Transcript Lecture #24 - Suraj @ LUMS

Lecture 24
Immunity
Immune System
Two functional divisions:
1) Innate (non specific) – first line of
defence.
2) Adaptive (specific) – if innate immune
response is breached then adaptive
response is activated.
Components of Immune Response
Soluble proteins
• Lysozyme
• Complement
• Interferons
Cells
• White blood cells
(leukocytes).
• Granulocytes – neutrophils
(70%), eosinophils (1.5%) ,
basophils (0.5%).
• Agranulocytes – monocytes
(4%) and lymphocytes T and
B cells (24%).
(1) Innate Immune Response
• Exterior defences – skin, mucosal surfaces,
lysozymes.
• Phagocytes – monocytes (macrophages)
• Natural Killer Cells
• Acute Phase Proteins – Complement and
Interferons (inflammation).
Inflammatory Response
• Damaged cells release chemical signals such as histamine,
prostaglandins and leukotrienes, that increase capillary
blood flow into the affected area.
• Increased capillary permeability caused by retraction of the
endothelial cells. Enables larger molecules than usual to
escape from the capillaries, and thus allows the soluble
mediators of immunity to reach the site of inflammation.
• In the earliest stages of inflammation, neutrophils are
particularly prevalent, but later monocytes and
lymphocytes also migrate towards the site of infection.
Soluble Factors of DefenceInterferons and Complement
• Cells within the body produce two different groups of
proteins, interferons and complement.
• They help to minimise the damaging effects of viruses and
bacteria that do manage to get through the surface barriers.
• Interferons are proteins that are produced by cells infected
by viruses. In general, they directly help to make
uninfected cells more resistant to viral attack and also
stimulate the immune system to respond to the viruses.
• Complement and complement activation
Complement is a group of different plasma proteins (C1 to
C9). Complement can be "activated" by the presence of
bacteria. Several of the activated complement proteins
combine (as Membrane Attack Complexes) to damage
bacterial membranes and cause the bacteria to die.
Complement
• The final five proteins form a
membrane attack complex
(MAC) that embeds itself into
the plasma membrane of the
attacker.
• Salts enter the invader,
facilitating water to cross the
membrane, swelling and
bursting the microbe.
• Complement also functions in
the immune response by
tagging the outer surface
(opsonisation) of invaders for
attack by phagocytes.
Innate Immune Response
INJURY/INFECTION
TISSUE
DAMAGE
INFLAMMATION
Mast cell
PMN
Macrophage
PG/LT
Platlets, kinins, complement, CRP
BLOOD VESSEL
HEALING
The Adaptive Immune Response
• The adaptive immune has two components:
1. Antibody Production – defend against
bacteria and viruses.
2. Cell-Mediated Immunity - cells in the body
that have been infected by viruses and
bacteria, protect against parasites, fungi, and
also kill cancerous body cells.
Antibodies
• Antibodies are proteins that circulate in the blood stream.
• The function of antibodies is to recognize substances (proteins,
viruses, bacteria, cells etc) as being either SELF or NON-SELF.
• The substances that are recognized by antibodies are called
ANTIGENS.
• NON-SELF ANTIGENS are targeted by antibodies for
destruction. .
• Two aspects of antibody function that are important in the
immunes response:
1. They recognize antigens by binding to a specific 3DIMENSIONAL SHAPE of the antigen.
2. We have the capacity to produce about 100 million
DIFFERENT antibodies. This means that we can produce
antibodies to substances or viruses that we've never
encountered.
Antibody Structure
• Antibodies consist of two
different kinds of protein
chains.
• LIGHT CHAINS and HEAVY
CHAINS.
• LIGHT CHAINS have
VARIABLE, JOINING and
CONSTANT domains.
• HEAVY CHAINS have
VARIABLE, DIVERSITY,
JOINING, and CONSTANT
domains.
Classes of Antibodies
• Antibodies bind to
specific antigens in a lockand-key fashion, forming
an antigen-antibody
complex.
• Also known as
immunoglobulins (Igs)
• There are five classes of
immunoglobulins: IgG,
IgA, IgD, IgE, and IgM
Isotype
Placental Binds mast Binds phagocytic Activates Additional
transfer cell surfaces cell surfaces complement features
–
–
–
+
First Ab in
development
and response
IgD
–
–
–
–
B-cell receptor
IgG
+
–
+
+
Involved in
opsonization and
ADCC. IgG1,
IgG2, IgG3, IgG4.
