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Innate immunity
Cells of nespecific immunity,
phagocytosis
Module IB, Cell
Blood cells lineage
Structure of the immune system
•
•
•
•
Lymphoid stem cells
Myeloid stem cells
They will develop in mature immune cells
Human immune system is formed by
– 1012 cells
– 1014 various molecules, usually proteins
• Dispersity - cells will localize whole body
• Movement during development and effector
function
Proportion of types of white cells in
periphery, adult healthy man
Cell type
Neu granulo
Proportion (%)
60-70
Eo granulo
1-3
Baso granulo
0-2
Mono
5-10
Lympho
20-40
First level of defense
• To establish an infection, the pathogen must to
overcome barriers
– the skin, which is impermeable to most agents a secretes
anti-bacterial fatty acids
– Mucus secretion blocks adherence to epithelial cells.
• Many secreted fluids are bactericidal
– lysozyme, spermine, gastric acid
• Gut commensals may block growth of pathogenic
bacteria
Second level of defense
• Immune reaction
Primary lymphatic organs
• Thymus - maturation of immune cells
• environment for T lymphocytes development –
epithelial cells, thymus hormones. Lymphoid cells
(similar to blasts)
• Bone marrow – source and maturation of immune cells,
dominantly B cells (equivalent to Bursa Fabricii in
birds)
Secondary lymphatic tissues
• Lymph nodes
• Spleen
• Mucosa associated lymphoid structure (MALT)
– Diffuse
• BALT - following principal bronchi, M cells are near
trachea bifurcation, most cells are B cells
• GALT - Peyer plaques, isolated lymphatic follicles, covered
by lymphoepitelial cells – M cells
• NALT – Nasal lymphoid tissue
– Organised aggregates of folicules: tonsils, Peyer plaques,
appendix
Primary and secondary lymphoid
organs – body localization
Lymphoid elements of the intestinal immune
system – inductive and effector site
Inductive site –
contact with the
Ag.
Germinal centers
- differentiation
of B cells
Effector site –
mast cells
MC mucosal – tryptase
MC conective tissue –
typtase + chymase
CD4+8+ T cells, IEL
are T cells
Traffic of immune cells
General Types of Immunity
• Innate (natural)
– First line of defense
– No previous exposure to agent required
– Nonspecific
• Physical and chemical mechanical barriers
• Adaptive (acquired)
– Specific response to infectious agent
– Immunological memory for invader
Innate Immunity
• Physical and chemical barriers
– Intact skin – effective physical barrier
• Low pH – bactericidal for many organisms
• Normal skin flora – helps prevent colonization
by pathogens
– Loss of normal flora allows resistant organisms or
fungi to proliferate
Innate Immunity, Cont.
• Mucous membranes of respiratory, gastrointestinal,
and urogenital tracts
– Ciliated epithelial cells – trap and sweep away airborne
particles and organisms
– Goblet cells – produce mucus to make epithelial surface
sticky
– Enzymes in secretions inhibit invasion by organisms
Innate Immunity, Cont.
Innate immune defenses located at different body
sites.
Innate Immunity, Cont.
• Plasma proteins – antimicrobial and antiviral
effects
– Acute phase reactants
– Complement system: cascades and components
– Cytokines – ex. Tumor necrosis factor alpha (TNF)
– Interferons (IFN)
– Opsonins – fibronectin
Cells of the Immune System, Cont.
• Leukocyte (WBC), phago cells
– Phagocytic cells primary to host defense
• Granulocytes – Neutrophil
• Monocyte/Macrophage
– Natural Killers
– Auxiliary cells
• Eosinophils
• Basophils
• Mast cells
Cells of innate immunity
•
•
•
•
•
Macrophages are phagocytes that are constitutively present in tissues and respond
rapidly to microbes that enter these tissues.
Neutrophils, an abundant type of phagocyte, and monocytes, the precursors of
tissue macrophages, are always present in the blood and can be quickly delivered
anywhere in the body.
Almost all tissues contain dendritic cells, which are APCs that are specialized to
capture microbial antigens, to transport them to lymphoid tissues, and to present
them for recognition by lymphocytes.
Naive lymphocytes (lymphocytes that have not previously encountered antigens)
migrate through these peripheral lymphoid organs, where they recognize antigens
and initiate adaptive immune responses. The anatomy of lymphoid organs
promotes cell-cell interactions that are required for antigen recognition by
lymphocytes and for the activation of naive lymphocytes, resulting in the
generation of effector and memory lymphocytes.
