Innate Immunity I,II

BY
Dr. Mervat Abdel-Aziz
Medical Microbiology, Immunology & Infection Control
 Structure of the Immune System

• The immune system is a mobile, circulating

system.
• However, there are some fixed anatomical
structures which are important to its function
 • 1- Primary lymphoid organ :lymphocyte
formation and maturation
A-Bone Marrow : Immune cells are formed
within the bone marrow during the
haematopoiesis process.
B- The thymus gland It is the site where
lymphocytes get matured and receive their
immunological “education” before being
released into the bloodstream.
 2- Secondary lymphoid organ
(lymphocyte meet antigen and activation)
• Lymph node: Mature lymphocytes migrate to
lymph nodes. These filter lymph and provide a
site for antigen presentation to the adaptive
immune system
• The spleen is basically a massive lymph node and
is, therefore, another site of antigen presentation
to mature lymphocytes.
(It is a part of the reticulo-endothelial system which
filters blood and removes aging cells, tissue debris,
pathogens and immune complexes. It also stores
red blood cells and immature monocytes.
• NB liver: also a site of antigen presentation
and contains its own cohort of phagocytes and
lymphocytes
• liver filters large volumes of potentially
contaminated venous blood from the
gastrointestinal (GI) tract.
• It also synthesizes acute phase proteins
 Cells of the Immune System

1- GRANULOCYTES
• (Family of white blood cells containing
granules in their cytoplasm)
 A- NEUTROPHILS
• normally make up 40-75% of all white blood
cells (2000-7500 /cmm on a full blood count)
• The first line of defense against all infections
• act by phagocytosing invading organisms and
presenting antigens to the immune system

• They have segmented nuclei and their cytoplasm is full of

pinky-purple intracellular granules
 2- EOSINOPHILS
• normally make up 1-6% of white blood
cells (40-400 /cmm on a full blood count)
• specifically act against multicellular parasites
(e.g. worms) by dissolving their cell surfaces
• they are also involved in IgE-mediated allergic
disorders such as asthma
• they have bilobed nuclei and intracellular granules which
stain brick red with eosin
 C- BASOPHILS
• normally make up 0-1% of white blood cells (≤10
/cmm on a full blood count)
• They are the circulating counterparts of tissue
mast cells.
• they may have roles in inflammation, parasitic
infections and allergic reactions
• mast cells/basophils have an important role in
type 1 hypersensitivity reactions through their
binding with IgE antibodies
• they have bilobed nuclei and large darkly staining
intracellular granules
 MONOCYTES & MACROPHAGES
(Large cells involved in phagocytosis
and antigen presentation).
 A-BLOOD MONOCYTES
• normally make up 2-10% of white blood
cells (200-800 /cmm on a full blood count)
• they are produced in the bone marrow and
travel in the bloodstream to their target
tissues, where they become macrophages
• they have roles in phagocytosis, antigen
presentation and cytokine production
• they are large cells with fine “ground-glass” granules and
horseshoe-shaped nuclei
 B- TISSUE MACROPHAGES
• These are tissue cells and therefore aren’t found on a full blood count
• They are derived from blood monocytes, which differentiate once they
reach their target tissues into macrophages.

• There are many types of macrophage which are specifically adapted to

different tissues – these include Küpffer cells in the liver, alveolar
macrophages in the lungs, osteoclasts in bone and microglial cells in
neurons

 they clear any pathogens, foreign debris and old or dead cells from their
tissues by phagocytosis
 they also perform antigen presentation and can activate memory cells
 Secrete cytokine
• NB Phagocytosis: They have processes on their cell membranes called
pseudopodia which extend around the target particle.
• once internalized, the phagosome is fused with another vesicle called a
lysosome containing either reactive oxygen species or enzymes, which
break down its contents

• NB like monocytes, they are large cells with horseshoe-shaped nuclei

 LYMPHOCYTES (AGRANULOCYTES)
(Small, specialised white blood cells with large
nuclei and no granules)

• Normally make up 20-45% of all white blood

cells (1300-3500 /cmm on a full blood count)
• There are three main subtypes of
lymphocytes: B cells, T cells and natural killer
(NK) cells
• B cells and T cells make up the majority of the
lymphocyte population.
• They are small cells with large round nuclei,
scanty bluish cytoplasm and no granules,
• The only way to differentiate them apart is by
using a special staining for specific cell surface
markers known as clusters of differentiation
(CDs).’

