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

“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

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

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

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

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

sarcoma40

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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

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

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

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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