9.6 From Notes - Adaptive Immunity: Lymphocytes and Antibodies

• Adaptive immunity, also known as acquired immunity, is the body's third line of defense, involving lymphocytes and antibodies.
• It activates when external barriers and inflammation are insufficient, enhancing initial defenses and providing long-term protection against reinfection.

Key Characteristics

• Inducible: Lymphocytes and antibodies are produced specifically in response to infection.
• Specific: It targets particular infectious agents, inducing specific sets of lymphocytes and antibodies.
• Long-lived: Provides lasting protection against specific pathogens due to long-lived and systemic effectors.
• Memory: Re-exposure to the same microorganism induces a rapid production of protective lymphocytes and antibodies for permanent protection.
• Develops more slowly than inflammation.
• Innate and adaptive immunity interact, with innate immunity components needed for adaptive response development and adaptive immunity products activating innate system components.

Humoral and Cell-Mediated Immunity

• Humoral Immunity: Uses antibodies in blood and secretions to defend against extracellular microbes and toxins, either directly inactivating the microorganism or activating inflammatory mediators.
• Cell-Mediated Immunity: Uses T cells.

Active vs. Passive Immunity

• Active Immunity: Is long-lived, developing after exposure to an antigen through infection or vaccination.
• Passive Immunity: Is temporary, resulting from receiving preformed antibodies or T cells from another source, like maternal antibodies.
• The immune response relies on specific antigen recognition by antibodies or B and T cell receptors, followed by intercellular communication.

Antigens and Immunogens

• Antigen: A molecule that can react with antibody binding sites or antigen receptors on lymphocytes.
• Immunogen: An antigen that can elicit an immune response.
• Factors influencing immunogenicity include being foreign, appropriate size (>10,000 daltons), chemical complexity, and sufficient quantity.
• Self-antigens do not typically trigger an immune response due to tolerance mechanisms.
• Tolerance is either central (elimination of autoreactive lymphocytes in primary lymphoid organs) or peripheral (suppression by Treg cells in secondary lymphoid organs).
• Epitope (antigenic determinant): The specific part of an antigen recognized by an antibody or lymphocyte receptor; macromolecules usually have multiple epitopes.
• Haptens: Small molecules that become immunogenic only when bound to larger carrier molecules.
• Allergens: Antigens that induce an allergic response.

Molecules That Recognize Antigens

• Antibodies (Immunoglobulins): Serum glycoproteins produced by plasma cells in response to antigen challenge.
  • IgG: Most abundant, provides long-term immunity, and allows placental transfer.
  • IgM: First produced, involved in agglutination, complement fixation, and acts as a B-cell receptor (BCR).
  • IgA: Found in blood and secretions, offering mucosal protection as sIgA in secretions.
  • IgD: Low serum levels, functions as a BCR.
  • IgE: Low serum levels, involved in allergies and defense against parasites.
  • Structure: Includes two identical heavy chains and two identical light chains with constant (C) and variable (V) regions.
  • Fab (antigen-binding fragment) and Fc (crystalline fragment responsible for biologic functions) portions.
  • Complementary-determining regions (CDRs) within the variable regions form the antigen-binding site, separated by framework regions (FRs).
  • Valence is the number of antigen-binding sites.
• B-Cell Receptor (BCR) Complex: A membrane-bound antibody, usually IgM or IgD, on B cells, associated with signaling molecules (Igα and Igβ).
• T-Cell Receptor (TCR): A heterodimeric protein (α and β chains, or γ and δ chains) on T cells with variable and constant regions.
  • It associates with the CD3 complex for signaling.
  • It recognizes processed antigens presented by MHC molecules.

Molecules That Present Antigens

• Major Histocompatibility Complex (MHC): Glycoproteins on cell surfaces, also known as Human Leukocyte Antigens (HLAs) in humans.
  • Encoded by polymorphic genes on chromosome 6; individuals inherit a haplotype from each parent.
  • MHC Class I: Present on all nucleated cells and platelets, presents endogenous antigens (from intracellular proteins, 8-10 amino acids), and interacts with CD8 on cytotoxic T cells.
  • MHC Class II: Present on Antigen-Presenting Cells (APCs), presents exogenous antigens (from extracellular organisms, >12 amino acids), and interacts with CD4 on helper T cells.
• CD1: Structurally similar to MHC class I, mainly on APCs and thymus cells, presents lipid antigens, and interacts with NK-T cells.

Antigen Processing and Presentation

• Antigen Processing and Presentation: APCs process antigens and present them on their surface via MHC molecules to lymphocytes.
• Exogenous antigens are phagocytosed, processed in lysosomes, and presented by MHC class II.
• Endogenous antigens are degraded by proteasomes, transported to the ER by TAP proteins, bind to MHC class I, and are presented on the cell surface.
• CD1 molecules in lysosomes bind and present lipid antigens.

