Acquired Immunity

Cell-mediated immune response

❖ T-lymphocytes
❖ eliminate intracellular microbes that survive within phagocytes or other
infected cells
Humoral immune response
❖ B-lymphocytes
❖ mediated by immunoglobulins (antibodies)
❖ eliminate extra-cellular microbes and their toxins
N.B : The normal Acquired immune response include interaction between cell
mediated & humoral immune response
Differentiate between cell mediated & Humoral immune response
Characters of acquired immune response Enumerate
1-Specificity
• Ab or cell recognize antigen that induce its formation and act only on it not
other Ag
2 – Discrimination
• Between "self" and "non-self", response only to molecules that are non-self
or foreign but not to those that are self
3-Diversity Define
• It can respond to millions of antigens.
• The lymphocyte population consists of many different clones, each clone
expresses an antigen receptor that is different from the receptors of all other
clones.
Clonal selection
• Each lymphocyte has a single antigen specificity and after stimulation by
antigen it proliferate and produce a clone of cells with the same specificity

4-Development of memory cells

• This memory cells give rapid and life-long immunity on re-exposure to
the same antigen
Organs of the immune system

Primary lymphoid organs Secondary lymphoid organs

Responsible for lymphopoiesis sites where naïve mature
Functions and maturation of lymphocytes lymphocytes will first be
Enumerate exposed to their specific
Antigens
Members TRMS
1. Tonsils
Bone marrow 2. Resp. tract
Thymus
( Complete) 3. MALT of GIT
4. Spleen
5. Lymph nodes
T-cell B-cell (Sites for Ag contact and
maturation maturation response)

Cells of immune system

1. B lymphocyte
2. T lymphocyte
o CD4 T cell (T- helper)
o CD8 T cell (T- cytotoxic )
3. Natural killer cells
4. Antigen Presenting cells (APCs)
o Macrophage
o Dendritic cells
o B- Lymphocyte
 Collections

acquired (Adaptive) immunity Innate immunity

adaPTive 1. Phagocytes
1. B lymphocyte a. Macrophage
2. T lymphocyte b. Neutrophils
Identify 2. Natural killer cells
Cells of both Innate & acquired immunity (Antigen presenting cell) (APC)
Enumerate
MDB
• Macrophage
• Dendritic cell
• B lymphocyte
Each cell must include [ 7 points ]
1. Percentage
2. Life span
3. Site
4. Stimulation
5. Receptor
6. Recognition of antigen
7. Functions
B lymphocytes

1 Percentage 30% of circulating small lymphocytes

2 Life span short life span (days or weeks)
1. lymph nodes germinal center,
3 Site 2. spleen white pulp
3. GALT ( Gut associated lymphoid tissue )
4 Stimulation By cooperation of T cells
5 Receptor IgM and IgD molecules on their surface
Recognition directly without a need for MHC restriction
6
of antigen
• Are important APCs
7 Functions
• Differentiate to plasma cells that secrete antibodies
 T lymphocytes

1 Percentage 65-80% of circulating small lymphocytes

2 Life span longer life span (months or years)
3 Site peripheral lymphoid organs to meet their specific antigen
4 Stimulation -----------------------------
5 Receptor TCR and CD3 molecules on their surface
T cell markers: Enumerate
Includes
- TCR,
- CD3
- CD4 or CD8
- CD2
- CD28
- CD40L on activated cell.
Functions
- These are required for interaction between T cells and APCs and for antigen
recognition
Recognition Recognize antigen presented on MHC molecules by APCs
6
of antigen
Bear MHC restricted:
- CD4 T-cells are MHC II restricted
- CD8 T-cells are MHC I restricted
7 Functions Stimulation of other cells of immune system
Differentiate between mature B cell & T cell
MHC restriction Define
It is an important process in presentation of antigens to T-cells
1. CD8 T-Lymphocyte Recognizing antigen by MHC-I complex on APC and
other cell as Virus-Infected Cell
2. CD4 T-Lymphocyte Recognizing antigen by MHC-II complex on APC
 T lymphocytes subpopulation
1. T helper cells (TH) (CD4)
o TH1
o TH2
o Regulatory T cells (Tregs)
o TH17
2. T cytotoxic (CD8)
CD4 T helper lymphocytes (TH)

