Immune Tox C&D 8 Flashcards
12-2 Organization of the Immune System: Lymphoid Tissue
Primary Lymphoid Organs
Classification:
Primary
Lymphoid Organs:
Bone Marrow
Thymus
12-2 Organization of the Immune System: Lymphoid Tissue
Secondary Lymphoid Organs
Classification:
Secondary
Lymphoid Organs: Spleen Lymph nodes Peyer's patches Skin-associated lymphoid tissue (SALT) Mucosal lamina propria (MALT) Gut-associated lymphoid tissue (GALT) Bronchial-associated lymphoid tissue (BALT) Nasal-associated lymphoid tissue (NALT) Cells lining the genitourinary tract
12-2 Organization of the Immune System: Lymphoid Tissue
Tertiary Lymphoid Organs
Classification:
Tertiary
Lymphoid Organs:
Lymphoid neogenesis in nonlymphoid organs
12-3 Innate vs Acquired Immunity
Characteristic:
Cell involved
Characteristic:
Cell involved
Innate Immunity: Neutrophils Macrophages NK/NKT cells DC
Acquired Immunity: T cells B cells Macrophages (accessory cell) DC (accessory cell)
12-3 Innate vs Acquired Immunity
Characteristic:
Primary soluble mediators
Characteristic:
Primary soluble mediators
Innate Immunity: Complement Perforin/granzyme Acute-phase proteins IFN-alpha/beta Other cytokines
Acquired Immunity:
ANtibody
Cytokines
Perforin/granzyme
12-3 Innate vs Acquired Immunity
Characteristic:
Specificity of response
Characteristic:
Specificity of response
Innate Immunity:
Limited
Acquired Immunity:
Yes (very high specificity)
12-3 Innate vs Acquired Immunity
Characteristic:
Receptors
Characteristic:
Receptors
Innate Immunity: TLR Complement receptors NLR Fc TCRgamma delta
Acquired Immunity:
TCRalpha beta
TCRgamma delta
Ig alpha beta
12-3 Innate vs Acquired Immunity
Characteristic:
Response enhanced by repeated antigen challenge
Characteristic:
Response enhanced by repeated antigen challenge
Innate Immunity:
No
Acquired Immunity:
Yes
12-4 Properties of Immunoglobulin Classes and Subclasses
Class: IgG
Biological Properties:
Complement fixation (selected subclasses)
Crosses placenta
Mean Serum Conc (mg/ml) & Human half-life (days) IgG1- 9 (21d) IgG2- 3 (20d) IgG3- 1 (7d) IgG4- 1 (21d)
12-4 Properties of Immunoglobulin Classes and Subclasses
Class: IgA
Biological Properties:
Secretory antibody
Mean Serum Conc (mg/ml) & Human half-life (days)
3 (6d)
12-4 Properties of Immunoglobulin Classes and Subclasses
Class: IgM
Biological Properties:
Complement fixation
Efficient agglutination
Mean Serum Conc (mg/ml) & Human half-life (days)
1.5 (10d)
12-4 Properties of Immunoglobulin Classes and Subclasses
Class: IgD
Biological Properties:
Possible role in antigen-triggered lymphocyte differentiation
Mean Serum Conc (mg/ml) & Human half-life (days)
0.03 (3d)
12-4 Properties of Immunoglobulin Classes and Subclasses
Class: IgE
Biological Properties: Allergic responses (mast-cell degranulation)
Mean Serum Conc (mg/ml) & Human half-life (days)
0.0001 (2d)
12-5 Characteristics of Selected Immune Cells
Macrophage
Properties:
Phagocytosis
Adherence
Surface receptors:
Complement
Fc region of Ig
Surface markers:
CD16
CD11b
CD64
Proliferation in response to:
CD40L+ cytokines
Effector functions: Cytokine production Bactericidal activity Tumor cell cytotoxicity Suppressor activity
12-5 Characteristics of Selected Immune Cells
DC
Properties:
Phagocytosis
Adherence
Surface receptors:
Complement
Fc region of Ig
Surface markers:
CD11c
CD11b
Proliferation in response to:
CD40L+ cytokines
Effector functions:
Cytokine production
Bactericidal activity
Tumor cell cytotoxicity
12-5 Characteristics of Selected Immune Cells
T Cells
Properties:
No Phagocytosis
No Adherence
Surface receptors:
Antigen receptors
No Complement
Some Fc region of Ig
Surface markers:
CD4
CD8
CD3
Proliferation in response to: Allogeneic cells (MLR) PHA ConA Anti-CD3 + IL-2
Effector functions: Cytokine production Tumor cell cytotoxicity Immunological memory Suppressor activity
12-5 Characteristics of Selected Immune Cells
B cells
Properties:
Phagocytosis
No Adherence
Surface receptors:
