Acquired Immunity Pt.2 (W3)

• MHC I


  Molecules that help recognise foreign antigens, bind to foreign peptide fragments and display them on the surface of infected cells, triggering activation of CD8+ T cells

  
• MHC II


  Molecules that help recognise foreign antigens, bind to foreign peptide fragments and display them on the surface of antigen presenting cells, triggering activation of CD4+ T cells

  
• MHC proteins play a crucial role in the immune system by presenting antigens to immune cells
• MHC I and MHC II are responsible for distinguishing between self and non-self molecules
• MHC Molecules


  • Bind to foreign peptide fragments and display them on the surface of infected cells or antigen presenting cells
  • Trigger activation of T lymphocytes (CD4+ or CD8+ cells)

  
• Human MHC


  Also known as human leukocyte antigen (HLA)
• Peptide loading of MHC-I


  1. Endogenous proteins are modified by ubiquitin

  2. Processed by proteasomes

  3. Trimmed by cytosolic proteases

  4. Peptides enter ER via TAP transporters

  5. MHC-I alpha chain is folded with help of chaperones

  6. Beta-2 microglobulin is added

  7. Complex is held together by tapasin

  8. Peptide-loaded MHC-I complex is transported to Golgi and then cell surface

  
• Uptake of protein and peptide loading of MHC-II


  1. Exogenous proteins are taken up and processed in early endosomes

  2. Cleaved into peptides by acid proteases

  3. MHC-II molecules are formed in ER with invariant chain

  4. Invariant chain is cleaved leaving CLIP

  5. HLA-DM facilitates insertion of peptide into MHC-II

  6. Peptide-loaded MHC-II complex is transported to cell surface

  
• MHC Class I


  • Expressed on all nucleated cells
  • Allows recognition of molecules produced within the cell, such as viral or tumor antigens, by CD8+ cytotoxic T cells
  • Helps mediate cellular immunity in eliminating intracellular pathogens

  
• MHC Class II

  • Expressed primarily on antigen-presenting cells
  • Presents extracellular antigens to CD4+ helper T cells
  • Leads to release of cytokines, inflammation, and activation of B cells
• Difference between MHC Class I and MHC Class II

  • Structure
  • Cell surface expression
  • Antigen source
  • Antigen processing
  • Peptide size
  • T cell interaction
  • Co-receptor
  • Immune function
  • Location

  
• MHC Class III molecules have physiological roles unlike Classes I and II, including components of complement system, cytokines, and heat shock proteins
• Requirements for Immunogenicity


  • Foreignness
  • High molecular weight
  • Chemical complexity
  • Degradability
• Immunological Adjuvant

  A substance used to enhance/augment the immune response against an immunogen
• Functions of Immunological Adjuvants

  • Increases biological half-life of immunogen
  • Increases production of local inflammatory cytokines
  • Improves antigen delivery, processing and presentation by antigen presenting cells

  
• Humoral Immunity


  Immunity generated by circulating antibodies, protects extracellular spaces where most pathogens multiply

  
• B Cell Production and Maturation


  1. Formed from hematopoietic stem cells in bone marrow

  2. Undergo positive selection for functional antigen receptors

  3. Undergo negative selection to eliminate self-reactive B cells
• B Cell Selection


  Positive selection: B cells with normal functional receptors survive

  Negative selection: Self-reactive B cells are eliminated by apoptosis, receptor editing, or induction of anergy
• B Cell Activation and Differentiation


  T cell-independent activation: BCR cross-linking by repetitive epitopes

  T cell-dependent activation: Requires cooperation with helper T cells, results in stronger immune response and memory

  
• Lymphoid tissues


  Where mature recirculating B cells bearing both IgM and IgD on their surface may become
• Binding to self molecules in the bone marrow


  Can lead to the death or inactivation of immature B cells
• B cell activation and differentiation

  Activation of B cells is based on the type of antigen that they encounter
• T Cell-Independent Activation of B cells

  1. Activation of B cells without the cooperation of helper T cells

  2. Occurs when BCRs interact with T-independent antigens

  3. T-independent antigens (e.g., polysaccharide capsules, lipopolysaccharide) have repetitive epitope units within their structure, and this repetition allows for the cross-linkage of multiple BCRs, providing the first signal for activation

  4. A second signal, such as interaction of toll like receptors with pathogen associated molecular patterns (PAMPs) (not shown), is also required for activation of the B cell

  5. Once activated, the B cell proliferates and differentiates into antibody-secreting plasma cells

  
• T cell-dependent activation of B cells


  1. More complex than T cell-independent activation, but the resulting immune response is stronger and develops memory

  2. T cell-dependent activation can occur either in response to free protein antigens or to protein antigens associated with an intact pathogen

