Download Immune system

THE IMMUNE SYSTEM
Dinithi Peiris
Department of Zoology
The Lymphatic System
•  A system of vessels, cells and organs
•  Vessels originate blindly and the structure is similar to
that of a vein with valves
•  The vessels transport a fluid called lymph that is similar
in composition to extra cellular fluid
•  Lymphatic system also consist of number of organs and
cells that are collectively referred to as white blood cells
Lymphatic System: Components
•  Lymph
–  Protein-containing fluid transported by lymphatic vessels
•  Organs
–  Lymphatic vessels: Transport the lymph at a low pressure.
Structurally and functionally similar to a vein. Lymphatic
vessels eventually joins with the venous system
–  Primary lymphoid organs: Organs involved in development
of cells of the lymphatic system eg: bone marrow, thymus
–  Secondary lymphoid organs: Organs involved in housing
cells of the lymphatic system and immune response eg:
lymph nodes, spleen
•  Cells
–  Granulocytes: neutrophils, eosinophils, basophils, and mast
cells
–  Agranulocytes: monocytes, macrophages, B and T
lymphocytes, and natural killer cells
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Lymphatic System: Components
•  Lymph
–  The fluid, lymph (=clear spring water), is what seeps
out of the blood at the peripheral capillaries.
–  Composition is similar to plasma without the proteins
–  Has bacteria, virus, cell debris
–  Lipid content is high
–  Lymphocytes content is high
•  Lymphatic vessels
–  Transport the lymph from tissue back to the
bloodstream
–  Starts usually along the side of a vein
–  Similar to a vein in structure and function (low
pressure system, use SK muscle and respiratory pump
to help flow, valves are present to prevent backflow)
–  Lymphatic vessels eventually joins with the venous
system through the left and right subclavian veins
Lymphatic System: Components
•  Organs
–  Primary lymphoid organs: Organs involved in
development of cells of the lymphatic system eg:
bone marrow, thymus
–  Secondary lymphoid organs: Organs involved in
housing cells of the lymphatic system and immune
response eg: lymph nodes, spleen
Lymphatic System: Components
•  Cells
–  Granulocytes:
Neutrophils
Eosinophils
Basophils
Mast cells
–  Agranulocytes: large nuclei and small amount of
cytoplasm Function in identification and inactivation/
destruction of pathogens
Monocytes
Macrophages
B lymphocytes
T lymphocytes (Thelper and Tcytotoxic)
Natural killer cells
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Neutrophil
Eosinophil
Cells of the Immune
system: Granulocytes
•  Neutrophils: granules stain at neutral pH, 3-5 lobed nucleus,
receptors for antibody & complement, migrate to site of
tissue damage/infection, major phagocyte, many hydrolytic
enzymes – digestion O2-dependent & O2-independent paths
•  Eosinophils: granules stain with acidic dyes, two-lobed
nucleus, connected by thin strand, migrate to tissues to
defend against protozoa and helminths, release cationic
proteins and oxygen metabolites that damage parasite’s
membrane
Basophil
Mast cell
Granulocytes
continued…
•  Basophils: granules stain with basic dyes, two-lobed
nucleus, non-phagocytic, secrete vasoactive agents
(histamine, serotonin, prostaglandin), affinity for IgE –
coats surface of the cell triggers cell to secrete vasoactive
agents eg: hay fever, asthma, eczema
•  Mast cells:reside in connective tissue, contains granules of
histamine and many other pharmacological agents,
contribute to inflammatory response, allergies and
hypersensitivities
Cells of the Immune system: Agranulocytes
Mononuclear cells:
•  Monocytes – circulate in blood for few days and then enters
into tissue and terminally differentiate into macrophages
•  Macrophages – larger, more organelles, receptors for
antibody and complement, two populations – fixed and
wandering
Lymphocytes
