Introduction to immunity
Basic immunology
Dr. Nahla Melake
Pathology Department- Immunology section - College of Medicine – Al-Imam
Mohammad Ibn Saud Islamic University
Objectives
ØDefine the immunology
ØDefine tasks and effects of immune system
ØDefine and classify immunity
ØOutline and briefly discuss the cells of immune system:
vMonocytes and Macrophages
vDendritic Cells
vMast cells
vPolymorphonuclear (PMN) Leukocytes
vLymphocytes
Definitions
• Immune
system = cells, tissues, and molecules that mediate resistance to
infections
study of structure and function of the immune system
• Immunology =
study of our protection from foreign macromolecules or
invading organisms and our responses to them
Foreign macromolecule, antigen e.g. virus protein, worms, parasite
(Everything that should not be in the body)
• Immunity = resistance of a host (Human) to pathogens and their toxic effects
• Immune response = collective and coordinated response to the introduction of
foreign substances in an individual mediated by the cells and molecules of the
immune system
Tasks of immune system
4 tasks:
1) Recognition: detect infection or harm
§ Intracellular (e.g. viruses and some bacteria and parasites)
§ Extracellular (e.g. most bacteria, fungi and parasites)
2) Effector Functions: eliminate infection
3) Regulation: control activity to avoid damage to the body
4) Memory: remember exposure, react immediately and strongly upon reexposure
Infection and immunity balance
immunity
infection
Disease =
Bolus of infection x virulence
immunity
Immunity
Body defense against
exogenous (microbes) and
endogenous (tumor cells)
agents.
Two Types of Immunity
Innate Immunity
- natural,
- non-adaptive, or
- non-specific
• First line of immune response
• Inborn resistance, genetically determined
• No need for prior exposure
• Not modified significantly by repeated exposure
• Response if innate immunity fails
Acquired Immunity
- adaptive, or
- specific
• Not genetically determined
• Develops during lifetime
• May be acquired naturally or artificially
• Modified by repeated exposure
Protection from
Invaders
Beneficial
Elimination of
Altered Self
Effects of the
immune system
Detrimental
(Harmful)
Discomfort and
damage
(inflammation)
Damage to self
(hypersensitivity or
autoimmunity)
Immune system
Collection of
Organs
Cells
Molecules (soluble factors)
Major lymphoid organs
Consist of:
§
Primary (central) lymphoid organs in which leukocytes develop ……. Bone
marrow and Thymus
§
Secondary (peripheral) lymphoid organs & tissues in which immune response
occur ……… Lymph nodes and Spleen
Bone marrow
§ Located in the middle of bones (vertebrae, pelvic, and leg bones)
§ It generates T cells, B cells, and macrophages
Thymus
§ Located in the front of the upper chest
§ It acts like a nursery for the development of T cells
Lymph nodes
§ Hundreds of lymph nodes are located throughout the body
§ It filters lymph fluid, removing antigens, bacteria, and cancer cells that get
trapped in their web like structure, where macrophages, antibodies, and T cells
can destroy them.
Spleen
§ Located in the upper left side of the abdomen
§ Filters out foreign organisms that infect your blood,
§ Removing old or damaged platelets and red blood cells,
§ Storing extra blood and releasing it as needed, and
§ Helping form some types of white blood cells
Other Organs:
§ Tonsils and adenoids
§ Payer’s patches
§ Appendix
§ Lymphatic vessels
The spleen can be
removed if it is
damaged, but that
lower resistance
to infection
§Accumulation of lymphoid tissues like
MALT (mucosa associated lymphoid tissue)
GALT (gut associated lymphoid tissue)
BALT (bronchus associated lymphoid tissue)
They are interconnected by the blood and lymphatic vessels through which
lymphocytes circulate
Cells of the immune system
There are a variety of types of
immune cells, but all arise from a
common bone-mar r ow progenitor
Not
involved
Granulocytes
White Blood cells (WBCs)
Macrophages
Dendritic Cells
B-lymphocytes
T-lymphocytes
Natural killer(NK)
cells
Mast cells
Monocytes and Macrophages
üRepresent 5-8 % of WBCs
üMonocytes circulating in the blood …… Macrophages in the tissues
üThey are important link between innate and acquired immune responses
Changes which occur during this transition:
a) Cells enlarge [5-10 x]
b) Intracellular organelles increase in number
and complexity
c) Cells acquire increased phagocytic ability
d) Increased secretion of many soluble factors
Macrophages
are
dispersed
throughout the body. Some
becoming fixed macrophages,
whereas others remain motile and
are called free, or wandering
macrophages
Monocyte
lung
liver
Bone
Brain
connective
tissues
Intestine
Macrophages play the following important roles:
1)
2)
3)
4)
5)
Phagocytosis
Opsonization
ADCC (Antibody-dependent cellular cytotoxicity)
APCs (Antigen presenting cells)
Secretion of cytokines (called monokines); IL-1, -6, -8, -12, -15, IFN,
TNF and prostaglandins
6) Synthesis of complement components
Macrophages are activated by a variety of stimuli:
1)
2)
3)
4)
5)
Activating signals comes from chemokines
Phagocytosis itself is an important activating stimulus
Cytokines secreted by T helper cells [IFN-gamma]
Mediators of the inflammatory response
Microbial products (such as LPS)
Dendritic Cells
• Originate in the bone marrow
Cells with dendriform (star shaped) which make them very efficient at contact with foreign material.
