IMMUNOLOGY
Lecture 1
Jennifer E. Woodward, PhD
E1545 Biomedical Science Tower
200 Lothrop Street
412-648-3926
woodwardje@upmc.edu
Outline
Day 1
• What is immunology?
• Cells, organs and tissues of the immune system
• Innate immunity
Outline
Day 2
• Adaptive immunity
– Antibodies
– T cells
• Antigen capture and presentation
• Antigen receptors and development of the
immune repertoire
Outline
Day 3
• Cell-mediated immune responses and effector
mechanisms
• Humoral immune responses and effector
mechanisms
Outline
Day 4
• Autoimmunity
• Transplantation
• Tumor Immunology
Definitions - 1
Immunology - is the study of all aspects of host
defense against infection and of adverse
consequences of immune responses.
Immune response – the collective and coordinated
response to the introduction of foreign substances
(pathogens) in an individual
Immune system – the molecules, cells, tissues and
organs that collectively function to provide
protection against pathogens
Definitions - 2
Elements of the Immune System
Molecules
– Complement
– Cytokines, chemokines
– Antibodies
Cells
– Granulocytes (neutrophils, basophils/mast cells,
eosinophils)
Lymphocytes: T cells, B cells, and NK cells
Tissues
– Bone marrow
– Thymus
– Lymph nodes
– Spleen
– Blood
Definitions - 3
Immunity – ability to resist infection
Why has the immune system evolved?
Protection / Defense against
– invading pathogenic micro-organisms
– cancer
Functions of the Immune System
1. Immune Recognition – specificity
a. Recognize subtle chemical differences that
distinguish one foreign pathogen from
another
b. Discriminate between foreign molecule
(antigen) and the body’s own cells and
proteins
Functions of the Immune System
2. Immune Response
Immune recognition → recruitment of a
variety of cells and molecules → mount an
appropriate response (Effector Response unique – depends on particular organism )
→ Eliminate or neutralize organism
Memory Response
Subsequent exposure to the same foreign
organism
Characterized by a more rapid and
heightened immune response
Invertebrates – simplest and most primitive
immune system
Vertebrates
Innate Immunity – primitive immune
system
Adaptive Immunity – highly evolved
immune system with specificity of a
response
Both innate and adaptive immunity work
together for a high degree of protection
Immunodeficiency Diseases – immune
system fails because of a deficiency
Autoimmunity – immune system becomes
too aggressive and reacts against self/host
Cells and Organs of the Immune System
WBC = Leukocytes
• Leukocytes are carried through the blood and lymph to
populate lymphoid organs and to participate in the
immune response
• Lymphocytes are the only leukocytes that possess
attributes of diversity, specificity, memory, and
self/non-self recognition
• All other leukocytes play an accessory role in adaptive
immunity
Hematopoiesis
formation and development of red blood cells
(erythrocytes) and white blood cells (leukocytes)
initiated in humans early during gestation in the fetal
yolk sac
All blood cells arise from a single type of cell called a
hematopoietic stem cell (HSC)
homeostatic regulation of hematopoiesis is by
programmed cell death (apoptosis)
Hematopoietic Stem Cells
Pluripotent (multipotent)
– ability to differentiate into other types of
cells
– self-renewing
– Differentiates along one of two pathways
which is determined by growth factors and
cytokines
1. Lymphoid progenitor cell
2. Myeloid progenitor cell
Progenitor cells have lost the capacity for self-renewal and are committed
to a particular lineage
Common lymphoid progenitor cells give rise to
B cells
T cells
NK cells
Some dendritic cells
Myeloid progenitor cells give rise to
progenitor of red blood cells
neutrophils
eosinophils
basophils
monocytes
mast cells
dendritic cells
megakaryocyte-platelet generating cell
Cells of the Immune System
• Lymphocytes
– central cell of the immune system
– constitutes 20-40% WBC
– responsible for adaptive immune response
– exhibits diversity, memory, specificity,
self/nonself recognition
– continuously circulating in blood
– can migrate into tissues and lymphoid
organs
3 populations of lymphocytes
• B cells
• T cells
• NK cells
Natural Killer Cells (NK Cells)
• large, granular lymphocytes
• do not express cell surface markers
typical of T or B cells
• 5-10% of lymphocytes in humans
• cytotoxic activity against tumor cells,
virus infected cells, etc.
