Unit 13: Adaptive Immune Response

Overview of Adaptive Immune Response

Definition: Second level of immunity, reliant upon the innate immune response as a prerequisite.
Key Characteristics:
  - Involvement of lymphocytes
  - Response to specific antigens
  - High specificity
  - Adaptability to infections
  - Memory formation that can confer potentially lifelong immunity

Components of Adaptive Immunity: The Lymphatic System

Association: Adaptive response is associated with the lymphatic system.
Functionality:
  - Covers the entire body
  - Involves lymphocytes and lymphoid structures
  - Focused in areas where pathogens enter:
    - Lymph nodes (neck, underarm, legs, groin)
    - MALT (Mucosa-associated lymphoid tissues)

Strategic Lymphoid Structures

GALT (Gut-associated lymphoid tissue):
  - Lymphoid tissue associated with the digestive tract
  - Includes tonsils, adenoids, appendix, and Peyer’s patches
  - Peyer’s patches are significant:
    - Contain M cells (antigen-collecting cells)
    - Under M cells are germinal centers filled with B cells and surrounded by T cells
BALT (Bronchus-associated lymphoid tissue):
- Initializes and regulates immune responses in the lungs
NALT (Nasal-associated lymphoid tissue):
- Plays a crucial role in the immune defense of the upper respiratory tract
CALT (Conjunctival-associated lymphoid tissue):
- Essential for protecting the eye’s surface

Components of Adaptive Immunity: Cells of Adaptive Immunity

Origin: All adaptive response cells arise in the bone marrow from stem cells.
Types of Cells:
  - Antigen-presenting cells (APCs):
    - Dendritic cells
    - Macrophages
    - B cells
  - Lymphocytes:
    - T cells
    - B cells

Antigen-Presenting Cells (APCs)

Role: Serve as a critical interface between innate sensing and adaptive activation.
Function:
  - Process and display antigen fragments on MHC (Major Histocompatibility Complex) molecules
  - Recognized by other immune cells (T cells).
  - Produce cytokines
Types of APCs:
  - Dendritic cells
  - Macrophages
  - B cells

Dendritic Cells

Importance: Key cells in the adaptive immune response.
Function:
  - Take up, process, and present antigens to T cells
  - Found in most tissues, particularly epithelial surfaces
  - Maturation:
    - Immature dendritic cells patrol peripheral tissues, capture antigens (via phagocytosis, macropinocytosis, receptor-mediated endocytosis) triggering maturation into APCs
    - Migrate to regional lymph nodes
    - Upregulate MHC II, co-stimulatory molecules, CCR7, subsequently priming T cells for activation

Macrophages

Function: Efficient phagocytes that present antigens via MHC II to T cells
Shortcomings: Less effective than dendritic cells in antigen presentation due to lower MHC II and costimulatory expression unless properly stimulated.

B Cells

APC Role: Act as APCs for T cells during T-dependent humoral responses
Mechanism: Use B cell receptor (BCR) to concentrate cognate antigens, internalize them, and display them via MHC II to T cells.

Lymphocytes

Lineage: Common lymphoid precursor gives rise to:
  - T cells
  - B cells
  - Natural killer cells (part of innate immunity, covered in Unit 12)

Differentiation and Maturation of Lymphocytes

Origin: All lymphocytes originate from hematopoietic stem cells in the bone marrow.
Maturation:
  - B cells: Mature in the bone marrow; a constant supply of new B cells exists.
  - T cells: Migrate to the thymus for maturation; after puberty, the thymus atrophies while T cells remain long-lived, capable of occasional division to maintain a responsive pool to infections.
  - In maturity, both B and T cells circulate throughout blood and tissues searching for antigens.
  - Naive lymphocytes: Lymphocytes that have not yet encountered an antigen.

Activation of Lymphocytes

Condition in Absence of Infection: Naive lymphocytes circulate but remain inactive without antigen exposure.
Upon Activation: They differentiate into various effector lymphocytes:
  - Plasma cells (from B cells)
  - Cytotoxic T cells (from T cells)
  - Helper T cells (from T cells)
  - Regulatory T cells
  - Memory cells

Types of Effector Lymphocytes

B Cells → Plasma Cells: Responsible for making and secreting antibodies.
T Cells → Types:
  - Cytotoxic T cells: Kill infected host cells and pathogens.
  - Helper T cells: Activate B cells and other immune cells.
  - Regulatory T cells: Suppress the immune response once the antigen is diminished.
Memory Cells: Long-lived lymphocytes responsible for immunological memory.

Antigen Receptors of Lymphocytes

Acquisition: When B and T cells mature, they acquire specific antigen receptors:
- B-cell receptor (BCR): An immunoglobulin (Ig) molecule with two antigen-binding sites to recognize free antigens.
- T-cell receptor: Similar structure but with a single antigen-binding site, recognizing antigens presented by APCs on MHC molecules.