• NK cells are a larger, more primitive lymphocyte

subtype which does contain some granules.
 A- B CELLS

• B cells represent about 10-15% of the total lymphocyte

population –
• important B cell surface markers include CD19, CD20 and
CD21, as well as MHC II (that is why they have a role in
antigen processing and presentation)
• Essential for humoral immunity, also known as the
antibody-mediated immune response
 the plasma cells are mature B cells which secrete
antibodies,
 memory B cells “remember” the offending foreign antigens
to allow the immune system to mount a quicker antibody
response to any subsequent infections
 B- T CELLS

• T cells represent about 75% of the total

lymphocyte population – this varies
depending on the activity of the immune
response.
• all T cells express CD3 on their surfaces, along
with T cell receptors (TCRs) which
recognize specific antigens presented in
an MHC I or MHC II molecule by the antigen
presenting cells
 T cell subtypes

• 1- helper T cells (CD4) facilitate the activation of the immune

response and stimulate division and differentiation of various
effector cells
• 2- cytotoxic T cells (CD8) provide cell-mediated immunity by
targeting and killing viral infected cells (and tumor cells)
• 3-regulatory T cells (CD25 + FOXP3) – also known as suppressor T
cells – play a vital role in limiting the immune response to prevent
excessive damage to tissues and organs
• 4-memory T cells (CD62 + CCR7) “remember” what has happened
to allow the immune system to mount a faster, more effective
response should the offending organism be foolish enough to
return
 C-NATURAL KILLER CELLS
• NK cells represent about 5% of the total lymphocyte population –
again, this varies depending on what’s going regarding the immune
response.
• They are a larger lymphocyte subtype with granules in their
cytoplasm – they are also known as large granular lymphocytes
(LGLs)

• They express CD16 and CD56.

• NK cells actually form part of both the innate and adaptive
immune systems and are able to destroy pathogens and infected
cells without the need for specific antigen recognition (No MHC
restriction).
• They are also particularly important in immunity against viral
infections and tumors.
 The normal immune response can be
broken down into four main components:

Pathogen recognition by cells of the innate

immune system, with cytokine release,
complement activation and phagocytosis of
antigens
The innate immune system triggers an acute
inflammatory response to contain the infection
Meanwhile, antigen presentation takes place
with activation of specific T helper cells
 humoral immunity from B cells and antibodies,
and cell-mediated immunity from cytotoxic CD8
T cell.
 Innate immuntiy Specific immnit
Aquired immunity
Immediately after infection Relatively delayed
This is the first line of defense
. It is very fast – it is established within
(require full recognition for organism)
about 4 hours

Less efficient More efficient

Non specific Specific
include Include:
1- Mechanical Barrier : and secretion B lymphocyte
2- a chemical response And T lymphocyte
3- Cell : Neutrophil, esinophil,
basophil, monocyte, macrophage , NK
4-inflammatory response.

No memory Memory present

 Mechanisms of Innate Immunity
I. Mechanical barriers and surface secretions
and flora
II. Chemical response
III. Cellular defense mechanisms
IV. Inflammation
1- INNATE CELLULAR IMMUNE RESPONSE

1- Phagocytes
blood monocytes, tissue macrophages
dendritic cells
and, most importantly, neutrophils:
(only appear in response to infection or injury,
and are therefore not found in a healthy tissue. )
• Phagocytes identify pathogens by
• recognizing pathogen-associated molecular
patterns (PAMPs)
• using pathogen recognition receptors
(PRRs):Toll like receptor
 After identification:
A- Internalize them, kill them and digest them
B- present the digested protein antigens to the
cells of the adaptive immune system via major
histocompatibility complexes (MHCs)
T cells can only react to an antigen if it is presented within an MHC complex.
This phenomenon is known as MHC restriction.

