The Immune System: Innate and Adaptive Body Defenses: Part B 21 The Immune System: Innate and Adaptive Body Defenses: Part B

Antibodies Immunoglobulins—gamma globulin portion of blood Proteins secreted by plasma cells Capable of binding specifically with antigen detected by B cells

Basic Antibody Structure T-or Y-shaped monomer of four looping linked polypeptide chains Two identical heavy (H) chains and two identical light (L) chains Variable (V) regions of each arm combine to form two identical antigen-binding sites

Basic Antibody Structure Constant (C) region of stem determines The antibody class (IgM, IgA, IgD, IgG, or IgE) The cells and chemicals that the antibody can bind to How the antibody class functions in antigen elimination

Antigen-binding site Hinge region Stem region (a) Heavy chain variable region Hinge region Heavy chain constant region Stem region Light chain variable region Light chain constant region Disulfide bond (a) Figure 21.14a

Classes of Antibodies IgM IgA (secretory IgA) A pentamer; first antibody released Potent agglutinating agent Readily fixes and activates complement IgA (secretory IgA) Monomer or dimer; in mucus and other secretions Helps prevent entry of pathogens

Table 21.3

Classes of Antibodies IgD IgG Monomer attached to the surface of B cells Functions as a B cell receptor IgG Monomer; 75–85% of antibodies in plasma From secondary and late primary responses Crosses the placental barrier

Classes of Antibodies IgE Monomer active in some allergies and parasitic infections Causes mast cells and basophils to release histamine

Table 21.3

Generating Antibody Diversity Billions of antibodies result from somatic recombination of gene segments Hypervariable regions of some genes increase antibody variation through somatic mutations Each plasma cell can switch the type of H chain produced, making an antibody of a different class

Antibodies inactivate and tag antigens Antibody Targets Antibodies inactivate and tag antigens Form antigen-antibody (immune) complexes Defensive mechanisms used by antibodies Neutralization and agglutination (the two most important) Precipitation and complement fixation

Neutralization Simplest mechanism Antibodies block specific sites on viruses or bacterial exotoxins Prevent these antigens from binding to receptors on tissue cells Antigen-antibody complexes undergo phagocytosis

Cross-linked antigen-antibody complexes agglutinate Agglutination Antibodies bind the same determinant on more than one cell-bound antigen Cross-linked antigen-antibody complexes agglutinate Example: clumping of mismatched blood cells

Precipitation Soluble molecules are cross-linked Complexes precipitate and are subject to phagocytosis

Complement Fixation and Activation Main antibody defense against cellular antigens Several antibodies bind close together on a cellular antigen Their complement-binding sites trigger complement fixation into the cell’s surface Complement triggers cell lysis

Complement Fixation and Activation Activated complement functions Amplifies the inflammatory response Opsonization Enlists more and more defensive elements

(cell-bound antigens) Adaptive defenses Humoral immunity Antigen-antibody complex Antigen Antibody Inactivates by Fixes and activates Neutralization (masks dangerous parts of bacterial exotoxins; viruses) Agglutination (cell-bound antigens) Precipitation (soluble antigens) Complement Enhances Enhances Leads to Phagocytosis Inflammation Cell lysis Chemotaxis Histamine release Figure 21.15

Cell-Mediated Immune Response T cells provide defense against intracellular antigens Two types of surface receptors of T cells T cell antigen receptors Cell differentiation glycoproteins CD4 or CD8 Play a role in T cell interactions with other cells

Cell-Mediated Immune Response Major types of T cells CD4 cells become helper T cells (TH) when activated CD8 cells become cytotoxic T cells (TC) that destroy cells harboring foreign antigens Other types of T cells Regulatory T cells (TREG) Memory T cells

(or regulatory T cells) Adaptive defenses Cellular immunity Immature lymphocyte Red bone marrow T cell receptor T cell receptor Maturation Class II MHC protein Class I MHC protein CD4 cell CD8 cell Thymus Activation Activation APC (dendritic cell) Memory cells APC (dendritic cell) CD4 CD8 Lymphoid tissues and organs Effector cells Helper T cells (or regulatory T cells) Cytotoxic T cells Blood plasma Figure 21.16

Comparison of Humoral and Cell-Mediated Response Antibodies of the humoral response The simplest ammunition of the immune response Targets Bacteria and molecules in extracellular environments (body secretions, tissue fluid, blood, and lymph)

Comparison of Humoral and Cell-Mediated Response T cells of the cell-mediated response Recognize and respond only to processed fragments of antigen displayed on the surface of body cells Targets Body cells infected by viruses or bacteria Abnormal or cancerous cells Cells of infused or transplanted foreign tissue

T cells must simultaneously recognize Antigen Recognition Immunocompetent T cells are activated when their surface receptors bind to a recognized antigen (nonself) T cells must simultaneously recognize Nonself (the antigen) Self (an MHC protein of a body cell)

Two types of MHC proteins are important to T cell activation Class I MHC proteins - displayed by all cells except RBCs Class II MHC proteins – displayed by APCs (dendritic cells, macrophages and B cells) Both types are synthesized at the ER and bind to peptide fragments

Class I MHC Proteins Bind with fragment of a protein synthesized in the cell (endogenous antigen) Endogenous antigen is a self-antigen in a normal cell; a nonself antigen in an infected or abnormal cell Informs cytotoxic T cells of the presence of microorganisms hiding in cells (cytotoxic T cells ignore displayed self-antigens)

