OBC 231 General Pathology Diseases of the Immune System. Dr. Huda Hammad Dr. Wael Swelam

Transcription

1 OBC 231 General Pathology Diseases of the Immune System Dr. Huda Hammad Dr. Wael Swelam

2 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Individuals who mount immune responses against an antigen are said to be sensitized to that antigen. When these responses are pathologic or excessive, the manifestations are called hypersensitivity. Normally, a system of checks and balances optimizes the eradication of infecting organisms without serious injury to host tissues. However, immune responses may be inadequately controlled or inappropriately targeted to host tissues. In these situations, the normally beneficial response is the cause of disease. 2

3 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Causes of Hypersensitivity Diseases Pathologic immune responses may be directed against different types of antigens, and may result from various underlying abnormalities: 1. Autoimmunity. 2. Reactions against microbes. 3. Reactions against environmental antigens. 3

4 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Causes of Hypersensitivity Diseases 1. Autoimmunity: Normally, the immune system does not react against an individual's own antigens (self-tolerance). Sometimes, self-tolerance fails, resulting in reactions against one's own cells and tissues that are called autoimmunity. The diseases caused by autoimmunity are referred to as autoimmune diseases. 4

5 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Causes of Hypersensitivity Diseases 2. Reactions against microbes: Many types of reactions against microbial antigens may cause disease. In some cases, the reaction may be excessive or the microbial antigen is unusually persistent. 5

6 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Causes of Hypersensitivity Diseases Reactions against microbes Antibodies produced against microbial immune complexes T-cell responses against persistent microbes sever inflammatory response Antibodies / T cells cross-react with a host tissue During the process of eradicating the infection host tissues injury Inflammatory Poststreptococcal glomerulonephritis Granulomas, e.g. Tuberculosis Rheumatic heart disease Cytotoxic T cells try to eliminate infected cells, and this normal immune response damages liver cells e.g. Viral hepatitis 6

7 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Causes of Hypersensitivity Diseases Tuberculos granuloma Viral hepatitis 7 Poststreptococcal glomerulonephritis Rheumatic heart disease

8 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Causes of Hypersensitivity Diseases 3. Reactions against environmental antigens: Most healthy individuals do not react strongly against common environmental substances (e.g., pollen, animal dander, or dust mites), but almost 20% of the population is "allergic" to these substances. 8

9 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Causes of Hypersensitivity Diseases These hypersensitivity diseases tend to be chronic, often debilitating, and pose therapeutic challenges. Since chronic inflammation is a major component of these disorders, they are sometimes grouped under the term immune-mediated inflammatory diseases. 9

10 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Hypersensitivity reactions are traditionally subdivided into four types. 1. Immediate (type I) hypersensitivity. 2. Antibody-mediated (type II) hypersensitivity. 3. Immune complex-mediated (type III) hypersensitivity. 4. T-cell-mediated (type IV) hypersensitivity. The first three are variations on antibody-mediated injury, whereas the fourth is cell mediated. This classification of immune-mediated disease is not perfect, because several immune reactions may coexist in one disease. 10

11 11

12 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immediate (type I) hypersensitivity 12 Some of these mediators are released within minutes from sensitized mast cells causing the intense immediate reactions associated with conditions such as systemic anaphylaxis. Others, such as cytokines, are responsible for the inflammation seen in late-phase reactions.

13 Sequence of events in immediate (type 1) hypersensitivity Action Vasodilation, increased vascular permeability Mediator Histamine PAF (platelet activating Factor) Leukotrienes C 4, D 4, E 4 Neutral proteases that activate complement and kinins Prostaglandin D 2 Smooth muscle spasm Leukotrienes C 4, D 4, E 4 Histamine Prostaglandins PAF Cellular infiltration Cytokines (e.g., chemokines, TNF) Leukotriene B 4 Eosinophil and neutrophil chemotactic factors (not defined biochemically) 13

14 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immediate (type I) hypersensitivity Often, the IgE-triggered reaction has two well-defined phases: (1) the immediate response: vasodilation, vascular leakage, and smooth muscle spasm, within 5 to 30 minutes after exposure to an allergen and subsiding by 60 minutes. (2) a second, late-phase reaction: in 2 to 8 hours later and may last for several days, inflammation and tissue destruction, such as mucosal epithelial cell damage. Dominated by neutrophils, eosinophils, and lymphocytes, especially T H 2 cells. 14

