Transcript Type of immune response

IMMUNOLOGY BASICS
Lactation Biology
Animal Science 337
Leo Timms
Iowa State University
MEANS OF AQUIRING IMMUNITY
1. ACTIVE: make own antibody
chance encounter w/Ag
a) natural
pregnancy
vaccination
b) artificial
introduce Ag via trt.
MEANS OF AQUIRING IMMUNITY
2. PASSIVE: transfer preformed antibody
a) natural : mother to fetus
(6 mo protection)
placental vs. colostral
b) artificial: immune therapy
Type of immune response
• Innate
• defense we are
born with
– phagocytic
cells
– complement
proteins
– anatomical *
– physiological *
• Adaptive/acquired
• defense that
develops with
exposure/time
– serum
antibodies
– T cells (CMI)
* 1st line of defense!!!
Mechanisms of immunity:
• Cellular
• Humoral
– cells responsible
– antibodies (in
for protection
serum) are
responsible for
– lymphocytes
protection
– phagocytes
Two Arms of The Immune System
Innate Immunity
Adaptive Immunity
Phagocytes
Lymphocytes
Neutrophils
Macrophages
T lymphocytes
B lymphocytes
pathogens
pathogens
Antigen
presentation
TH1 Cytokines
chemokines
Antigen
presentation
TH1 Cytokines
TH1 or TH2 Cytokines
Cytotoxicity
Antibodies
© Jeanne L. Burton, Michigan State University
Cells of the Immune System
Myeloid-lineage cells of the innate immune system
PMN
M
Tissue macrophage
B
B cell
Circulating neutrophil
TH
Helper T cell (TH)
TC
Cytotoxic T cell (TC )
Lymphoid-lineage cells of the adaptive immune system
© Jeanne L. Burton, Michigan State University
• large cell (10-25 um dia)
• main purpose: phagocytosis / kill
• act non specifically
• “chemotactic” capability
• potent phagocytosis when activated
by T lymphocytes (lymphokines)
• Express Ag on surface to T / B cells
• multilobulated nucleus
• lysosomal granules
• phagocytosis and kill
• 1st white blood cell to infection site
• die and release contents
• irritate surrounding tissue / recruit cells
• Phago. improved by opsonization with Ig
Macrophages and neutrophils are needed to kill extracellular bacteria,
such as those the infect the mammary glands of dairy cows
Tissue
macrophage
Blood
IL-1, IL-6,
IL-8,TNF-a
M
PMN
TNF-a
IFN-g
Circulating
neutrophil
PMN
No memory
M or
PMN cells
develop
Infected
Gland
Extracellular bacteria
Inflammatory
neutrophil
© Jeanne L. Burton, Michigan State University
Inflammation: part of innate immunity
• poor at phagocytosis
• granules contain histamine / serotonin
• vasodilators / permeability factors
• requires binding of 2 IgE for release
lymphocytes
• small (5 – 15 um)
• No lysosomes : all “brain” until activated
• distinguish self from non self
• specific : recognize specific antigens
• MEMORY**
• need presentation of Ag by macrophage
• interactions
- antigen
- macrophage
- T cell (Th)
- B cell
- cytokines
cytokines
• interactions
- antigen
- macrophage
- T cell (Th)
- cytokines
T helper (Th)
T suppressor
T killer
others
Role of the Immune System
in Homeostasis
• Bidirectional interaction with other systems
– Reproduction
• “Self control” to prevent rejection of the fetus
• Stimulation of placental growth
• Linked to breeding success (rodents!)
