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INNATE IMMUNITY
 BARRIERS
 CELLS: LYMPHOCYTES,
MACROPHAGES, PLASMA CELLS, NK
CELLS
 CYTOKINES/CHEMOKINES
 PLASMA PROTEINS: Complement,
Coagulation Factors
 Toll-Like Receptors, TLR’s
Innate immunity
 A hallmark of the innate immune system is that
it has no memory of a previous encounter with a
foreign organism. The system is good at dealing
with extracellular bacteria, fungi and
intracellular viruses.
ADAPTIVE
IMMUNITY
CELLULAR, i.e., direct
cellular reactions to antigens
HUMORAL, i.e.,
antibodies
Adaptive (acquired) immunity
Refers to antigen-specific defense mechanisms that
take several days to become protective and are
designed to remove a specific antigen. This is the
immunity one develops throughout life. There are two
major branches of the adaptive immune responses:
1. Humoral immunity : involves the production of
antibody molecules in response to an antigen and is
mediated by B-lymphocytes.
2. cell-mediated immunity : involves the production of
cytotoxic T-lymphocytes, activated macrophages,
activated NK cells, and cytokines in response to an
antigen and is mediated by T-lymphocytes.
CELLS
of the IMMUNE SYSTEM
 LYMPHOCYTES, T
 LYMPHOCYTES, B
 PLASMA CELLS (MODIFIED B CELLS)
 MACROPHAGES, aka “HISTIOCYTES”, (APCs, i.e.,
Antigen Presenting Cells)
 “DENDRITIC” CELLS (APCs, i.e., Antigen Presenting
Cells)
 NK (NATURAL KILLER) CELLS
NK CELLS
MHC
Major Histocompatibility Complex
 A genetic “LOCUS” on Chromosome 6, which codes
for cell surface compatibility
 Also called HLA (Human Leukocyte Antigens) in
humans and H-2 in mice
 It’s major job is to make sure all self cell antigens are
recognized and “tolerated”, because the general
rule of the immune system is that all UN-recognized
antigens will NOT be tolerated
GENERAL SCHEME of
CELLULAR EVENTS
 APCs (Macrophages, Dendritic
Cells)
 T-Cells (Control Everything)
 CD4 “REGULATORS” (Helper)
 CD8 “EFFECTORS”
 B-Cells Plasma Cells AB’s
 NK Cells
CYTOKINES
 Cytokines are produced by a broad range of cells,
including immune cells like macrophages, B
lymphocytes, T lymphocytes and mast cells, as well
as endothelial cells, fibroblasts, and various stromal
cells;
 MEDIATE INNATE (NATURAL) IMMUNITY, IL-1, TNF,
INTERFERONS
 REGULATE LYMPHOCYTE GROWTH (many interleukins,
ILs)
 ACTIVATE INFLAMMATORY CELLS
 STIMULATE HEMATOPOESIS, (CSFs, or Colony
Stimulating Factors)
CYTOKINES/CHEMOKINES
 CYTOKINES are PROTEINS produced by MANY
cells, but usually LYMPHOCYTES and
MACROPHAGES, numerous roles in acute and
chronic inflammation, AND immunity
TNF, IL-1, by macrophages
 CHEMOKINES are small proteins which are
attractants for PMNs
 They are important in health and disease, specifically
in host responses to infection, immune responses,
inflammation, trauma, sepsis, cancer, and
reproduction.
MHC MOLECULES
(Gene Products)
 I (All nucleated cells and platelets), cell surface
glycoproteins, ANTIGENS
 II (APC’s, i.e., macs and dendritics, lymphs), cell
surface glycoproteins, ANTIGENS
 III Complement System Proteins
IMMUNE SYSTEM DISORDERS
WHAT CAN GO WRONG?
 HYPERSENSITIVITY REACTIONS, I-IV
 “AUTO”-IMMUNE DISEASES, aka “COLLAGEN”
DISEASES (BAD TERM) Inflammation NOT due
to external pathogens, MHC failure.
 IMMUNE DEFICIENCY SYNDROMES, IDS:
 PRIMARY (GENETIC)
ACQUIRED)
 SECONDARY (
HYPERSENSITIVITY
When the immune systems cause harm to the
body, it is referred to as a hypersensitivity
Four Types of Hypersensitivity Reactions:
 Type I (Anaphylactic) Reactions
 Type II (Cytotoxic) Reactions
 Type III (Immune Complex) Reactions
 Type IV (Cell-Mediated) Reactions
1.Anaphylactic hypersensitivity
• systemic anaphylaxis - the allergin is usually
picked up by the blood and the reactions occur
throughout the body. Examples include severe
allergy to insect stings, drugs, and antisera.
