Professional Documents
Culture Documents
+ Inflammation
Cellular and humoral defences
Adaptive immunity Antibodies, cytokines, T helper cells,
cytotoxic T cells
Summary of the Immune Response
Immune system organs and
tissues
Lymphoid tissues
Lymphoid tissues: the sites where
– the generation,
– maturation,
– habitation and
– activation of the immune cells take
place.
Lymphoid tissues
Cells of the Immune
System
Categories of Innate or
Nonspecific Immunity
Type of natural immunity
Species immunity (B.anthracis infect human not chicken).
Absence of specific tissue or cellular receptors for attachment
(colonization) by the pathogen.
Temperature of the host and ability of pathogen to grow.
Lack of the exact nutritional requirements to support the growth of the
pathogen.
Lack of a target site for a microbial toxin.
Individual immunity:
Age.
Sex.
Stress.
Diet, malnutrition..
Intercurrent disease or trauma.
Therapy against other diseases.
Racial immunity: (sickle cell anaemia).
Type of defensive barriers
1. Anatomical Barriers
2. Microbial Antagonism
Neutrophil Eosinophil
Neutrophil
Lymphocyte
Basophil
Monocyte
Intracellular Killing Pathways
Intracellular Killing
Oxygen Oxygen
Dependent Independent
Myleoperoxidase Myleoperoxidase
Dependent Independent
5. Inflammatory barriers
HIV utilizes chemokine receptors CCR5, CXCR4 for entry into target cells
Effecter mechanism of Innate
Immunity
Recognition mechanisms of innate immunity
Toll-like receptors:
bacterial cell wall components, viral nucleic acids
Collectins, mannose receptor:
distinctive cell surface polysaccharides
Alternative pathway of complement:
cell surfaces lacking protective anti-complement proteins
Anti-microbial peptides:
acidic phospholipids on outside of membrane
Interferon-induction:
double-stranded RNA (replication of viral genome)
Virus replication-induced cell stress:
induction of apoptosis, expression of stress-
induced molecules that alert NK cells
Recognition mechanisms of innate
immunity
Microbes evolve rapidly, so innate immunity
must focus on broadly expressed molecules
characteristic of broad groups of microbes
(“pathogen-associated molecular patterns”
PAMPs); “pattern recognition receptors”
Molecules recognized tend to be structural
elements that are common to broad classes of
microbes and are very hard to change (only
useful to think of them as “patterns” in some
cases)
The Epithelial Layer: The initial barrier to
infection
1. Physical barrier of the epithelial layer (toughness of barrier varies by
location due to other functions: air exchange, nutrient uptake, etc.)
2. Mucus/cilia to remove particles (lung, intestines)
3. Acid pH of the stomach
4. Anti-microbial peptides secreted by some epithelial cells (small
intestines, small airways of lungs)
5. Commensal bacteria (compete with pathogenic bacteria)
6. Secretory IgA (adaptive immunity)
7. Intraepithelial lymphocytes (adaptive immunity)
Anti-Microbial Peptides
Made by neutrophils and some
epithelial cells (small intestines, small
airways)
Short, cationic peptides (most 29-35
amino acids long)
Interact strongly with acidic
phospholipids and thought to form
pores in membrane (eucaryotic
membranes often have negative charge
on carbohydrate rather than on
phospholipid of outside of bilayer; may
account for greater effect of peptides on
microbes )
Differentially active against different
micro-organisms.
They are classified into three major
groups: (i) peptides with an α-helical
conformation (insect cecropins,
magainins, etc.), (ii) cyclic and open-
ended cyclic peptides with pairs of
cysteine residues (defensins, protegrin,
etc.), and (iii) peptides with an over-
representation of some amino acids
(proline rich, histidine rich, etc.).