Effector and memory lymphocytes circulate in the blood, home to peripheral sites
of antigen entry, and are efficiently retained at these sites. This ensures that
immunity is systemic (i.e., that protective mechanisms can act anywhere in the
body).
Characteristics of innate immunity
fylogenetically
conserved
identification of
„danger“ patterns
determines „context“ for
specific immunity
INNATE
IMMUNITY
ontogenically
conserved
relationship to
other
systems
immediate
reactivity
Adaptive immune response
• Antigen specific B cells
– immunoglobulin secretion, Ag specific antibodies
are responsible for eliminating invading
microorganism
• T cells help B cells to produce antibodies,
eradicate IC pathogens - activating Mo, direct
killing
• Antigen presenting cells - they display the
antigen to lymphocytes and collaborate with
them in the response
Innate and Adaptive Immune
response - summary
Feature
Phyllogenic age
Main target
Physical barriers
Soluble factors
Nonspecific
Specific
Phylogenetically old, conserved struct.
Young
„Common“ infectious agents
Persistent infect.
skin and mucosal membranes
none
enzymes (lysozyme, complement)
antibodies
Acute phase reaction proteins (CRP)
Cytokines (IF)
Cells
Macrophages, PMN, NK cells
T and B cells
Foreign recognition “identification“ of dangerous patterns specific – „foreign“
Target structures PAMPs, conservative
structural details – epitopes
Recognition struct. Membrane PRR (TLR), solubile PRR membrane BCR, TCR,
antibodies
Receptor distrib. Non-clonal, all cells of one type
clonal
Specificity
no
yes
Memoryno
yes
Innate and acquired
immune response
work together to
recognize antigens
(and eliminate
pathogens)
PHAGOCYTOSIS
cell factor of
innate immunity
macrophages
presentation
of antigens
dendritic
cells
granulocytes
source of
cytokines
ingestion of
microbes
PHAGOCYTOSIS
is the ability of specialised cells:
to engulf
to kill
to destroy
microbes and foreign particules
Multistep leukocyte-endothelial interactions
mediating leukocyte recruitment into tissues
Adhesion molecules
Adhesion mol. Ligand Relevance
Defective expression
Selectin family
CD15
Transient adhesion and rolling
Defective
on Neu, Eo, Mono
CD15 expression
of Leu on endothelium
- severe ID, similar to CD18 def
L-selectin
CD34, GlyCAM on high
Transient adhesion for
(CD62L) rolling
endothelial venules
No human disease
homing molecule - lymph nodes
Immunoglobulin super-gene family
strengthen the interaction btw APC and T cells
ICAM 1, 2, 3, CD28 – CD80, 86, TCR, BCR, MHC I and II
Adhesion molecules and leukocyte-endothelial
interaction
β2 integrin family – leukocyte integrins
Adhesion mol. Ligand Clin rel. of interaction
CD18/CD11
all Neu
ICAM-1 on endothelium
Tight adhesion btw
leuko and endothelium
Defective
expression
Severe ID –
leucocytosis,
bacterial,
fungal
infection
ACTIVATION
OF PHAGOCYTES
ENDOGENOUS:
proinflammatory
cytokines
chemokines
CSF
C3a
C5a
PAF
LT
EXOGENOUS:
bacterial
components
LPS, CpG,
„danger patterns“
(PAMP)
Characteristics of innate immunity ACTIVATION
• receptors directed against high number of structures
on microorganisms
• germline coded receptors (in opposition to: BCR, TCR
– individual, not inherited)
• only few genes for those receptors
• receptors for limited number of conserved molecular
patterns (common for microorganisms,
distinguishable from self patterns) – Pathogen
Associated Molecular Patterns - PAMPs
Pattern recognition receptors (PRR)
PAMP
LPS
Lipoproteins
Peptidoglycan
Lipoarabinom
annan
Flagellin
CpG (bacterial
DNA)
Heat shock
proteins
Microbes
Most G - bacteria
Most bacteria
Most bacteria
mycobacteria
PRR
LBP, CD14, TLR4
TLR2
CD14, TLR2
TLR2, MBP
G- bacteria
Most bacteria
TLR5
TLR9
Most bacteria
TLR4, TLR2
Toll - like receptors
• Example of PRRs
• TLRs originally described in insects
• Mammalian cells use to identify important
bacterial components - LPS, CpG
• After activation, TLR activate transcription
factors - activation of immune response genes
• Toll-like receptors, after PAMP recognition,
activate signaling pathways inducing
antimicrobial effector response
Structure, Location, and Specificities of TLRs
Fig. 4-2
© 2011 by Saunders,
an imprint
Elsevier Inc.