•  Three cell populations: B cells, T cells, natural killer
B – mature in bone marrow, to lymphoid organs
T – mature in thymus, to blood, lymphoid organs
NK – circulate, destroy infected cells, cancer cells
Monocytes
Macrophages
Lymphocyte
Natural killer cell
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Functions of the Lymphatic System
•  Maintenance of blood volume in cardiovascular
system (return of “lost” fluid from the
capillaries)
•  Transport of fats and fat soluble material from
digestive system
•  Filtration of foreign material to defend against
infection (through the lymph nodes and spleen)
•  Defending the body from various pathogens and
parasites
Organization of the defense mechanism
•  First Line of Defense: Non specific
–  Physical and chemical barriers
•  Second Line of Defense: Non specific
–  Phgocytosis
–  Interferons
–  Complement system
–  Inflammation
–  Natural killer cells
–  Fever
•  Third Line of Defense: Specific
–  Cell mediated defense
–  Humoral defenses
Physical and chemical barriers
•  Skin: Acts as an physical and chemical barrier
–  Keratinized and therefore a dry and dead layer,
inhospitable to microorganisms
–  Constant replacement resulting in the removal of many
adhering microorganisms
–  pH = 5-6 due to fatty acids present in secretions of the
sebaceous glands. Too acidic for many microorganisms
•  Other barrier systems:
–  Secretions containing lysozyme, antibodies -tears, saliva
–  Secretions to trap microorganisms - earwax, mucus
–  Acidic environments - digestive acids in stomach, vagina
–  Elimination mechanisms - vomiting, urination, defecation
–  Resident bacteria (normal flora) – secrete antibodies
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Phagocytosis (“cell eating”)
Engulfing any foreign body
by neutrophils, monocytes,
macrophages, eosinophils
•  Pinocytosis macromolecules
internalized via nonspecific membrane
envagination (sipping)
•  Receptor-mediated
endocytosis macromolecules
selectively internalized
via specific receptors
.
•  Engulfment of
foreign body
(phagosome)
•  Merging with
lysosome
(phagolysosome)
•  Digestion of the
foreign body
(digestive
vacuole)
•  Absorption of
nutrients
•  Elimination of
unnecessary
material
Eukaryotic Cells, Bacteria, and Viruses
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Interferon
Family of glycoproteins secreted by viral infected cells
that induces virus resistance in neighboring cells
(a)
(b)
(c)
(d)
The Complement (C’) System
•  The Complement system consists of a complex series of
fifteen proteins, many of which are proteineases
•  It is a primitive form of defense against infection, being
conserved throughout evolution
•  It performs three vital functions:
cell activation
cytolysis
opsonization
•  Is one of the first systems activated in the response to
infection.
•  The Complement system can be considered as a cascade
of interacting proteins, acting in a defined manner,
resulting in the initiation of important innate biological
effects
Overview of the classical pathway
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Overview of the alternate pathway
Biological Functions of Complement
C5b6789
C3b
iC3B
C4B
Anaphylatoxins:
C3a, C4a, C5a
C3b
Chemotaxins:
C3a, C5a, C5b67
Inflammatory response
•  Process: tissue damage leads to release of histamine by
basophils/mast cells, blood vessels dilate, complement marks
bacteria, phagocytic cells arrive and remove invading
microorganisms
•  Signs: redness, warmth, swelling, pain
.
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Other Non Specific Chemical Defenses
•  Fibronectin – A glycoprotein that binds bacteria to
block attachment and enhance removal
•  β-lysin – A cationic polypeptide secreted by platelets
that disrupts cell membrane of Gram-positive bacteria
•  Tumor necrosis factor alpha (TNF-α) - Secreted by
phagocytes & some T cells in response to LPS, M.
