Transcript MICR 201 Microbiology for Health Related Sciences

Lecture 12: Disorders associated with the immune system
Edith Porter, M.D.
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 Hypersensitivity
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Type I (anaphylactic) reactions
Type II (cytotoxic reactions
Type III (immunecomplex reactions)
Type IV (delayed cell-mediated) reactions
 Autoimmune diseases
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Tolerance
Cytotoxic autoimmune diseases
Immune complex autoimmune diseases
Cell mediated autoimmune disease
 Transplant rejection
 Immunodeficiencies
▪ Congenital
▪ Acquired
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Immune response against an innocuous (harmless)
antigen
 Antigen is now called allergen
 4 types
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 Type I: anaphylactic reactions (soluble allergen, IgE and
mast cells)  “Allergy”
 Type II: antibody mediated cytotoxicity (cellular allergen,
IgG or IgM and complement)
 Type III: immune complex reactions (soluble allergen, IgG,
complement)
 Type IV: T- cell mediated reactions (allergen,
macrophages, T cells)
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via complement activation
Allergen is taken up by
macrophages and activates TH
cells
Tuberculin reaction
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“Allergy”
Involve IgE antibodies and mast cell derived histamine
IgE is captured by mast cells in the absence of antigen
When allergen binds and cross-links surface IgE, mast cells
degranulate
 Release histamine containing granules
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 Vasopermeability increased
 Mucous production increased
 Constriction of airways
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Localized
 Hives, hay fever, or asthma from contact or inhaled antigens
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Systemic
 Shock from ingested or injected antigens
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Drops of fluid containing
various allergens are placed
on top of the skin.
A light scratch is made with
a needle to allow the
substances to penetrate into
the skin.
Reddening and swelling
within minutes indicate
hypersensitivity
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Involves allergen on cells or matrix
associated, IgG antibodies, complement
Complement activation via classical
pathway causes cell lysis or uptake by
macrophages
Most familiar example is drug
hypersensitivity
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Alternatively, complex
is phagocytosed by
macrophages
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Initially observed when
serum from immune animals
was injected into patients
IgG antibodies and soluble
allergen form complexes
that lodge in basement
membranes
Complement activation and
inflammation
 Kidney: glomerulonephritis,
kidney dysfunction
 Small blood vessels  arthritis
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Delayed cell-mediated reactions
Do not involve antibodies
Caused mainly by T cells
Allergen is taken up by host cell and presented
to T cells
 Uptake by macrophages and presentation via MHC II:
T helper cell response; example tuberculin test
 Uptake by any nucleated cell and presentation via
MHC I: CTL response; example contact dermatitis
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Apparent only at least one day after allergen
contact
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Cell infiltrate
Used in TB diagnostic
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Example: Poison ivy
contact dermatitis
Lipid soluble allergen is
absorbed through skin
and crosses cell
membranes
Allergen modifies self
peptides
Presentation of
modified self peptide
via MHC I to CTL
Destruction of
modified cell
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via complement activation
Allergen is taken up by
macrophages and activates TH
cells
Tuberculin reaction
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Unwanted immune response to self antigens
Normally, self-reacting B-cells and T-cells are
deleted during fetal development (self tolerance)
 Autoimmunity is the consequence of loss of selftolerance
 Chronic disease that is continuously ongoing,
since self antigen cannot be eliminated
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Type II — Antibodies react with cell-surface
antigens in specific organs
Type III (Immune Complex) — IgM and/or IgG
react with soluble cell material, complexes
are deposited, initiate complement
activation, inflammation
Type IV — Mediated by cytotoxic T cells
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Stimulating autoantibodies against
growth receptors on
thyroid gland
 Cross reactive
autoantigens in the
eyes
 Patients develop
goiter, bulging
staring eyes
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Autoantibodies against
acetylcholine receptor on
muscle cells
Muscle weakness
Repetitive movements very
difficult!
In particular eye bulb muscles
affected
Life threatening when muscles
for respiration are affected
Can be transferred to fetus
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Auto-antibodies against nuclear
components (DNA, histones,
ribosomes, snRNP, etc)
 Immune complexes activate
complement
 Complexes transported via Fc-rec. on
phagocytes or via complement rec. on
erythrocytes to spleen/liver for
sequestration
 Excess complexes are deposited in
small blood vessels
 Local inflammation in skin, joints and
kidneys, multi-organ damage
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Insulin Dependent
Diabetes Mellitus
 Early, sudden onset
(adolescence)
 Initially mediated by
autoantibodies against
beta cell antigen
 Later phases include
cytotoxic T-cell response
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Immunohistochemistry
Insulin = brown
Glucagon = black
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Unwanted normal response against
foreign antigen
 Mainly MHC I based
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 Every nucleated cell expresses MHC
Type I molecules
 MHC I molecules differ from person to
person
 MHC I molecules from a different
person are recognized as foreign
 Cytotoxic T cells attack the transplant
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Cross reactive antibodies
 NK cell dependent cytotoxicity
 Complement attack with lysis
 Macrophage attacks
Lymphocyte
Infiltrate
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Formerly erythroblastosis fetalis
Can be prevented by i.v anti-rhesus at the time of delivery
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Immune competent cells are transplanted
 Bone marrow transplant
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Immune cells from graft attack the host
Typical symptoms include diarrhea and
kidney failure
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Opportunistic infections
Recurrent infections with otherwise harmless
organisms
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Inherited
Chronic granulomatous dis