B Lymphocytes (B cells)
• named for site of maturation
– Bursa of Fabricius
– bone marrow in humans, mice, etc.
• mature B cells contain membrane bound immunoglobulin (Ig) on
surface as receptor for antigen
• can bind soluble antigen – no MHC required
• Mature B cells also express B220, class II, CR1, CR2, B7-1, B7-2,
and CD40
• can divide and differentiate when interact with antigen, APC and
T cells to generate
– plasma cells - lower level of membrane Ag; synthesize and
secrete Ab; terminally differentiated cells (effectors) which die
in 1-2 weeks
– memory B cells
T Lymphocytes (T Cells)
• mature in thymus
• T cell receptor (TCR) is the membrane receptor for
antigen
• do not recognize free/soluble antigen – must see antigen
in context of MHC
• contain distinctive membrane molecules – TCR, CD3
complex, CD4 or CD8, CD28, CD45
T Lymphocytes (T Cells) – cont.
•
T helper (TH) cells
– provide help
– effectors secrete cytokines that play a role in activation of cells of the immune
response
– TH1 secrete cytokines that support inflammation and activate T cells and
macrophages
– TH2 activate mainly B cells and immune responses dependent on Ab
– CD4 on surface recognizes MHC class II
•
T cytotoxic (Tc) cells
– cytotoxic
– when recognize Ag on MHC, activate, proliferate and differentiate into
cytotoxic T lymphocytes (CTL) which recognize and eliminate cells
– CD8 on surface recognizes MHC class I
•
T suppressor (Ts) cells
– subpopulation or new population of Tc or TH with a suppressor function
– Suppress/downregulate humoral and cell-mediated immune responses
B and T Cells
•
•
•
resting B and T cells are small, motile, and non-phagocytic
Naïve or unprimed – no reaction with Ag
– in Go phase of cell cycle
– short life-span
Enter cell cycle when interact with Ag
– Go from Go to G1 then S1, G2 and M
– Enlarge in size to lymphoblast (higher cytoplasm to nucleus ratio; more
organelle complexity)
– Proliferate and differentiate into
• Effector cells – function to eliminate Ag; short lifespan –few days to a
few weeks; distinguish by molecules on surface
or
• memory cells – persistent; responsible for lifelong immunity
Mononuclear Phagocytes
• Monocytes (circulate in blood) and macrophages (in
tissues).
• During hematopoiesis in bone marrow, granulocytemonocyte progenitor cells differentiate into
promonocytes which enter into blood and mature into
monocytes and move into tissues to differentiate into
macrophages
Difference between
Monocytes and Macrophages
•
•
•
•
•
cell ↑ 5-10X
intracellular organelles ↑ in number and complexity
↑ phagocytic ability
produce high levels of hydrolytic enzymes
secrete a variety of soluble factors
Macrophages (MØ) have different functions in different
tissues
– Alveolar MØ – lung
– Histocytes - connective tissue
– Kupffer cells – liver
– Mesangial cells – kidney
– Osteoclasts – bone
• MØ are activated by phagocytosis of Ag
• Activated MØ are more effective at eliminating
pathogens because of a greater phagocytic activity
– ↑ ability to kill ingested microbes
– ↑ secretion of inflammatory mediators
– ↑ ability to activate T cells
– ↑ production of cytotoxic proteins
– ↑ levels of MHC class I, therefore, more
effective APC
Granulocytic Cells
Based on morphology and cytoplasmic staining
• phagocytic
– Neutrophils = Polymorphonuclear
leukocytes (PMNs)
– Eosinophils
• non-phagocytic
– Basophils
Neutrophil
•
•
•
•
•
PMN
comprise 50-70% circulating WBC
multi-lobed nucleus
produced in the bone marrow
released in peripheral blood – circulate 7-10 hrs with subsequent
migration in tissues and die within a few days
• large number released as first cells if an infection
• lytic enzymes in 1º and 2 º granules when actively phagocytosing
• kill microbes similar to macrophages but exhibit a larger production of
oxygen and nitrogen intermediates
Eosinophil
•
•
•
•
•
phagocytic
bilobed nucleus that stains red with acidic dye
constitutes 1-3% of circulating WBC
play role in combating parasitic organisms
content of granules are damaging to parasitic
membranes
Basophil
• <1% of circulating cells
• non-phagocytic
• release pharmacologically active substances from
granules