tuberculosis, etc. that activates macrophages involved
in inflammatory response and promotes fever
•  Interleukins – IL-1 and IL-6 generated as a result of
inflammatory response promotes fever which helps in
fighting infections as
•  Pathogens do not fair well under high temperature
•  Immune responses are accelerated by high temperature
Natural Killer Cells
•  Natural killer cells are large granular lymphocytes
•  NK cells recirculate via the blood and can reach
virtually any location
•  NK cells are present in low number in lymph nodes,
spleen, blood, and peritoneum
NK Cell Functions
Innate Immune Functions
•  Early resistance to viruses and
bacteria by production of IFN-γ and
lysis of virus infected cells
Induction of inflammation
•  NK cells are involved in the induction
of inflammatory responses in some
organs
Surveillance and resistance to cancer
•  NK cells have a role in surveillance and
resistance to at least some types of
cancer
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Mechanisms of NK Cell Action
Secretion of Perforin and
Granzymes
•  Perforin has considerable
sequence homology with
complement component C9
•  It self assembles to form
pores in the target cell
membrane and destroy its
semi permeable nature
•  Granzymes (A and B) are
enzymes that induce
apoptosis (cell death) of
the target cells
Non Specific Defense Mechanisms
•  All the immune mechanisms considered thus far are
termed as NON SPECIFIC DEFENSE MECHANISMS
•  The characteristic features of non specific defenses
are
–  It is not directed against a specific target
–  It has no memory and therefore each disease event will
be considered as a new event
–  Many pathogens can evade this defensive barrier
Third Line of Defense
Specific Defense Mechanisms
Properties of specific immune response:
•  Restricted to vertebrates primarily
•  Lag phase to response
•  Antigen-specific
•  Results in the induction of memory cells
•  Highly variable
Specific Immune response: Humoral and cell mediated
•  B cells: humoral or antibody-mediated immunity
•  T cells: cell-mediated immunity, action by cells
–  Helper T cells: stimulate other immune cells
–  Cytotoxic T cells: kill abnormal and foreign cells in a
specific manner (specific type of cancer cells)
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Antibodies
•  B cells produce molecules called Antibodies (globulins)
•  Initially known as γ-globulins and now they are called
Immunoglobulins (Igs)
•  Expressed as secreted and B- cell membrane-bound
forms
•  Has three major
functions
•  Opsonization
•  Neutralization
•  Complement
activation
Cell Mediated Immunity - T Lymphocytes
•  Helper T cells: Secrete cytokines that regulate functions of
both cytotoxic T lymphocytes and B lymphocytes
•  Cytotoxic T lymphocytes: Destroy virally infected cells or
cancer cells by secretion two chemical mediators GRANZYME
and PERFORINb
What makes us sick?
•  “enemies” in the environment in the form of
microbes and chemicals are constantly
attacking our bodies, disrupting homeostasis
•  sometimes immune system homeostasis is
disrupted on its own
it may over-react to
antigens such as
with allergies
↓
↓
↓
it may under-react as
with human
immunodeficiency virus
infection (HIV)
it may react to self
proteins as with
autoimmune disease
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Over-reaction to antigens
• the immune system reacts to antigens (allergens) that don’t
cause a reaction in most people – like pollen
Pollen grains
Mast cell
©Dennis Kunkel Microscopy, Inc., www.DennisKunkel.com
•  a type of antibody called IgE binds to the allergen
causing mast cells to produce chemicals called
histamines. Common symptoms include:
–  runny nose and itchy, watery eyes, with repeated exposure
resulting in a more rapid onset of symptoms
•  treatments
–  antihistamines are given to counteract the histamines
–  shots containing low doses of an allergen can help a person to
become desensitized to that specific antigen
Reaction to Self
Occurs when the immune system sees “self” antigens
as “nonself”
•  may be due to genetic factors, infectious agents,
gender, and age
•  the autoimmune response results in tissue damage
–  Some damage occurs in only one or a few organs, in other
cases it may be body-wide (systemic)
•  ~ 3.5 % of people have autoimmune diseases
–  On average, women are 2.7 times more likely to develop
these diseases than men
•  most have no known cause or cure - treatment is
aimed at controlling symptoms
Why does the immune system
attack the body that it’s
supposed to protect?
•  failure to recognize some cells as “self”
–  in rheumatic fever, the streptococcus antigen is very
similar to a protein in heart tissue, so the body
mistakenly identifies heart tissues as foreign
•  cells seen as foreign are attacked and destroyed
–  may be only a few select cells or organs (organ-specific) –
e.g., multiple sclerosis, juvenile diabetes, rheumatic fever
–  may be systemic - e.g., systemic lupus erythematosus,
rheumatoid arthritis
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Examples of autoimmune diseases
•  Organ-specific
–  Multiple Sclerosis
–  Juvenile Diabetes
•  Systemic
–  Systemic Lupus
Erythematosus
–  Rheumatoid arthritis
Under-reaction to antigen
Immunodeficiencies
•  occur when some part of the immune system
is defective or missing
–  T cells, B cells, phagocytes, or complement
•  these deficiencies are grouped as:
–  primary: inherited or congenital
•  severe combined immunodeficiency
(SCID)
–  secondary: acquired
•  HIV infection
David Vetter 1972-1984,
the original bubble boy
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