Host Defense and Vaccination

Immune System & Host Defense

  • Primary function: Host defense.
  • Revision of major concepts: major immune cells, major mediators, immune response to different pathogens, vaccines, and adjuvants.

Cells of the Immune System

  • Innate System:
    • Myeloid cells (e.g., neutrophils, macrophages).
    • NK cells.
  • Adaptive Immune System:
    • Lymphocytes: T cells and B cells.
  • Two systems must work together.

T Cell Activation Example

  • Two signals needed for T cell activation.
    • Signal 1: TCR (T cell receptor) signaling through recognition of cognate peptide presented by dendritic cells.
    • Signal 2: CD28 on T cells engaging with co-stimulatory molecules (CD80 or CD86) on dendritic cells.
  • Signal 2 is dependent on activation of the innate system.
  • Innate system provides the second signal required for T cell activation.

Host-Pathogen Interaction

  • Microbial entry, establishment of a niche, induction of host response, pathogen elimination or persistence (chronic infection).
  • Acute infection example:
    • Innate immune response: Rapid (seconds, minutes, hours).
    • Recruitment of neutrophils and macrophages.
    • Adaptive immune system: Complete control of infection; more sophisticated mechanisms to combat infection.

Viral/Bacterial Control Phases

  • Early phase:
    • Type I interferon, NK cells.
  • Later phase:
    • Effector lymphocytes (T cells, B cells).
    • B cells produce antibodies to neutralize the virus.
    • CD8 T cells kill infected cells.
  • Innate and adaptive systems are complementary.

Innate System: Pattern Recognition Receptors (PRRs)

  • Sensing molecules expressed where microbes may be present (cell surface, endosomal, cytosolic).
  • Examples:
    • Toll-like receptors (TLRs):
      • Surface: TLR2, TLR4 (sense extracellular bacteria).
      • Endosomal: TLR3, TLR8, TLR9 (sense viral infection).

Ligands Recognized by Sensing Molecules

  • PAMPs: Pathogen-Associated Molecular Patterns (microbe-derived).
  • DAMPs: Damage-Associated Molecular Patterns (host-derived).
  • DAMPs are released by damaged cells during infection/inflammation, triggering inflammation.

Natural Killer (NK) Cells

  • Innate lymphocytes that can kill infected cells.
  • Produce inflammatory cytokines (interferon-gamma, TNF) to activate macrophages.
  • Antibody-dependent cell-mediated cytotoxicity (ADCC): kill infected cells coated with antibodies via Fc receptor binding.
  • Collaboration between adaptive and innate systems.

Soluble Mediators: Complement System

  • Activated by classical, alternative, and lectin pathways.
  • Mechanisms of action:
    • Membrane attack complex (MAC) formation leads to lysis of infected cells.
    • Release of cleaved components (C3a, C5a) triggers local inflammation and immune cell recruitment.
  • Regulation of inflammation.

Adaptive System: B and T Cells

  • B cells: antibody production.
  • T cells:
    • CD4 T cells (helper cells).
    • CD8 T cells (cytotoxic T cells).

Immune Response to Pathogens

  • Extracellular bacteria/pathogens:
    • Humoral response (antibody-dependent control).
  • Intracellular bacteria/parasites:
    • Cell-mediated immunity.
    • Pathogens reside inside phagocytes.
    • Antibodies cannot penetrate cells.
    • Some pathogens live in the cytoplasm or in vacuoles of phagolysosomes.

Antigen Processing and Presentation

  • Endogenous antigens (cancer cells, viral infection):
    • Processed and presented via MHC class I.
  • Exogenous antigens:
    • Presented via MHC class II.
  • MHC class I presents peptides to CD8 T cells.
  • MHC class II presents antigens to CD4 T cells.
  • Differential location of pathogens triggers different T cell responses due to different MHC processing and presentation pathways.

Immunopathology

  • Host response to microbes can cause tissue damage.
  • Example: Immunopathology of COVID-19.
    • Severe COVID: lymphocyte reduction (T and B cells), increased myeloid cells (neutrophils, macrophages, monocytes).
    • Massive cytokine production (inflammatory cytokines).
    • Increased antibody production.
    • Motor organ inflammation with rare virus detection in inflamed tissues.
    • Treatment: immunosuppression (e.g., anti-dexamethasone, anti-IL-6 receptor antibodies).