– Endocrine
• Immune (autoimmune) diseases
– CNS
• Repair
• Neurogenesis
Bob Luebke
• Neurotransmitter/cytokine production andITB/ETD/NHEERL
Basics of Immunology
The Immune Response
Innate Immunity
-Phylogenetically ancient
-Limited recognition
-Rapid (minutes – hours)
- No cell proliferation required
-Limited memory (? mammals)
Adaptive (Acquired) Immunity
-First appeared in jawed fishes
- Infinite array of specificities
- Slow (days)
-Requires proliferation and differentiation
-Long-lasting memory
Bob Luebke
ITB/ETD/NHEERL
Basics of Immunology
• The adaptive immune
response to antigen
– Recognition as foreign
• First encounter: usually initiated
by innate immune system cells
• Receptor-mediated
– Antigen processing and
presentation
• B cells, macrophages, dendritic
cells
– Gene transcription, mediator
release, cellular proliferation
Bob Luebke
ITB/ETD/NHEERL
Organs of the Immune System
Bone Marrow: source of immune
system cells
Bob Luebke
ITB/ETD/NHEERL
Immune System Anatomy
Bob Luebke
ITB/ETD/NHEERL
Organs of the Immune System
Thymus: source of naive T cells
Bob Luebke
ITB/ETD/NHEERL
Fate of T Cells in the Thymus
Positive selection: optimal binding to self Ag prevents apoptosis
Negative selection: superoptimal binding to self Ag induces apoptosis
Bob Luebke
ITB/ETD/NHEERL
B cells: Tolerance to “Self”
Anergy: low expression of
IgM on surface; can’t bind Ag
Clonal ignorance: too few
copies of Ag in the periphery
Bob Luebke
ITB/ETD/NHEERL
Thymus size and architecture:
May be very sensitive to xenobiotics
Also sensitive to acute toxicity
Figure from IPCS: ENVIRONMENTAL HEALTH CRITERIA 180 PrinciplesBob
and Luebke
Methods for Assessing Direct Immunotoxicity Associated with ITB/ETD/NHEERL
Exposure to Chemicals
Organs of the Immune System
Spleen: Antigen trapping and presentation,
clonal expansion, cellular export
Bob Luebke
ITB/ETD/NHEERL
Organs of the Immune System
Lymph nodes: Antigen trapping and presentation,
clonal expansion, cellular export
Bob Luebke
ITB/ETD/NHEERL
Cells of the Immune System
Innate Immune System: Granulocytes
Neutrophil (“PMN”)
First responders
Phagocytosis and killing
of bacteria
Inflammation
Eosinophil
Allergy
Killing parasite larvae
Basophil
Circulating mast cells
Allergy/anaphylaxis
Bob Luebke
ITB/ETD/NHEERL
Cells of the Immune System
Innate Immune System: Granulocytes
Neutrophil (“PMN”)
First responders
Phagocytosis and killing
of bacteria
Inflammation
Bob Luebke
ITB/ETD/NHEERL
Cells of the Immune System
Innate Immune System: Monocytes
©Dennis Kunkel Microscopy,
Inc.
Monocyte/macrophage
Phagocytosis and killing of bacteria
Antigen processing
Inflammation
Macrophage with ingested
asbestos fiber (encarta.msn.com)
Bob Luebke
ITB/ETD/NHEERL
Cells of the Immune System
Adaptive Immune System: Lymphocytes
Peripheral blood
Activated B cell
Activated T cell (SEM)
B cells: Mature into plasma cells, secrete antibody (IgM, IgG, IgA, IgE, IgD)
T cells: T helper - produce stimulatory and regulatory cytokines
T cells: T cytotoxic/suppressor – contact-dependent cytotoxicity,
regulation of immune response
NK cells: direct killing of cells (innate arm of IS)
Bob Luebke
ITB/ETD/NHEERL
Cell Mediated Immunity
T Lymphocytes
• Recognize Ag only with MHC proteins
• Produce Lymphokines (not antibodies)
• Cell Mediated Immunity
T-Cell Subpopulation
CD-4
Help B-Cells produce Antibody
T-Cell
CD-8
Cytotoxicity Reactions
Cell-mediated immunity
• T cells can only recognize and
respond to processed fragments
of protein.
• T cells are suited for cell to cell
interaction and target body cells
infected by virus, bacteria and
abnormal or cancerous body cells
Cytotoxic T cells
Cell-mediated immunity: T-cells
• Activation of T cells—T cell receptors bind to
antigen presented by the antigen-MHC
complex.
• CD4 and CD8 proteins interact with antigen
and help maintain MHC-antigen coupling.
