Immune System
• Innate and adaptive immune systems
have co-evolved and show a high
degree of interaction and
interdependence.
• If innate immune response is poor, the
adaptive immune response will be
feeble.
• In other words, recognition by the innate
sets the stage for an effective immune
response.
Innate Immunity (Less specific and first line of defense)
• Most ancient line of defense,
• Some form found in all multicellular plants and animals
• Defense against infection that are ready for immediate activation prior to attack by
the pathogen.
Adaptive Immunity or acquired (More specific)
• More recent evolutionary and evolved in jawed vertebrates.
• It complements innate Immunity
• Induced by the exposure to microbes and counters infection with a
specific response.
Types of
defensive
barriers in
Innate
Immunity
• Anatomic,
• Physiologic,
• Phagocytic, and
• Inflammatory
Anatomical Barriers to Infection
Skin
• Mechanical barrier retards entry of microbes.
• Acidic environment (pH 3–5) retards growth of microbes
Mucous Membrane
• Normal flora compete with microbes
for attachment sites and nutrients.
• Mucus entraps foreign microorganisms.
• Cilia propel microorganisms out of
body.
(Influenza virus, N. gonorrhorae )
Physiologic barriers
• Temperature
• Low pH
• Chemical mediators
(Lysozyme, Interferon, Complement, antimicrobial
peptides,Collectins, surfactants etc)
Skin and other epithelial barriers to infection
Antimicrobial Proteins and
Peptides Kill Would-be
Invaders
Psoriasin prevents colonization of the skin by E. coli
The
immune
system
(Epithelia
disrupted by
wounds, abrasions,
and insect bit)
Senses/detects the
presence of a pathogen
Mounts a response
• Soluble or membrane bound molecules
(receptors) that recognize molecular
patterns or motifs absent in the host but
present in the pathogen.
Sensors
• Pattern Recognition Receptors (PRRs)
on host cell recognize Pathogen
Associated Molecular Patterns (
PAMPs).
• PAMPs: combination of sugars,
lipoproteins and some nucleic acid
motifs.
Phagocytic cells – (Efficient at internalization,
degradation and scavenging)
• Phagocytic cells - Macrophages, neutrophils, and dendritic cells
in tissues and monocytes in the blood.
Resident macrophages sentinels for the immune system.
To engulf, internalize and destroy
foreign particles.
To secrete a variety of biologically
active molecules
Functions
To present antigen
To retain antigen for prolonged
period of time.
Monocytes arise from
hematopoietic stem cells
and can differentiate into
macrophages and DC
• Macrophages and related cell (6-16 days)
• Take care of old and dying cell
• -Normal tissue microphages are immunologically
quiescent (low O2 requirement and no cytokine
secretions).
• -Receptors expressed depends upon state of activation,
location, life cycle, local milieu etc
Phagocytes cross the endothelium
and enter the site of infection
-Polymorphonuclear Granulocyte
(Neutrophils, eosinophils, Basophils
and mast cells)
-Movement of phagocytic cell
(Rolling, adhesion and extravasation)
-Phagocytosis
(Attachment, pseudopod formation,
digestion)
Steps in the phagocytosis of a bacterium
• Microbes are Recognized by Receptors on Phagocytic Cells.
PAMPs or MAMPs - recognize by pattern recognition receptors
(PRRs).
Phagocyte recognition of soluble proteins that have bound to
microbial surfaces
(Process Opsonization, and protein- opsonins eg
MBL,ficolins,CRP and C1q).
Phagocytosed Microbes are Killed by Multiple Mechanisms
•
•
•
•
Antimicrobial proteins and peptides (defensins and cathelicidins)
low pH,
Acid activated hydrolytic enzymes
Oxidative attack
Reactive oxygen species (ROS)- NADPH oxidase enzyme complex
Reactive nitrogen species (RNS)- inducible nitric oxide synthase
• Phagocytosis Contributes to Cell Turnover and the Clearance of Dead
Cells
Damage-associated molecular patterns (DAMPs).
“eat me”- phosphatidyl serine and “don’t eat me”- CD47 signals.
(Phagosomes, Endocytosis, receptor-mediated endocytosis, pinocytosis)
Induced Cellular Innate Responses
• Cellular Pattern Recognition Receptors Activate Responses to
Microbes and Cell Damage.
• Toll-Like Receptors Recognize Many Types of Pathogen
Molecules
Toll-like receptor (TLR)
structure and binding
of PAMP ligands
Effectors of Innate
Responses to infection
Localized protective event elicited by injury which
serves to destroy, dilute or wall off both the
injurious agents and injured tissue
(Hallmarks of Acute Local Inflammation)
4-Inflammation
Induced by
proinflammatory
mediators
• Chemokines (IL-8, monocyte chemotactic
protein)
• Cytokines (TNF-α, IL-1, IL-6, IFN-γ, TGF-β )
• Components of the complement cascade
(C3a, C5a)
• Plasma mediators (bradykinin,
fibrinopeptides)
• Lipid mediators (leukotrienes,
prostaglandins, thromboxane)
major
events
Inflammator
y
Responses
Vasodilation
An increase in capillary
permeability
Influx of phagocytes
Local increase in
temperature and pain
This achieves
a two-fold
objective
• It limits the exposure of tissue to the
external environment (thereby limiting entry
of potentially harmful agents).