• localized anaphylaxis - the allergin is usually
found localized in the mucous membranes or the
skin. Examples include allergy to hair, pollen, dust,
dander, feathers, and food.
• Disorders - Atopy ( Atopic syndrome )
- Asthma
- Anaphylaxis
 The process of anaphylaxis consists of the
following sequential events:
 First exposure:
to an antigen (allergen),such as bee venom,
results in production of IgE class of antibodies
by plasma cells.
 The surface of mast cells contains specific
receptors for IgE.
 IgE molecules are bound to their receptors
on the surface of mast cells and basophils.
 Second exposure:
results in binding of the antigen to IgE on
the mast cells .
 This then triggers the release of mast cell
granules, which are :
• Histamine -causes constriction of
smooth muscles ( ex bronchioles ),
vasodilatation, Increased capillary
permeability, increase bronchial mucus
secretion.
• Chemotactic factors for eosinophils,
proteases.
• Leukotrienes -causes bronchial spasms.
• Prostaglandins
 Histamine: Dilates and increases permeability of
blood vessels (swelling and redness), increases
mucus secretion (runny nose), smooth muscle
contraction (bronchi).
 Prostaglandins: Contraction of smooth muscle of
respiratory system and increased mucus secretion.
 Leukotrienes: Bronchial spasms.
 Anaphylactic shock: Massive drop in blood
pressure. Can be fatal in minutes.
Mast Cells and the Allergic
Response
2. Antibody-dependent
cytotoxicity
 Mechanism: Either IgG or IgM is
made against normal self antigens
as a result of a failure in immune
tolerance, or a foreign antigen
resembling some molecule on the
surface of host cells enters the body
and IgG or IgM made against that
antigen then cross reacts with the
host cell surface.
The binding of these antibodies to the
surface of host cells then leads to:
 Opsonization of the host cell.
 Activation of the classical complement
pathway causing MAC lysis
( membrane attack complex ) of the cells.
 ADCC (Antibody-Dependent CellMediated Cytotoxicity ) destruction of
the host cells.
Complement system
 It consists of series of proteins synthesised by
liver as acute phase reactants.
 1. Augments host immune defenses
 2.Lysis bacteria directly with MAC
 3. Participates in cytotoxic immunity and
immune complex hypersensitivity reactions.
 The multiple activities of the complement




system:
Lysis
Opsonization
Activation of inflammatory response
Clearance of immune complexes
 C3a……….Anaphylotoxin
 C3b………..opsonin
 C5a………..Anaphylotoxin, Adhesion,
Chemotactic
 C5b67…………..Chemotactic complex
 C5b6789…………………MAC
 MAC; Membrane attack complex
OPSONIZATION
MAC LYSIS
ADCC
•
Disorders:
-Mismatched blood group
-Autoimmune hemolytic anemia
-Thrombocytopenia
-Erythroblastosis fetalis
-Goodpasture's syndrome
-Membranous nephropathy
3. Immune complex-mediated
Mechanism: This is caused when soluble
antigen-antibody (IgG or IgM) complexes,
which are normally removed by
macrophages in the spleen and liver, form
in large amounts and overwhelm the body .
These small complexes lodge in the
capillaries, pass between the endothelial
cells of blood vessels - especially those in
the skin, joints, and kidneys - and become
trapped on the surrounding basement
membrane beneath these cells.
• The antigen/antibody complexes then
activate the classical complement
pathway. This may cause:
 Massive inflammation, due to complement
protein C5a triggering mast cells to release
inflammatory mediators;
 Influx of neutrophils , due to complement
protein C5a , resulting in neutrophils
discharging their lysosomes and causing
tissue destruction and further inflammation
 MAC lysis of surrounding tissue cells, due to
the membrane attack complex, C5b6789n;
 Aggregation of platelets, resulting in
more inflammation and the formation of
microthrombi that block capillaries;
 Activation of macrophages , resulting in
production of inflammatory cytokines and
extracellular killing causing tissue
destruction.
• Associated disorders:
 serum sickness, a combination type I and
type III hypersensitivity.
 autoimmune acute glomerulonephritis.
 rheumatoid arthritis.
 systemic lupus erythematosus.
the skin lesions of syphilis and leprosy.
 Arthus reaction.
 Post streptococcal glomerulonephritis.