• stain with basic dye
• role in allergic responses
Mast Cell
• mast cell precursor forms in the bone marrow and
released into blood as an undifferentiated cell but
differentiates when leaves blood and enters tissues
• found in skin, connective tissues, and various epithelial
tissues of the respiratory, genitourinary and digestive
tracts
• cytoplasmic granules contain histamine and
pharmacologically active substances important with
basophils in allergies
Dendritic Cell (DC)
• contains long membrane extensions called dendrites
• mature DCs present Ag to T cells
• express high levels of both MHC class II and B7
family of costimulatory molecules
• more potent APC than MØ and B cells
Immune system is composed of many organs and tissues
• 2 groups of organs
– primary lymphoid organs – environment for the development
and maturation of lymphocytes
– secondary lymphoid organs – site where mature lymphocytes
can interact with antigen
• These organs are connected by blood vessels and the
lymphatic system
once mature lymphocytes leave primary lymphoid organs,
they circulate in blood and lymphatic system
lymphatic system – network of vessels that collect fluid
from tissues that has escaped from capillaries of the
circulatory system and ultimately returns to the blood
Thymus
• Site of T cell development and maturation
• Flat, bilobed organ above the heart
• function – generate and select a repertoire of T cells that protect
the body from infection
• lack of thymus
– Nude mice
– DiGeorge’s syndrome
• reaches maximum size at puberty and then atrophies with age
Bone Marrow
• site of B cell origin and development in primates and
rodents; in birds, B cells develop in the Bursa of
Fabricius
• B cells proliferate and differentiate within the bone
marrow
• stromal cells within the bone marrow interact directly
with B cells and secrete cytokines for development
Lymphatic System
• As blood circulates under pressure, the fluid component (plasma)
seeps through capillaries into tissues. A large portion of this fluid
returns to the blood through capillary membranes. The remainder
of the fluid is called lymph, which flows through spaces in
connective tissue into a network of open lymphatic capillaries then
into larger collecting vessels called lymphatic vessels, the largest
being the thoracic duct which enters into the left subclavian vein
near the heart.
• The fluid flows by squeezing of body muscles rather than by heart
pumping. Therefore, fluid goes in in one direction only.
Lymphatic System – cont.
Function
– capture fluid lost from blood and return to blood
to ensure a steady state of fluid within the
circulatory system
– picks up foreign antigen that has gained access to
tissue and carried to various organized lymphoid
tissues such as the lymph nodes which traps
antigen as lymph passes from tissues to the
lymphatic vessels, thus becoming progressively
rich with lymphocytes
– transporter of lymphocyte and antigen from
connective tissue to organized lymphoid tissues
where lymphocytes may interact with trapped
antigen
Secondary (2º) Lymphoid Organs
• Located along vessels of lymphatic system
• most highly organized 2º lymphoid organs which have not only
lymphoid follicles but also distinct areas of T cell and B cell activity
surrounded by a fibrous capsule
– lymph nodes
– spleen
• less organized lymphoid tissue collectively called mucosal associated
lymphoid tissue (MALT) found in various areas of the body
–
–
–
–
Peyer’s Patches – small intestine
Tonsils
Appendix
lymphoid follicle in lamina propria of smalls intestines and mucus
membrane lining of upper airways, bronchi, and genital tract
Lymph Nodes
• site where immune responses are mounted against
antigen in lymph
• encapsulated bean-shaped structure containing a
reticular network full of lymphocytes, macrophages
and dendritic cells
• located at junction of lymphatic vessels
• encounter antigen that enter the tissue
Spleen
• Major role in mounting immune response to antigens
in bloodstream
• Large ovoid 2º lymphoid organ in abdominal cavity
• Specializes in filtering blood and trapping blood borne
antigens
• Unlike lymph node, not supplied by lymphatics