1 Percentage 65% of peripheral T cells

2 Life span Same as T lymphocyte [ longer life span (months or years)]
1. the thymic medulla
3 Site 2. tonsils
3. blood
4 Stimulation -----------------------------
5 Receptor CD4 + other T cell markers
Recognition recognize antigen on the surface of APC in association with
6
of antigen class II MHC molecules
• They activate major cells as macrophage, CTLs, NK
7 Functions
cells and Abs producing B cells.
Notes
• Principal orchestrator of immune response
 • Are attacked by HIV virus
• Types
o TH 1
o TH 2
o TH 17
o Regulatory T cells
All these types arise from naïve TH0

Mechanism of differentiation

TH 1 differentiation
Cell 1
• macrophage secrete IL-12 (A) ( Identify )
• NK cells secrete IFN-γ (A) (Identify )
Induce differentiation of naïve TH0 to TH1 (Cell 2)

Cell 2 ( TH1 ) secretes

• A: IFN-γ,
• B: TNF-β, IL-2
• IL-3 and GM-CSF (Granulocyte-macrophage colony-stimulating factor)
Activate
1. CMI: Activate macrophages, NK cells and CTLs (Mainly )
 2. Humoral immunity: Enhance production of selected classes of Abs that
participate in opsonization and ADCC (IgG)

Cross regulatory activity Explain

• IFN-γ and IL-12 ➔ Increase production of TH1
• IL-4 and IL-10 ➔ Inhibit production of TH1

TH 2 differentiation
Cell 1
• Several cells secrete IL-4 (A)
Induce differentiation of naïve TH0 to TH2 (Cell 2)

Cell 2 ( TH2 ) secretes

• A : IL-4
• B: IL -5, IL-6, IL-13, TGF β
• IL-3 and GM-CSF

Activate
1. Humoral immunity: B cell activation and differentiation into plasma cell ➔
Enhance production of all classes of Abs (Mainly )
2. CMI: Stimulate eosinophils and mast cells (parasitic and allergic reactions)

Cross regulatory activity Explain

• IL-4 and IL-10 ➔ Increase production of TH2
• IFN-γ ➔ Inhibit production of TH2
 TH1 TH2
Interleukins IFN-γ, IL-2, TNF-β, , IL-3 IL-4, IL -5, IL-6, IL13, TGF-
produced and GM-CSF β , IL-3 and GM-CSF
Production
IFN-γ / IL-12 IL-4 , IL-10
enhanced by
Production
IL-4, IL-10 IFN-γ
inhibited by
Surface molecules
CD26, CXCR3, CCR5 CCR3, CCR4
more expressed
Cell mediated immunity Humoral immunity
By Activation of → 1-B cell differentiation
Main functions
macrophages, NK and TC. 2-Antibody production of all
classes
Compare between TH1 & TH2
Regulatory T cells (Tregs)
• Form 5-10% of T helper cells and are CD4+ CD25+ and Foxp3+ (unique
marker is necessary for its development and function).
• Secrete TGF-β and IL10 (immunosuppressive cytokines).
CD8 Cytotoxic T-lymphocytes (CTLs)

