INNATE IMMUNE SYSTEM

• Innate is also called non-specific immunity

• This is first line of defense against invading
organism.
• The innate system has anatomical features
that function as barriers to infection.
• Elements of the innate system include
anatomical barriers, secretory molecules and
cellular components.
 ANATOMICAL BARRIERS
1.Mechanical factors
• This are the epithelial surfaces especially the
skin.
• Desquamation of the skin epithelium helps it
remove bacteria and other infectious agents.
• Movement of cilia and peristalsis helps keep air
passages and G.I.T free from micro- organisms.
• Flushing action of tears and saliva help prevent
infection of eyes and mouth.
• The trapping effect of mucus in the respiratory
tract and G.I.T help in the protect lungs and
digestive system from infections.
 2.Chemical Factors
• Fatty acids and sweat inhibit growth of bacteria,
lysozyme and phospholipase found in tears,
saliva and nasal secretions can break down
bacterial cell wall.
• Low pH of sweat and gastric secretions prevent
growth of bacteria.
• Defensins in lungs and G.I.T have microbicidal
properties.
• Surfactants in lungs act as opsonins.
 3.Biological factors
• The normal bacterial flora in skin or G.I.T can
prevent the colonization of pathogenic
bacteria by secreting toxic substances or by
competing with pathogenic bacteria for
nutrients or attachment to cells.
 HUMURAL
1.Compliment system
Once activated compliment can lead to increased
vascular permeability, recruitment of phagocytic
cells and lysis an opsonization of bacteria.
2.Coaggulation system
Some products of this system are directly
microbicidal e.g beta-lysin, protein produced by
platelets during coaggulation can lyse gram +ve
bacteria by acting as a cationic detergent.
3.Lactoferrin and transferrin
• By binding iron, an essential nutrient for
bacteria, these proteins limit bacterial growth.
4.Interferons
• Are proteins that can limit virus replication in
cells.
5.Lysozyme
• Breaks down cell wall of bacteria.
6.Interleukin-1 (Il-1)
• Induces fever and the production of acute
phase proteins, some of which are alpha
microbicidal because they can opsonize
bacteria.
 CELL BARRIERS TO INFECTION
1.Neutrophils
• Polymorphonuclear cells are recruited to the
site of infection where they phagocytose
invading organisms and kill them
intracellularly.
• In addition , PMNs contribute to collateral
tissue damage that occurs during
inflammation
2.Macrophages
• Tissue macrophages and newly recruited monocytes
which differentiate into macrophages, also function in
phagocytosis and intracellular killing of
microorganisms.
• In addition, macrophages are capable extracellular
killing of infected or altered self target cells.
• They also contribute to tissue repair and act as
antigen-presenting cells, which are required for
induction of specific immune responses.
3.Natural killer (NK) and lymphokine activated
killer (LAK) cells
• NK and LAK cells can non specifically kill virus
infected and tumor cells. These cells are not
part of the inflammatory response but are
important in nonspecific immunity to viral
infections and tumor surveillance.
4.Eosinophills
• Eosinophills have proteins in granules that are
effective in killing certain parasites.
ADDITIONAL NOTES
Introduction: Categories of Immune
response

IMMUNE RESPONSE

INNATE ACQUIRED

Cell
1st line 2nd line humoral
mediated
 Summary of events
• Pathogens enter the body through epithelial surfaces or by direct
infection of blood.
• Various mechanisms come to play to contain the infection.
• Innate response (0-4 hrs), early induced response (4-96hrs) and
adaptive response (96 hrs).
• Innate response is the 1st line of defense.
o Mechanical and chemical barriers initially prevent pathogen entry
o If pathogens penetrate epithelial surfaces an inflammatory response is
induced and recruits effector molecules and cells of the immune response
from local blood vessels.
o Clotting is induced downstream to prevent spread of infection.
• Delivery of pathogen to local lymphoid tissue induces adaptive
immunity.
Summary of events contd
 History of Innate immunity
• 1884 Metchnikoff describes phagocytosis and develops
the cellular theory of Immunity
• 1889 Hans Buchner discovers complement
• 1890 Richard Pfeiffer describes endotoxin
• 1901 Bordet and Genou describe complement fixation
• 1977 NK cells that kill tumors are described
• 1994 Invariant chain TCRs are discovered
• 1997 Role of TLRs in the mammalian immune system
established
• 2001 NOD2 associated with Crohn’s disease
 Definition of innate immune response

• Also called natural or native immune

response.
• Present before infection and has evolved to
specifically recognize pathogens.
• Distinguishes self from non-self perfectly.
 Innate Immunity: Functions