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2012Copyright
by Saunders,
an imprint
of ofElsevier
Inc.
Toll-like receptor (TLR)-mediated innate and
adaptive immune responses and their roles in
the immune system.
•
Clinical relevance of TLR
• Toll-like receptors – role in the initiation of human
diseases and represent potential targets for
therapeutic intervention.
– TLR ligands serve as components of common vaccine
adjuvants
– TLR9 recognition of nucleic acids may help trigger
systemic lupus erythematosus and rheumatoid arthritis
– TLR 1, 2, 4, and 5 are expressed in atherosclerotic plaques
– TLR agonists can skew the immune response from a Th2allergic immune phenotype to a protective Th1 immune
phenotype in asthma
DRUGS WHICH STIMULATE TOLL-LIKE
RECEPTORS
• In several situations, it is desirable to
stimulate the immune system. For example, it
would be helpful to boost the immune response
to cancers and some vaccines. Drugs have
been developed which bind Toll-like receptors
and give additional stimulus to the immune
system.
• For example, CpG is an unmethylated DNA
sequence normally only found in bacteria. CpG
binds to TLR9 and by activating the immune
system can be used to help to treat cancers
and improve responses to vaccines.
1. Phagocytes – granulocytes
(neutrophil)
Phagocytes, including neutrophils and macrophages,
are cells whose primary function is to identify,
ingest, and destroy microbes
- typical effector cells
- short lived cells
- Chemotaxis
- Killing mechanisms
- – pH, enzymes: proteinases - elastase, kolagenase,
gelatinase, lysozyme, kathepsin G, defensine,
-
oxygen radicals – metabolic burst
lipid mediators- inflammatory cells influx (LTB4,
PAF, TxA2)
Neutrophils
• Neutrophils, also called polymorphonuclear
leukocytes, are the most abundant population of
circulating white blood cells and mediate the
earliest phases of inflammatory reactions
• Major role – remove infectious agents
• Most abundant cell in circulation
– Normal – 55-75% of total WBCs
• Nucleus
– Mature PMN – multi-lobed (segmented)
– Immature PMN – nonsegmented “bands”
Neutrophils, Cont.
(a)
(b)
FIGURE 2-2 (a) Segmented neutrophil, peripheral
blood, Wright stain; (b) Segmented neutrophil and
macrophage in Gram-stained smear.
2. Phagocytes – Monocytes, Macrophages
Monocytes and macrophages develop from immature
hemopoetic progenitor cells in the bone marrow.
Mature monocytes enter to the circulation, resident
macrophages are located in the tissue
Monocytes and macrophages express class II MHC
antigens (HLA DR, DP, DQ)
Receptors for „foreign structures“ (PRR: TLR, lectins)
Opsonisation:
Fc receptors
Complement receptors, CR 1 – 3
• The mononuclear phagocyte system consists of
cells whose primary function is phagocytosis and
that play central roles in innate and adaptive
immunity
• Once they enter tissues, these monocytes mature
and become macrophages. Macrophages in
different tissues have been given special names
to designate specific locations
Cellular components of innate immune
response - Mononuclear phagocyte cells
Maturation of mononuclear
phagocytes and dendritic cells
3. Dendritic cells
• Dendritic cells are the most important APCs for activating
naive T cells, and they play major roles in innate responses to
infections and in linking innate and adaptive immune
responses.
• They have long membranous projections and phagocytic
capabilities and are widely distributed in lymphoid tissues,
mucosal epithelium, and organ parenchyma Interdigitating
dendritic cells constantly, quietly endocytose extracellular
antigens
• They became activated and behave as APC (when PAMP is
recognized - LPS, mannose)
• Activated by endogenous signal - release of IFN- (from virally
infected cells), HSP from necrotic cells
• Activation of DC will cause expression of
B7 - costimulatory molecules
ROLE OF DENDRITIC CELL IN INNATE IMMUNITY
capture
and processing
of antigens
in tissues
DENDRITIC
CELL
migration
into lymphatic
nodes
presentation
of antigens
to T cells
Interactions between epithelial cells and
dendritic cells in the airways
• Dendritic cells (DCs)
sample the airway
lumen by forming
dendritic extensions
between epithelial
cells.