Defensins link innate and adaptive immunity
TLR
MIP3α
(CCL20)
Immature DC Memory T Cells PMNs
(Ag Sampling)
Recognition of an infection once it gets past the
epithelial barrier
Deficiency: Infections
Pentraxins
Acute phase serum proteins;
C-reactive protein (CRP): binds C-
polysaccharide of S. pneumoniae; promotes
phagocytosis of apoptotic cells;
noninflammatory clearance via C1q/factor H
Serum amyloid P (SAP): binds chromatin; KO
phenotype - anti-DNA Ab’s and less sensitive to
some bacteria 2o increased inflammation
Proteins of the complement
system (nomenclature)
Induction of
Inflammation
following
recognition of or mast cell
pathogens
Inflammatory mediators:
Cytokines, chemokines
and lipids
TNF
NOD (nucleotide-binding oligomerization domain) 1 & NOD2
recognize peptidoglycan substructures and promote innate
immune responses
MyD88(Myeloid
differentiation primary
response protein)
pathway and
TRIF pathway;
Transcription
factors and
MAP kinases
Pathways of NF (Nuclear Factor)-kB
activation •B-Cell Activation Factor
Inhibitor of kB kinase
Classical Alternative
pathway Pathway
(some TNF
receptor
family
members)
Genes regulated by NF-kB
Inflammation
Pro-inflammatory cytokines (TNF, IL-1) signal to
endothelial cells to make them:
Leaky to fluid (influx of plasma; containing antibodies,
complement components, etc.)
Sticky for leukocytes, leading to influx of neutrophils first,
then monocytes, lymphocytes
Systemic effects: fever, acute phase response
Component Function
Bradykinin, histamine, leukotrienes, Inflammatory Agents (IA) which act on the vascular
serotonin, prostaglandins system to produce increased blood flow and permeability
Fever, tachycardia,
tachypnea, hypotension,
organ dysfunction due to
widespread endothelial
injury
SR Mφ HPCR
TNF
IL-1 PROCOAGULANT
IL-6 APC
LPS IL-8
CD14 MyD88 NFκB
LPS
TLR4 Lipoproteins
LPS
LB
P
LBP
LPS
sCD14 IL-1, IL-6, IL-8
SELECTINS
TLR
NFκB
Inflammation: Neutrophils vs. Monocytes
Opsonins
Complement components (C3b)
Collectins (mannose-binding lectin)
Antibodies
Phagocytic receptors
Receptors for opsonins (complement
receptors, Fc receptors)
Pattern recognition receptors
(mannose receptor, etc.)
Receptors for apoptotic cells
Phagocytosis
and killing
Primary granules:
Antimicrobial peptides
Lysozyme
(degrades peptidoglycan)
Proteases (elastase,etc.)
Secondary granules:
phagocyte oxidase
Lysosomes:
Digestive enzymes
Phagocytosis and killing
•Phagocyte oxidase (=NADPH oxidase): makes reactive
oxygen intermediates (superoxide anion, hydrogen peroxide)
+Myeloperoxidase: hypochlorous acid
phagolysosome
Chronic granulomatous
cytoplasm disease: genetic defect in
phagocyte oxidase (most
commonly gp91,
which is X-linked)
Production of interferon by infected cells
Degradability
Ag processing by Ag Presenting
Cells (APC)
Chemical Nature of Immunogens
Proteins
Polysaccharides
Nucleic Acids
Lipids
Some glycolipids and phosopholipids can be
immunogenic for T cells and illicit a cell
mediated immune response
Types of Antigens
T-independent T-dependent
Polysaccharides Proteins
Properties • Structure
Polymeric structure
Polyclonal B cell
Examples
activation Microbial proteins
Yes -Type 1 (TI-1) Non-self or Altered-self
No - Type 2 (TI-2) proteins
Resistance to degradation
Examples
Pneumococcal
polysaccharide,
lipopolysaccharide
Flagella
Antigenic Determinants
Recognized by B cells and Ab F
e
Composition
Proteins, polysaccharides, nucleic acids,
haptens
Sequence (linear) determinants
Conformational determinants
Size
4-8 residues
Number
Limited (immunodominant epitopes)
Located on the external surfaces of the Ag
Antigenic Determinants
Recognized by T cells
Composition
Proteins
(some lipids)
Sequence determinants
Processed
1. Increases in:
a) Chronic infections
b) IgD myelomas
Clinical Implications of Human
Immunoglobulin Classes-IgE
1. Increases in:
a) Atopic skin diseases such as eczema
b) Hay fever
c) Asthma
d) Anaphylactic shock
e) IgE-myeloma
2. Decreases in:
a) Congenital agammaglobulinemia
