Download Lecture 11- Immunity 2

Lecture 11
Immune System & its Diseases II
Dr. Yasmine Lashine
MD, PhD
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ILOs
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Distinguish between innate and adaptive immunity.
Recall the cells involved in the immune response and define their roles.
Compare and contrast the origin, maturation process, and general function of B and
T lymphocytes.
Name several antigen-presenting cells and describe their roles in adaptive defenses.
Understand the mechanisms and key players of humoral immunity.
Define cellular immunity and describe the process of activation.
Describe the roles of different types of T cells and their functions in the body.
Discuss the possible mechanisms of graft rejection and the role of MHC molecules.
Compare and contrast the types and subtypes of hypersensitivity disorders in terms
of examples, pathogenesis, clinical features, key players, antigens…
Define self-tolerance, and describe its development in B and T lymphocytes.
Give examples of immune deficiency diseases and differentiate between primary
and secondary immune deficiencies.
Understand the pathogenesis of HIV infection and rheumatoid arthritis.
Cite examples of autoimmune diseases and understand their mechanisms.
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Outline
1. Types of Hypersensitivity Reactions
• Type I Hypersensitivity Reactions
• Type II Hypersensitivity Reactions
- Complement-dependent Reactions
- Antibody-mediated Cellular Cytotoxicity
- Cellular Dysfunction
• Type III Hypersensitivity Reactions
• Type IV Hypersensitivity Reactions
- Delayed-Type Hypersensitivity
- T cell-Mediated Cytotoxicity
2. Transplant Rejection
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Type I Hypersensitivity Reactions
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http://www.healthspablog.org/allergy/allergy-to-dust-invented-new-vaccine
Type I Hypersensitivity Reactions
Inhalation
Ingestion
Environmental antigens (allergens)
Injection
Activation of
Th2 cells
Cytokine release
Activation of TH2 cells and
production of IgE antibody
Production of
IgE antibodies
from B cells
Attachment of
IgE to mast
cells
Re-exposure to the allergen
Sensitization of mast cells by
IgE antibody
Activation of mast cells
and Mediators release
Clinical manifestation
Inhalation, ingestion, or injection
TH2 subset of CD4+ helper T cells
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Leukocyte activation
Amplification of Th2-initiated reaction
Stimulation of cell mucus secretion
5-30 min to 1 hour
2-8 hours to several days
The dominant inflammatory cells in the latephase reaction are neutrophils, eosinophils, and
lymphocytes, especially TH2 cells
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Type I Hypersensitivity Reactions
Mediators of immediate hypersensitivity reaction
Vasoactive amines released from granule stores:
• Histamine causes vasodilation, increased vascular permeability, smooth muscle
contraction, and increased secretion of mucus.
• Adenosine causes bronchoconstriction and inhibits platelet aggregation.
• Chemotactic factors for neutrophils and eosinophils.
Newly synthesized lipid mediators:
• Prostaglandin D2 (PGD2) Causes intense bronchospasm and increased mucus secretion
• Leukotrienes C4 and D4 (LTC4, LTD4) are the most potent vasoactive and spasmogenic
agents . LTB4 is highly chemotactic for neutrophils, eosinophils, and monocytes
• Platelet-activating factor (PAF): platelet aggregation, bronchospasm, chemotaxis
Cytokines:
• TNF and chemokines recruit and activate leukocytes.
• IL-4 and IL-5 amplify the Th2-initiated immune reaction.
• IL-13 stimulates epithelial cell mucus secretion.
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Type I Hypersensitivity Reactions
Local manifestation
Skin contact :
urticaria
Ingestion :
GIT manifestation
as vomiting and
diarrhea
Inhalation
Seosonal allergy
Runny and stuffy nose
Sneezing
Sore throat
Redness in the eyes
Asthma
Coughing
Wheezing
Shortness of breath
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Type I Hypersensitivity Reactions
systemic manifestation
Drugs as penicillin
Parenteral administration of
Antigens as snake venom or bee sting
Itching , urticarial , skin erythema
 Profound respiratory difficulty
( bronchoconstriction and increased mucous secretion)
 Laryngeal edema
Upper airway obstruction
 Vomiting , abdominal pain and diarrhea
Systemic vasodilatation
Anaphylactic shock
Circulatory collapse
Within minutes
Death
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Type I Hypersensitivity Reactions
Clinical and pathologic manifestation
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Epinephrine!