• DCs form tight
junctions with
epithelial cells through
their expression of
occludin (not shown)
and claudin family
members, as well as
zonula occludens 1
(ZO1).
Follicular Dendritic Cells
• Follicular dendritic cells (FDCs) are cells with membranous
projections that are found intermingled in specialized
collections of activated B cells, called germinal centers, in
the lymphoid follicles of the lymph nodes, spleen, and
mucosal lymphoid tissues.
• FDCs are not derived from precursors in the bone marrow
and are unrelated to the dendritic cells that present
antigens to T lymphocytes.
• FDCs trap antigens complexed to antibodies or complement
products and display these antigens on their surfaces for
recognition by B lymphocytes. This is important for the
selection of activated B lymphocytes whose antigen
receptors bind the displayed antigens with high affinity
Opsonisation of
antigen – the
role of
antibody,
complement
etc.
Phagocytosis ingestion
INGESTION
GRANULOCYTE
BACTERIA
Ig
FcR
Ag
A
C
T
I
V
A
T
I
O
N
C3b
CR
lectin
sacharide
lectinophagocytosis
T cell Activation by an Activated APC
IL-1
IL-6
IL-12
IL-12 Receptor
CD28
“Signal 3”
CD4+
B7
T cell
LPS
T Cell
Receptor
“Signal 2”
TLR4
“Signal 1”
Peptide
MHC II
Signal 1: Specificity
Signal 2: Activation
Signal 3: Differentiation
Antigen Presenting Cell (APC)
Monocytes, macrophages and DC versus
Neutrophils
• Monocytes, macrophages and dominantly
dendritic cells are capable to present Ag
efficiently
• Neutrophils do not present Ag!
NK cells
• Natural killer (NK) cells are lymphocytes distinct from T and B
cells
• important roles in innate immune responses mainly against
intracellular viruses and bacteria. Natural killer cells destroy
infected and malignant cells
• The term natural killer derives from the fact that these cells are
capable of performing their killing function without a need for
clonal expansion and differentiation, which is required for
effector responses of the immune system's other killer cells, the
cytotoxic T lymphocytes (CTLs).
1. Possess Fc receptors that bind IgG: FcR - link to IgG coated target
cells (process called antibody dependent cellular cytotoxicity ADCC)
2. The killer activating receptors recognize a number of different
molecules, killer inhibitory molecules recognize MHC-I
Functions of activating and inhibitory
receptors of NK cells
Granulocytes
• A Neutrophil
• B Mast cell
• C Basophil
• D Eosinophil
Other inflammatory cells - function
• Neutrophils – release enzymes - proteinase (elastase, kolagenase),
oxygen radicals, lipid mediators
• Eosinophils
– weak phagocytes
– on activation, kill parasites by releasing cationic proteins,
reactive oxygen metabolites
– secrete leukotrienes, prostaglandins, various cytokines
• Basophils and mast cells - blood basophils do not
develop into the tissue mastocytes.
– On activation, (FcR) secrete inflammatory mediators
Eosinophils
• Eosinophils are blood granulocytes that express
cytoplasmic granules containing enzymes that
are harmful to the cell walls of parasites but can
also damage host tissues
• Some eosinophils are normally present in
peripheral tissues, especially in mucosal linings of
the respiratory, gastrointestinal, and
genitourinary tracts, and their numbers can
increase by recruitment from the blood in the
setting of inflammation.
Eosinophil migration to sites of
allergic inflammation
Mast cells
• Mast cells are bone marrow-derived cells
that are present in the skin and mucosal
epithelium and contain abundant
cytoplasmic granules filled with cytokines
histamine, and other mediators.
• Stem cell factor (also called c-Kit ligand) is a
cytokine that is essential for mast cell
development
Basophils
• Basophils are blood granulocytes with many structural
and functional similarities to mast cells.
• Like other granulocytes, basophils are derived from bone
marrow progenitors (a lineage different from that of mast
cells), mature in the bone marrow, and circulate in the
blood.
• Although they are normally not present in tissues,
basophils may be recruited to some inflammatory sites.
• Like mast cells, basophils express IgG and IgE receptors,
bind IgE, and can be triggered by antigen binding to the IgE.
• Because basophil numbers are low in tissues, their
importance in host defense and allergic reactions is
uncertain.
Activation of mast cells and basophils
The signal-transduction cascade induced after
FcεRI aggregation