1 Percentage 35% of peripheral T-cells

2 Life span Same as T lymphocyte [ longer life span (months or years)]
• bone marrow
3 Site
• GALT
4 Stimulation -----------------------------
5 Receptor CD 8 + other T cell markers
• recognize antigen on surface of target cells (infected
Recognition
6 APC or other infected nucleated cell) in association
of antigen
with MHC-I
7 Functions • kill the virus infected cell or tumor cell or graft cell
Mechanisms of cell killing (cytotoxicity) by CTLs; Explain
1. Cytolytic proteins:
o CTLs release Cytolytic proteins as Perforins, Granzymes
o Perforins form pores in the cell membrane and facilitate granzymes
entry into cytoplasm
 o Granzymes stimulate apoptosis of target cell.
2. Fas – Fas ligand:
o CTLs express a membrane protein Fas Ligand (FasL),
o bind to its target protein Fas on many cell types and stimulate
apoptosis of target cell
Compare between CD4 & CD 8 Cells
Natural Killer (NK) Cells
• Large granular lymphocytes lack surface markers of B and T cells (CD3-)
1 Percentage 5-10 % of the peripheral lymphocytes.
2 Life span -----------------------------
Innate immunity present in all sites of innate immunity as a
3 Site
second line of defence
4 Stimulation IL-12, IL-15, , INF-α and β
• CD3- ,
• CD16+ (Marker differentiate it from other
5 Receptor immune cells as it binds to Fc part of IgG)
(Identify)
• CD56+
Recognition • Not MHC restricted and presence of MHC I on
6
of antigen normal cell inhibits NK cell
• Kill any MHC-I negative cells as tumor - graft cell -
7 Functions virus infected cell and also intracellular bacteria (non-
specific)
Enumerate characters of NK cells
The mechanisms of killing (cytolysis) by NK cell
1. Enzymes perforins, granzymes form pores in bacterial cell membrane
2. Production of INF-γ
o activation of macrophages to destroy phagocytosed organism (I, II like
CTLs)
3. LAK conversion Killing
o IL-2 activated NK cells are called Lymphokine activated killer (LAK)
best for tumor killing so used in cancer immunotherapy
 4. Kill by ADCC (antibody dependent cellular cytotoxicity )

ADCC (antibody dependent cellular cytotoxicity )

Definition
• Destruction of antibody coated abnormal cell
Cells can do it = Cells of innate immunity
• NK cells
• macrophages
• neutrophils
• eosinophils
Mechanism
• These cells have receptors for Fc of IgG
• The Fc of IgG bind to Fc receptor of these cells then these cells release
extracellular lytic enzymes , TNF , Perforins leading to extracellular
killing

N.B:NK cell is the immune cell that kill without MHC molecule (identify)

NK cells CTLs
Functions innate and acquired immunity Function in acquired immunity
Antigen Spontaneous killing need specific recognition of
recognition ( no previous recognition of antigen
antigen)
Specificity non-specific specific
MHC Not MHC restricted MHC restricted
restriction
ADCC Occurs No ADCC
Markers CD16, 56, 2 TCR, CD3, 8, 2
Compare between NK and CTL
 Antigen presenting cells (APCs)
Dendritic cells
• Most efficient APCs
• Express MHC I, II molecules
• Found under skin and mucosa of most organs
Macrophage
1 Origin Derived from myeloid stem cells in BM
• Free in blood (Monocytes),
2 Site
• fixed in tissues (Macrophages)
• Activated and attracted to the site of Ags by different
3 Stimulation
cytokines including INF-Ȣ and C5a
Recognition • Ingest, process and present Ags in association with
4
of antigen MHC II (Identify)
Functions Enumerate
1. Phagocytosis
2. Kill by opsonization “ Enhanced phagocytosis”
3. APC
4. ADCC
5. Secrete IL-1 , IL-6 , IL-12 , IL-15 , IL-8 , interferons , TNF-α ➔ which are
important for inflammatory and immune response
6. Secrete prostaglandins which enter in formation of Complement
components which it important for immune response
 Opsonization “ Enhanced phagocytosis”
• Macrophage has receptors for IgG & C3b
• When antigen enter body and IgG is released to interact with
antigen leading to activation of complement system and the
cascade reach C3b
Mechanism
• C3b and IgG combine to their receptors on Macrophage then
macrophage has two choices
o Kill antibody coated antigen which is called ADCC
o Phagocytosis antibody coated antigen which is called
Opsonization

Cell Mediated Immunity

Definition
• is an immune response that does not involve antibodies, but rather
involves the activation of macrophages and NK-cells, the production of
antigen-specific cytotoxic T -lymphocytes, and the release of various
cytokines in response to an antigen.

