Chapter 15: The Adaptive Immune Response

General Characteristics of the Adaptive Immune Response Involves specialized white blood cells known as lymphocytes Response is highly specific (molecular specificity) Response generates memory Can discriminate between self and non-self (tolerance)

Immune cells are born in bone marrow and thymus gland Migrate to lymphoid tissue Body- circulatory system Cells sample the environment of the body In the secondary lymph organs, B-cells, T-cells, and Dendritic cells exchange information. T-cells activate B-cells into plasma cells that make antibodies. T-cells also activate Dendritic cells and Macrophages to kill cells. T-cells also inactivate cells that present antigens from self – healthy body cells (prevents autoimmunity) Cells circulate looking for the invader labeled with antibodies Antibody on microbe NKcell

Hematopoietic stem cell (in bone marrow) Common lymphoid progenitor Lymphoblasts B cellT cell Erythroblast Megakaryoblast Common myeloid progenitor Monoblast MyeloblastPutative mast cell precursor LymphocytesRed blood cell (erythrocyte) Platelets (thrombocytes) Megakaryocyte Mast cell White blood cells (leukocytes) Dendritic cell Macrophage Natural killer (NK) cell Monocyte Granulocytes EosinophilNeutrophil Basophil Self- renewal From Last week: Innate and Adaptive immune cells—how they relate

The Cells of the Immune System Four types of leukocytes (white blood cells) –Granulocytes contain cytoplasmic granules Neutrophils engulf and destroy Basophils involved in allergic reactions, inflammation (Mast cells) Eosinophils fight parasitic worms –Also involved in allergic reactions Common lymphoid progenitor Lymphoblasts B cellT cell Erythroblast Megakaryoblast Common myeloid progenitor MonoblastMyeloblastPutative mast cell precursor Lymphocytes Red blood cell (erythrocyte) Platelets (thrombocytes) Megakaryocyte Mast cell White blood cells (leukocytes) Dendritic cell Macrophage Natural killer (NK) cell Monocyte Granulocytes EosinophilNeutrophilBasophil Self- renewal

The Cells of the Immune System Four types of leukocytes (cont…) –Mononuclear Phagocytes monocytes (circulate in blood) and develop into Macrophages and Dendritic cells –Dendritic Cells Sentinel cells, function as “scouts” Engulf material in tissues, bring it to cells of adaptive immune system for “inspection” Common myeloid progenitor Monoblast Dendritic cellMacrophage Monocyte Self- renewal

Four types of leukocytes (cont…) Lymphocytes Responsible for adaptive immunity B cells, T cells highly specific in recognition of antigen Generally reside in lymph nodes, lymphatic tissues Natural killer (NK) cells lack specificity Common lymphoid progenitor Lymphoblasts B cellT cell Lymphocytes Natural killer (NK) cell

Lymphocytes are responsible for the adaptive immune response

Anatomy of the Lymphoid System Primary Lymphoid Organs –where the cells are made –Bone marrow and thymus Lymphatic Vessels— transport cells, and receive fluid from tissue— lymph Secondary lymphoid Organs- where cells get together and exchange antigen information –Lymph nodes, spleen, tonsils, peyer’s patches, MALT and SALT SALT (skin associated lymph tissue) MALT (mucosal associated lymph tissue) and

Lumen of intestine Antigens Absorptive epithelial cell M cell Dendritic cell Area where B cells gather Lymphatic vessels that drain to local lymph nodes Peyer’s patch Area where T cells gather Macrophage Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Peyer’s Patch is example of secondary lymphoid organ

Lymphatic vessel Excess tissue fluid becomes lymph Tissue fluid Blood flow VenuleArteriole Filtration Absorption Capillary Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Lympth nodes—where the cells communicate Lymph vessels take in fluid from tissue

What promotes an immune response? Antigens –Any molecule that reacts with antibody, B cell receptor or T cell receptor –Composition is usually proteins or polysaccharides –Foreign substance with MW of 10,000 daltons –Examples of antigens: bacterial capsules, cell walls, flagella, toxins of bacteria