Costimulatory Signals for Activation

Requirement: Both B and T cells need a second costimulatory signal generated and regulated by the innate immune response to become fully activated and effective.
Inactivation Safeguard: Contact with antigen without this costimulatory signal leads to automatic inactivation of the lymphocyte (anergy), which prevents autoimmune reactions (peripheral tolerance).

Clonal Selection of Lymphocytes

Definition: The process whereby certain lymphocytes are destroyed while others mature, occurring in bone marrow (B cells) and thymus (T cells).
Process:
- Precursor cells produce lymphocytes, each specific for a different antigen due to genetic rearrangement, creating millions of variant antigen receptors on lymphocyte surfaces.
Clonal Deletion: Is part of clonal selection, wherein newly formed lymphocyte groups that react against self-antigen are eliminated (central tolerance).
Remaining Lymphocytes: Maturation leads to specificity for nonself antigens. If an antigen is encountered, the lymphocyte activates, divides, and proliferates to form clones that are antigen-specific. Lymphocytes not encountering an antigen will die.

Key Points of Clonal Selection

Diversity Generation: Generates vast numbers of unique antigen receptors.
Specificity: Each receptor corresponds to a distinct antigen.
Clonal Uniformity: All progeny of a matured lymphocyte will carry the same receptor type.

Survival of Lymphocyte Populations: B Cells

Production: Millions of B cells produced daily.
Survival Factors: Dependent on signals (cytokines) from peripheral lymphoid tissue which can activate, proliferate, or induce apoptosis in inactive B cells to maintain population constancy.
Memory Cell Formation: Some activated B cells differentiate into memory cells.

Survival of Lymphocyte Populations: T Cells

Sources of Signals: T cells receive survival signals from specialized epithelial cells in the thymus and dendritic cells in peripheral lymphoid tissue.
Migration: T cells leave the thymus and migrate to the lymph nodes, where signaling leads to activation, proliferation (up to fourfold in 24 hours for 3-5 days), and either migration into tissue or retention in the node.
Apoptosis and Memory Cell Formation: Activated effector T cells eventually undergo apoptosis, with some transitioning to memory cells for quick responses to future antigen encounters.

Lymphoid Tissues

Circulation and Location: Following maturation, lymphocytes are carried by blood into peripheral lymphoid tissues, circulating continually to find antigens or die if no antigen is found.
B Cells: Produced in the bone marrow; an overwhelming majority do not encounter their specific antigen before death.
T Cells: Fully mature upon leaving the thymus, maintained in smaller numbers, and presumed to renew within peripheral tissue.

Antigen Presentation

Definition: Display of antigens on the surface of APC recognized by T cells; B cells do not require antigen presentation.
Types of Antigens:
- Self Antigens: Integral to immunological memory and contribute to tolerance.
- Nonself Antigens: Molecules not inherently recognized as self.
Main Types of APCs: Dendritic cells, macrophages, and B cells.

Major Histocompatibility Complex (MHC)

Functionality: Antigens must be fragmented and displayed on the cell surface via MHC glycoproteins.
Class Types:
- MHC Class I: Found on all nucleated cells and identifies self; presents intracellular antigens to CD8 cytotoxic T cells.
- MHC Class II: Exclusively on immune cells (especially APCs) and presents antigens to CD4 helper T cells.

Activation of T Cells

Mechanisms Involved:
  - Dendritic Cells: Secrete chemokines to attract naive T cells and present various antigens; produce costimulatory molecules for T cell activation.
  - Macrophages: Must be activated to express class II MHC; engulf and degrade microorganisms, generating antigen-MHC II complexes that prompt T-cell activation.
  - B Cells: Surface immunoglobulin acts as an antigen receptor, this receptor/antigen complex is internalized, combined with MHC II, and presented to T cells to initiate their activation.

Functions of Activated Effector T Cells

Types of Effector T Cells:
  - Cytotoxic (CD8) T Cells: Release cytotoxins to kill infected cells or pathogens.
  - Helper (CD4) T Cells: Release cytokines to activate other immune cells.
  - Regulatory T Cells: Turn off the immune response once antigens are cleared.
Migratory Behavior: Most leave lymphoid tissues post-activation, binding to targets with high affinity.

Cytotoxic T Cells: Immune Response

Mechanism of Action: Crucial in targeting pathogens that invade and replicate within host cells, avoiding antibody-mediated elimination.
Activation: Stimulated by antigen-MHC I complexes and other effector signals, leading to their proliferation and search for affected cells.
Killing Method:
  - Induces apoptosis in infected cells.
  - Kills via cytotoxic granule release:
    - Perforins: Create pores in target cell membranes.
    - Granulysin and Granzyme: Induce target cell apoptosis and degrade cytokines.
Cytokine Release: Interferon and TNF part of the innate immune response, promoting further immunity.