Functions
1. Host defenses against Intracellular infection are mediated by CMI as
intracellular bacteria, virus Infected cell
2. CMI mediate defense against: tumour cell & graft cell
Effects
1- Beneficial effects: defense against tumor cells, virus infected cells &
intracellular microbes.
 2- Harmful effects: as in type IV hypersensitivity, autoimmune diseases and
graft rejection
Phases Of CMI
Antigen processing and presentation
Protein antigens processed and converted to peptides then bind to MHC molecules
on Antigen Presenting Cell (APCs) to be presented to T-cells
Extracellular proteins Endogenously synthesized
proteins
1. internalized into vesicular
compartment of APCs
General (Dendritic, macrophages, B- are degraded to peptides
steps cells)
2. They are degraded to
generate peptides
MHC These peptides bind into groove
They bind to class I MHC in
restriction of class II MHC molecules endoplasmic reticulum
Peptide-MHC II complex is Peptide-MHC I complex is
transported to surface of APCs to
expressed on surface of
T cell be presented to CD4 TH cells nucleotide cells to be
represented to CD8 cytotoxic
cells
Secretion of cytokines by TH Killing of presenting cells by
Outcome
cells CTLs
Compare between Extracellular & Intracellular proteins processing
Activation of T-cells Explain / Describe signals for T cell activation
Signal name On APC On T-cell

Ag antigenic -MHCII with TCR-CD3

1st signal
recognition complex on APC . complex on T cell.

2nd co-
activation of B7 on APCs
stimulatory with CD28 on T cells
T cell
signal
 3rd co- Co-
stimulatory activation of CD40 on APC. with CD40L on T cell
signal T cell
Turn off T-cell signals
Responsible protein (Identify)
➢ CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a molecule
closely related to CD28
Mechanism
➢ interacts with B7 giving a signal to
o turn off the synthesis of IL-2,
o limiting the extent of the immune response : differentiate T cell into
Memory cell
Notes
1. First signal : CD4 and CD8 molecules are co-receptors that stabilize the
interaction of TH cells and TC-cells respectively with APCs
2. 3rd Co signal : Results in APCs (Macrophage) activation (Identify)
3. Anergy : Absence of second co stimulatory signal (T cell recognize antigen
well but can’t kill it )
Polyclonal activation of lymphocytes:
- Molecules stimulate large numbers of cells without antigen specificity
(specific Ag stimulate only a small number of B and T cells).
Superantigens (SAgs):
Definition
• Antigens that activate multiple clones of T lymphocytes without
specificity
Examples
1. Staph. aureus toxic shock syndrome toxin (TSST) and
2. Strept. pyogenes toxin A
3. The gpl20 of HIV
Pathogenesis
 ▪ SAgs cause a large percent of T cells to be stimulated → release of large
amounts of cytokines → cause systemic toxicity ( Result of super antigen
stimulation ( Identify)) .
▪ The affected lymphocytes after release of cytokines become exhausted and
refractory to further stimulation (anergic)
Q: Compare between antigens & super antigens
Antigens Superantigens
Processed in APCs yes no
Presentation by MHC yes no
into the peptide-binding
Binding to MHC outside the groove
groove

variable regions of both variable region of β chain

TCR bind by
chains only

Cytokines released The required levels Very high harmful levels

Development of memory Occurs Does not occur

St. aureus enterotoxin and

Example All ordinary antigens
TSST.
Outcome Acquired immunity Anergy
Active at very low
Effective concentration Optimal concentration
concentration
Justify : Activation of T cell by super-antigen is different from antigen
activation
• Super-antigen bind outside MHC groove to variable beta chain only of
TCR
• They aren’t processed by APCs