• Function as APC (Capture antigen or bring it to the lymphoid organs where an
immune response is initiated).
§ They express class I and II MHC (Major histocompatibility complex) molecules.
§ Present in Blood, LNs, Epithelial cells
§ Examples: Langerhan cells (skin)
Mast Cells
§ Released from bone marrow as undifferentiated and differentiate in the
tissues (skin, connective tissue, mucosal epithelium, etc.)
§ Morphology and function similar to basophils
§ Have Fc receptors for IgE (FceRs)
§ Play a very important role in the allergic response
§ Produce a variety of cytokines
Polymorphonuclear leukocytes (PMNs)
§ Granulocytes
§ Three cell types: neutrophils, eosinophils and basophils, based on their staining.
§ Important for removal of bacteria and parasites from the body. They engulf these
foreign bodies and degrade them using their powerful enzymes.
Neutrophil
Higher numbers suggestive of bacterial infection
§
50-70% of circulating WBC
§
Multi-lobed nucleus with poorly stained fine granules.
§
It contains bactericidal enzymes (lysozyme, NADPH oxidase, lactoferrin and
B12-binding protein, defensins, elastase and myeloperoxidase)
§
Efficient phagocytes
§
DO NOT function as APCs
§
Have receptor for Fc region of IgG & C3b
§
Neutrophils are 1st cells to arrive
§
Most important cells of the innate immune system
Eosinophil
§ 1-3% of circulating WBCs
§ Bi-lobed nucleus and a heavily granulated cytoplasm.
§ DO NOT act as APCs.
§ Have receptors for Complement
§ The major role of the eosinophil is believed to be against parasites
üEosinophils bind to IgE on the surface of a worm
the contents of the
granules (hydrolytic enzymes) cause damage to the worm's tegument.
üMajor Basic Protein (MBP) is highly toxic to worms
§ Classically seen with:
üAtopic allergies
üWorm infections
üCollagen Vascualr diseases
üNeoplastic disorders
üSkin rash
Basophil
§
<1% of circulating WBC
§
Only present in the bloodstream
§
Lobed nucleus--more variable, large coarse granules
§
They play a major role in the allergic response
release histamine,
serotonin, heparin, prostaglandin, ….etc into the bloodstream
§
Has Fc receptors for IgE (FceRs)
§
When an individual is exposed to an allergen, allergen specific IgE is produced.
This
IgE
binds
to
the
surface
of
basophils.
Upon re-exposure to the allergen, the allergen binds to IgE on the surface of
basophils resulting in degranulation [effector phase].
Lymphocytes
§
Agranulocytes
§
Responsible for the specific immune response.
§
20-40 % of circulating WBC in blood
§
Extravasate and enter the tissues – return 99% of cells in lymph
§
T and B lymphocytes are small, motile, non-phagocytic cells which cannot be
distinguished from each other morphologically.
§
Small 6µm, contain a single nucleus, little visible cytoplasm around their
nucleus
§
Once stimulated with antigen enlarges 15µm into a blast cell, Lymphoblasts
further differentiate into effector cells or memory cells. [Plasma cells, T-helper
cells, T-cytotoxic cells].
Different maturational stages of lymphocytes can be
distinguished by their expression of membrane CD
molecules (CD = Cluster of Differentiation)
Cell surface markers
CD markers on different cells:
Monocyte
Granulocyte
B lymphocyte
T lymphocyte
T helper lymphocyte
T cytotoxic lymphocyte
Natural killer cell
CD45+, CD14+
CD45+, CD15+
CD45+, CD19+
CD45+, CD3+
CD45+, CD3+, CD4+
CD45+, CD3+, CD8+
CD45+, CD16+, CD56+, CD3-
Depending on the life span:
Short lived – 2 weeks
effector cells
Long lived – 3yrs or more or for life
immunological memory
T lymphocytes and B lymphocytes and natural killer cells
T-lymphocytes
T-lmphocytes migrate from bone marrow to
enter thymus
T-cell subpopulation
1) CD4 T helper lymphocytes (TH)
o
65% of peripheral T cells
o
Predominant in the thymic medulla, tonsils and blood
o
Activate major cells as macrophage, CTLs, NK cells and Abs producing B
cells.
o
Recognize antigen on the surface of APC in association with MHC II
o
Secrete several cytokines
o
There are two main subsets of TH cells (THI and TH2), also there is
regulatory T cells (Tregs) and TH17 (All arise from naïve TH0)
o
The subsets are differentiated on basis of the cytokine they produce
2) CD8 cytotoxic T-lymphocytes (CTLs)
o
35% of peripheral T-cells
o
CTLs recognize antigen on surface of target cells (infected APC or other
infected nucleated cell) in association with MHC-I
o
They are activated and kill the virus infected cell or tumour cell
Mechanisms of cytotoxic effect of CTLs
1) CTLs release cytolytic proteins as Perforins, Granzymes and Serglycin.
