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Lecture 12: Disorders associated with the immune systemEdith Porter, M.D.
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Hypersensitivity▪ Type I (anaphylactic) reactions▪ Type II (cytotoxic reactions▪ Type III (immunecomplex reactions)▪ Type IV (delayed cell-mediated) reactions
Autoimmune diseases▪ 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
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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Allergen is taken up by macrophages and activates TH cells
Tuberculin reaction
via complement activation
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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
Vasopermeability increased Mucous production increased Constriction of airways
Localized Hives, hay fever, or asthma from contact or inhaled antigens
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 11
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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
Apparent only at least one day after allergen contact
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Cell infiltrate
Used in TB diagnostic13
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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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Allergen is taken up by macrophages and activates TH cells
Tuberculin reaction
via complement activation
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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 self-tolerance
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 auto-antibodies 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 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 Cross reactive antibodies
NK cell dependent cytotoxicity Complement attack with lysis Macrophage attacks
LymphocyteInfiltrate
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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
Immune cells from graft attack the host
Typical symptoms include diarrhea and kidney failure
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Opportunistic infectionsRecurrent infections with otherwise
harmless organisms
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Inherited Chronic granulomatous
disease▪ Neutrophil defect ▪ Lack of oxidative burst
Complement deficiencies Agammaglobulinemia▪ No antibodies
Severe Combined Immune Deficiency▪ No B-cells, no T-cells
Acquired Immunosuppressive drugs HIV infection
Chronic granulomatous disease
Burst + Burst –Neutrophils
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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 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
2 copies of RNAReverse
transcriptase IntegraseProtease
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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
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
Active production Budding and release of infectious virions Cell to cell fusion
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HIV-1 USA, Western Hemisphere
HIV-2 Western Africa Almost normal life span
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
lymphadenopathyCategory B
Persistent Candida albicans infectionsCategory C
Clinical AIDS▪ CMV, TB, Pneumocystis, toxoplasmosis, Kaposi's
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Protozoa Cryptosporidium Toxoplasma
Viruses Herpes simplex Varizella zoster
Bacteria Mycobacterium
tuberculosis Mycobacterium
avium intracellulare
Fungi Pneumocystis Histoplasma Candida Cryptococcus
Intracellular organisms that require T-mediated defense!!!42
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Deficient tumor control T-helper cells activate NK cells CTL can kill specific tumor cells
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
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 Combination therapy
HAART (highly active anti-retroviral therapy)
Often requires up to 40 pills a day45
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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% 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 died14,000 new infections every day http://www.who.int/vaccine_research/diseases/
hiv/en/47
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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. 49
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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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