  
• 1. independent antigens


  Have repeating epitopes that can induce B cell recognition and activation without involvement from T cells

  
• Plasma cells


  • Antibody factories that secrete large quantities of antibodies
  • After differentiation, the surface BCRs disappear and the plasma cell secretes pentameric IgM molecules that have the same antigen specificity as the BCRs
  • The T cell-independent response is short-lived and does not result in the production of memory B cells

  
• T cell dependant B cell activation

  1. Interaction and Internalization

  2. Antigen Processing and Presentation

  3. Recognition by Helper T Cells

  4. Linked Recognition

  5. Activation and Differentiation

  
• T cell dependant B cell activation (cont)


  1. Initial IgM Secretion

  2. Cytokine Stimulation

  3. Class Switching (Isotype Switching)

  4. Genetic Rearrangement

  5. Retained Epitope Specificity

  
• Characteristics of Primary vs Secondary Antibody Responses

  • Definition
  • Appearance
  • Antibody Peak
  • Affinity of Antibody
  • Responding Cells
  • Lag Phase (during which no antibody can be detected in serum)
  • Types of Antibodies
  • Amount of Antibody
  • Antibody level over time

  
• Why do antibody levels remain elevated longer during the secondary antibody response?
• Cell-mediated Immunity (Cellular Immunity)


  • Once a pathogen enters a cell, it can no longer be detected by the humoral immune response; instead, the cell-mediated immune response must take over to kill the infected cell before it can allow the virus or bacteria to replicate and spread
  • Cell-mediated immunity involves cytotoxic T cells recognizing infected cells and bringing about their destruction
  • Once a cytotoxic T cell (TC) is activated, it will clone itself, producing many TC cells with the correct receptors; some portion of the cells are active and will help destroy infected cells, while others are inactive memory cells that will create more active TC cells if the infection returns
  • Helper T cells (TH cells) also aid in cell-mediated immunity by releasing signaling molecules known as cytokines which can recruit natural killer cells and phagocytes to destroy infected cells and further activate TC cells; they do not directly destroy pathogens

  
• T Cell Production and Maturation

  1. Formed from multipotent hematopoietic stem cells (HSCs) in the bone marrow

  2. The first steps of differentiation occur in the red marrow of bones, after which immature T lymphocytes enter the bloodstream and travel to the thymus for the final steps of maturation

  3. Once in the thymus, the immature T lymphocytes are referred to as thymocytes

  4. The maturation of thymocytes within the thymus can be divided into positive and negative selection, collectively referred to as thymic selection
• T cell positive and negative selection

  1. To check whether the thymocytes able to act on MHC. If they interact with MHC they receive surviving signals if not will go through apoptosis. If bind to MHC I: CD8+ and if bind to MHC II: CD4+

  2. If strongly binds to APC MHC, will undergo apoptosis because that increases chances of autoimmune diseases
• Classes of T Cells

  • Helper T cells
  • Regulatory T cells
  • Cytotoxic T cells
• 1. Cell Receptors


  • The TCR comes from the same receptor family as the antibodies IgD and IgM, and thus shares common structural elements
  • Similar to antibodies, the TCR has a variable region and a constant region, and the variable region provides the antigen-binding site
  • However, the structure of TCR is smaller and less complex than the immunoglobulin molecules
  • Whereas immunoglobulins have four peptide chains and Y-shaped structures, the TCR consists of just two peptide chains (α and β chains), both of which span the cytoplasmic membrane of the T cell
• T helper cell activation and differentiation

  1. Helper T cells are activated by antigen-presenting cells (APCs)

  2. APCs present processed foreign epitopes in association with MHC II

  3. The activation process involves three steps: TCR recognition, CD4 interaction, and cytokine secretion

  4. The activated helper T cell proliferates, dividing by mitosis to produce clonal naïve helper T cells that differentiate into subtypes with different functions

  
• Subtypes of Helper T Cells

  • TH1 cells
  • TH2 cells
  • TH17 cells
  • Memory helper T cells
• Cytotoxic T cell activation and differentiation


  1. Cytotoxic T cells (CTLs) are activated by APCs/ infected cells

  2. Activation process (similar to helper T cells): Recognition, CD8 interaction, Cytokine production

  3. Differentiation: Effector CTLs, Memory cells

  4. TH1 cell stimulation: Cytokines from TH1 cells also stimulate CTL proliferation and differentiation

  5. Effector function: CTLs recognize and kill infected cells through antigen presentation of pathogen-specific epitopes associated with MHC I

  
• Humoral versus cell-mediated response


  • Humoral
  • Cell Mediated
• THANK YOU!