 Lupus Nephritis.
 Extrinsic allergic alveolitis
(Hypersensitivity pneumonitis)
 Delayed hypersensitivity
• cell-mediated rather than antibodymediated.
• T8-lymphocytes become sensitized to an
antigen and differentiate into cytotoxic Tlymphocytes while effector T4lymphocytes become sensitized to an
antigen and produce cytokines . CTLs,
cytokines, eosinophils, and/or
macrophages then cause harm rather than
benefit.
Summary of Hypersensitivity reactions
Production of antibodies to substances most tolerate, ie allergies.
 Type I (acute) - Most common, starts within seconds and
most often ends within 30 minutes.
 Anaphylaxis – causes edema, mucus, and congestion
 Asthma – reaction to inhaled allergen.
 Causes massive release of histamine and spasmatic contraction
of the bronchioles.
 Anaphylactic shock – systemic response to an injected
allergen.
 Can cause bronchiolar constriction, circulatory shock, and
possible death.
 Type II (antibody-dependant cytotoxic)- as in
transfusion reaction.
 Type III (immune complex)- large antibody-antigen
complexes that get trapped under the tunic interna of blood
vessels and cause inflammation.
 Type IV (delayed)- occur 12 to 72 hours after exposure.
Delay commonly associated with travel time to lymph nodes.
Cosmetics and poison ivy hapten commonly do this.
Hypersensitivity
Production of antibodies to substances most tolerate, ie allergies.
 Type I (acute) - Most common, starts within seconds and
most often ends within 30 minutes.
 Anaphylaxis – causes edema, mucus, and congestion
 Asthma – reaction to inhaled allergen.
 Causes massive release of histamine and spasmatic contraction
of the bronchioles.
 Anaphylactic shock – systemic response to an injected
allergen.
 Can cause bronchiolar constriction, circulatory shock, and
possible death.
 Type II (antibody-dependant cytotoxic)- as in
transfusion reaction.
 Type III (immune complex)- large antibody-antigen
complexes that get trapped under the tunic interna of blood
vessels and cause inflammation.
 Type IV (delayed)- occur 12 to 72 hours after exposure.
Delay commonly associated with travel time to lymph nodes.
Cosmetics and poison ivy hapten commonly do this.
T helper cell function
They help the activity of other
immune cells by releasing T
cell cytokines. These cells
help, suppress or regulate
immune responses.
•
Examples:
- The cell or tissue damage done during
diseases like tuberculosis, leprosy, smallpox,
measles, herpes infections, candidiasis, and
histoplasmosis
- the skin test reactions seen for
tuberculosis and other infections.
- contact dermatitis like poison ivy.
- type-1 insulin-dependent diabetes where CTLs
destroy insulin-producing cells.
- multiple sclerosis, where T-lymphocytes and
macrophages secrete cytokines that destroy the
myelin sheath that insulates the nerve fibers of
neurons.
- Crohn’s disease and ulcerative colitis.
- psoriasis.
Table 5 - Comparison of Different Types of hypersensitivity
characteristics
type-I
(anaphylactic)
type-II
(cytotoxic)
type-III
(immune
complex)
type-IV
(delayed type)
antibody
IgE
IgG, IgM
IgG, IgM
None
antigen
exogenous
cell surface
soluble
tissues & organs
response time
15-30 minutes
minutes-hours
3-8 hours
48-72 hours
appearance
weal & flare
lysis and necrosis
erythema and erythema and
edema, necrosis induration
histology
basophils and
eosinophil
antibody and
complement
complement
monocytes and
and neutrophils lymphocytes
Allergic Contact Dermatitis Response to
Poison Ivy Hapten
Autoimmune Diseases
A. Type II (Cytotoxic) Autoimmune Reactions
Involve antibody reactions to cell surface
molecules, without cytotoxic destruction of
cells.
 Grave’s Disease:
 Antibodies attach to receptors on thyroid gland and
stimulate production of thyroid hormone.
 Symptoms: Goiter (enlarged thyroid) and bulging
eyes.
 Myasthenia gravis:
 Progressive muscle weakness. Antibodies block
acetylcholine receptors at neuromuscular synapse.
 Affects 25,000 Americans (mainly women).
 Today most patients survive when treated with drugs
or immunosuppressants.
SLE
 Systemic lupus erythematosus, often
abbreviated as SLE or lupus, is a systemic
autoimmune disease (or autoimmune connective
tissue disease) that can affect any part of the
body. As occurs in other autoimmune diseases,
the immune system attacks the body's cells and
tissue, resulting in inflammation and tissue
damage. It is a type III hypersensitivity reaction
in which bound antibody-antigen pairs (immune
complexes) precipitate and cause a further
immune response.