• Provides a barrier to prevent the spread of

infection
– Physical
• Skin (epithelial cells); Wounds, burns, insect bites
• Mucosal surfaces (respiratory, GI, Reproductive)
– Mechanical (tight junctions, movement)
– Chemical (fatty acids, enzymes, pH,
antimicrobial peptides)
– Microbiological (normal flora)
 Innate Immunity: Functions

• Identifies and eliminates pathogens

– Non-adaptive recognition systems
– Activates molecules that target the microbe and aid in it’s
identification
• These factors may be surface expressed (TLR), released from
immune cells (antibodies) or present within circulatory system
(complement)
 Innate Immunity: Functions

• Initiates an inflammatory response

– Reaction to injury or infection
• Trauma to tissues or cells
• Presence of foreign material (splinter)
• Infectious agents (viruses, bacteria, fungi)
– Delivers immune cells and effector molecules to
the site of injury/infection
– Components
• Granulocytes, macrophages, inflammatory mediators
• Blood vessels (endothelium)
• Plasma proteins
 Innate Immunity: Functions

• Provides signals to alert the adaptive

immune system to activate an effective
specific immune response
– Antigen processing and presentation
(activation of T helper cells)
– Upregulation of co-stimulatory molecules
• MHC class II, CD80/86
– Induction of cytokine/chemokine response
• IL-4, IL-12
 Components of the innate immune response.

• 1st line
1. Epithelial barriers
2. Chemical/biochemical inhibitors
3. Normal flora
• 2nd line
1. Cells
2. Soluble molecules
3. Pattern Recognition receptors
4. Inflammatory barriers
 1 line defenses-Mechanical
st

• Mechanical barriers
1. Intact Epithelial cells-tight junctions
2. Flow of secretions across epithelium – when flow is
obstructed infection is common.
3. Mucociliary elevator –coated pathogens are easily expelled.
4. Mucous coat-coat pathogen and prevent adherence to
epithelia.
5. Blinking reflex and tears
6. The hair at the nares
7. Coughing and sneezing reflex
1st line defenses-Chemical/Biochemical
• Chemical barriers
1. Acid pH in the stomach, upper SI and vagina provides
a chemical barrier.
2. digestive enzymes
3. Hydrolytic enzymes in saliva
4. Surfactant in the lungs coat (opsonize) bacteria and
facilitate phagocytosis.
5. Proteolytic enzymes in the SI
6. Lysozyme in saliva and tears digest cell membranes
7. Antibacterial peptides
Antimicrobial peptides
 1 line defenses-Normal flora
st

• E.g. E. coli in the gut and lactobacillus in the

vagina
• Competition for nutrients
• Production of inhibitory substances e.g..
colicins produced by e. coli.
 CELLULAR COMPONENT OF THE INNATE
IMMUNE RESPONSE
• Granulocytes
– Neutrophils
– Eosinophils
– Basophils (blood)
– Mast cells (tissues)
• Mononuclear Phagocytes (RES)
– Monocytes (blood)
– Macrophages (tissue)
• Natural killer cells
• Dendritic cells
Origin of blood cells
 Granulocytes: Neutrophils
• Present in blood (60-70% of WBC)
• Not normally present in tissues
• Short lifespan – 2-3 days.
• Extravasate to tissues during inflammation
• Functions:
– First cell to respond to infection or injury (inflammatory site)
– Ingest and kill pathogens
– Release cytotoxic/proinflammatory mediators (ROS,
proteolytic enzymes, bioactive lipids, chemokines)
• Granules
 Primary – acid hydrolases, myeloperoxidases, lysozyme
and antibiotic peptides (defensins, seprocidins,
cathelicidins)
 Secondary – lactoferrin and lysozyme
 Granulocytes: Eosinophils
• 2-5% of leucocytes
• Bi-lobed nucleus
• Many cytoplasmic granules
• Granules contain Major Basic Protein which
 Is toxic to worms
 Induce histamine release from mast cells
 Activate neutrophils and platelets
 Provoke bronchospasm
 Granulocytes: Basophils and mast cells
• Basophils <0.2% of circulating leucocytes
• Mast cells found in tissues and
indistinguishable from basophils
• Granules contain histamine
• Histamine release activated by an allergen
thro cross-linking with IgE.
 Mononuclear Phagocytes: Monocytes

• Blood - monocytes (1-6% WBC)

