Immunology
-- Natural Defenses
Mhairi Sutherland
Outline
Components of whole blood Blood cells
Differentiation Function
Immune system
Innate Adaptive
Components of whole blood
Serum vs. Plasma
Serum: cell-free liquid, minus the clotting factors Plasma: cell-free liquid with clotting factors in solution (must use an anticoagulant)
Blood cells
Red blood cells
Chickens are nucleated; mammals are not nucleated.
White blood cells Platelets
Blood cell differentiation
The distribution of lymphoid tissues in the body Lymphocytes arise in the stem cells in the bone marrow and then differentiate in the bone marrow (B cells) or thymus (T cells). T and B cells migrate via the peripheral blood to the peripheral/secondary lymphoid organs: lymph nodes, spleen, addendix, Peyer‟s patch etc. Lymphocytes become activated by antigen in these secondary lymphoid tissues (and lymphocytes will recirculate between the blood and these organs until they encounter antigen) The afferent lymphatic vessels carry APC cells from infected tissues to the lymph nodes where they activate T cells
Activated T cells (after they have undergone proliferation and differentiation) leave via the efferent lymphatic vessels
White blood cells (leukocytes)
Granulocytes
Neutrophils Eosinophils Basophils
B cells T cells (many types) NK cells
Lymphocytes
Monocytes/Macrophages Dendritic cells
Divisions of leukocytes
Granulocytes Neutrophils
Band cells
Eosinophils Basophils (segmented or not)
Mononuclear cells Lymphocytes (many types) Monocytes Dendritic cells
Immune system cells
Innate immunity Granulocytes (i.e. neutrophils) Macrophages Dendritic cells Natural killer (NK) cells
Adaptive immunity Lymphocyte
B cells T cells
Cytotoxic T cells (CTLs) Helper T cells (Th)
Memory cells
Neutrophils
Granulocyte Phagocytes Short life span (hours) Very important at “clearing” bacterial infections Cytoplasmic granules
Eosinophils
A granulocyte A cell-killing cells
Orange granules contain toxic compounds
Important in parasitic infections
Basophils
A granulocyte A cell-killing cells
Blue granules contain toxic and inflammatory compounds
Important in allergic reactions
Lymphocytes
Many types; important in both humoral and cell-mediated immunity B-cells produce antibodies T- cells
Cytotoxic T cells Helper T cells
Memory cells NK cells
Monocytes/Macrophage
Monocyte is a young macrophage There are tissuespecific macrophages MØ process antigen, are phagocytes and produce cytokines (esp., IL1 & IL6)
Dendritic cells
Found mainly in lymphoid tissue Function as antigen presenting cells (APC) Most potent stimulator of T-cell response
Cytokines
Low molecular weight, soluble proteins that are produced in response to an antigen and function as chemical messengers for regulating the innate and adaptive immune system Innate immune system
Macrophages and Dendritic cells
Tumor necrosis factor-alpha (TNF-) Interleukin-1 (IL-1) Interleukin-12 (IL-12)
Adaptive immune system
T-lymphocytes
Interleukin-2 (IL-2) Interleukin-4 (IL-4)
Innate vs. adaptive immunity
Innate immunity First line of defense (present in all individuals at all times) Immediate (0 – 4 hours) Non-specific Does not generate lasting protective immunity Adaptive immune response (late: > 96 hours) Is initiated if innate immune response is not adequate (> 4 days) Antigen-specific immunity Generates lasting protective immunity (e.g. Antibodies, memory T-cells)
Immune system divisions
Innate immunity First line of defense Adaptive (acquired) immunity Takes time to develop Humoral immunity (antibody–mediated specific immunity) Cell-mediated immunity (The aspect of the adaptive immune response where antigen-specific T cell have a main role)
Active immunity
Passive or maternal immunity
Injection of Immunoglobulin Absorption of maternal antibodies
Innate immune system
The first line of defense:
Penetration of the epithelial surface of the body by microorganism (e.g. bacteria) Engulfment of microorganism by macrophages, neutrophils, and dendritic cells Release of cytokines and chemokines Inflammation
(Immunology animation: Janeway)
http://www.blink.biz/immunoanimations/#
Killing by granulocytes
Macrophages and neutrophils recognize pathogen by means of cell-surface receptors Example: mannose receptor, CD14 receptor, scavenger receptors, glucan receptor etc. Binding of MØ/neutrophils with pathogen leads to phagocytosis Bound pathogen is surrounded by phagocyte membrane Internalized (phagosome) Killing of pathogen (Phagolysosome*) Oxidative burst (synthesis of hydrogen peroxide (H 2O2)or free oxygen radicals) Acidification Antimicrobial peptides (e.g. defensins) * Phagolysosome = lysosome +phagosome
