/Science Source Anaphylaxis Allergic symptoms are usually localized to the site of antigen entry However, if large amounts of mast cell (or basophil) histamine enter the circulation, systemic symptoms may cause severe hypotension and bronchiolar constriction Anaphylaxis can cause death due to circulatory and respiratory failure It can be elicited in some sensitized people by the antigen in a single bee sting  Autoimmune Disease Inappropriate immune attack triggered by body proteins acting as antigens The immune attack, mediated by autoantibodies and self-reactive T cells, is directed against body cells that contain these proteins Examples: Type 1 diabetes mellitus Rheumatoid arthritis Multiple sclerosis Myasthenia gravis Diapedesis Margination Summary of Lecture 4 - Immunology Adaptive Immune System How are lymphocyte receptors formed? RAGs and TdTs Class Switching Elimination of lymphocytes that detect self antigens Cell-Mediated Response – Cytotoxic T Cells kill infected body cells Endogenous antigens expressed by body cells with MHC I Cytotoxic T Cells (TC) Checkpoint Inhibition Factors effecting immunity and different types of Immune Responses Blood types