They form pores in the cell membrane and facilitate granzymes entry into
cytoplasm and stimulate apoptosis of target cell
2) CTLs express a membrane protein Fas Ligand (FasL), that bind to its target
protein Fas on many cell types and stimulate apoptosis of target cell by
degrading DNA of target cells and of intracellular microbes.
B-lymphocytes
B-cell subpopulation
According to expression of CD5 or not
Ø B1 cell (CD5+)
Ø B2
B1
cell (CD5-)
B2
Development
early
late
BCR
mIgM
mIgM and mIgD
CD5
+
-
Reproduction
self-renewing
from pre-B cell in BM
Ab type
IgM >IgG
IgG >IgM
Ab avidity
low
high
Function
innate immunity
adaptive immunity
Function of B cell:
Ø Produce the antibody ----
HI (Humoral Immunity)
Ø Present antigen ----APC
Ø Participate in
immunological regulation
What is avidity?
o Antibodies and antigens are multivalent, meaning they possess more than one binding
site.
o The measure of the total binding strength of an antibody at every binding site is termed
avidity.
o Avidity is also known as the functional affinity.
Natural Killer
(NK) Cells
Ø Large granular lymphocytes (5-10 % of Lymphocytes)
Ø It is CD3 –ve, CD16 +ve and CD56 +ve
Ø Its function:
o Mainly in innate immunity
o Kill tumor cells
o Kill virus /bacteria infected cells (Intracellular pathogens)
o Graft cells
Ø Recognize Foreign Ag independent of MHC
Ø Activated by Cytokines (IL-2, IL-12, IL-15, IFN-α, IFN-β)
Ø Secrete IFN-γ
Ø NK cells activated by IL-2 is called lymphokine activated killer (LAK) which is
used in cancer immunotherapy.
NK cells differ from CTLs in the following
1)
2)
3)
4)
Non-specific
Act spontaneously (no recognition nor activation)
Not MHC restricted
It is ADCC
Mechanism of NK cells:
1) Have granules that contain perforins which create pores in target cell
membrane
2) Have granzymes that enter through pores and induce apoptosis of target cells
3) Mediate Ab-dependent cellular toxicity (ADCC), kill opsonized or Ab-coated
cells (It has Fc receptors, CD16, for IgG)
Release of granules with perforins and proteases
Kills both host cells and microbes
Why NK cells do not kill normal cells?
§ Because activation and recognition of target cells is
regulated by a combination of
1)Killer activating receptors (KARs) and
2)Killer inhibitory receptors (KIRs) on NK cells
o Normally, KIRs bind to MHC-I which present among all normal cells, so inhibit
NK cells action (Tumour cells and viral infected cells are lake in MHC-I)
o Activation of KARs is induced by Binding of KARs to stress molecules on
infected cells
Uninfected cell / Normal cell
Microbe infected cell / cancer cell
Some cell surface proteins are missing
Toll-like receptors
(TLRs)
§ Transmembrane proteins
§ Present on Macrophage, Denderitic cells, epithelial cells
§ Important part of innate immune system:
ü They look out for microbes (or their components)
ü They bind to the microbes (or their components)
ü They trigger a cascade of events to kill or protect against pathogens
ed
nc e
ha
En mun e
im ons
p
res
Secretion of
Cytokines /
Interferon
Cascade of events
look out
Inflammation
TLR
binding to
microbe
Phagocytosis
of infected
cell
Bind to
Apoptosis of
infected cell
f
go l
lin d cel
l
i
K te
ec
inf
Molecules of Immune system
§ Antibodies
§ Complement
§ Cytokines
§ Interleukines
§ Interferons
Immune dysfunction
Sometimes the immune system fails to protect the host adequately or misdirects its
activities to cause discomfort, debilitating disease, or even death. There are several
common manifestations of immune dysfunction:
• Allergy and asthma
• Allergy and asthma are results of inappropriate immune responses, often to
common antigens such as plant pollen, food, or animal dander.
• Graft rejection and graft-versus-host disease
• Transplantation of cells or an organ from another individual is viewed by the
immune system as a foreign invasion
• Autoimmune disease: Immune attack upon self antigens e.g.
o Multiple sclerosis is due to an autoimmune attack on the brain and CNS
o Crohn’s disease is an attack on the tissues in the gut
o Rheumatoid arthritis is an attack on joints of the arms and legs.
• Immunodeficiency
• If any of the many components of innate or specific immunity is defective
because of genetic abnormality, or if any immune function is lost because of
damage by chemical, physical, or biological agents