Phagocytosis
Mannose receptor Scavenger receptor
Lipid mediators Lysosome
Phagosome
LPS receptor (CD14)
Cytokines
The macrophage expresses receptors for many bacterial constituents
Bacteria binding to macrophage receptors initiate the release of cytokines and small lipid mediators of inflammation
Phagolysosome
Macrophages engulf and digest bacteria to which they bind
Cell killing – NK cells
NK cells do not require prior immunization or activation They attach to „target‟ cells Cytotoxic granules are released onto surface of cell Effector proteins penetrate cell membrane and induce programmed cell death
Inflammation
Inflammatory cells migrate into tissue, releasing inflammatory mediators that cause pain
Chemokines
Cytokines
Bacteria trigger macrophages to release cytokines and chemokines
Proteins
Fluids
Vasodilation and increased vascular premeability cause redness, heat, and swelling
Adaptive immune system
Initiated by ingestion of pathogen by an immature dentritic cell
Antigen-presenting cell (APC)
Dendritic cells, macrophages, and B cells
Migrate through lymph to the regional lymph nodes Interact with naive T lymphocytes (present antigen to activate T cells)
Proliferation Differentiation
(Show annimation: Janeway (2001) IV (The immune response – 8-2: Dentritic-cell migration
Differentiation of APC
Dendritic cell Macrophages B cell
Antigen-presenting cells are distributed differentially in the lymph node
Lymphocytes (effector cells of the adaptive immune system)
Antigen receptors with single specificity (T and B cells) Gene re-arrangement
T and B cells have 2 distinct recognition systems for detecting pathogens
T cells - recognize intracellular pathogens (T cell receptors, TCR) B cells – recognize extracellular pathogens (immunoglobins, BCR)
Clonal selection Interaction of antigen and lymphocyte receptor Activation of lymphocyte Differentiation (progeny with identical specificity)
Clonal selection
A single progenitor cell gives rise to a large number of lymphocytes, each with a different specificity
Self antigen Pool of naïve lymphocytes Foreign antigen
Self antigen
Removal of potentially self-reactive immature lymphocytes by clonal deletion
Proliferation and differentiation of activated specific lymphocytes to form a clone of effector cells
Effector cells eliminate antigen
Humoral immune response
Cell-surface immunoglobulin receptors (BCR) detect extracellular pathogens
V region; At binding
Once activated, secrete immunoglobulins as soluble antibodies Variable region (2 identical antigen-binding sites) Constant region (determines how antibody disposes of the pathogen once it is bound)
Fc region
Antibodies
Production of antibodies
Pathogen (virus or bacteria)
Pathogen is internalized and degraded
B cell B cell binds pathogen
Plasma cells
TH 1
MHC II
B cell B cell proliferation
Peptides from the pathogen are presented (MHC II) to the T cell resulting in the activation of the B cell
B cells differentiate into antibody-secreting plasma cells
Produce antibodies against pathogen
Antibody classes
IgM (pentimer) IgG [Ab] IgA (Dimer) IgD IgE
Primary Secondary
Antibody interactions
Antibodies can participate in host defenses in 3 main ways: Neutralization
Opsonization
Ab bind and neutralize bacterial toxins, bacteria and virus particles – preventing interaction with host cells Ingestion by macrophages
Allows recognition by phagocytes or NK cells (antibodydependent cell mediated cytotoxicity, ADCC) Ingestion or killing Activation of complement system Ingestion by phagocytes
Complement activation
Antigen recognition by T-cells
T cells detect presence of intracellular pathogens
T cells receptors Peptide fragments Major histocompatibility complex (MHC)
MHC I (cytotoxic T cells /CD8) MHC II (T helper (1 and 2)/ CD4)
Cell death
Antigen recognition by T-cells
Cytotoxic T cells recognize antigen presented by MHC I and kills the cell
Kills
TH1 cells recognize antigen presented by MHC II and activates macrophages
Activates
TH2 cells recognize antigen presented by MHC II and activates B cells
Activates
MHC I
Cytotoxic T cell
Virusinfected cell
TH 1
MHC II
TH 2
Macrophage
MHC II
B cell
Dead intracellular bacteria
Apoptotic cell
Anti-toxin antibodies
Th1 and Th2 response
To Th1 Th2
INF-
IL-4 IL-10
NK
IL-2
IL-5
TNF-
IL-8
MØ
IL-6
IL-13
Tc
B cell PMN