15 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immediate (type I) hypersensitivity Clinical and Pathologic Manifestations : Systemic anaphylaxis: Within minutes of an exposure in a sensitized host, itching, urticaria (hives), and skin erythema appear, followed in short order by profound respiratory difficulty caused by pulmonary bronchoconstriction and accentuated by hypersecretion of mucus. Laryngeal edema may exacerbate matters by causing upper airway obstruction. 15

16 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immediate (type I) hypersensitivity Clinical and Pathologic Manifestations : Systemic anaphylaxis: The musculature of the entire gastrointestinal tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea. Without immediate intervention, there may be systemic vasodilation with fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes. 16

17 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immediate (type I) hypersensitivity Clinical and pathologic manifestations : Local reactions generally occur when the antigen is confined to a particular site, such as : 1. Skin (contact urticaria), 2. Gastrointestinal tract (ingestion diarrhea), or 3. Lung (inhalation bronchoconstriction). 17

18 18

19 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Antibody-mediated (type II) hypersensitivity Caused by antibodies directed against target antigens on the surface of cells or other tissue components. The antigens may be normal molecules intrinsic to cell membranes or extracellular matrix, or they may be adsorbed exogenous antigens (e.g., a drug metabolite). 19

20 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Antibody-mediated (type II) hypersensitivity Antibody-mediated abnormalities are the underlying cause of many human diseases; examples include: Autoimmune hemolytic anemia. 2. Autoimmune thrombocytopenic purpura. 3. Pemphigus vulgaris. 4. Vasculitis caused by ANCA. 5. Goodpasture syndrome. 6. Acute rheumatic fever. 7. Myasthenia gravis 8. Graves disease (hyperthyroidism). 9. Insulin-resistant diabetes. 10. Pernicious anemia.

21 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Antibody-mediated (type II) hypersensitivity Mechanisms of Antibody-Mediated Diseases: A. 21

22 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Antibody-mediated (type II) hypersensitivity Mechanisms of Antibody-Mediated Diseases: C. Antibodies can bind to cell surface receptors or essential molecules, and cause functional derangements (either inhibition or unregulated activation) without cell injury, e.g. myasthenia gravis, Grave s disease (hyperthyroidism). 22

23 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immune complex-mediated (type III) Caused by antibodies binding to antigens to form complexes that circulate and may deposit in vascular beds and stimulate inflammation, typically secondary to complement activation. Tissue injury in these diseases is the result of the inflammation. The antigens in these complexes may be exogenous antigens, such as microbial proteins, or endogenous antigens, such as nucleoproteins. It is only when these complexes are produced in large amounts, persist, and are deposited in tissues that they are pathogenic. 23

24 Immune complex-mediated (type III) Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases 1) Formation of antigen-antibody complexes in the circulation. Systemic 2) Deposition of the immune complexes in various tissues, thus initiating 3) An inflammatory reaction in various sites throughout the body Local Excess amount of initial antibody immune complexes precipitated at the site of injection and trigger the same inflammatory reaction as in systemic immune complex disease 24

25 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases Immune complex-mediated (type III) 25 Disease Antigen Involved Clinicopathologic Manifestations Systemic lupus erythematosus Poststreptococcal glomerulonephritis Nuclear antigens Streptococcal cell wall antigen(s); may be "planted" in glomerular basement membrane Nephritis, skin lesions, arthritis, others Nephritis Polyarteritis nodosa Hepatitis B virus antigen Hepatitis B virus antigen Reactive arthritis Bacterial antigens (Yersinia) Acute arthritis Serum sickness Arthus reaction (experimental) Various proteins, such as foreign serum protein (horse anti-thymocyte globulin) Various foreign proteins Arthritis, vasculitis, nephritis Cutaneous vasculitis

26 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases T-cell-mediated (type IV) hypersensitivity Mechanisms of T-cell-mediated (type IV) hypersensitivity reactions: 26