Helper T Cells: Immune Activation

Process: Antigens presented via MHC class II on APCs stimulate naive helper T cells, resulting in their proliferation and differentiation into immature effector T cells.
Types:
  - TH1 Cells: Activate macrophages for enhanced pathogen clearance.
  - TH2 Cells: Support antiparasitic and allergic responses, activate eosinophils and B cells.
  - TH17 Cells: Stimulate neutrophils for protection against extracellular bacteria.
  - TFH Cells: Provide signals to activate B cells for antibody production.

Regulatory T Cells

Development: Arise from the thymus or from naive CD4 T cells.
Function: Produce inhibitory cytokines to modulate immune response and prevent autoimmunity by suppressing dendritic cell and T cell activation after antigen removal.

The Humoral (B Cell) Response

Mechanism: Primarily carried out by B lymphocytes, leading to antibody production.
B Cell Activation:
- Antigen binding to receptors or via helper T cell assistance.
After Activation: Some B cells proliferate and become plasma cells (massive antibody producers) while others become memory cells.

Antibodies (Immunoglobulins)

Definition: Products of plasma cells found in blood and extracellular spaces that contribute to the adaptive immune response in multiple ways:
  - Neutralization: Prevent toxins and viruses from functioning and inhibit bacterial attachment.
  - Opsonization: Facilitate the uptake of pathogens by phagocytes.
  - Complement Activation: Initiate the classical complement pathway.

Structure of Immunoglobulin Molecules

Formation: All immunoglobulin (Ig) molecules exhibit a Y-shape, composed of:
  - Four polypeptide chains (2 light, 2 heavy chains).
  - The amino terminal forms the variable region (antigen-binding site).
  - The remaining part forms the constant region.

Binding Properties of Antibodies

Specificity: Recognize specific antigen parts (epitopes) based on size, shape, and chemical properties.
Binding Mechanism: Involves hydrophobic forces, electrostatic interactions, and hydrogen bonds aiding stability of the antigen-antibody complex.

Immunoglobulin Isotypes

Types: Five isotypes based on different constant regions:
- IgG, IgM, IgA, IgE, IgD.
Functionality: Each has specialized roles including:
  - Recognition by phagocyte receptors.
  - Formation of antigen-antibody complexes.
  - Delivery mechanism to tissues and secretions.

Overview of Isotype Functions

IgA: Present at epithelial surfaces, offers mucosal immunity.
IgE: Plays a role in allergic reactions, found bound to mast cells and basophils.
IgG: In blood, highly effective in several immune functions, including pathogen neutralization and opsonization.
IgM: First antibody produced during an immune response; effective in activating the complement system.

Timing of Immunoglobulin Responses

Primary Response: Activation of naive B cells leads to IgM production initially, transitioning to IgG over time. Symptoms arise as infections take root, lessening once IgG resolves it.
Secondary Response: Faster and more potent, IgM response accelerates to IgG due to memory cell presence, clearing pathogens before symptomatic manifestation.

Antibody Activation of Immune Cells

Activation of Immune Cells: Antibodies can stimulate numerous immune cells that have receptors engaged by their constant region initiating responses for pathogen clearance.
- Phagocytic cells attracted to site of infection via mediators released by NK cells and mast cells.

B-Cell Activation in Cooperation with T Cells

Mechanism of Cooperation: Antigen binding triggers internal signaling within B cells, engaging antigen presenting on MHC II, activating T-helper cells stimulating B cell proliferation and differentiation into plasma cells producing specific antibodies.
- This essential process involves trapping T cells within peripheral lymphoid tissues to facilitate efficient responses.

Course of Adaptive Response

Overview: Integration of cellular and humoral responses leading to effective eradication of pathogens.
Memory Cell Formation: Some B and T cells remain for rapid responses to subsequent antigen encounters.

Immunological Memory

Significance: A hallmark of the adaptive immune response evident in both T and B cells following infections or vaccinations.
Mechanism: Sustained memory cell population maintains long-term immunity; interleukins assist in memory T cell upkeep.

Natural and Artificial Immunity

Acquisition Types:
  - Naturally Acquired Immunity:
    - Active: Infection leads to an immune response.
    - Passive: Antibody transfer from mother to infant.
  - Artificially Acquired Immunity:
    - Active: Immunization via vaccines elicits immune responses.
    - Passive: Antibody administration post-exposure to specific pathogens.

Overall Immune Response

Synchronicity: Innate and adaptive immune responses function complementary to effectively address infections.
Timelines: The adaptive response is typically triggered days following the innate response, aiming definitively to clear established infections.

Conclusion

Outcome: Effectively controlling and eliminating infections while forming robust defenses against reinfection through immunological memory.