Adaptive Immunity An introduction Immunity Innate immunity defenses

Adaptive Immunity An introduction

Immunity • Innate immunity: defenses against any pathogen • • Macrophages Dendritic cells (DCs) NK cells Paneth cells • Adaptive immunity: induced resistance to a specific pathogen • Rarely cross-protective

Humoral vs cell-mediated Humoral • Antibody-mediated (think B cells) • Control extracellular pathogens Cell-mediated • T cell-mediated • Control intracellular pathogens

Figure 17. 8 Differentiation of T cells and B cells. Stem cells develop in bone marrow or in fetal liver Stem cell (diverges into two cell lines) Red bone marrow of adults Thymus Differentiate to B cells in adult red bone marrow Differentiate to T cells in thymus B cell T cell Migrate to lymphoid tissue such as spleen, but especially lymph nodes

The Nature of Antigens • Antigen (Ag): a substance that causes the body to produce specific antibodies or sensitized T cells • Antibodies (Ab) interact with epitopes, or antigenic determinants • Hapten: antigen is combined with carrier molecules

Figure 17. 1 Epitopes (antigenic determinants). Antibody A Epitopes (antigenic determinants) on antigen Antigens: components of cell wall Binding sites Bacterial cell Antibody B

The Nature of Antigens • Antigen (Ag): a substance that causes the body to produce specific antibodies or sensitized T cells • Antibodies (Ab) interact with epitopes, or antigenic determinants • Hapten: antigen is combined with carrier molecules

Figure 17. 2 Haptens. Hapten molecules Carrier molecule Hapten-carrier conjugate

The Nature of Antibodies • Antibodies are soluble B cell receptors • B cells that recognize an epitope of an antigen on a pathogen do so through the B cell receptor • If that B cell develops into a plasma cell, the antibodies will have an identical specificity • Globular proteins called immunoglobulins • The number of antigen-binding sites determines valence B cell receptor

Figure 17. 3 ab The structure of a typical antibody molecule. vy ea ai ch Li H Antigenbinding site n gh tc ha in Fc (stem) region Hinge region Antibody molecule Epitope (antigenic determinant) Antigenbinding site Enlarged antigen-binding site bound to an epitope

Figure 17. 3 c The structure of a typical antibody molecule. Antibodies Antibody molecules shown by atomic force microscopy (see page 64)

Ig. G Antibodies Monomer 80% of serum antibodies Fix complement In blood, lymph, and intestine Cross placenta Enhance phagocytosis; neutralize toxins and viruses; protect fetus and newborn • Half-life = 23 days • • •

Ig. M Antibodies • • • Pentamer 5– 10% of serum antibodies Fix complement In blood, in lymph, and on B cells Agglutinate microbes; first Ab produced in response to infection Half-life = 5 days Disulfide bond J chain

Ig. A Antibodies • • • Dimer 10– 15% of serum antibodies In secretions Mucosal protection Half-life = 6 days J chain Secretory component

Ig. D Antibodies • • • Monomer 0. 2% of serum antibodies In blood, in lymph, and on B cells On B cells, initiate immune response Half-life = 3 days

Ig. E Antibodies • • • Monomer 0. 002% of serum antibodies On mast cells, on basophils, and in blood Allergic reactions; lysis of parasitic worms Half-life = 2 days

Activation of B Cells • Major histocompatibility complex (MHC) expressed on mammalian cells • T-dependent antigens • Ag presented with (self) MHC to TH cell • TH cell produces cytokines that activate the B cell • T-independent antigens • Stimulate the B cell to make Abs

Figure 17. 6 T-independent antigens. Polysaccharide (T-independent antigen) Epitopes B cell receptors

Activation of B Cells • Major histocompatibility complex (MHC) expressed on mammalian cells. Present extracellular antigens to immune cells • T-dependent antigens • Ag presented with (self) MHC to TH cell • TH cell produces cytokines that activate the B cell • T-independent antigens • Stimulate the B cell to make Abs

Figure 17. 4 Activation of B cells to produce antibodies. Extracellular antigens Ag fragment MHC class II with Ag fragment displayed on surface Antibodies B cell Immunoglobulin receptors coating B cell surface Immunoglobulin receptors on B cell surface recognize and attach to antigen, which is then internalized and processed. Within the B cell a fragment of the antigen combines with MHC class II. Plasma cell TH cell Cytokines MHC class II–antigenfragment complex is displayed on B cell surface. Receptor on the T helper cell (TH) recognizes complex of MHC class II and antigen fragment and is activated— producing cytokines, which activate the B cell. The TH cell has been previously activated by an antigen displayed on a dendritic cell (see Figure 17. 10). B cell is activated by cytokines and begins clonal expansion. Some of the progeny become antibody-producing plasma cells.