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http://www.firstaidanywhere.com/bee-sting-first-aid.html
Type I Hypersensitivity Reactions
 Type I HS in Parasitic Infections
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Case
• Every springtime, a young healthy man is bothered by
episodes of nasal congestion accompanied by sneezing and
watery eyes. He has no cough. On physical examination he
is afebrile. There is swelling of his nasal passageways, but
no other findings. His condition improves with use of
loratadine. His problems are most likely produced by
release of chemical mediators from which of the following
cell types?
• Neutrophil
• Mast cell
• CD4+ cell
• NK cell
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Type II Hypersensitivity Reactions
Antibody-Mediated Diseases
This reaction is mediated through Antibodies that are directed against target antigens on the
surface of cells or other tissue components
Cell-mediated
cytotoxicity
Complementdependent
ADCC
reactions
Antibody
mediated
cellular
dysfunction
Type II
hypersensitivity
reaction
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Type II Hypersensitivity Reactions
Complement-dependent reactions
Opsonization and phagocytosis
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Type II Hypersensitivity Reactions
Complement-dependent reactions
Examples:
 Transfusion reactions
 Erythroblastosis fetalis (hemolytic disease of the
newborn)
 Autoimmune hemolytic anemia
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Type II Hypersensitivity Reactions
Complement-dependent reactions
Transfusion reactions
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Type II Hypersensitivity Reactions
Complement-dependent reactions
Erythroblastosis fetalis
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Type II Hypersensitivity Reactions
Antibody-Dependent Cellular
Cytotoxicity (ADCC):
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Cell-mediated killing of parasites
Type II Hypersensitivity Reactions
Antibody mediated cellular dysfunction
Graves Disease
Myasthenia Gravis
Antibodies against the thyroid-stimulating
hormone receptor stimulate thyroid epithelial
cells to secrete thyroid hormones, resulting in
hyperthyroidism
Antibodies against acetylcholine receptors in the
motor end plates of skeletal muscles inhibit
neuromuscular transmission, with resultant
muscle weakness
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Type II Hypersensitivity Reactions
Antibody mediated cellular dysfunction
Graves Disease
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Type II Hypersensitivity Reactions
Disease
Target Antigen
Mechanisms of
Disease
Autoimmune
hemolytic anemia
Erythrocyte membrane
proteins
Opsonization and
Hemolysis, anemia
phagocytosis of erythrocytes
Acute rheumatic
fever
Streptococcal cell wall
Inflammation, macrophage
antigen; antibody crossactivation
reacts with myocardial
antigen (Molecular mimicry)
Myasthenia gravis
Acetylcholine receptor
Antibody inhibits
Muscle weakness,
acetylcholine binding, down- paralysis
modulates receptors
Graves disease
(hyperthyroidism)
TSH receptor
Antibody-mediated
Hyperthyroidism
stimulation of TSH receptors
Examples of Antibody-Mediated Diseases
(Type II Hypersensitivity)
Clinico pathologic
Manifestations
Myocarditis, arthritis
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Immune Complex Diseases
(Type III Hypersensitivity)
Endogenous
Antigen
DNA
Antigenantibody
Deposition in blood vessels
Immune
Exogenous
Complex
Microbial
Antigen
Complement activation
Vasculitis
Arthritis
Glomerulonephritis
Antigen-antibody complex deposition
Can cause Local injury when affecting particular
organs as kidney or joints , and can also cause
Systemic injury by affecting multiple organs
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Systemic Immune-Complex Disease: Serum sickness
The use of horse anti-thymocyte globulins for
the treatment of severe aplastic anemia
5 days after injection
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Production of specific antibodies
Formation of antigen-antibody
complex
Deposition of immune
complex
Inflammatory reaction and clinical
manifestation occurs -10 days
Fever – Urticaria-Arthralgias
Lymph node enlargement-Proteinuria
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Type III Hypersensitivity
Disease
Antigen Involved
Clinicopathologic
Manifestations
Systemic lupus
erythematosus
Nuclear antigens
Nephritis, skin lesions,
arthritis, others
Poststreptococcal
glomerulonephritis
Streptococcal cell wall
Nephritis
antigen(s); may be "planted"
in glomerular basement
membrane
Serum sickness
Various proteins, such as
Arthritis, vasculitis, nephritis
foreign serum protein (horse
anti-thymocyte globulin)
Arthus reaction
(experimental)
Various foreign proteins
Cutaneous vasculitis
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Case
• A 9-year-old boy has a sore throat. A throat culture grows
group A hemolytic streptococcus. He receives antibiotic
therapy. However, 17 days later he develops dark-coloured
urine. Laboratory studies show 3+ blood on urinalysis. A
renal biopsy is performed. On immunofluorescence staining
the biopsy shows granular deposition of IgG and
complement around glomerular capillary loops. Which of
the following immune hypersensitivity mechanisms is most
likely responsible for this pattern of findings?
