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Lecture 12: Disorders associated with the immune system Edith Porter, M.D. 1.

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Presentation on theme: "Lecture 12: Disorders associated with the immune system Edith Porter, M.D. 1."— Presentation transcript:

1 Lecture 12: Disorders associated with the immune system Edith Porter, M.D. 1

2  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 2

3  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) 3

4 4 Allergen is taken up by macrophages and activates TH cells Tuberculin reaction via complement activation

5  “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 5

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8  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 8

9  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 9

10 10 Alternatively, complex is phagocytosed by macrophages

11  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

12  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 12

13 Cell infiltrate Used in TB diagnostic 13

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15 15  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

16 16 Allergen is taken up by macrophages and activates TH cells Tuberculin reaction via complement activation

17  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 17

18  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 18

19  Stimulating auto- antibodies against growth receptors on thyroid gland  Cross reactive autoantigens in the eyes  Patients develop goiter, bulging staring eyes 19

20  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 20

21  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 21

22  Insulin Dependent Diabetes Mellitus  Early, sudden onset (adolescence)  Initially mediated by autoantibodies against beta cell antigen  Later phases include cytotoxic T-cell response 22 Immunohistochemistry Insulin = brown Glucagon = black

23  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 Lymphocyte Infiltrate 23

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25  Formerly erythroblastosis fetalis  Can be prevented by i.v anti-rhesus at the time of delivery 25

26  Immune competent cells are transplanted  Bone marrow transplant  Immune cells from graft attack the host  Typical symptoms include diarrhea and kidney failure 26

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28  Opportunistic infections  Recurrent infections with otherwise harmless organisms 28

29  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 29

30  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) 30

31  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 31

32  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 32

33  Enveloped with protein spikes  gp 120  gp 41  2 copies of RNA  Reverse transcriptase  Integrase  Protease 33

34  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 34

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37  via CD4 and chemokine Receptor CCR 37

38  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 38

39  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 39

40  Category A  Asymptomatic or persistent lymphadenopathy  Category B  Persistent Candida albicans infections  Category C  Clinical AIDS ▪ CMV, TB, Pneumocystis, toxoplasmosis, Kaposi's sarcoma 40

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42  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

43  Deficient tumor control  T-helper cells activate NK cells  CTL can kill specific tumor cells  New Herpes viridae are involved  Lymphoma, Kaposi sarcoma 43

44  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 44

45  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 day 45

46  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 46

47 ~20,000,000 have already died 14,000 new infections every day 47

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49  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

50 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. 50


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