–
+
–
–
Involved in
allergic responses
–
–
–
IgM
IgE
IgA
– Two subclasses;
IgA1, IgA2. Also
found as dimer (sIgA) in secretions
Antibody Structure and Combinatorial
Synthesis Provides Antibody Diversity
• The number of different genes encoding antibody domains:
LIGHT CHAINS
Variable Regions ---------------- 300 different types
Joining Regions ------------------ 4 different types
Constant Regions ---------------- 2 different types
• HEAVY CHAINS
Variable Regions ---------------- 400 different types
Diversity Regions --------------- 20 different types
Joining Regions ------------------ 4 different types
Constant Regions ---------------- 5 different types
• Only Variable, Diversity and Joining regions contribute to antibody
diversity. Thus, for light chains there are (300 x 4 = 1200) different
possible combinations, for Heavy Chains, there are (400 x 20 x 4 =
32,000) different possible combinations, and in total (1200 x 32,000
= 38,400,000) possible combinations.
Cells of Adaptive Immune Response
• B-Cells, or B-lymphocytes These are the cells
that synthesize and secrete antibodies.
• They are of two types: ANTIBODYPRODUCING cells and MEMORY cells.
• Memory B-Cells are important because those are
the type of cells that are produced when you're
vaccinated. They remain in storage and are ready
to begin producing antibodies if you are
challenged sometime in the future by the same
antigen.
Cells of Adaptive Immune Response
• T-Cells, or T-lymphocytes - there are three types
of T-Cells, but we'll only talk about two of them.
• HELPER T-CELLS (TH cells) help to turn on the
immune response.
• KILLER T-CELLS (TC cell) kill viral-infected
cells as part of the response.
Antibody (Humoral) Response
Cell Mediated Response
Immunodeficiency Diseases
• Result from the lack or failure of one or more parts of the
immune system. Genetic disorders, Hodgkin's disease,
cancer chemotherapy, and radiation therapy can cause
immunodeficiency diseases.
• Severe Combined Immunodeficiency (SCID) results from
a complete absence of the cell-mediated and antibodymediated immune responses. Affected individuals suffer
from a series of seemingly minor infections and usually die
at an early age.
• Acquired Immunodeficiency Syndrome (AIDS) is
currently receiving the most attention among the
immunodeficiency diseases. AIDS is a collection of
disorders resulting from the destruction of T cells by the
Human Immunodeficiency Virus (HIV), a retrovirus.
HIV
• When HIV replicates in the human T cells, it buds from the T
cell plasma membrane encased in a coat derived from the T cell
plasma membrane.
• HIV selectively infects and kills T helper cells.
• The viral RNA is converted into DNA by the enzyme reverse
transcriptase; this DNA can become incorporated into a human
chromosome for months or years.
• When the infected T cell is needed in the immune response, the
viral genes are activated and the virus replicates.
• The infected cell is destroyed and a new T4 cell infection
occurs.
• Gradually the number of T4 cells, the master on switch for the
immune system, decline.
Sites of Activity
• Defense mechanisms can take place almost
anywhere damage or disease agents can occur.
• on the epithelial surfaces of the body
• in the interstitial fluid of the connective tissues
• ... under epithelial surfaces
• ... within organs
• in the lymph
• in the blood.
• The cells involved in the immune response are
organised into tissues and organs to perform and
function more efficiently.
Assignment 7
Q. What is the Major Histocompatibility
Complex (MHC) and how is it responsible
for organ transplant rejection?
The Lymphoid System
• Primary lymphoid organs – bone marrow
and thymus.
• Secondary lymphoid organs – lymph nodes
small bean shaped organs (back of throat,
under armpit, groin area), tonsils, adenoids,
the spleen.
Primary Lymphoid Organs
• Bone marrow contains tissue that produces
lymphocytes. B-lymphocytes (B-cells) mature in
the bone marrow.
• T-lymphocytes (T-cells) mature in the thymus
gland. The thymus secretes a hormone, thymosin,
that causes pre-T-cells to mature (in the thymus)
into T-cells.
Secondary Lymphoid Organs
• Lymph nodes are areas of concentrated
lymphocytes and macrophages.
• The spleen is similar to the lymph node except
that it is larger and filled with blood. The spleen
serves as a reservoir for blood, and filters or
purifies the blood and lymph fluid that flows
through it.
• If the spleen is damaged or removed, the
individual is more susceptible to infections.
Immunity to Bacteria
• Bacteria are usually dealt with by
phagocytosis.
• Bacteria have adapted and evolved
mechansims to a) avoid phagocytosis –
capsule. b) avoid digestion – cell wall. c)
damage phagocyte – exotoxins.
Immunity to Viruses
• Viruses are smaller, unable to replicate outside the host cell.
• Different viruses affect different cell types. (E.g Epstein-Barr
virus infects B cells via a specific receptor called CR2.
• There are different phases of viral infection :–
i) typical infection starts with local invasion of an epithelial cell
surface – IgA and IFN.
ii) followed by systemic spread or viraemia – antibodies.
iii) replication in target organs – complement, cells, antibodies, IFN
• Interferons stimulate virally infected cells to make a protein that
blocks viral mRNA transcription.
Immunity to Fungi
• Normally only cause superficial infections.
• Spores entering through lungs can cause
serious systemic infection.
• Survival mechanisms are similar to those of
bacteria