• It walls off the damaged area so that any
harmful agent that may gain entry cannot
easily spread to other parts of the body.
A complex interplay of factors responsible for the initiation of the inflammatory response
Inflammatory Responses
Inflammatio
n Results
from Innate
Responses
Triggered
by
Infection,
Tissue
Damage,
or Harmful
Substances
Initiation of a local inflammatory
(a) The four sequential but
overlapping steps in
neutrophil extravasation.
(b) Cell-adhesion molecules
and chemokines involved in
the first three steps of
neutrophil extravasation
Overview of the cells and mediators involved in a local acute inflammatory response
The
resolution of
inflammation
is promoted
by
• Lipoxins
• Serine protease inhibitor
• Endogenous anti-inflammatory molecules
(adrenaline, noradrenaline and 5hydroxytryptamine)
• cAMP
• Glucocorticoids (annexin-1)
• Cyclopentanone prostaglandins
Acute Phase Reaction
Systemic response initiated by
a sudden rise in circulating
cytokines such as IL-1, IL-6
and TNF-α
Overview of the organs and mediators involved
in a systemic acute-phase response
Natural Killer Cells (NK Cells)
• NK cells are preprogrammed to respond immediately to appropriate
stimuli, releasing from preformed secretory granules effector proteins that
kill altered cells by inducing apoptosis.
• NK cells also secrete cytokines helps to activate and shape the adaptive
response.
Interactions
Between the
Innate and
Adaptive
Immune Systems
Differential signaling through dendritic cell PRRs influences helper T cell
Key elements
of Innate Immune
system
• Anatomical Barriers
(Physical and Chemical barriers)
• Cellular response to
infection
Phagocytosis
Inflammation
Ubiquity of
Innate
Immunity
• Virtually all plant and animal species,
and even some fungi, have antimicrobial
peptides similar to defensins.
• Most multicellular organisms have
pattern recognition receptors containing
leucine-rich repeats (LRRs)
Plant innate immune
responses
Pathogens Have
Evolved
Mechanisms to
Evade Innate and
Inflammatory
Responses
• Pathogens avoid elimination by innate –
Streptococci, virus
Why
Acquired /
adaptive
immunity?
• How to deal with this situation
• Get help from other cells and molecules with
much better ability to recognise pathogens/their
products.
• Therefore, cells evolved = differentiate between
self and non-self.
Adaptive immunity?
• Adaptive immunity is the body’s ability to recognize and defend itself
against distinct invaders and their products.
• Attributes of adaptive immunity
• Antigenic Specificity
• Diversity
• Immunologic memory
• Self/non self recognition
Adaptive immunity is not independent of innate immunity
Adaptive
immunity
defends
against
infection of
body fluids
and body cells
• Acquired immunity has two branches: the
humoral immune response and the cellmediated immune response.
• In the humoral immune response antibodies
help neutralize or eliminate toxins and
pathogens in the blood and lymph.
• In the cell-mediated immune response
specialized T cells destroy affected host cells
The Adaptive Immune System Requires
Cooperation Between Lymphocytes and AntigenPresenting Cells
B LYMPHOCYTES
The binding of the antigen to the antibody causes the cell to divide rapidly; its progeny
differentiate into memory B cells and effector B cells called plasma cells.
T LYMPHOCYTES
T-cell receptor
Humoral
Immunity But
Not Cellular
Immunity Is
Transferred
with Antibody
Humoral immunity – B Cell
(recognizes an enormous variety
of epitopes).
Cell mediated Immunity - T cells
(recognizes protein epitopes
displayed together with MHC
molecules on self-cells )
Overview of the humoral and
cell-mediated branches of the
immune system
Cell-membrane
molecules
responsible for
antigen recognition
by the immune
system:
• Membrane-bound
antibodies on B cells
• T-cell receptors
• Class I MHC
molecules
• Class II MHC
molecules
The role of MHC molecules in antigen recognition by T
cells
Complex Antigens Are Degraded (Processed) and Displayed
(Presented) with MHC Molecules on the Cell Surface
Antigen
Selection of
Lymphocytes
Causes
Clonal
Expansion
Maturation and clonal selection of B lymphocytes
Differences in the primary and secondary response to injected antigen (humoral response) and to a skin graft
(cell-mediated response) reflect the phenomenon of immunologic memory