Adaptive Immunity and Immunization

Learning Objectives

  • Define the two branches of adaptive immunity based on cell types and functions.

  • Distinguish between active and passive forms of natural and artificial immunity.

  • Compare the processes by which MHC class I and class II receptors recognize foreign antigens.

  • Identify cells functioning as antigen-presenting cells (APCs).

  • Discuss the distinction between T-cell development and T-cell activation.

  • Contrast the biological functions of various T-cell subsets.

  • Describe the structure and function of T-cell receptors.

  • Diagram the process of antigen presentation involving MHC receptors and T-cell interactions.

  • Describe the structure and function of B-cell receptors.

  • Compare T-cell-dependent vs. T-cell-independent B-cell activation concerning mechanisms and outcomes.

  • Differentiate the structure and function of the five classes of antibodies.

  • Explain differences in primary and secondary antibody responses.

  • Explain the consequences of antibody-antigen binding.

  • Outline natural and artificial means of acquiring immunity.

  • Compare various vaccination types.

  • List criteria for an effective vaccine.

  • Describe the concept of herd immunity.

Review of Major Host Defenses

  • Three lines of defense:

    • First Line of Defense:

    • Innate, nonspecific mechanisms consisting of:

      • Physical Barriers: Skin, mucous membranes.

      • Chemical Barriers: Enzymes, pH levels.

      • Genetic Barriers: Specific host susceptibility.

    • Second Line of Defense:

    • Immediate Response involves a cellular and chemical system activated if pathogens breach surface defenses.

    • Key components:

      • Interferons: Proteins that inhibit viral replication.

      • Phagocytosis: Process by which phagocytes engulf and digest pathogens.

      • Complement System: A group of more than 30 plasma proteins that enhance the body’s ability to remove microbes and promote inflammation through a cascade of reactions. When activated, the system performs several key functions:

      • Opsonization: Tags pathogens for destruction by phagocytes.

      • Lysis of Pathogens: Forms a membrane attack complex (MAC) to create pores in microbial membranes, leading to cell death.

      • Inflammation: Attracts phagocytes and other immune cells to the site of infection and increases vascular permeability.

      • Clearance of Immune Complexes: Helps remove antigen-antibody complexes from circulation.

      • Inflammation: Localized response to infection or injury.

    • Third Line of Defense:

    • Specific host defenses developed uniquely for each pathogen.

    • Involves B and T lymphocytes, antibodies, and cytotoxicity.

    • Characterized by specificity and memory against pathogens.

Characteristics of Adaptive Immunity

  1. Discrimination: Ability to differentiate between self (body's own cells) and non-self (foreign substances).

  2. Diversity: Presence of a variety of cellular receptors and antibodies to recognize trillions of different foreign substances.

  3. Specificity: Selectivity in immune response—acquired immunity selectively targets specific pathogens as compared to nonspecific mechanisms.

  4. Memory: Lymphocytes remember past encounters with pathogens and respond rapidly to subsequent infections.

Key Players in Adaptive Immunity

  • Antigens: Substances triggering immune responses, often derived from pathogens.

  • Antigen-Presenting Cells (APCs): Cells (e.g., B cells, dendritic cells, macrophages) that process and display antigens for T-cells.

  • T cells and B cells: Key lymphocytes that collaborate to neutralize pathogens; functionally distinct in their actions against foreign agents.

Antigen Processing and Presentation

  • T-cells can only recognize antigens that are processed and presented by APCs.

  • Types of APCs:

    • B cells

    • Dendritic cells

    • Macrophages

    • Neutrophils

  • Antigens are processed, then displayed on the APC surface for lymphocyte recognition.

Major Histocompatibility Complex (MHC)

  • Also known as Human Leukocyte Antigen (HLA), located on chromosome 6.

  • Individuals have unique MHC profiles; closely related individuals have more similar profiles.

  • Despite being the same species, each individual presents unique molecules which can be antigenic to others.

Types of Adaptive Lymphocytes

  • B Cells:

    • Site of Maturation: Bone marrow

    • Function: Humoral immunity, production of antibodies.

    • Surface Markers: Immunoglobulin receptors (Ig).

    • Requires Antigens: No.

  • T Cells:

    • Site of Maturation: Thymus

    • Function: Cell-mediated immunity.

    • Surface Markers: T-cell receptor (TCR) and several CD markers (e.g., CD4, CD8).

    • Requires Antigens: Yes (needs MHC presentation).

Immune Receptors on Lymphocytes

  • Major Functions:

    • Identify and attach to foreign antigens.

    • Promote self-antigen recognition.

    • Process and transmit chemical signals for immune action.

  • B-Cell Receptors (BCRs): Bind free antigens.

  • T-Cell Receptors (TCRs): Bind processed antigens presented by MHC molecules on APCs.

Principle Stages of Adaptive Immune Function

  1. Lymphocyte Development and Clonal Deletion: Process involving differentiation of stem cells into lymphocytes, ensuring specificity.

  2. Antigen Presentation and Clonal Selection: Presentation of antigens activates lymphocytes tailored to respond.

  3. Lymphocyte Activation:

    • B-lymphocyte response: Involves antibody production.

    • T-lymphocyte response: Involves cell-mediated actions.

Stage 1: Development of Lymphocytes

  • Lymphocytic stem cells in the bone marrow differentiate into T or B cells.

  • B cells mature in the bone marrow; T cells migrate to the thymus.

  • Migration to secondary lymphoid tissues occurs post-maturation, where they await antigen exposure.

Clonal Deletion and Tolerance

  • Each lymphocyte expresses a unique receptor, programmed for specific antigen recognition.