• Tissues - macrophages
– mature form of monocytes
– found in tissues (gastrointestinal tract, lung, liver,
brain, skin, spleen); reticuloendothelial system (RES)
• Functions:
– Inflammation- respond to injury, infection, other foreign
substances
– Phagocytoze and kill pathogens
– Wound repair, angiogenesis
– Antigen presentation (activate adaptive immunity)
– Tumor surveillance and cytotoxicity
• Activated by TLR binding to ligand
 Natural killer cells
• 10-15% 0f circulating lymphocytes.
• Larger than typical lymphocytes with more cytoplasm.
• Possess dense (peroxidase neg) granules.
• Do not express conventional receptors, TCR or Ig.
• Express
• CD16 (FcγRIII)
• CD2
• CD56 – neural adhesion molecule
• IL-2 receptor
• Functions
• Nonspecific cytotoxicity to virus infected cells
• Involved in ADCC –Kill cells linked to Ab via the CD16
• Produce cytokines e.g. IFN- γ for proliferation and differentiation of other
cells.
 Dendritic cells

• Immature cells travel in blood and enter tissues

where they ingest antigen.
• Exposure to Ag causes maturation.
• Mature cells migrate to local lymphoid tissue and
activate antigen specific T-lymphocytes.
• Critical to transition from innate to adaptive immunity
• Binding of PRR stimulates DC activation and
maturation, which leads to T cell activation
 SOLUBLE MOLECULES OF THE
INNATE IMMUNE RESPONSE
• Cytokines
• Acute phase proteins
• Antimicrobial peptides
• complement
 Soluble molecules: Cytokines
• Soluble polypeptide signaling proteins that
generate and augment the immune response by
recruiting and activating the necessary cells.
• Produced by many cells in response to stimuli;
some have many targets and multiple functions,
and others have a unique or synergistic biologic
effect when combined with other cytokines.
• They are involved in all levels of the immune
reaction, including recognition, differentiation,
and cell proliferation.
 Cytokines contd

• Classification
• Interferons
• IFN-α and IFN β produced by virus infected cells. IFN γ produced by activated
T-Helper cells type 1.
• Have antiviral activity.
• Also activate phagocytic bacterial, fungal, parasitic and tumor cell killing.
• Interleukins (Important role in inflammation).
• Lymphokines – from many cells (earlier thought to be from lymphocytes) e.g.
IL2-IL6,9,10,13, TNF β.
• Monokines – predominantly from mononuclear phagocytes. E.g. IL-1 α and β,
IL 12, IL 15, TNF α.
• Hemopoietic growth factors
• Chemokines
• Involved in leucocyte movement around the body.
 Chemokines
• Most chemokines have 4 cysteine residues which form
disulphide bonds
• CC class – The first two cysteines are adjacent
(example: MCP-1, RANTES)
• CXC class- The first two cysteines are not adjacent
(example: IL-8)
• C class – Only has 2 cysteines not 4 (example:
Lymphotactin)
• CX3C class – Has 3 amino acids between the first two
cysteines and a different N-terminal
Functions of chemokines
 COMPLEMENT
Definition : series of heat-labile serum proteins

Site : serum and all tissue fluids except urine and CSF

Synthesis : in liver – appear in fetal circulation during 1st 13 W

Function : Responsible for certain aspects of

immune response and inflammatory response

Activation : antigen-antibody complex or endotoxin, capsule

series of proteins activated sequentially

Inactivation: inhibitors in plasma (short lived)

Biological effects: either beneficial or harmful to host

Complement contd
 Effects of compliment

Beneficial effects:
• Cytolysis:
– MAC form pores in its membrane.
• Opsonization:
– Opsonin (C3b) to surfaces of foreign organisms or particles.
– Phagocytic cells express C3b receptors so promote phagocytosis.
• Inflammatory response :
– Small fragments released during complement activation have several
inflammatory actions:
• C5a is chemotactic for neutrophiles and macrophages.
• C5a activate phagocytes and neutrophils
• C3a,C4a and C5a are anaphylatoxins and Cause degranulation of mast
cells and release of histamine and other inflammatory mediators.
 Effects of complement contd
• Immune complex clearance:
– C3b facilitate binding of immune complex to several surfaces and
enhance removal by liver and spleen.
– binds erythrocytes to blood vessels , make them as easy prey for
phagocytosis
– C3 deficiency associated with Immunocomplex disease and
susceptibility to recurrent infections
• Enhancement of antibody production:
– Binding of C3b to its receptors on activated B cells (CR2)
greatly enhances antibody production.
– Patient who are deficient in C3b produce much less antibody
than normal individuals and more susceptible to pyogenic
infection
• Read on the conditions associated with
complement deficiencies
 INFLAMATION
• Hallmarks of Inflamtion
– Tumor
• Swelling
– Rubor Described by the Romans
>2000 years ago
• Redness
– Calor
• Heat
– Dolar
• Pain
– Functio laesa
Added by Galen
• Loss of function