Antigen receptors
Complement
Fc region of Ig
Surface markers:
Ig
CD19
B220
Proliferation in response to:
LPS
Anti-Ig + IL-4
CD40 + cytokines
Effector functions: Antibody production Cytokine production Immunological memory Suppressor activity
12-5 Characteristics of Selected Immune Cells
NK cells
Properties:
No Phagocytosis
No Adherence
Surface receptors:
Complement
Fc region of Ig
Surface markers:
CD16
CD11b
Proliferation in response to:
N/A
Effector functions:
Cytokine production
Tumor cell cytotoxicity
12-6 Cytokines: Sources and Functions in Immune Regulation
IL-1
Source:
Macrophages
Epithelial cells
Physiological Actions: Activation and proliferation of T cells Proinflammatory Induces fever and acute-phase proteins Induces synthesis of proinflammatory cytokines
12-6 Cytokines: Sources and Functions in Immune Regulation
IL-2
Source:
T cells
Physiological Actions:
Primary T-cell growth factor
Growth factor for B cells and NK cells
12-6 Cytokines: Sources and Functions in Immune Regulation
IL-4
Source:
Th2 cells
Mast cells
Physiological Actions:
Proliferation of activated Th2 and B cells
B-cell differentiation and IgE isotype switching
Antagonizes IFN-gamma
Inhibits Th1 responses
12-6 Cytokines: Sources and Functions in Immune Regulation
IL-5
Source:
Th2 cells
Mast cells
Physiological Actions:
Proliferation and differentiation of eosinophils
12-6 Cytokines: Sources and Functions in Immune Regulation
IL-6
Source: Macrophages Th2 cells B cells Endothelial cells
Physiological Actions:
Enhances B-cell differentiation and Ig secretion
Induction of acute-phase proteins by liver
Proinflammatory
Proliferation of T cells and increased IL-2 receptor expression
12-6 Cytokines: Sources and Functions in Immune Regulation
IL-10
Source:
Tregs
Bregs
Macrophages
Physiological Actions:
Inhibits T-cell and macrophage responses
12-6 Cytokines: Sources and Functions in Immune Regulation
IL-12
Source:
DCs
Macrophages
Physiological Actions:
Activates NK cells
Induces Th1 responses
12-6 Cytokines: Sources and Functions in Immune Regulation
IL-13
Source:
Th2 cells
Physiological Actions:
Stimulates B-cell growth
Inhibits Th1 responses
12-6 Cytokines: Sources and Functions in Immune Regulation
IL-17
Source: Th17 NK cells gamma delta T cells Neutrophils
Physiological Actions:
Proinflammatory
Inhibits Tregs
12-6 Cytokines: Sources and Functions in Immune Regulation
IFN-alpha/beta (Type I IFN)
Source:
Leukocytes
DCs
Fibroblasts
Physiological Actions:
Induction of MHC I expression
Antiviral activity
Stimulation of NK cells
12-6 Cytokines: Sources and Functions in Immune Regulation
IFN-gamma
Source:
T cells
NK cells
Physiological Actions:
Induction of MHC I and MHC II
Activates macrophages
12-6 Cytokines: Sources and Functions in Immune Regulation
TGF-beta
Source:
Macrophages
Megakaryocytes
T cells
Physiological Actions:
Enhances monocyte/macrophage chemotaxis
Enhances wound healing: angiogenesis, fibroblast
Proliferation, deposition of extracellular matrix
Inhibits T- and B- cell proliferation
Inhibits antibody secretion
Primary inducer of isotype switch to IgA
12-6 Cytokines: Sources and Functions in Immune Regulation
GM-CSF
Source:
Macrophages
Endothelial cells
Fibroblasts
Physiological Actions:
Stimulates growth and differentiation of monocytes and granulocytes
12-7 Models of Host Resistance Bacterial Parasite Fungal Viral Tumor
Model: Pathogen
Bacterial:
Listeria monocytogenes
Streptococcus pneumoniae
Parasite:
Trichinella spiralis
Fungal:
Candida albicans
Viral:
Influenza A2
Tumor:
B16F10 melanoma
12-8 Possible Mechanisms of Chemical-Induced Immune Modulation
Direct:
Functional changes
Mechanism:
Functional changes
Examples: Altered antibody-mediated responses Altered cell-mediated responses Altered release of preformed mediators Altered host resistance Inability of one or more cell types to perform a required activity, for examples: production of antibody release of cytokines processing and presentation of antigen proliferation and differentiation receptor-mediated signal transduction