• Blood and antigen are carried by splenic artery
• Surrounded by a capsule which extend a number of
trabeculae to form compartmentalized structure
Mucosal Associated Lymphoid Tissue
(MALT)
• organized lymphoid tissue which can be either loose,
barely organized structural tissue, to well organized
tissues
– tonsils
– Peyer’s Patches
– appendix
• defends the mucous membrane that lines the digestive,
respiratory, and urogenital system which are major
sites for pathogen entry
• function as a large population of antibody producing
plasma cells
GI – Mucous Membranes
• M cells
– Specialized epithelial cells of mucous membranes
that promote immune response by delivery of small
samples of antigen from the urogenital tract, and
lamina of the respiratory and digestive tracts to
underlying mucosal associated lymphoid tissue
– Flat cells that have deep cavities for capturing
antigen, macrophages, B cells and T cells across
basolateral membranes
Many different cells, organs, and tissues of the
immune system are dispersed throughout the
body, yet the various components communicate
and collaborate to produce an effective
response to an infection
Innate Immunity
Innate Immunity
•
•
•
•
ancient line of defense
highly conserved between different species
first line of defense against infection
cellular and molecular components are present before
onset of disease/infection and recognize classes of
molecules peculiar to frequently encountered
pathogens
• mechanisms of action – non-specific, broad reactivity –
occurs within hours of invasion
• Phagocytic cells (neutrophils and macrophages) are
involved
• Broad Reactivity
• Phagocytosis – main mechanism of action
Innate Immunity
4 types of defensive barriers
anatomic
physiologic
phagocytic
inflammatory
Anatomic and Physical Barriers
Tend to prevent entry and is truly the 1st line of
defense
– skin
– mucous membrane
•
•
•
•
conjunctiva
alimentary
respiratory
urogenital tract
– non-specific mechanisms – saliva, tears, mucus
secretions
Physiologic Barriers
• body temperature
• pH
• soluble and cell associated molecules
– lysozyme
– interferon
– complement
Many molecules in innate immunity have the
ability to recognize (pattern recognition) a
given class of molecules only found in microbes
and not in multicellular organisms
Ex: macrophages recognize LPS
Organisms have developed/evolved ways to
escape these defense mechanisms and
invade body
Ex: Influenza virus
Gonorrhea
Phagocytosis
Ingestion of
extracellular
particular
material/uptake by
cell of material from
the environment
Steps of
Phagocytosis
4 Cardinal Signs of Inflammation
1)
2)
3)
4)
rubor = redness
tumor = swelling
calor = heat
dolar = pain
5)
loss of function
Inflammatory Response = Inflammation
Complex sequence of events induced by tissue
damage caused by a wound or an invading pathogen
3 major events of an inflammatory response
1.
2.
3.
vasodilation
increased capillary permeability
influx of phagocytes
Mediated by chemical mediators which are released
from invading microorganisms, damaged cells in
response to tissue injury, several plasma enzyme
systems or various WBC that are participating in the
inflammatory response
Influx of Phagocytes
A Multi-step Process
• Adherence of cells to endothelial wall of blood vessels
(margination)
• Emigration between capillary endothelial cells into tissues
(diapedesis – extravasation)
• Migration through tissue to site of invasion (chemotaxis)
Phagocytes release lytic enzymes when accumulate at site and begin to
phagocytize bacteria. The lytic enzyme can damage nearby healthy
cells.
Pus is the accumulation of dead cells, digested material and fluid.
Chemical Mediators
– released by Invading microorganisms
– released from damaged cells in response to tissue
injury
– generated in several plasma enzyme systems
– produced by participating WBC
Once inflammatory response subsides and most of
debris is cleared by phagocytic cells, tissue repair
and regeneration of new tissue begins.
Capillaries grow into fibrin clot, connective tissue
fibroblasts replace fibrin and clot, and clot
disappears. Scar tissue forms when fibroblasts and
capillaries accumulate.