• Types of T-cells
– Helper T cells (CD4)
– Cytotoxic T cells (CD8)
– Memory T-cells
05 Dec. 2007
Immunity.ppt
37
Antigen-presenting cells
Antigen-presenting cells
T-Cell Activation
Goal:
“ Activation and clonal expansion of CD4 and CD8 Cells”
T cell activation
T cells must accomplish a double recognition.
• They must recognize nonself (antigen) and self
(MHC protein of a body cell) (Antigen recognition) .
• Co-stimulation by binding to other proteins on
APC
• Cytokines (IL 1 and 2) are released by APC or
T cell following co-stimulation
Antigen recognition and costimulation lead to activation.
Antigen binding without costimulation leads to anergy in T and
B cells.
Specific Antigen Recognition
Class II MHC
CD4
Peptide
TCR
APC
B7
MHC II
CD24
TCR
CD28
T-Cell
TCR
Activated T cell
• Activation leads to enlargement,
differentiation and proliferation of T
cells.
• T cells that are reproduced are clones
of originally activated T cell.
• Activation, differentiation and
proliferation occurs in secondary lymph
organs and tissue.
• Activation leads to release of
T-Cell Activation
paracortical area
(periarteriolar sheats)
Lymphocyte activation
T Cell-mediated Immunity
Principal function-Response to
intracellular pathogens and cells
expressing foreign antigens
Recirculation-Naïve T cells circulate
between the blood stream and the
lymphatic system
Priming of T Cells
• Three types of effector T cells
– CD8 (TC)
– CD4 (TH1)
– CD4 (TH2)
• Each type
– Responds to different types of Ags
– Activated by different Ag presentation
– Has different effector function
T Cell Effector Types
• CD8
– Viruses and intracellular bacteria
– MHC I
– Cytotoxic effector cells
• CD4 TH1
– Bacteria and parasites in APCs
– MHC II
– Effectors activate macrophages, CTLs and induce B cells to
produce opsonins
• CD4 TH2
– Extracellular bacteria and toxin producers
– MHC II
– Activate B cells to produce multiple antibody classes
T- Helper Subsets
Different types of T- Helper
subsets
Th-1
• Hypersensityvity Reactions
• Produce IL2 and Gamma IFN
• Cell mediated cytotoxicity (virucidal activity)
Th-2
• Principal role in B-cell activation
• Produce IL-4 and IL-5 (no IL-2 or Gamma
IFN)
• Antibody mediated activity (bactericidal
activity)
‫‪APCs‬‬
‫”أفمن وعدناه وعدا حسنا فهو القيه كمن متعناه متاع الحياة الدنيا ثم‬
‫هو يوم القيامة من المحضرين“ القصص ‪61‬‬
‫‪• Dendritic cells‬‬
‫‪• Macrophages‬‬
‫‪• B cells‬‬
Dendritic Cells
• Antigen presentation is sole function
• Antigenic uptake is followed by migration
to lymph nodes
• Expression of MHC I, MHC II and B7
• Loses phagocytic property
• Secretes chemokines
Macrophages
• Involved in both innate and adaptive
immunity
• May destroy pathogens or present Ag to T
cells
• Expression of MHC I, MHC II and B7
B Cells
• Binds soluble antigens
• Constitutively expresses MHC II
• Induced to express B7
NK Cells
• 5% of lymphocytes
• Nonspecific cytotoxicity
• No TCR/CD3
• Not MHC restricted
• No memory
Immunity.ppt
61
Cell-mediated immunity
• T cells can only recognize and respond to
processed fragments of protein.
• T cells are suited for cell to cell interaction and
target body cells infected by virus, bacteria and
abnormal or cancerous body cells or cells that
are transplanted or infused.
• Antibodies can only inactivate an antigen and
NOT destroy it.
• Antibodies prepare an organism for destruction
T-Cell Activation
• Lymphokines produced by lymphocytes
• Cytokines produced by other cells
Autocrine
Paracrine
HUMORAL IMMUNITY (Ab or AMI)
• Antigen + Macrophage + T cell + B cell
cytokines
• Antibodies or Immunoglobulins
• SPECIFICITY!