SLE
 The disease occurs nine times more often in
women than in men, especially in women in
child-bearing years ages 15 to 35.
LUPUS (SLE)
 Etiology: Antibodies (ABs) directed against




the patient’s own DNA, HISTONES, NONhistone RNA, and NUCLEOLUS
Pathogenesis: Progressive DEPOSITION and
INFLAMMATION to immune deposits, in skin,
joints, kidneys, vessels, heart, CNS, LIVER.
Morphology: “Butterfly” rash (NOT discoid)
, skin deposits, glomerolunephritis
Clinical expression: Progressive renal and
vascular disease, POSITIVE A.N.A.
INSULIN-DEPENDENT DIABETES
MELLITUS (IDDM)
 Synonym
• Type I diabetes, DM-type I
 Accounts for 5% to 10% of diabetes in US
 Female to male ratio of 1:1
 Effector mechanisms
• CD8 T cells and autoantibodies against beta cells
• Glutamic acid decarboxylase (GAD)
• Insulin
PATHOPHYSIOLOGY OF IDDM
 Pancreatic beta cells are damaged by
• Infectious agents
• Mumps virus, rubella virus, coxsackie B virus
• Toxic chemicals
 Damaged beta cells present antigens which
trigger immune attack in genetically susceptible
INSULIN-DEPENDENT DIABETES
MELLITUS (IDDM)
 Symptoms
•
•
•
•
•
Increased thirst
Frequent urination
Increased hunger
Weight loss
Fatigue
RHEUMATOID ARTHRITIS (RA)
 Characterized by inflammation of synovial membrane of joints
and articular surfaces of cartilage and bone
 Involved joints are swollen, warm, painful, and stiff on arising
or following inactivity.
 Vasculitis is a systemic complication
 Affects 3% to 5% of U.S. population
 Female to male ratio of 3:1
 HLA DR4 is genetic risk factor
↑
Destructive Rheumatoid
Synovitis
NORMAL Bi-Layered
Synovium
MULTIPLE SCLEROSIS (MS)
 Chronic unpredictable disease of CNS with four
possible clinical courses
 Characterized by patches of demyelination and
inflammation of myelin sheath
 Prevalence higher in Northern Hemisphere
• North of 37th parallel (125 cases /100,000)
• South of 37th parallel (70 cases /100,000)
 Female to male ratio of 2:1
MULTIPLE SCLEROSIS (MS)
 Effector mechanisms
• Myelin basic protein is primary autoantigen for CD4
TH1 cells
 Radiology diagnosis
• MRI for detecting demyelinating lesions (plaques)
Immunodefeciency disorders
 Defect in B- cell, T- cell, complement or






phagocytic cells.
Risk factors
A. prematurity
B. autoimmune diseases
C. lymphoproliferative disorders
D. infections
E. immunosuppressive drugs
ImmunoDefiency
Syndromes (-IDS)
PRIMARY (GENETIC) (P-
IDS)
SECONDARY
(ACQUIRED) (A-IDS)
PRIMARY
 CHILDREN with repeated, often severe infections,






cellular AND/OR humoral immunity problems,
autoimmune defects
B-cell disorders
BRUTON (X-linked agammaglobulinemia)
COMMON VARIABLE
IgA deficiency
T cell disorders
DI GEORGE (THYMIC HYPOPLASIA) 22q11.2
 Combined B and T cell disorders
 SCID (Severe Combined Immuno Deficiency)
 Wiskott Aldrich syndrome
 Ataxia telangiectasia
(A)IDS
(SECONDARY IDS)
 Etiology: HIV
 Pathogenesis: Infection, Latency,
Progressive T-Cell loss
 Morphology: MANY
 Clinical Expressions: Infections, Neoplasms,
Progressive Immune Failure, Death, HIV+,
HIV-RNA (Viral Load)
• AIDS – Acquired
Immunodeficiency diseases
– Acquired after birth, like HIV.
– HIV targets helper T cells
– Most patients with AIDS die
of opportunisitic infections.
– Opportunistic infection:
An infection that occurs
because of a weakened
immune system.
Opportunistic infections
are a particular danger for
people with AIDS. The HIV
virus itself does not cause
death, but the
opportunistic infections
that occur because of its
effect on the immune
system can.