Figure 17. 5 Clonal selection and differentiation of B cells. Stem cells differentiate into mature B cells, each bearing surface immunoglobulins against a specific antigen. Antigen B cell III complexes with its specific antigen and proliferates. B cells I II IV Memory cells Some B cells proliferate into longlived memory cells, which at a later date can be stimulated to become antibody-producing plasma cells. See Figure 17. Other B cells proliferate into antibody-producing plasma cells. Plasma cells secrete antibodies into circulation. Antigens in circulation now attached to circulating antibodies Cardiovascular system

Figure 17. 7 The results of antigen–antibody binding. Agglutination (see also Figure 18. 5) Reduces number of infectious units to be dealt with PROCTECTIVE of complement MECHANISM OF BINDING Activation (see also Figure 16. 9) ANTIBODIES Causes inflammation and TO ANTIGENS cell lysis Complement Bacteria Bacterium Antibody-dependent cell-mediated cytotoxicity Opsonization (see also Figure 16. 9) (see also Figure 17. 16) Antibodies attached to target cell cause destruction by macrophages, eosinophils, and NK cells Coating antigen with antibody enhances phagocytosis Phagocyte Epitopes Neutralization Blocks adhesion of bacteria and viruses to mucosa Lysis Large target cell (parasite) (see also Figure 18. 9) Virus Bacterium Eosinophil Toxin Blocks attachment of toxin Perforin and lytic enzymes

T Cells and Cellular Immunity • T cells mature in the thymus • Thymic selection eliminates many immature T cells

Table 17. 2 Principal Cells That Function in Cell-Mediated Immunity

T Cells and Cellular Immunity • T cells respond to Ag by T-cell receptors (TCRs) • T cells require antigen-presenting cells (APCs) • Pathogens entering the gastrointestinal or respiratory tracts pass through: • M (microfold) cells over • Peyer’s patches, which contain APCs

Figure 17. 9 M cells. (a) M cell on Peyer’s patch. Note the tips of the closely packed microvilli on the surrounding epithelial cells. Antigen M cell Microvilli on epithelial cell TH cell Pocket B cells Macrophage Epithelial cell (b) M cells facilitate contact between the antigens passing through the intestinal tract and cells of the body’s immune system.

T Helper Cells • CD 4+ or TH cells • TCRs recognize Ags and MHC II on APC • TLRs are a costimulatory signal on APC and TH • TH cells produce cytokines and differentiate into: • • TH 1 cells TH 2 cells TH 17 cells Memory cells

T Helper Cells • TH 1 produce IFN-g which activates cells related to cell-mediated immunity, macrophages, and Abs • TH 2 activate eosinophils and B cells to produce Ig. E • TH 17 stimulate the innate immune system. Also involved in autoimmune diseases

Figure 17. 11 Lineage of effector T helper cell classes and pathogens targeted. Antibodies B cell TH 1 cells TH 2 cells Recruits neutrophils; provides protection against extracellular bacteria and fungi TH 17 cells TH cell IL-17 IL-4 TH 17 cells Cell-mediated immunity; control of intracellular pathogens, delayed hypersensitivity reactions (page 535); stimulates macrophages. IFN-g TH 1 cells TH 2 cells Fungi Extracellular bacteria Neutrophil Macrophage Mast cell Basophil Eosinophil Intracellular bacteria and protozoa Important in allergic responses, especially by production of Ig. E Stimulates activity of eosinophils to control extracellular parasites such as helminths (see ADCC, page 495). Helminth

Figure 17. 10 Activation of CD 4+T helper cells. An APC encounters and ingests a microorganism. The antigen is enzymatically processed into short peptides, which combine with MHC class II molecules and are displayed on the surface of the APC. A receptor (TCR) on the surface of the CD 4+T helper cell (TH cell) binds to the MHC–antigen complex. If this includes a Toll-like receptor, the APC is stimulated to secrete a costimulatory molecule. These two signals activate the TH cell, which produces cytokines. TH cell receptor (TCR) APC (dendritic cell) The cytokines cause the TH cell (which recognizes a dendritic cell that is producing costimulatory molecules) to become activated. T helper cell Antigen Microorganism carrying antigens Antigen fragment (short peptides) Complex of MHC class II molecule and antigen fragment Cytokines Costimulatory molecule, (required to activate T cells that have not previously encountered antigen)

T Cytotoxic Cells • CD 8+ or TC cells • Target cells are self-cells carrying endogenous antigens • Activated into cytotoxic T lymphocytes (CTLs) • CTLs recognize Ag + MHC I • Induce apoptosis in target cell • CTL releases perforin and granzymes

Figure 17. 12 Killing of virus-infected target cell by cytotoxic T lymphocyte. Processed antigen presented with MHC class I Processed antigen T cell receptors MHC class I Virus-infected cell (example of endogenous antigen) A normal cell will not trigger a response by a cytotoxic T lymphocyte (CTL), but a virusinfected cell (shown here) or a cancer cell produces abnormal endogenous antigens. Virus-infected cell Infected target cell is lysed Cytotoxic T lymphocyte (CTL) The abnormal antigen is presented on the cell surface in association with MHC class I molecules. CD 8+T cells with receptors for the antigen are transformed into CTLs. CTL The CTL induces destruction of the virus-infected cell by apoptosis.