• MEMORY
• (immunity: short, long, or no term)
Antibodies are produced by antigen-activated B
lymphocytes and, in cattle, come in six isotypes
Fab = antigen binding = Fab
variable region
IgM (m)
IgG1 (g1)
IgG2 (g2)
IgG3 (g3)
IgA (a)
IgE (e)
L
L
Fc = biological
function
constant region
(Fc-m)
H H
© Jeanne L. Burton, Michigan State University
L = light chain
H + heavy chain
Antibodies
Functions
• Variable region (Fab) bind
specifically-neutralize, ppt
or agglutinate
**** antigen binding region
• Constant region (Fc) –
- activate effector cells or
complement
- opsonin end
Immunoglobulin classes
• IgD is attached to B-cell
plasma membrane
• IgM is released during
primary response
• IgG functions in late
primary and secondary
response
• IgA found in body
secretions
• IgE causes release of
histamine
Antibody Isotypes-5
Antibody defense: PLANe
• Precipitation
• Lysis: Complement fixation and activation
• Agglutination
• Neutralization
• Enhancing phagocytosis
Opsonization
• Free IgG binds Fc
receptors with low
affinity
• IgG bound to Ag,
binds to Fc receptors
with high affinity
• Cross-linking
receptors sends
signal
IgG:
IgG1
IgG2
• Principle Ab in serum
• 14 – 18 mg / ml
• IgG1: 11 mg/ml
• IgG2: 7 mg/ml
• fixes complement
• late response to Ag
IgG1
• selective transfer (colostrum)
• fetal / neonatal defense
• toxin inactivation
• principal milk / colostrum Ig
(farm species)
IgG2
10 opsonin
for
phagocytosis
IgM
IgE
• largest Ig
• pentamer
• serum (1-3 mg/ml)
• fixes complement
• 1st Ig produced
to Ag challenge!
• Binds to mast cells
basophils
• ACTIVATION
• RELEASE OF
- histamine - serotonin
The various Fc portions of antibody molecules have very different
biological functions, including pathogen blocking, complement
fixation, toxin neutralization, and opsonization of bacteria for
enhanced phagocytosis by neutrophils and macrophages
IgM = blocking &
complement
fixation
IgG1 = endotoxin
IgG2 = opsonization
neutralization &
& neutrophil
complement fixation
phagocytosis
serum
complement
© Jeanne L. Burton, Michigan State University
• 3 different forms in serum
• different form in secretion ( secretory piece)
• serum: 1-3 mg/ ml
• activates complement: serum (yes) milk (no)
IgA
Secretory piece
• local immunity and secretions
• prevents bacterial adherence
• maternal milk: very important
• primary Ig in colostrum (humans)!
Type
Number of
ag binding
sites
Site of action
Functions
IgG
2
•Blood
•Tissue fluid
•CAN CROSS
PLACENTA
•Increase
macrophage activity
•Antitoxins
•Agglutination
IgM
10
•Blood
•Tissue fluid
Agglutination
IgA
2 or 4
•Secretions (saliva,
tears, small intestine,
vaginal, prostate,
nasal, breast milk)
•Stop bacteria
adhering to host
cells
•Prevents bacteria
forming colonies on
mucous membranes
IgE
2
Tissues
•Activate mast cells
 HISTAMINE
•Worm response
CYTOKINES / LYMPHOKINES
•
1.
2.
3.
4.
Small polypeptide messengers
• very powerful in low doses
• multiple uses
• hormones
Interleukins
Interferon: viral
Colony Stimulating factors: GCFS
Tumor Necrosis Factor (TNF)
inflammation / cell movement / traffic
OTHER IMMUNE FACTORS
• Complement: 9 specific serum proteins
- interaction of components provide
numerous biological events
• Lactoferrin: Iron binding protein
*** competes with bacteria for iron
• Lactoperoxidase ( LP/ SCN- / H2o2 syst.)