.
• C- a transcription factor is activated which
results in the release of proinflammatory
cytokines and the initiation of the
inflammatory response
 The Mechanism of Phagocytosis:
Four main phases:
chemotaxis,adherence, ingestion, digestion
1- Chemotaxis is the chemical attraction of
phagocytes to microorganisms.

chemotactic chemicals :
microbial products, damaged tissue cells,
cytokines released by other white blood cells,
and peptides derived from complement system.
2- Adherence is the attachment of the
phagocyte’s plasma membrane to the surface of
the microorganism or other foreign material

• facilitated by the attachment of pathogen-

associated molecular patterns (PAMPs) of
microbes to receptors, such as Toll-like
receptors (TLRs), on the surface of phagocytes.
 Opsonization; facilitated or enhanced
• Microorganisms can be more readily phagocytized if they are
first coated with certain serum proteins that promote
attachment of the microorganisms to the phagocyte.
• This coating process is called opsonization.
• The proteins that act as opsonins include some components
of the complement system and antibody molecules.
INNATE II
 3- Ingestion During this process, the
plasma membrane of the phagocyte
extends projections called pseudopods

• surrounding the microorganism with a sac

called a phagosome, or phagocytic vesicle

• The membrane of a phagosome has enzymes

that pump protons (H+) into the phagosome,
reducing the pH to about 4. At this pH,
hydrolytic enzymes are activated
4- Digestion In this phase of phagocytosis, the
phagosome pinches off from the plasma
membrane and enters the cytoplasm

• It contacts lysosomes that contain digestive

enzymes and bactericidal substances.

• On contact, the phagosome and lysosome

membranes fuse to form a single, larger
structure called a phagolysosome
 Lysosomal enzymes
• 1-lysozyme, which hydrolyzes peptidoglycan in
bacterial cell walls.
• 2- lipases, proteases, ribonuclease, and
deoxyribonuclease, hydrolyze other
macromolecular components of microorganisms
• 3- also contain enzymes that can produce toxic
oxygen products such as superoxide radical (O2–),
hydrogen peroxide (H2O2), nitric oxide (NO),
singlet oxygen (1O2−), and hydroxyl radical (OH·)
• .(Toxic oxygen products are produced by a
process called an oxidative burst)
• enzyme myeloperoxidase converts chloride (Cl−) ions and
hydrogen peroxide into highly toxic hypochlorous acid (HOCl).
• The acid contains hypochlorous ions, which are found in
household bleach and account for its antimicrobial activity.
• After enzymes have digested the
phagolysosome contains indigestible material
and is called a residual body.
• This residual body then moves toward the cell
boundary and discharges its wastes outside
the cell
 Natural killer cells (NK cells)

 Unlike T cells, they do not require activation by specific

antigens, which means they are able to respond
immediately when exposed to a pathogen
 “Self” cells are protected from the destructive action
of NK cells by the inhibitory effects of MHC I, which is
expressed on the surface of all nucleated body cells
 Normally, NK cells cannot attack healthy “self” cells.
However, MHC I expression is often suppressed if cells
are infected with viruses, or have become cancerous.
NK cells can, therefore, perform additional vital roles in
viral immunity and tumor rejection.
 NK cells do this by releasing toxic granules to induce
apoptosis
 2-Inflammatory Response

• The acute inflammatory response (innate

immune cells, proinflammatory cytokines and
complement proteins).
• to localize and contain the infection in the
period of hours after its onset, (when the
innate immune system is running out of
stream and the specific cellular immune
response is still trying to get going.)
The main features of this process are:

• 1- Vasodilation and increased blood flow – this leads

to erythema and warmth
• 2- Increased vascular permeability – this allows an
inflammatory cell infiltrate to extravasate and reach
the site of infection, and also causes tissue oedema
and swelling
• 3- Release of inflammatory mediators such as
bradykinins and prostaglandins which increase pain
sensitivity in the infected area
• 4-Microvascular coagulation – this is induced by local
tissue damage, and acts to confine the infection and
prevent its spread.
 Neutrophil chemotaxis – neutrophils migrate to the
site of infection and begin their clean-up operation,
phagocytosing pathogens and debris.
 Systemic features such as fever and
raised inflammatory markers such as C-reactive
protein (CRP) and ferritin – this produces unpleasant
“flu-like” symptoms such as hot flushes, sweats, chills,
rigors, headache, nausea, myalgia, arthralgia and
fatigue
 Upregulation of costimulatory molecules such as
MHC-II and B7 to encourage activation of the adaptive
immune system.
• MHC : Major histocompatability complex
• MHC I : All nucleated cell
• MHC II : Macrophage , B cell
 Vesicular antigen Cytosolic Antigen ( viral)
(Macrohage) presented presented on MHC I
on MHC II to
to T Hepler cell (CD4) T cytotoxic (CD8)
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