b) Hypogammaglobulinemia due to faulty
metabolism or synthesis of immunoglobulins
Antigen Presentation and MHC Molecules
Functions of T lymphocytes
Primary defense against intracellular microbes
Activation of other cells (phagocytes, B cells)
Killing of infected cells (i.e., CTL)
Key features:
Mediated by interactions with other cells
Allows surface molecules, cytokines to act at short
range (enhances specificity)
Different classes of T lymphocytes are most
effective against different types of microbes
Phagocytosed (extracellular) microbes: helper T cells
stimulate antibody production, macrophages
Cytoplasmic (endogenous microbes): CTLs kill infected
cells and eliminate reservoirs of infection
The challenge for T lymphocytes
Very few lymphocytes in the body are specific for
any one microbe (or antigen)
Specificity and diversity of antigen receptors: the immune
system recognizes and distinguishes between 107 109
antigens
The frequency of antigen responsive lymphocytes is
typically 1 in 105 to 106
Lymphocytes must be able to locate microbes that
enter anywhere in the body
APCs are Required to Present Antigenic Peptide
Fragments to T cells
Mannose receptors, and expression of
Ctype Lectin receptors CCR7, and upregulation of
and Tolllike receptors MHC I & II, and coreceptors
Why are dendritic cells the most efficient APCs
for initiating immune responses
Location
At sites of microbe entry (epithelia), tissues
Express receptors (CCR1,2, and 5) that recognize
inflammatory cytokines
Receptors for capturing microbes
Such as mannose and Ctype lectin receptors and Toll
like receptors (TLRs) which function as pattern
recognition receptors and have very active endocytic
machinery
Migration to T cell zones of lymphoid organs
Role of CCR7 (ligands are Mip3β and SLC)
Colocalize with naïve T cells
Maturation during migration
Increase levels of MHC molecules, induce costimulators
(B7 molecules, CD40) and decrease endocytic capacity
Conversion from cells for antigen capture into cells for
antigen presentation and T cell activation
Dendritic cell subsets
Immature dendritic cells capture antigens from
sites of entry
Mature (activated) DCs present antigen to and
activate naïve T cells in lymphoid organs
DC1, DC2 subsets may stimulate differentiation to
different T cell subsets (Th1, Th2)
Some DCs (i.e., immature) may induce tolerance
Problems:
Lack of definitive markers
Most studies based on culture derived DCs
Maturation of Dendritic Cells
MHC
Functions of Different Antigen Presenting Cells
MHC
A genetic locus discovered on the basis of
transplantation
Different individuals express products of different MHC
alleles and reject grafts from one another
Human MHC: HLA (human leukocyte antigens)
Mouse MHC:H2
The peptide display molecules of the immune
system
Different alleles of MHC molecules display distinct
but overlapping sets of peptides
Determines which protein antigens are recognized in
different individuals
MHC molecules determine how antigens in different
cellular compartments are recognized by different
classes of T cells
MHC (major histocompatibility complex)restricted
antigen recognition by T cells
A T lymphocyte recognizes an antigen on an antigen
presenting cell (APC) that also expresses an MHC allele
that the T cell sees as “self”
First indication that T cells recognize complex of protein
(peptide) antigen bound to MHC molecules
Antigen receptors of T cells have dual specificities:
1. For peptide antigen (responsible for specificity of immune
response), and
2. For polymorphic residues of self MHC molecules (responsible
for MHC restriction)
T cells learn self MHC restriction during maturation in the
thymus: only T cells that “see” MHC molecules in the thymus
(can only be self MHC molecules) are selected to survive
Features of Class I and Class II MHC Molecules
Feature Class I MHC Class II MHC
Nomenclature
Human HLAA, B, or C HLADR, DQ, DP
Mouse H2K, H2D, H2L IA, IE
Similar effects
on class I MHC and
the activation of
CD8 T cells.