** antioxidant / oxygen radicals
Cell Adhesion Molecules
• Selectins
• Mucins
• Integrins
• Immunoglobulin superfamily
Adhesion Molecules
T-Cell
APC
LFA3
LFA1
Endothelial Cell
Torloni MD
B7
IL1
CD28
TCR
CD4
IL2
IL2
IL2
IL2
T-Cell
Clonal Expansion
1- CD4 Cells are stimulated by contact with
antigen
IL1
CD4
Macrophage
CD4 Cell
MHC II
IL2
receptors
IL2
CD4
2- T-Cell finds B-Cell with that specific
Antigen
IL2
B-Cell
IL5
IL2
IL6
Plasma Cell
2- T-Cell causes that specific B-Cell to
expand
IL4
Prolifereation
Memory B Cell
Triggering of IL1
B7
IL1
CD28
TCR
CD4
IL2
IL2
Stimulation of B-Cells
T-Cell
2- Release
LFA3
B-Cell
LFA1
1- Binding
No antigen specificity
LFA3
T-Cell
B-Cell
2- Antigen specificity
B-Cell
LFA1
Plasma Cell
Prolifereation
Memory Cell
1- Binding
3- B-Cell Proliferation
First exposure
Re-exposure
Time
Activation of Cytotoxic T-Cells
• Recognize Ag in conjunction with MHC-1
• All host cells express class I antigens
• Serve as 1st line of defense against changed “self” antigens
- Virus infected cells
- Tumor cells
TNF-
T-Cells with same specificity
T Cell
MIF ,MAF
TdTH
CF
IL-1
NK Cell
IL-1
IL-1
Mast Cell
BCDF,
B Cell
BCGF
IL-2
IL-2
T8 (suppressor)
T8 (cytotoxic)
IgG, IgM, IgA, IgE, IgD
Cytokines
Effect
1) TNF- produced
2) TNF- binds to
receptor
3) Recptor and TNF
are internalized
outside cell
cytoplasm
4) TNF-  + receptor
are degraded
5) Endonuclease is activated
6)Endonuclease cuts DNA
7) Fragmented DNA appears in cytoplasm
8) Cell function is disrupted
Activation of lysosymes &
production of free radicals
also occurs.
Role of Cytokines : Interleukin-1
Acute Effects:
Macrophage
IL-2 production
IL2 receptor production
B-Cell Proliferation
NK Cell Activity
Acute phase reactants
LPS
Toxins
Foreign material
Fever
Monocyte
PMN demargination
PMN degranulation
Prostaglandin release (fibroblasts & monocytes)
Chronic Effects:
Muscle wasting
Depression
Sleep disturbance
Loss of appetite
Role of Cytokines : Interleukin-2
• Detected 2 - 6 hrs after after antigen stimulation
• Short half life
• Amplifies Cellular Immune response locally
• Stimulates B-Cell proliferation
• Induces IgG2 production
• activity of NK cells
• Induces LAK cell activity*
*Kills cells resistant to NK cell - independent of MHC
Role of Cytokines : Interleukin-3
• “ Hemopoiteic growth factor”
Stimulates Proliferation of Hematopoietic Precursors:
- Myeloids
- Megakariocytic
- Erythrocytic
- T- Cell
- B- Cell
permeability
phagocytosis
Half Life = Less than 30 minutes
SEM Picture of a Mast Cell
TEM of a Mast Cell
A
Antigens from plasma
bind to pre-formed IgE
attached to mast cells
B
Antigen binding causes
activation of histamine
release mechanism from
mast cells.
C
Histamine is released
from mast cells and
causes increase in
vascular permeability
Pluripotential Stem Cell
Committed Stem Cells
IL3
IL3
BFU-E
CFU-Meg
CFU-GM
CFU-G
CFU-Ba
CFU-Eo
CFU-E
CFU-Ms
CFU-B
CFU-T
CFU-M
B
T
Lymphocytes
Role of Cytokines : Interleukin-4
“ promotes resting B-Cell expansion”
•
•
•
•
•
•
•
•
Produced by T-Helper cells
Activation / Proliferation of B cells previously stimulated by antigen
Enhances expression of MHC II molecules
Induces production of CD-23 on B Cells surface
Induces IgG 1 synthesis
Essential in IgE formation
Role in converting other cytokines
Similar to IL-13
IL-4
Role of Cytokines : Interleukin- 5
IL-5
Th-Cell
B-Cell
Prolifereation
IL-6
Memory Cell
Plasma Cell
IL5 induces production of IGM and class
switching to IGA