Cytoplasm of any tissue cell Cisternae of endoplasmic reticulum (ER) 2 Endogenous antigen peptides enter ER via transport protein. Endogenous antigen is degraded by protease. 1 Endogenous antigen peptide is loaded onto class I MHC protein. 3 Endogenous antigen— self-protein or foreign (viral or cancer) protein Loaded MHC protein migrates in vesicle to the plasma membrane, where it displays the antigenic peptide. 4 Transport protein (ATPase) Antigenic peptide Plasma membrane of a tissue cell Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Figure 21.17a

Class II MHC Proteins Bind with fragments of exogenous antigens that have been engulfed and broken down in a phagolysosome Recognized by helper T cells

Class II MHC is synthesized in ER. Cytoplasm of APC 1a Class II MHC is synthesized in ER. Invariant chain prevents class II MHC from binding to peptides in the ER. 3 Vesicle fuses with phagolysosome. Invariant chain is removed, and antigen is loaded. 2a Class II MHC is exported from ER in a vesicle. Cisternae of endoplasmic reticulum (ER) Phagosome 1b Extracellular antigen (bacterium) is phagocytized. 4 Vesicle with loaded MHC migrates to the plasma membrane. Phagosome merges with lysosome, forming a phagolysosome; antigen is degraded. 2b Lysosome Extracellular antigen Plasma membrane of APC Antigenic peptide Extracellular fluid (b) Exogenous antigens are processed and displayed on class II MHC of antigen-presenting cells (APCs). Figure 21.17b

T cell activation is a two-step process APCs (most often a dendritic cell) migrate to lymph nodes and other lymphoid tissues to present their antigens to T cells T cell activation is a two-step process Antigen binding Co-stimulation

T Cell Activation: Antigen Binding CD4 and CD8 cells bind to different classes of MHC proteins (MHC restriction) CD4 cells bind to antigen linked to class II MHC proteins of APCs CD8 cells are activated by antigen fragments linked to class I MHC of APCs

T Cell Activation: Antigen Binding Dendritic cells are able to obtain other cells’ endogenous antigens by Engulfing dying virus-infected or tumor cells Importing antigens through temporary gap junctions with infected cells Dendritic cells then display the endogenous antigens on both class I and class II MHCs

T Cell Activation: Antigen Binding TCR that recognizes the nonself-self complex is linked to multiple intracellular signaling pathways Other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition) Antigen binding stimulates the T cell, but co-stimulation is required before proliferation can occur

Adaptive defenses Cellular immunity Viral antigen Dendritic cell engulfs an exogenous antigen, processes it, and displays its fragments on class II MHC protein. 1 Class lI MHC protein displaying processed viral antigen Dendritic cell CD4 protein Immunocompetent CD4 cell recognizes antigen-MHC complex. Both TCR and CD4 protein bind to antigen-MHC complex. 2 T cell receptor (TCR) Immunocom- petent CD4 T cell Clone formation CD4 cells are activated, proliferate (clone), and become memory and effector cells. 3 Helper T memory cell Activated helper T cells Figure 21.18

T Cell Activation: Co-Stimulation Requires T cell binding to other surface receptors on an APC Cytokines (interleukin 1 and 2 from APCs or T cells) trigger proliferation and differentiation of activated T cell

T Cell Activation: Co-Stimulation Without co-stimulation, anergy occurs T cells Become tolerant to that antigen Are unable to divide Do not secrete cytokines

T Cell Activation: Co-Stimulation T cells that are activated Enlarge, proliferate, and form clones Differentiate and perform functions according to their T cell class

Include interleukins and interferons Cytokines Mediate cell development, differentiation, and responses in the immune system Include interleukins and interferons Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to Release interleukin 2 (IL-2) Synthesize more IL-2 receptors

Other cytokines amplify and regulate innate and adaptive responses IL-2 is a key growth factor, acting on cells that release it and other T cells Encourages activated T cells to divide rapidly Used therapeutically to treat melanoma and kidney cancers Other cytokines amplify and regulate innate and adaptive responses

Roles of Helper T(TH) Cells Play a central role in the adaptive immune response Once primed by APC presentation of antigen, they Help activate T and B cells Induce T and B cell proliferation Activate macrophages and recruit other immune cells Without TH, there is no immune response

Helper T Cells Interact directly with B cells displaying antigen fragments bound to MHC II receptors Stimulate B cells to divide more rapidly and begin antibody formation B cells may be activated without TH cells by binding to T cell–independent antigens Most antigens require TH co-stimulation to activate B cells

TH cell help in humoral immunity Activated helper T cell TH cell binds with the self-nonself complexes of a B cell that has encountered its antigen and is displaying it on MHC II on its surface. 1 T cell receptor (TCR) Helper T cell CD4 protein MHC II protein of B cell displaying processed antigen TH cell releases interleukins as co-stimulatory signals to complete B cell activation. 2 IL- 4 and other cytokines B cell (being activated) (a) Figure 21.19a

Roles of Cytotoxic T(TC) Cells Directly attack and kill other cells Activated TC cells circulate in blood and lymph and lymphoid organs in search of body cells displaying antigen they recognize

Roles of Cytotoxic T(TC) Cells Targets Virus-infected cells Cells with intracellular bacteria or parasites Cancer cells Foreign cells (transfusions or transplants)

Cytotoxic T Cells Bind to a self-nonself complex Can destroy all infected or abnormal cells