 Chronic granulomatous disease
▪ Neutrophil defect
▪ Lack of oxidative burst
 Complement deficiencies
 Agammaglobulinemia
▪ No antibodies
 Severe Combined Immune
Deficiency
▪ No B-cells, no T-cells
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Acquired
Burst +
Burst –
Neutrophils
 Immunosuppressive drugs
 HIV infection
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1981: In US, cluster of Pneumocystis and
Kaposi's sarcoma in young homosexual men
discovered
The men showed loss of immune function
1983: Discovery of virus causing loss of
immune function
 HIV
 By Montagnier (France) and Gallo (US)
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Evidence indicates HIV-1
and HIV-2 arose from
different evolutionary lines
 HIV-2: mutation in a simian
immunodeficiency virus
(SIV) of mangabey
monkeys in West Africa
 HIV-1: SIV carried by
chimpanzees in Central
Africa
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 Chimpanzee virus appears to
be a hybrid of two mangabey
SIVs
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Crossed the species barrier into humans in
Africa in the 1930s
 Humans eating infected monkeys
 Humans being bitten by infected monkeys
Patient who died in 1959 in Congo is the oldest
known case
 Spread in Africa as a result of urbanization
 Spread in world through modern transportation
and unsafe sexual practices
 Norwegian sailor who died in 1976 is the first
known case in Western world
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Enveloped with protein
spikes
 gp 120
 gp 41
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2 copies of RNA
Reverse transcriptase
Integrase
Protease
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Requires CD4 and a chemokine receptor
 Individuals with certain mutations in one of the chemokine receptors are
immune to HIV infection
Primarily, T cells are infected
Additional cell targets are monocytes and macrophages, epithelial
cells
 Major steps of infection
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Attachment via gp 120
Fusion via gp41
Entry of virion without envelope
Uncoating
Reverse transcription
Incorporation of viral cDNA into host genome
Viral RNA and viral mRNA production
Capsid and enzyme production (reverse transcriptase, integrase, protease)
Assembly , packaging, and release
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via CD4 and chemokine
Receptor CCR
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Viral RNA is reverse transcribed into DNA
Viral DNA is integrated into host genome
Latent infection as provirus
Latent virion
 Viruses are not released but remain in a vacuole in the
cell
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Active production
 Budding and release of infectious virions
 Cell to cell fusion
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HIV-1
 USA, Western Hemisphere
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HIV-2
 Western Africa
 Almost normal life span
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Clades
 No proof reading
 High mutation rate of HIV
 Many new subtypes
 Clades differ from each other by ~ 30% or more
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Category A
 Asymptomatic or persistent lymphadenopathy
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Category B
 Persistent Candida albicans infections
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Category C
 Clinical AIDS
▪ CMV, TB, Pneumocystis, toxoplasmosis, Kaposi's sarcoma
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Protozoa
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 Mycobacterium
 Cryptosporidium
tuberculosis
 Mycobacterium avium
intracellulare
 Toxoplasma
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Viruses
 Herpes simplex
 Varizella zoster
Bacteria
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Fungi
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Pneumocystis
Histoplasma
Candida
Cryptococcus
Intracellular organisms that require T-mediated defense!!!
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Deficient tumor control
 T-helper cells activate NK cells
 CTL can kill specific tumor cells
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New Herpes viridae are involved
Lymphoma, Kaposi sarcoma
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Antibody detection
 Seroconversion takes up to 3 months
 HIV antibodies detected by ELISA, confirmed by
western
 Rapid (20 min) test available
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Plasma viral load is determined by PCR or nucleic
acid hybridization
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Types of drugs
 Reverse transcriptase inhibitors
▪ Prevent viral DNA synthesis
 Protease Inhibitors
 Fusion inhibitors which target gp41
 Integrase inhibitors prevent integration of
HIV cDNA into host chromosome
 Virus decoys (material to which virus
binds instead of to cells)
 Boosting immune system
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Combination therapy
 HAART (highly active anti-retroviral
therapy)
 Often requires up to 40 pills a day
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Use of condoms and sterile needles
Health-case workers use universal precautions
 Wear gloves (double glove during invasive surgery),
gowns, masks, goggles
 Do not recap needles
 Risk of infection from infected needle stick injury is 0.3%
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Vaccine development
 So far unsuccessful: > 30 vaccine candidates tested
▪ Rapid mutation, differing clades
▪ Infected cells not very susceptible to CTL attack
▪ Latent infections
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~20,000,000 have already died
14,000 new infections every day
http://www.who.int/vaccine_research/diseases/hiv/en/
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Hypersensitivities are immune responses to an
innocuous antigen, which is called allergen.
 Autoimmune diseases are immune responses to
self antigens.
 Transplant rejection: normal but harmful and
unwanted immune reactions
 Immune deficiencies can be acquired or inherited
and result in recurrent infections due to
opportunistic organisms.
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2) The chemical mediators of anaphylaxis are
A) Found in mast cells.
B) Antibodies.
C) Antigens.
D) Antigen-antibody complexes.
E) The proteins of the complement system.
9) A healthy immune system destroys cancer cells
with
A) Tumor-specific antigens.
B) CTLs.
C) IgG antibodies.
D) IgE antibodies.
E) CD4+ T cells.
16) Which of the following statements about type I
hypersensitivities is false?
A) They are cell-mediated.
B) They involve IgE antibodies.
C) The symptoms are due to histamine.
D) Antibodies are bound to host cells.
E) The symptoms occur soon after exposure to an
antigen.
33) During asymptomatic phase I of HIV disease,
HIV infection is diagnosed by
A) Measuring viral RNA.
B) Measuring antibodies against HIV.
C) Counting CD4+ T cells.
D) Counting CD8+ T cells.
E) Testing for seroconversion.
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