Innate Immunity
Dr/ Yara El sayed Marei
Lecturer of Medical Microbiology
and Immunology
The immune system is divided
functionally into 2 divisions:
Innate Immunity (Natural or Non
specific or inborn): initiate the initial
protection against infections
Adaptive Immunity (specific): develop
more slowly and mediates the later and
more effective defense.
Development of the Immune System
-The lymphoid system is composed of primary lymphoid organs
as bone marrow and thymus (haemopoiesis, lymphopoiesis and
maturation of lymphocytes) and secondary lymphoid organs as
lymph nodes, spleen and tonsils (mature lymphocytes will be
exposed to their specific antigens)
-All the cells of the immune system arise from Hematopoietic
stem cells (HSCs), in the bone marrow that differentiate into
cells of lymphoid or myeloid progenitors. The lymphoid stem
cells differentiate into: B lymphocytes, T lymphocytes and NK
cells while the myeloid stem cells differentiate into: monocyte-
macrophages, eosinophils, mast cells and neutrophils.
Development of the Immune System
ery pl neu mφ
nk
CD8+ CTL
CD4+
TH1
thy
TH2
mye
lym
Features of the Innate Immunity:
- Inborn resistance that is present the first time a
pathogen is encountered, present at birth and all
the times.
- It does not require prior exposure.
- It provides defense against wide range of
microorganisms.
- No acquired memory after first exposure.
- Does not attack the self components
ss
Recognition of microbes by the Innate Immune
System
- The components of innate immunity recognize
structures that are specific for microbial pathogens
Pathogen-Associated Molecular Patterns (PAMPs).
-The innate immune system also recognizes endogenous
molecules that are produced by damaged and dying
cells; damage-associated molecular patterns
(DAMPs).
Ex:-
- LPS of gm-ve bacteria
- Teichoic & lipoteichoic acids of gm+ve bacteria
- Flagellin of bacterial flagella.
- RNA which is found in many viruses
- Unmethylated DNA. (eukaryotes have many
times more cytosines, with methyl groups
attached
- Zymosan in fungi
Pattern (pathogen) Recognition Receptors
(PRRs)
- Cell-associated recognition molecules of the innate
immune system, expressed by phagocytes.
- When PRRs bind to PAMPs and DAMPs, they
activate signal transduction events leading to:
- Phagocytosis
- Secretion of cytokines as IL-1, TNFα and IL-6 and
chemokines which attract white blood cells leading
to inflammation
-
ss
Types of PRRs:
1-Mannose receptor recognizes bacterial
carbohydrates
2-Scavenger receptors recognizes lipids
3-Toll-like receptors
A number of receptors (about 12) that can
recognize different types of PAMPs.
4-Receptors for opsonins:
Opsonins
are various proteins that coat microbes and promote their
phagocytosis.
Macrophages and neutrophils have receptors for these opsonins:
-CD14 which bind LPS binding protein
-Receptors for Mannose binding protein
-Receptors for C reactive protein.
-FcyRI which binds IgG
-CR1 which binds C3b
Components of the innate immunity
A- First line of natural defense: (simple barriers)
1- Skin:
- Intact skin physically prevents microorganism from entering
the tissue beneath.
- Lactic acid and fatty acids in the sweat are toxic to many
organisms.
- Defensins in the skin of mammals have broad-spectrum
antibiotic effect.
2- The epithelial surface (mucus membrane)
- Mm lining respiratory and digestive tracts are bathed in a
protective layer of mucus which can trap, dissolve and sweep
away foreign substances
- Epithelial cells produce defensins.
- Hair lining the mm of anterior nares help in trapping foreign
substances which can be expelled by sneezing.
- Cilia lining the trachea have a lashing movement to outside
which help cleaning the mm.
- Mucus membrane of urinary tract is cleansed by flushing of
urine.
3- Lysozyme in tears and saliva is bactericidal.
4- Acidic pH in stomach and vagina helps in
destroying many bacteria.
5- Commensals (normal flora or microbiota):
Present on the skin, conjunctiva, at the portal of entry as upper
part of respiratory tract, mouth, GIT, genitourinary tract.
They suppress the growth of pathogenic bacteria and fungi
by:
- Competition for adherence sites and food.
- Production of inhibitory substances as acids and Colicin.
B- Second line of natural defense:
I- Circulating proteins of innate immunity:
1- Lysozyme (mucopeptidase): present in all body secretion except
CSF and urine. It can destroy peptidoglycan mainly of gram+v
bacteria.
2- Mannose-binding lectins (MBL): An opsonin that binds to sugar
mannose
3- C-reactive protein An opsonin
4- LPS binding protein: An opsonin that binds to LPS of gm-ve
bacteria
5- Complement: An opsonin
A naturally-occurring, self-regulating system consisting of about 30
proteins. Activation results in phagocytosis or lysis of the organism
II- Cells of the innate immunity:
1- Phagocytes:
-The word 'phagocyte' literally means 'eating cell’.
-These are immune cells that engulf, or 'phagocytose', pathogens or
particles.
Perform two general functions:
- First, they are able to internalize and kill microbes
- Second, they produce various cytokines that promote
inflammation.
There are 3 main types:
A- Polymorphnuclear leucocytes (PMNL) mainly
neutrophils:
- Have abundant granules which store bactericidal agents as:
lysozyme, proteinases, collagenases, elastasis, lactoferrin, cathepsin
G, defensins.
Neutrophils, along with eosinophils and basophils, are known as granulocytes due to the
presence of granules in their cytoplasm, or as polymorphonuclear cells (PMNs) due to
their distinctive lobed nuclei.