Characteristics of Adaptive Immunity

  • Specificity and memory.
  • Serum Antibody Data
    • Primary response: first exposure to antigen X produces a relatively small anti-X response.
    • Secondary response: second injection with antigens X and Y results in:
      • Enhanced anti-X antibody production (faster and greater magnitude).
      • Moderate anti-Y antibody production (primary response).
    • Memory cells (T and B cells) mediate enhanced secondary response.

CD8+ T Cell Response

  • Viral growth kinetics:
    • Virus titer builds up quickly, peaks, and is eliminated by innate and adaptive immunity.
    • CD8+ T cells peak after viral infection peak.
  • Three phases of CD8+ T cell response:
    • Expansion: rapid increase in CD8+ T cell number.
    • Contraction: most cells die.
    • Memory: few cells survive, providing long-lasting memory.
  • Terminal effector T cells: expand dramatically but are eliminated after virus clearance.
  • Memory cells: increase, but remain relatively stable, allowing for a stronger secondary response upon re-exposure.

Immunization

  • Enhance immunity against infection.
  • Two types of immunity:
    • Active Immunity: host response to microbe or microbial antigen (e.g., vaccination).
      • Exposure to infection or vaccination leads to memory cells.
      • Re-EXposure to pathogen triggers recall response.
    • Passive Immunity: adoptive transfer of antibodies or T cells.
      • Serum collected from immune individuals/animals and transferred to another individual.
      • Provides specificity but does not establish long-term memory.

Passive Immunity: Antibody Transfer

  • Neutralizes toxins.
  • Serum sickness: immune response against animal antibodies after repeated exposure.
  • Solution: use human plasma or antigen-specific monoclonal human antibodies.

Mechanism of Transferred Antibody in Viral Infection

  • Neutralize invading pathogens.
  • Enhance uptake of virus via opsonization and phagocytosis.
  • Activate complement cascade via the classical pathway.
  • Bind to Fc receptor on NK cells, leading to killing of infected cells.

Adaptive Immunity and Vaccination Study (COVID-19)

  • mRNA vaccines reduce viral incidence.
  • Increased vaccination rate correlates to control of infection.
  • Active immunity works better in younger individuals.

Vaccine Definition and Components

  • Biological product that induces immune response to confer protection against infection/disease upon exposure to the same pathogen.
  • Must contain antigens expressed by the pathogen.
  • Clinical endpoint: protection against infection/disease severity.
  • Immune correlates of protection: predict protection upon re-exposure.

Adjuvants

  • Boost immune response, especially in recombinant vaccines.
  • Essential in inducing primary T and B cell response.
  • Many adjuvants are microbial products/PAMPs.
  • Examples: alum, AS04 (modified LPS), CpG 118 (DNA from microbes).
  • Activate innate immune response, upregulate co-stimulatory molecules (signal 2), and enhance T cell response.
  • Increase immunogenicity of weak antigens.
  • Enhance the speed and duration of immune response.
  • Stimulate humoral and cell-mediated immune response.

Types of Vaccines

  • RNA/DNA vaccine.
  • Recombinant protein (protein + adjuvant).
  • Viral vectors (adenovirus).
  • Whole organism vaccines:
    • Inactivated vaccines (killed pathogens).
    • Live attenuated vaccines (weakened organisms).

COVID-19 Vaccines

  • RNA vaccine.
  • Viral vectors.
  • Whole virus (inactivated).
  • Protein subunit.

mRNA Vaccine Mechanism

  • Spike protein construct in lipid nanoparticles.
  • Cells uptake the construct and produce spike protein.
  • Spike protein expressed on cell surface interacts with B cells.
  • Spike protein picked up by dendritic cells, migrate to the lymph nodes.
  • CD8 and CD4 T cells are activated.
  • CD4 T cells differentiate into TFH cells, promote B cell activation and antibody production.

Summary

  • Host defense against infection is the primary function of the immune system.
  • Mediated by both innate and adaptive immunity.
  • Different effective mechanisms control different types of microbes.
  • Host response can sometimes cause disease (immunopathology).
  • Vaccines save lives.