Molecules That Hold Cells Together

• Adhesion Molecules: Adhesion molecules (e.g., CD2, CD58, CD80, CD28, CD40, CD154, ICAM, LFA) facilitate interactions between lymphocytes and APCs, providing costimulatory signals.
• Cytokines: Soluble proteins that mediate intercellular communication, influencing proliferation, differentiation, and activation of immune cells.
  • Interleukins (IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-17, IL-22), interferons (IFN-α, IFN-β, IFN-γ), tumor necrosis factors (TNF-α, TNF-β), and transforming growth factor-beta (TGF-β).

Generation of Clonal Diversity

• Generation of Clonal Diversity: Occurs in primary lymphoid organs (thymus for T cells, bone marrow for B cells), producing diverse B and T cells with varied antigen receptors.
• Somatic recombination of gene segments (V, D, J) in immunoglobulin and TCR loci creates diversity in the variable regions and CDRs.
• Developing B and T cells express unique surface markers (e.g., CD4, CD8, CD21, CD40).
• Central tolerance eliminates autoreactive B and T cells in the bone marrow and thymus.
• Immunocompetent but naïve B and T cells migrate to secondary lymphoid organs.

Clonal Selection

• Clonal Selection: Initiated by exposure to foreign antigen in the secondary lymphoid organs.
• Antigen binds to specific BCRs or is processed and presented by APCs to T cells, leading to selection of clones.
• Selected lymphocytes proliferate and differentiate into effector and memory cells.

T-helper (Th) cells (CD4+)

• Th1: Activate macrophages and cytotoxic T cells (Tc).
• Th2: Help B cells differentiate into plasma and memory B cells.
• Th17: Promote inflammation by recruiting neutrophils and macrophages, and induce antimicrobial protein production.
• Treg: Suppress the immune response and maintain peripheral tolerance.
• B-cell clonal selection: Antigen binding to BCR and costimulatory signals from Th2 cells lead to proliferation and differentiation into plasma cells and memory B cells.
• Class-switch recombination allows plasma cells to produce different antibody classes against the same antigen, influenced by Th2 cytokines.
• T-cell clonal selection: Antigen presentation by MHC class I to CD8+ T cells, along with costimulatory signals and cytokines, lead to differentiation into effector Tc cells and memory T cells.

Humoral Immune Response (Antibody-Mediated)

• Primary response: Slow antibody production, with IgM appearing first, followed by IgG.
• Secondary response: Rapid and larger production of primarily IgG due to memory B cells.

Cellular Immune Response (T Cell-Mediated)

• Effector T cells (Tc, Treg) and memory T cells protect against intracellular pathogens, tumors, and regulate immune responses.
• Superantigens (SAgs): Microbial molecules that bind to TCRs and MHC class II molecules outside normal antigen-binding sites, causing T-cell activation and excessive cytokine production.

Functions of Antibodies

• Direct effects: Neutralization of pathogens or toxins by blocking their binding to host cells, and agglutination or precipitation of antigens.
• Indirect effects: Activation of the complement system, and opsonization by facilitating phagocytosis.

Secretory Immune Response (Mucosal Immunity)

• Protects external body surfaces via lymphoid tissues in respiratory, gastrointestinal, and genitourinary tracts.
• IgA is the dominant antibody class in secretions, preventing pathogen attachment and invasion; lymphocytes migrate specifically to mucosal areas.

IgE Function

• IgE: Involved in defense against parasitic worms by triggering mast cell degranulation and eosinophil activation, and it is the main mediator of allergic responses.

T-Lymphocyte Function

• T-Cytotoxic Lymphocytes (Tc cells): Kill virus-infected or cancerous cells by recognizing antigen presented by MHC class I through perforin, granzymes, and Fas ligand interaction.
• Natural Killer (NK) Cells: Kill abnormal cells lacking MHC class I expression, involved in antibody-dependent cell-mediated cytotoxicity (ADCC) via Fc receptors for IgG (CD16); NK-T cells recognize lipid antigens presented by CD1.

T Cells That Activate Macrophages (Th1)

• Secrete cytokines (IFN-γ) that activate M1 macrophages for increased phagocytosis, enhance adhesion via CD40L/CD40 interaction; Th2 cells activate M2 macrophages for tissue repair, and Th17 cells recruit phagocytes and induce antimicrobial proteins.
• T-Regulatory Lymphocytes (Treg cells): Suppress the immune response and maintain tolerance to self-antigens.

Maternal Immunity

• Maternal IgG is actively transported across the placenta to provide protection during the first few postnatal months; levels decline as the neonate's own IgG production increases.
• The fetus's ability to produce antibodies is limited, with IgM being produced but an IgG response being delayed; IgA production is also underdeveloped at birth.