Small molecules are not recognized as antigens until bound to another

Players of the Adaptive Immune Response Activation Proliferation and differentiation Effector action and consequence Innate immunity Dendritic cell Naive cytotoxic T cell Infected “self” cell undergoes apoptosis Adaptive immunity (cell-mediated) Adaptive immunity (humoral) AntibodiesAntibodies bind antigen Naive B cell Plasma cells Naive helper T cell Infected “self” cell Macrophage with increased killing power Macrophage that has engulfed invaders Activates T cells that bind antigens representing “danger” Produce antibodies Deliver cytokines Deliver “death packages” T c cells T H cells Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. activated

Bacterial cell Antibodies Epitopes (antigens) Epitopes (antigens) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Antibodies bind antigens

Plasma membrane B-cell receptor (BCR) T-cell receptor (TCR) Antigen Antigen-binding site B cellT cell Antigen-binding site CD marker Antigen Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Variable region Constant region (c) Heavy chain Antigen- binding site Light chain Fab region Fc region (a)(b) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Structure of an antibody

Selected B cell receives confirmation from a specific T H cell that a response is warranted (not shown here; process is illustrated in figure 15.11) Hematopoietic stem cell Antigen X B cell ZB cell Y B cell X recognizing antigen X B cell W Antibodies: These neutralize the invader and tag it for destruction. Plasma cells (effector B cells): These descendants of activated B cells secrete large quantities of antibody molecules that bind to antigen X. Memory B cells: These long-lived descendants of activated B cells recognize antigen X when it is encountered again. Activated B cells: These cell scan proliferate because their B-cell receptors are bound to antigen X and the cells have received required signals from T H cells. Activation Proliferation and differentiation Effector action Naive B cells: Each cell is programmed to recognize a specific epitope on an antigen; B-cell receptors guide that recognition. Immature B cells: As these develop, a functionally limitless assortment of B-cell receptors is randomly generated. Development Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. How are B cells activated?

That’s great. But, how do the cells know what is foreign and what is self? (self vs. non-self recognition) Self markers also known as MHC markers MHC (major histocompatibility complex) MHC Class I-produced by all body cells (signal SELF—material from inside the cell) MHC Class II-produced by dendritic cells, B cells, and macrophages (PRESENT NON-SELF— potential invader—material outside the cell) –These cells are also called antigen presenting cells (APCs)

B cell degrades antigen into peptide fragments. B-cell receptor binds to antigen. B-cell receptor 21 Endosome T-cell receptor Peptide fragments are presented on MHC class II molecules. No T H cell recognizes antigen fragment; B cell becomes anergic. B cell internalizes antigen. T H cell recognizes antigen fragment and activates B cell. Cytokine delivery 4 Antigen fragment MHC class II molecule Harmless antigen presented. Microbial antigen presented. Antigen 5b 5a 3 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. B cell activation by Helper T cell Anergic cells undergo cell death- elliminated

T-independent antigens activate B-cells without T cells

Opsonization by C3b Inflammatory response Lysis of foreign cells Complement system protein Complement System Activation Bacterium Phagocyte Opsonization Neutralization Virus Toxin Infected “self” cell Antibody-Dependent Cellular Cytotoxicity (ADCC) Natural killer cell Cross-Linking Bacterium Flagellum Bacterium Immobilization and Prevention of Adherence Kills cell What can happen when antibody binds antigen.

There are 5 classes of antibodies IgM IgG IgA IgE IgD

Months Maternal IgG Total IgG 0 Before birthInfant ageBirth Infant IgG Percent of normal average adult level of IgG Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Fig. 15.9

Naïve B cells produce IgM, then IgG antibodies

Secondary response Primary response Ag IgM IgG Time after antigen (Ag) injection Months Days Months Days IgG Concentration of antibody Ag Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Primary and secondary response to antigen

More about T cells —distinguish self from non-self Have own T cell receptor (TCR) Do not make antibodies Must recognize MHC markers which “present” antigen

T cells differ from B cells Must use MHC markers on host cells to recognize antigens

