Transcript Immunology-Y1 - WordPress.com

Immunology
Prof. Dr. Ibrahim ElMorsy
Objectives
•
•
•
•
•
•
•
Define immunity, tolerance ,and susceptibility.
Define innate immunity, acquired immunity, genetic immunity.
Define antigen, hapten, and antibody (immunoglobulin) and complement.
Define cell-mediated immunity (CMI) and humoral immunity (HI).
Define « primary immune response » and « secondary immune response ».
List and define the different types of hypersensitivity reactions.
Define autoimmunity and give examples on auto-immune disorders
Immunity
•
Body defence against invasion by foreign bodies.
The immune system has two lines of defense:
•
innate (non-specific) immunity .
•
adaptive (Specific) immunity.
1. Innate immunity
Characters:
•
First line of defense
•
Rapid defense
•
The same on re-exposure to Ag
•
No memory cell
2. Adaptive immunity
Characters:
•
2nd line of defense
•
Delayed as response to infection
•
Specific for microbes & antigen (can differentiate
antigen)
•
Has memory cell which remember microbes and
give strong immune response on re-exposure
Components of Innate immune system
1-Barriers to infection:
a-Physical (Skin)
b-Mechanical (cilia)
c-Chemical (stomach HCL)
d-Biological (commensal bacteria)
2-Cells: Phagocytes (Macrophage and
neutrophil) and NK cells
3-Complement system
4-Cytokines (Interleukines)
5- Plasma proteins (CRP)
Components of specific IS
•
B lymphocyte:
Produce antibodies that neutralize
and eliminate extracellular
microbes and toxins (humoral
immunity).
•
T lymphocyte:
Eradicate intracellular microbes
(cell mediated immunity).
Tolerance
•
•
Definition:
Tolerance refers to the specific immunological non-reactivity to an antigen
resulting from a previous exposure to the same antigen. When an antigen induces
tolerance, it is termed tolerogen.
Mechanism of tolerance induction
Clonal deletion:
Auto-reactive
T-cells
are
eliminated in the thymus following
interaction with self-Ag during
their
differentiation
(negative
selection).
Suppressor cells:
Both low and high doses of Ag may
induce suppressor T cells, which
can specifically suppress immune
responses of both B and T cells.
Antigen Binding Molecules Of The
Immune System
• Immunoglobulins (Igs)
• T cell receptors (TCR)
• MHC molecules.
Antigen Presenting Cells:
–
–
–
Dendritic cells.
Macrophages.
B lymphocytes.
Antigen Presenting Cells
•
Occurance: in the epithelium of the skin, gastrointestinal tract, respiratory
tract (the common portal of entry of microbes).
•
Functions:
– Capture and transport antigens to the peripheral lymphoid tissues
– process antigens
– Present the peptides derived from these antigens to T lymphocytes.
•
They are rich in class II MHC molecules and to lesser extent MHC-I
Pathways of antigen processing & presentation:
–
Class II MHC pathway:
•
Protein antigen taken from extracellular environment.
•
Proteins are degraded by lysosomal proteases.
•
The resulting peptides are presented to CD4+ (T helper cells) cells with
class II MHC (self receptors) molecules.
– Class I MHC pathway:
• intracellular microbes (viruses or tumour cells).
• Proteins are degraded by a structure called proteosome.
• The resulting peptides are presented to CD8+ (T cytotoxic) cells
with class I MHC molecules.
Antigens
•
Antigen: Substance recognized
by immune system which may
be
– Simple or complex
– Carbohydrate,
lipid, protein,
nucleic acid,
phospholipids
– B cell recognize
any biological Ag
– T cell recognize
peptide Ag
presented on
macrophage
•
Epitopes (antigenic
determinants):
– Smallest part on Ag which
bind with BCR & T cell
receptors
– determines the specificity
of Ag
– if Ag contain multiple
epitopes , it is called
multivalent Ag
3 functional types:
a. Immunogens:
•
Large Ag with epitopes capable of
binding with immune receptor &
inducing immune response.