Presentation of Extracellular and Cytosolic Antigens
Antigen processing
Conversion of native antigen (globular protein)
into peptides capable of binding to MHC
molecules
Occurs in same cellular compartments as
synthesis and assembly of MHC molecules
Determines which source of antigen generates
peptides that are displayed by class I or class II
MHC
Uses cellular organelles that serve basic
“housekeeping” functions in most cells
The class II MHC pathway of processing of
internalized vesicular protein antigens
The class I MHC pathway of processing
of endogenous cytosolic protein antigens
How class I and class IIassociated antigen presentation
influence the nature of the host T cell response
Functions of APCs
Capture antigens and take them to the “correct”
place
To peripheral lymphoid organs, through where naïve
lymphocytes circulate
Display antigens in a form that can be recognized
by specific lymphocytes
For T cells: MHCassociated peptides (cytosolic peptides
to class I, vesicular peptides to class II)
For B cells: native antigens; APCs include macrophages,
follicular dendritic cells in germinal centers
Provide “second signals” for T cell activation
Costimulators and cytokines induced by microbes; ensure
that T cells respond best to microbial antigens
B cell mediated immune
response
B - LYMPHOCYTE
•Production of antibody in response to
infection is the main contribution of B
(Bursa of Fabricius)
Fabricius cells to adaptive
immunity
•Each B cell is programmed to make one
specific antibody
•Stimulation by specific antigen is required
for secretion of antibody
GENERATION AND SELECTION OF
B CELLS
1. Pro – B cells
Rearrangement of heavy-chain immunoglobulin
2. Immature B cell
IgM molecule expressed on cell surface, Both pro-B and immature B
cells-independent of antigen
3. Selection for self tolerance
B cells (newly expressed surface IgM) stimulated by self antigens
are:Eliminated or inactivated
they are prevented from developing further and secreting antibodies
that bind self cells or tissues
4. Survival in periphery
consequence of competition ,most B cells die by apoptosis
5. Mature B cells (or naïve B cells) express IgM
6. Activated B cells- cells that encounter their specific antigen
B-Cell Subtype
Plasma B cells (also known as plasma cells) are large B
cells that have been exposed to antigen and are
producing and secreting large amounts of antibodies,
Memory B cells are formed from activated B cells that
are specific to the antigen encountered during the
primary immune response.
B-1 cells express IgM in greater quantities than IgG and
its receptors show polyspecificity, found predominantly in
the peritoneal and pleural cavities.
Recirculating follicular B cells (aka “conventional B
cells”, B2 cells): circulate between LN follicles and blood
conventional B cells most texts refer to.
Marginal zone B cells: reside in marginal zone of
spleen where they can respond to particulate antigen in
blood (bacteria, etc.)
B cells mediated immune response
Characteristics of TD-Ag:
Possess T cell epitope and B cell epitope
Need Th cells participation
Both CMI and HI
Produce several types of antibodies: IgG
Produce immune memory
B cells recognize antigen
CD40
B T helper TCR
B MHC II
cell cell
cell
1. Antigen presentation to
Th cell B7 CD28
CytokiImmunoglobulin 2. B7 expressed
receptor 3. Th cell is
ne
recep activated
tor and
expresses
CD40
CD40 ligand,
ligan Cytokines
d secreted
B B B B T helper
cell cell cell cell cell
5. B cell activated
Cytokine
ells proliferate, differentiate, secrete Ig
Interaction between Th cell and B cell
Th cell
Ag processing activation
B cell
activation
Memory B cell
1. Neutralization
2. ADCC—NK,macrophage
• Opsonization – macrophage
• Activate complement system
5. Participate in hypersensitivity-I,II,III
1. Neutralization:
* to neutralize microbial toxins and animal venoms
* to prevent viruses and bacteria from infecting cells
2. ADCC—NK
1. Primary response
2. Secondary response
____________________________________________
Primary IR Secondary IR
____________________________________________
latent phase long short
peak concentration low high
maintaining time short long
Ab type mainly IgM mainly IgG
Ab titer low high
affinity low high
____________________________________________
Primary and secondary antibody responses to protein
antigens differ qualitatively and quantitatively
Cell-mediated cytotoxic
responses
Humoral and cellular immunity
Cytotoxic T cells (TC cells, or CD8+ T cells destroy virally infected cells and
CTLs). tumor cells, implicated in
transplant rejection, transformed
into regulatory T cells
Memory T cells central memory T cells (TCM quickly expand to large numbers
cells) and effector memory T of effector T cells upon re-
cells (TEM cells). exposure to their cognate antigen
•ADCC appears to
involve a number of
different
mechanisms, but
not complement
mediated lysis.
•Important in killing
virus infected cells
and helminths.
Sources: All the material from internet.