T C cells recognize antigens presented on MHC class I molecules. All nucleated cells present endogenous antigens on MHC class I molecules. Endogenous antigen MHC class I molecule CD8 T-cell receptor CD4 MHC class II molecule Exogenous antigen T H cells recognize antigens presented on MHC class II molecules. B cells and macrophages present exogenous antigens on MHC class II molecules. T-cell receptor (b) (a) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

B cell degrades antigen into peptide fragments. B-cell receptor binds to antigen. B-cell receptor 21 Endosome T-cell receptor Peptide fragments are presented on MHC class II molecules. No T H cell recognizes antigen fragment; B cell becomes anergic. B cell internalizes antigen. T H cell recognizes antigen fragment and activates B cell. Cytokine delivery 4 Antigen fragment MHC class II molecule Harmless antigen presented. Microbial antigen presented. Antigen 5b 5a 3 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Effector function of Helper-T cells

Effector functions of Cytotoxic T cells

Natural Killer Cells…lymphocyte but not a T cell

Activation of T Cells Dendritic cells in the tissue collect particulate and soluble antigen and then travel to the secondary lymphoid tissues. Dendritic cells presenting microbial peptides produce co-stimulatory molecules. Naive T cells that recognize antigen presented by dendritic cells expressing co-stimulatory molecules can become activated. Lymphoid organ MHC class II molecule MHC class I molecule Co-stimulatory molecule T-cell receptor CD4CD8 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Figure 15.20

Activation of T Cells Dendritic cells in the tissue collect particulate and soluble antigen and then travel to the secondary lymphoid tissues. Dendritic cells presenting “self” peptides or other harmless material do not produce co-stimulatory molecules. Dendritic cells presenting microbial peptides produce co-stimulatory molecules. Naive T cells that recognize antigen presented by dendritic cells expressing co-stimulatory molecules can become activated. Naïve T cells that recognize antigen presented By dendritic cells not expressing co-stimulatory molecules become anergic. Activated T cells proliferate and differentiate. Lymphoid organ MHC class II molecule MHC class I molecule Co-stimulatory molecule T-cell receptor CD4CD8 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Figure 15.20

Activation of T Cells Dendritic cells in the tissue collect particulate and soluble antigen and then travel to the secondary lymphoid tissues. Dendritic cells presenting “self” peptides or other harmless material do not produce co-stimulatory molecules. Dendritic cells presenting microbial peptides produce co-stimulatory molecules. Naive T cells that recognize antigen presented by dendritic cells expressing co-stimulatory molecules can become activated. Naïve T cells that recognize antigen presented By dendritic cells not expressing co-stimulatory molecules become anergic. Activated T cells proliferate and differentiate. Anergic T cells cannot respond and eventually undergo apoptosis. Lymphoid organ MHC class II molecule MHC class I molecule Co-stimulatory molecule T-cell receptor CD4CD8 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Figure 15.20

Antibody dependent cell mediated cytotoxicity

Dendritic cell (gathers antigen for presentation to naive T cells) Primary lymphoid organs Immature B cells (bone marrow) Immature T cells (thymus) Secondary lymphoid organs Naïve B cells Naïve cytotoxic T cells (CD8) Naïve helper T cells(CD4) Macrophage (engulfs and destroys invaders; limited killing powers) Infected “self” cell (harbors antigen within the cell) Extracellular antigen Dendritic cells that have gathered antigen in the periphery present it to naïve T cells; co-stimulatory molecules are expressed if the material collected represents “danger.” Peripheral tissues T C cells T H cells Memory cytotoxic T cells Memory helper T cells T H cells activate B cells that present specific antigen Plasma cells secrete antibodies. Antibodies (tag extracellular antigen for removal ) Memory B cells T H cells activate macrophages that present antigen via MHC class II molecules; also produce cytokines that determine other responses. T C cells induce apoptosis in infected “self” cells; also produce cytokines that alert neighboring cells. Activated macrophage (engulfs and destroys invaders; enhanced killing powers ) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Figure 15.24