• Type I
• Type II
• Type III
• Type IV
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Type IV Hypersensitivity
(Cell-Mediated)
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Tuberculin reaction
Antigen challenge test in an individual already
sensitized to the tubercle bacillus by a previous
infection
8-12 hours after injection
Intracutaneous injection of tuberculin
local area of erythema and induration appears,
reaching a peak (typically 1-2 cm in diameter) in
24 to 72 hours
HIV ?
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Type IV Hypersensitivity
Delayed – Type hypersensitivity
Granulomatous Inflammation
 The initial CD4+ T-cell infiltrate is progressively
replaced by macrophages over a period of 2 to 3
weeks.
 These macrophages become large, and flat
(epithelioid cells).
 The epithelioid cells occasionally fuse under the
influence of cytokines (e.g., IFN-γ) to form
multinucleated giant cells.
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Type IV Hypersensitivity
(Cell-Mediated)
T –cell mediated cytotoxicity
 CD8+ CTLs is the main key player in this
reaction kill antigen-bearing target cells.
 Class I MHC molecules bind to intracellular
peptide antigens and present the peptides
to CD8+ T lymphocytes, stimulating the
differentiation of these T cells into effector
cells called CTLs.
 CTLs play a critical role in resistance to virus
infections and some tumors.
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Transplant Rejection
Immunologic rejection of transplanted tissue is considered the major
barrier to transplantation of organs between individuals of the same
species (allografts ).
Cell mediated
hypersensitivity
Directed
against
donor’s MHC
molecules
Antibody
mediated
hypersensitivity
Tissue
rejection
Classic acute rejection in a non-immunosuppressed host occurs within
10 to 14 days and includes both DTH and CTL
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Transplant Rejection
Direct recognition
Host T cells directly recognize the allogeneic
(foreign) MHC molecules that are expressed on
graft cells.
Indirect recognition
Host CD4+ T cells recognize donor MHC
molecules after these molecules are picked up,
processed and presented by the host's own
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APCs.
Transplant Rejection
T –cell mediated rejection
 CTLs kill cells in the grafted tissue, causing parenchymal and,
perhaps more importantly, endothelial cell death (resulting in
thrombosis and graft ischemia).
 Cytokine-secreting CD4+ T cells trigger DTH reactions, with
increased vascular permeability and local accumulation of
mononuclear cells (lymphocytes and macrophages).
Antibody mediated rejection
 Antibodies directed against graft MHC molecules bind to the graft
endothelium and cause injury (and secondary thrombosis) via
complement activation and recruitment of leukocytes.
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Transplant Rejection
T –cell mediated rejection
 CTLs kill cells in the grafted tissue,
causing parenchymal and, perhaps
more importantly, endothelial cell
death (resulting in thrombosis and
graft ischemia).
 Cytokine-secreting CD4+ T cells
trigger DTH reactions, with increased
vascular permeability and local
accumulation of mononuclear cells
(lymphocytes and macrophages).
Antibody mediated rejection
 Antibodies directed against graft
MHC molecules bind to the graft
endothelium and cause injury (and
secondary thrombosis) via
complement activation and
recruitment of leukocytes.
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Transplant Rejection
Hyperacute rejection
 A special form of rejection occurring in the setting
where preformed antidonor antibodies are present in
the circulation of the host before transplant.
 Transplantation in this setting results in immediate
rejection (within minutes to hours) because the
circulating antibodies rapidly bind to the endothelium
of the grafted organ, with subsequent complement
activation and vascular thrombosis.
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References
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Basic Pathology 8th and 9th Edition, by Kumar, Cotran and Robbins
Previous lectures by Dr. Nabila Hamdi
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