  • Clonal deletion occurs to eliminate self-reactive lymphocytes, ensuring tolerance.

Clonal Selection and Expansion

  • Introduction of an antigen selects specific lymphocytes encoded for recognition of that antigen.

  • Triggered lymphocytes undergo clonal expansion, producing clones responsive to the antigen.

Stage 2: Antigen Presentation

  • Exogenous Antigen Processing: Class II MHC bind external antigen fragments for CD4+ T-helper cells.

  • Endogenous Antigen Processing: Class I MHC bind internal antigen peptides, presenting them to CD8+ T-cells (e.g., to signal infections or malignancy).

Stage 3 and 4: T Cell Challenge and Response

  • Naïve T cells remain inactive until antigen presentation occurs.

  • After activation, proliferate into effector and memory cells:

    • T-helper cells (CD4+): Activate immune responses, enhance antibody production, and help regulate immune activity.

    • Cytotoxic T lymphocytes (CTL)/(CD8+): Kill infected cells after recognizing presented antigens via Class I MHC.

T Cell Activation Process

  • APCs present antigens directly to CD4+ (Th cells) and CD8+ (CTL) T cells.

  • Activation also requires IL-2 from activated Th cells for CTLs.

  • Development of memory T cells ensues post-proliferation.

Stage 3 and 4: B Cell Challenge and Response

  • B cells interact directly with antigens through their B-cell receptors (BCRs).

  • However, many require assistance from activated T-helper cells for full activation and differentiation into plasma cells, which produce antibodies.

B-Cell Activation Mechanisms

  1. T-cell-dependent Activation:

    • Activation requires interaction between TH2 cells, antigen-presenting B cells, and released growth factors.

  2. T-cell-independent Activation:

    • Occurs through direct binding of certain antigens (e.g., polysaccharides) without T-cell help.

    • Produces antibodies with lower affinity and does not develop memory cells.

Antibodies (Immunoglobulins)

  • Large Y-shaped proteins synthesized by plasma cells in response to specific antigens.

  • Found in blood serum, tissue fluids, and mucosal surfaces typing specific binding sites.

Classes of Immunoglobulins

  • IgG: Most abundant; crosses placental barrier; produced in primary and subsequent immune responses.

  • IgA: Present in mucosal secretions and blood; important for mucosal immunity.

  • IgM: First antibody produced upon encountering an antigen (typically forms pentameric structures).

  • IgD: Functions mainly as a receptor on B cells.

  • IgE: Expressed in allergic reactions and responses to parasitic infections; among the lowest in serum concentration.

Antibody-Antigen Interactions

  • Opsonization: Coating pathogens with antibodies to enhance recognition by phagocytes.

  • Neutralization: Antibodies block viral binding sites, preventing attachment and entry into host cells.

  • Agglutination: Cross-linking pathogens to form aggregates, facilitating removal.

  • Complement Fixation: Activation of complement proteins leading to lysis of pathogens.

  • Precipitation: Clumping of soluble antigens for removal.

Primary Response to Antigen

  • Following the initial exposure, the immune response produces IgM followed by increased IgG concentrations.

Secondary Response to Antigen

  • Re-exposure to an antigen results in a quicker and stronger immune response facilitated by memory cells, with IgG produced rapidly (anamnestic response).

Categories of Acquired Immunities

  1. Active Immunity:

    • Generated through exposure to antigens; results in long-lasting memory.

    • Takes time to develop.

  2. Passive Immunity:

    • Transfer of preformed antibodies; immediate action but short-lived.

    • Does not create memory.

  3. Natural Immunity:

    • Acquired through everyday life experiences.

  4. Artificial Immunity:

    • Gained via medical procedures such as vaccinations.

Checklist for Effective Vaccines

  • Low side effects and toxicity.

  • Protection against natural pathogen forms.

  • Stimulates both antibody and cell-mediated responses.

  • Long-lasting memory effects.

  • Minimal doses/boosters required.

  • Cost-effective, stable, and easily administered.

Vaccine Trial Phases (FDA Standards)

  • Phase I: Initial safety testing on 20-100 healthy volunteers.

  • Phase II: Expanded testing on several hundred volunteers for efficacy.

  • Phase III: Large-scale trials on hundreds/thousands, assessing safety and effectiveness.

Vaccine Safety Monitoring

  • Post-licensure safety monitoring for rare events among vaccinated populations.

  • VAERS: Database for reporting adverse events linked to vaccinations.

  • Vaccine Safety Datalink (VSD): Resource for ongoing safety evaluations.

Vaccine Preparation Types

  1. Killed or Inactivated Vaccines: Non-replicating but induce immunity.

  2. Live Attenuated Vaccines: Weakened pathogens promoting strong immunity with fewer doses.

  3. Subunit Vaccines: Contain specific antigenic parts; can be isolated chemically or genetically engineered.

  4. Genetically Engineered Vaccines: Crafted from genetically-modified microbes or agents.

Whole Cell Vaccines

  • Live, fully virulent organisms can provide long-lasting protection; require fewer boosters.

  • Killed vaccines typically necessitate higher doses and more frequent boosters for effectiveness.

Study Findings on Vaccine Hesitancy

  • In a study with 17,229 participants, misconceptions about flu vaccines and the measles vaccine's safety (related to autism) were prevalent.

  • WHO identified vaccine hesitancy as a major global health threat in 2019.

Herd Immunity Concept

  • Illustrated the impact of vaccination on disease spread:

    • Without immunity, disease spreads uncontrollably.

    • Partial immunization leads to some spread.

    • Widespread immunization effectively contains outbreaks.