•
Always a macromolecule (protein,
polysaccharide).
b. Haptens
• A small Ag with epitopes capable of binding
with immune receptor & without inducing
immune response
• BUT can produce immune response only when
conjugated with large carrier molecule (as a
protein) → immune response against epitopes
of hapten & carrier.
c. Tolerogens
• Self Ag normally not stimulate immune
system
• Lack of immune response against self Ag
called self tolerance
Superantigens (SAGs)
•
•
Proteins produced by pathogens.
Not processed by antigen
presenting cells.
•
They induce massive T cell
activation
Large numbers of activated T
cells release large amount of
cytokines leading to systemic
toxicity and diseases.
•
•
Examples :
– Staphylococcal enterotoxins
– Staphylococcal toxic shock syndrome toxin-1 (TSST-1)
•
SAGs and diseases:
– Staphylococcal toxic shock syndrome .
– Staphylococcal scalded skin syndrome .
Immunoglobulins (Igs) (antibodies)
Def:
Immunoglobulins are glycoproteins
which mediate humoral or
antibody mediated immunity.
The structure of antibodies:
•
•
•
Y shaped molecules of 4
polypeptide chains
2 identical heavy chain (1
variable domain (VH) & 3 or 4
constant domains (CH)
2 identical light chain (1
variable domain (VL) & 1
constant domains (CL)
Ig classes (isotypes)
Immunoglobulin classes
Immunoglobulins →divided
into five different
classes → according to
the difference in
structure in constant
domains of heavy chain:
•
1. Gamma heavy chains
→ IgG (Monomeric)
•
2. Alpha heavy chains →
IgA (Dimeric)
•
3. Mu heavy chains →
IgM (Pentameric)
•
4. Epsilon heavy chains
→ IgE
•
5. Delta heavy chains →
IgD
Complement System
A system of circulating and membraneassociated proteins that function in
both the innate and adaptive
immunity.
Component nomenclature:
•
Components C1 – C9, factor B, D,
and P.
•
Fragments
of
complement
components: each can be cleaved
into 2 fragments indicated by a
lowercase letter (e.g. C5a, C5b,
C4a, C4b…).
Complement activation
•
In innate immunity, complement
can be activated in two ways:
1- the alternative pathway
2- the mannan-binding lectin
pathway.
•
Complement can also be activated
in the adaptive immune system via
the
3- classical pathway.
End result of the three pathways
is formation of a complement cell
membrane
complex
made
of
C5b6789 which kills organisms by
lysis and hollows formation.
Cell-Mediated Immunity
•
Eradicates infections
caused by intracellular
microbes.
•
Consist of the
activation of naïve T
cells to proliferate and
differentiate into
effector cells (CD4+ T
helper cells and CD8+
cytolytic cells; CTLs)
and the elimination of
the intracellular
microbes.
Types of cell-mediated immunity:
•
CD4+
T
cells
activate
macrophages to kill ingested
microbes that are able to
survive inside phagocytes.
•
Helper cells of the TH1
subset activate macrophages
by
secretion
of
the
macrophage-activating cytokine
(IL-2), IFN-γ.
•
CD8+ T cells kill any cell
containing
microbes
or
microbial
proteins
in
the
cytoplasm
(intracellular)
by
direct
cell
cytotoxicity,;
eliminating the reservoir of
infection .
Activation of T cells:
Activated by two signals
•
The 1st signal: peptide Ag+
MHC on the surface of APCs
recognized by TCR.
•
The 2nd co-stimulatory signal:
is the interaction of B7 molecule
on APCs with CD28 on T cells.
•
In absence of 2nd signal,
exposure of T cells to antigen
lead to anergy
(unresponsiveness) .