B- Mononuclear phagocytes (macrophages):
- These may be wondering cells in connective tissue (histiocytes),
and blood (monocytes), or fixed reticuloendothelial cells as those
lining blood vessels and lymph sinuses in liver (Kupfer cells),
spleen, lung, bone marrow, LN.
C- Dendritic Cells
- Present in epithelia and most tissues of the body:
-mainly the skin (where they are often called Langerhans cells),
- The inner mucosal lining of the nose, lungs, stomach, and intestines.
They are named for their resemblance to neuronal dendrites as they
have many long narrow processes but dendritic cells are not connected
to the nervous system.
Dendritic cells are very important in the process of antigen presentation,
and serve as a link between the innate and adaptive immune systems.
Steps of phagocytosis:
1- Migration (chemotaxis):
Chemotactic factors produced by microbes, injured tissue,
some complement factors and cytokines attract phagocytic
cells to the site of infection.
2- Adhesion (attachment)
- Binding of phagocyte to pathogen through receptors
followed by phagocytosis.
- Attachment is greatly enhanced if the organism is coated by
an antibody or by activated complement C3b or both and
this process is called opsonization.
3- Ingestion (engulfment)
- Pseudopodia surround the pathogen, then fuse to form a vacuole
called a phagosome
- Formation of phagolysosomes by fusion with lysosomes
(vacuoles containing a broad spectrum of digestive enzymes)
4- Digestion/killing: occurs inside phagolysosomes by 2 systems:→
a-The oxygen-dependent killing system:
- Oxygen is converted to reactive oxygen intermediates as:
superoxide anion, hydrogen peroxide and hydroxyl radical
(oxygen burst)- kill microbes directly by oxidizing their nucleic
acid and proteins
b- The oxygen-independent killing system:
by lysozomal granules content which include: lysozyme, lactoferrin,
defensins, hydrolytic and proteolytic enzymes.
5- Egestion: of undigested materials by a process that is reverse of
ingestion
Animation of Phagocytosis by Enhanced Attachment (Opsonization)
2- Natural killer (NK) cells:
- Large granular lymphocytes that originate from BM.
-First line of defense that naturally kill tumor cells and
virally infected cells without prior exposure
-NK cells are activated in response to interferons (Type I
interferons) or cytokines released from activated
phagocytic cells (neutrophils or dentritic cells ) which are
IL-12 and IL-15.
-NK cells work to control viral infections by secreting:
IFNγ and TNFα.
IFNγ : -Activates macrophages for phagocytosis
TNFα: acts to promote direct NK tumor cell killing.
Natural Killer cells :
NK cells destroy compromised host cells, such as tumor cells or virus-infected cells,
recognizing such cells by a condition known as "missing self." This term describes
cells with abnormally low levels of a cell-surface marker called MHC I (major
histocompatibility complex)
Normal body cells are not recognized and attacked by NK cells because they
express intact self MHC antigens.
Leukocyte Players of
Innate Immune Responses
III- Interferons:
- Proteins of small molecular weight.
- 2 types:
Type I IFNs: IFNs α and β
Type II IFNs: IFNs γ
- α and β are important in non-specific defense against viral
infection.
- They are released by any virally infected cell and when taken
by other cells, protect them from the same virus and other
viruses.
- The protection through inducing formation of a translation
inhibition protein which inhibits translation of viral genes.
IV- Inflammatory response:
- "early-warning" system whose signs include erythema (redness);
edema (swelling); fever; pain.
- Histamine and prostaglandin and other inflammatory mediators
released by macrophages as IL1, IL6, IL8, IL12, TNFα, leukotrienes
(inflammatory cytokines) cause dilatation of local arterioles and
capillaries (Increases capillary permeability) with pouring of plasma in
the inflamed area (edema). The area becomes swollen, red,
temperature increases from the increased blood flow.
- The edema fluid carries proteins of innate immunity and fibrin.
- Inflammatory mediators also induce the expression of adhesion
molecules (integrins and selectin) on leucocytes and endothelial
cells that cause leucocytes to adhere to endothelial cells of blood
vessels, then migrate out of the capillaries (extravasation)
towards the irritant.
- PNLs phagocytose microorganisms and digest them then undergo
apoptosis.
- Macrophages engulf leukocyte debris and microorganisms and
pave the way for resolution of the local inflammatory process.
- Among the factors capable of inducing fever (pyogenes) are the
endotoxin of gm-ve bacteria and IL1 released by macrophages.
Inflammatory response
The release of histamine and prostaglandin causes local vessel dilation resulting in:
• more WBCs to site
• increased blood flow redness and warmth
• increased capillary permeability
• phagocytes move out of vessels into intracellular fluid (ICF)
• edema (swelling) due to fluids seeping from capillaries
Cellular response
Antimicrobial Peptides
Vertebrates, invertebrates, even plants and fungi
secrete antimicrobial peptides that protect them from
invasion by bacteria and other pathogens.
For humans, the best-studied antimicrobial peptides
are the
- Defensins,
-Hepcidin, and
- Cathelicidins
Defensins
They attack the outer surface of the cell membrane surrounding
the pathogen causing lethal holes.
Hepcidin
- Secreted by the liver and controls the level of iron in the blood
and ECF by regulating its release from intracellular stores.
- Many pathogens require iron for their virulence and by
blocking the release of iron into the blood, hepcidin starves
them of this essential factor.
Cathelicidins
Synthesized by macrophages, neutrophils, epithelial cells and
skin. In macrophages, cathelicidin synthesis promotes killing
of engulfed bacteria like M. tuberculosis