Figure 17. 13 Apoptosis.

Figure 17. 20 The dual nature of the adaptive immune system. Humoral (antibody-mediated) immune system Cellular (cell-mediated) immune system Control of freely circulating pathogens Control of intracellular pathogens Intracellular antigens are expressed on the surface of an APC, a cell infected by a virus, a bacterium, or a parasite. Extracellular antigens A B cell binds to the antigen for which it is specific. A T-dependent B cell requires cooperation with a T helper (TH) cell. T cell Cytokines activate T helper (TH) cell. Cytokines activate macrophage. Cytokines B cell The B cell, often with stimulation by cytokines from a TH cell, differentiates into a plasma cell. Some B cells become memory cells. Cytokines from the T H cell transform B cells into antibody-producing plasma cells. Plasma cells proliferate and produce antibodies against the antigen. Activation of macrophage (enhanced phagocytic activity). TH cell Cytotoxic T lymphocyte Plasma cell A T cell binds to MHC–antigen complexes on the surface of the infected cell, activating the T cell (with its cytokine receptors). Memory cell Some T and B cells differentiate into memory cells that respond rapidly to any secondary encounter with an antigen. Lysed target cell The CD 8+T cell becomes a cytotoxic T lymphocyte (CTL) able to induce apoptosis of the target cell.

T Regulatory Cells • Treg cells § CD 4 and CD 25 on surface • Suppress T cells against self

Antigen-Presenting Cells • Digest antigen • Ag fragments on APC surface with MHC • B cells • Dendritic cells • Activated macrophages

Figure 17. 14 A dendritic cell.

Figure 17. 15 Activated macrophages Resting (inactive) macrophage

Natural Killer (NK) Cells • Granular leukocytes destroy cells that don’t express MHC I • Kill virus-infected and tumor cells • Attack parasites

ADCC • Antibody-dependent cell-mediated cytotoxicity

Figure 17. 16 Antibody-dependent cell-mediated cytotoxicity (ADCC). KEY Macrophage Cytotoxic cytokines Lytic enzymes Perforin enzymes Eosinophil Extracellular damage Fc region Large parasite Epitope Antibody (a) Organisms, such as many parasites, that are too large for ingestion by phagocytic cells must be attacked externally. Fluke Eosinophils (b) Eosinophils adhering to the larval stage of a parasitic fluke

Figure 17. 16 a Antibody-dependent cell-mediated cytotoxicity (ADCC). KEY Macrophage Cytotoxic cytokines Lytic enzymes Perforin enzymes Eosinophil Extracellular damage Fc region Large parasite Epitope Antibody (a) Organisms, such as many parasites, that are too large for ingestion by phagocytic cells must be attacked externally.

Figure 17. 16 b Antibody-dependent cell-mediated cytotoxicity (ADCC). Eosinophils Fluke Eosinophils adhering to the larval stage of a parasitic fluke.

Cells Communicate via Cytokines Cytokine Representative Activity Interleukin-1 (IL-1) Stimulates TH cells in presence of antigens; attracts phagocytes Interleukin-2 (IL-2) Proliferation of antigen-stimulated CD 4+ T helper cells, proliferation and differentiation of B cells; activation of CD 8+ T cells and NK cells Interleukin-12 (IL-12) Inhibits humoral immunity; activates TH 1 cellular immunity

Cells Communicate via Cytokines Cytokine Representative Activity Chemokines Induce the migration of leukocytes TNF-α Promotes inflammation Hematopoietic cytokines Influence differentiation of blood stem cells IFN- and IFN- Response to viral infection; interfere with protein synthesis IFN- Stimulates macrophage activity

Immunological Memory • Antibody titer is the amount of Ab in serum • Primary response occurs after initial contact with Ag • Secondary (memory or anamnestic) response occurs after second exposure

Figure 17. 17 The primary and secondary immune responses to an antigen (T cell-dependent). Antibody titer in serum Ig. G Ig. M Initial exposure to antigen Time (days) Second exposure to antigen

Types of Adaptive Immunity • Naturally acquired active immunity • Resulting from infection • Naturally acquired passive immunity • Transplacental or via colostrum/breastmilk • Artificially acquired active immunity • Injection of Ag (vaccination) • Artificially acquired passive immunity • Injection of Ab

Terminology of Adaptive Immunity • • Serology: the study of reactions between antibodies and antigens Antiserum: the generic term for serum because it contains Ab Globulins: serum proteins Immunoglobulins: antibodies