Sequence of events of a prototypical immune response
Immune response is a complex
and
highly
regulated
sequence
of
events
involving several cell types
that interact with each
other either directly or
through cytokines. It is
triggered when an Ag
enters
the
body
and
encounter APCs:
• 1-:APCs capture:
a minute amount
of the Ag by
phagocytosis.
• 2-:Antigen
processing:
APCs
process the Ag to
very
small
fragments
(peptides).
•
3-:Antigen presentation:
the
APCs
present
peptides plus class II
MHC molecules to T
helper cell.
•
4-:Binding of peptideMHC complex to TCRs →
activation of helper T
lymphocytes
•
5-:Secretion
of
cytokines:
by
the
activated TH cells. IL-2
is one of the cytokines,
that act on the producing
TH
cells
themselves
leading
to
their
proliferation
and
activation.
IFN-γ
activate macrophages &
phagocytosis.
6- Activation of B lymphocytes:
while TH cells are being
activated;
some
B
cells
recognize and bind antigen
through their BCRs. B cell
activation need 2 signals to be
activated.
The first signal is binding of
the Ag to BCR,
The second one is provided
by helper factors (cytokines)
secreted by TH cells
e.g.IL-2, IL-4, IL-5. The
second signal is called T cell
help.
7-
B cell proliferation
and differentiation:
activated
B
lymphocyte
can
differentiate
into
either
-memory
B
lymphocytes
-plasma cells which
secrete antibodies
8-
Activation
of
cytotoxic T cells: Tc
lymphocytes
recognize Ag on the
surface of target
cell
(e.g.virusinfected cell) which
express class I MHC
molecules. Tc cell
activation
requires
also IL-2 & IFN-γ
from
a
nearby
activated TH cell.
The activated CTLs
kill the target cell.
Humoral (Antibody-Mediated) Immunity
•
•
Humoral immunity is mediated by secreted antibodies
Its physiologic function is defense against extracellular microbes and
microbial toxins.
Primary and Secondary Immune Response
The primary response
•
When we are exposed to an antigen for the first time, there is a lag of
several days (10 days) before specific antibody becomes detectable.
•
This antibody is IgM. After a short time, the antibody level declines.
The secondary response (Booster immune response)
• If at a later date we are re-exposed to the same antigen, there is
● more rapid appearance of antibody,
● greater amount.
● IgG class.
● remains detectable for months or years.
•
If at the same time that we are re-exposed to an antigen, we are exposed to a
different antigen for the first time, the specific response to this new antigen are
those of another primary response:
Primary
Response
Secondary
Response
Slow in Onset
Rapid in Onset
Low in Magnitude
High in Magnitude
Short Lived
Long Lived
IgM
IgG (Or IgA, or IgE)
•
This phenomenon is possible because the immune system
possesses specific immunologic memory for antigens.
•
During the primary response, some B lymphocytes, become
memory cells which are long lived. Thus we can see that the
secondary response requires the phenomen known as class
switching (IgM to IgG).
Hypersensitivity
Classification
Hypersensitivity reactions are classified into four types:
• type I, type II, type III (immediate reactions)
• type IV (delayed reactions)
Type I Hypersensitivity
Antigens = Allergens
•
•
•
Inhalants: Pollen grains, Fungal allergens
Injectants: drugs (Penicillin)
Contact: Antiseptic spray
Type I hypersensitivity is known as
immediate or hypersensitivity. The
reaction may involve:
■ Skin (urticaria and eczema),
■ Eyes (conjunctivitis),
■ Nasopharynx (rhinorrhea, rhinitis),
■ Bronchopulmonary tissues (asthma)
■ Gastrointestinal tract
(gastroenteritis).
■ The mechanism of reaction involves production of IgE, in response
to certain antigens (allergens).
■ IgE has very high affinity for its receptor on mast cells and
basophils.