12-8 Possible Mechanisms of Chemical-Induced Immune Modulation
Direct:
Structural changes
Mechanism:
Structural changes
Examples:
Alterations in surface receptors or ligands
Histopathological changes in lymphoid organs
12-8 Possible Mechanisms of Chemical-Induced Immune Modulation
Direct:
Compositional changes
Mechanism:
Compositional changes
Examples:
Alterations in CD3+, CD4+, CD8+, B220+, and/or Ig+ in spleen
Alterations in CD4+, CD8+, CD4+/CD8+, and/or CD4-/CD8- in thymus
Changes in hematological cellular parameters
Alterations in circulating Ig
Alterations in CFU profile in bone marrow
12-8 Possible Mechanisms of Chemical-Induced Immune Modulation
Direct:
Metabolic activation
Mechanism:
Metabolic activation
Examples:
Conversion to a toxic metabolite
12-8 Possible Mechanisms of Chemical-Induced Immune Modulation
Indirect:
Effects secondary to other target organ toxicity
Mechanism:
Effects secondary to other target organ toxicity
Examples:
Induction of acute-phase proteins as a result of liver injury
Increased corticosteroid release from the adrenal gland
12-8 Possible Mechanisms of Chemical-Induced Immune Modulation
Indirect:
Hormonal changes
Mechanism:
Hormonal changes
Examples:
Alteration in neuroendocrine regulation
Alteration in autonomic output from the CNS
Altered release of steroids from sex organs
12-9 Cellular Models of Immunotoxicology
T cell type
Cell line (species): EL-4 (mouse) Jurkat E6 (human)
Effector Response:
IL-2
Stimulus:
EL-4: Phorbol ester
Jurkat: Phorbol ester + Ca ionophore
or anti-CD3 + anti-CD28
12-9 Cellular Models of Immunotoxicology
B cell type
Cell line (species): CH12.LX (mouse) BCL-1 (mouse) SKW (human) Daudi (human)
Effector Response:
IgM
Daudi: NONE (signal transduction)
Stimulus:
LPS
SKW: LPS or alpha IgM + CD40L
Daudi: alpha IgM
12-9 Cellular Models of Immunotoxicology
Macrophage
Cell line (species):
RAW 264.7 (mouse)
J774.1 (mouse)
U937 (human)
Effector Response:
RAW: Nitric oxide, IL-1
J744.1: Nitric oxide, IFN-gamma
U937: TNF-alpha, IL-1alpha, IL-6, IL-8
Stimulus:
LPS
12-10 Tier Approach for Immunotoxicology Testing
Tier 1
Procedures: Hematology Body weight Organ weights (spleen, thymus, kidney, liver) Spleen cellularity Bone marrow cellularity and CFU Immunopathology AFC assay Proliferative responses NK assay
12-10 Tier Approach for Immunotoxicology Testing
Tier 2
Procedures: Surface marker analysis Secondary (IgG) AFC assay CTL assay DTH response Host resistance studies
12-11 Suggested Testing Configurations: Three Tests with 100% Concordance
AFC, DHR, Surface markers AFC, NK, DHR AFC, NK, Thymus: body weight AFC, DHR, Thymus: body weight Surface markers, NK, DHR Surface markers, DHR, T-cell mitogens Surface markers, DHR, Thymus: body weight Surface markers, DHR, LPS response
12-12 Chemical Agents know to be associated with autoimmunity Drugs antigenic chemical: methyl dopa hydralazine isoniazid procainamide halothane
Antigenic Chemical: Clinical Manifestations (determinant):
Methyl dopa: Hemolytic Anemia (Rhesus antigens)
Hydralazine:
SLE-like syndrome (Myeloperoxidase)
Isoniazid:
SLE-like syndrome (Myeloperoxidase)
Procainamide:
SLE-like syndrome (DNA)
Halothane: Autoimmune hepatitis (liver microsomal proteins)
12-12 Chemical Agents know to be associated with autoimmunity Nondrug chemicals: Vinyl chloride Mercury Silica
Antigenic Chemical: Clinical Manifestations (determinant):
Vinyl chloride:
Scleroderma-like syndrome (abnormal protein synthesized in liver)
Mercury: Glomerular neuropathy (glomerular basement membrane protein)
Silica:
Scleroderma (most likely acts as an adjuvant)
12-13 Chemicals Implicated in Autoimmunity
Scleroderma
Systemic lupus erythematosus
Scleroderma:
Solvents (toluene, xylene)
Tryptophan
Silicones
Systemic lupus erythematosus:
Phenothiazines Penicillamine Propylthiouracil Quinidine L-DOPA Lithium carbonate Trichloroethylene Silicones