■ A subsequent exposure to the same allergen cross links the cellbound IgE and triggers the release of various active substances
(Histamine, serotonin, kallikrines, bradykinines and leukotrines which
cause the signs and symptoms of anaphylaxis).
Treatment
•
•
•
A- Avoidance of exposure.
B- Symptomatic treatment (Adrenalin, anti-histamnics and bronchodilators).
C- Immunotherapy to stabilise mast cells and prevent degranulation
Type II hypersensitivity
■ Also known as cytotoxic hypersensitivity and may affect a variety
of organs and tissues.
■ The antigens are normally endogenous, although exogenous
chemicals (haptens) which can attach to cell membranes can also
lead to type II hypersensitivity.
■ Primarily mediated by IgM or IgG classes →
◘Complement mediated lysis.
◘Phagocytes and Killer cells may also play a role
(ADCC).
Types
A- RBCs lysis:
» 1- Incompatible blood transfusion.
» 2- Erythroblastosis faetalis:
» 3- Autoimmune hemolytic disease.
B- WBCs lysis:
» 1- Granulocytopenia.
» 2- Systemic Lupus Erythematosis
C- Platelet destruction
Type III Hypersensitivity
(immune complex hypersensitivity)
■ It is mediated by soluble immune complexes. They are mostly of the IgG,
although IgM may also be involved.
■ The antigen may be:
■ exogenous (chronic bacterial, viral or parasitic infections).
■ endogenous (non-organ specific autoimmunity: e.g. (SLE).
Mehanism
■ The Ag is soluble and not attached to the organ involved.
■ Soluble Ag-antibody complexes which penetrate the enothelium
of blood vessel and deposited on the vascular basement
membrane.
■ This will stimulate the complement and chemotactic factors like
C5a is released which attract neutrophils which infiltrate the
area and release lysosomal enzymes leading to destruction of
the basement membrane.
Types
1- Hypersensitivity pneumonitis
2- Postreptococcal glomerulonephritis:
3- Autoimmune disease: Rheumatoid Arthritis, SLE
Type IV Hypersensitivity
■ Type IV hypersensitivity is also known as cell mediated or delayed type
hypersensitivity.
•Example is: Contact dermatitis characterized by itching
■ Mechanisms of damage in delayed
hypersensitivity include T lymphocytes
and monocytes and/or macrophages.
Cytotoxic T cells cause direct damage
whereas Th1 cells secrete cytokines
which activate cytotoxic T cells and
recruit and activate monocytes and
macrophages, which cause the bulk of the
damage.
The delayed hypersensitivity lesions
mainly contain monocytes and a few T
cells.
AUTOIMMUNITY
Definition
Breakdown of mechanisms responsible for self-tolerance and
induction of an immune response against components of the self
resulting to tissue injury.
Effector mechanisms in autoimmune diseases: Both antibodies and
effector T cells and their products can be involved in the damage in
autoimmune diseases.
General classification:
A- Organ specific autoimmune
diseases: the immune response
is directed against antigen(s)
associated with a target
organ e.g.
•
Endocrine glands
Hashimoto thyroiditis
Type I diabetes mellitus
•
Blood
Autoimmune haemolytic
anaemia
Autoimmune thrombocytopenia
•
Myasthenia gravis
B- Non-organspecific autoimmune
diseases
(systemic): the
immune response is
directed against an
antigen or many
antigens throughout
the body.
•
It includes:
Rheumatoid arthritis
Systemic lupus
erythaematosus
Etiology of autoimmunity disease
Various theories:
■ Sequestered antigen (release of hidden antigens).
■ Escape of auto-reactive clones to the blood.
■ Loss of suppressor cells.
■Cross reactive antigens (immune system made against
foreign antigen reacts with body tissue that looks like
the foreign antigen) .
Treatment
1-Anti-inflammatory–Immunosuppresive.
2-Anti-TNF, Oral Ag, Anti-IL-12, Anti-CD4, Anti-T cell
receptors.
Thank you