27 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases T-cell-mediated (type IV) hypersensitivity Mechanisms of T-cell-mediated (type IV) hypersensitivity reactions: B. Direct cell cytotoxicity, mediated by CD8+ T cells. 27

28 Hypersensitivity Diseases: Mechanisms of Immune Mediated Injury Types of Hypersensitivity Diseases T-cell-mediated (type IV) hypersensitivity This group of diseases has received great interest because many of the newly designed biologic therapies developed to target abnormal T-cell reactions. Several autoimmune disorders, as well as pathologic reactions to environmental chemicals and persistent microbes, are now known to be caused by T cells. 28

29 Disease Type 1 diabetes mellitus Multiple sclerosis Specificity of Pathogenic T cells Antigens of pancreatic islet βcells (insulin, glutamic acid decarboxylase, others) Protein antigens in CNS myelin (myelin basic protein, proteolipid protein) Clinicopathologic Manifestations Antigens of pancreatic islet βcells (insulin, glutamic acid decarboxylase, others) Demyelination in CNS with perivascular inflammation; paralysis, ocular lesions Rheumatoid arthritis Unknown antigen in joint synovium (type II collagen?); role of antibodies? Demyelination in CNS with perivascular inflammation; paralysis, ocular lesions Peripheral neuropathy; Guillain- Barré syndrome? Inflammatory bowel disease (Crohn's disease) Protein antigens of peripheral nerve myelin Unknown antigen; may be derived from intestinal microbes Demyelination in CNS with perivascular inflammation; paralysis, ocular lesions Chronic inflammation of ileum and colon, often with granulomas; fibrosis, stricture Contact dermatitis 29 Environmental chemicals, e.g., poison ivy (pentadecylcatechol) Dermatitis, with itching; usually short-lived, may be chronic with persistent exposure

30 30

31 31

32 Rejection of transplants Transplantation problems Surgical difficulties Graft rejection Organ shortage 32

33 Transplant Immunology Outline: Graft compatibility Rejection = Autograft Isograft Allograft Xenograft Recipient recognizes graft as foreign, and destroys it Within same person Between identical twins Between genetically different people Between different species 33

34 Histocompatibility Histocompatible: antigenically similar to the host Histoincompatible: antigenically different from the host MHC antigens are the MOST IMPORTANT ABO antigens are also important Minor histocompatiblity antigens are less important 34

35 Compatibility: HLA complex Gene collection on chromosome 6 Three regions: class I, class II, class III Class I gene products HLA-A, HLA-B, HLA-C expressed on nearly all cells present antigen to T C cells Class II gene products DP, DQ, DR expressed on antigenpresenting cells present antigen to T H cells 35

36 36

37 37

38 Compatibility MHC class I II III Region A B C DP DQ DR C4, C2, BF Gene products HLA- A HLA- B HLA- C DP DQ DR C' proteins TNF- TNF- 38

39 Compatibility parents a/b c/d four possible haplotype combinations of children a/c a/d b/c b/d 39

40 Compatibility HLA alleles A B C DR DQ DP a 1 7 w haplotypes b c 2 8 w w d w

41 Compatibility a ice cream pop fruit cookie veggie yum yum haplotypes b De w c Vault 41 d

42 Compatibility: HLA inheritance The more matching alleles between donor and host, the better! Matching the class II antigens is more important than matching the class I antigens. One or two class I mismatches = no big deal One or two class II mismatches = big deal Mismatches in both class I and II = very big deal 42

43 graft survival, % number of mismatches 100 Class I Class II or or or 2 1 or 2 1 or 2 3 or 4 1 or time after transplant, months 43

44 Transplant Immunology Outline Introduction Graft compatibility Graft rejection 44

45 Rejection Any two people (except identical twins) will express some HLA proteins that are different. Every recipient will recognize, and react against, at least some foreign antigens in the graft Rejection is complex, with lots of killing mechanisms. 45

46 Rejection How do recipient cells know which cells to kill? 46

47 Rejection Two mechanisms of rejection T-cell-mediated rejection Antibody-mediated rejection 47

48 T-cell mediated rejection CD8+ CTLs kill graft cells directly CD4+ cells trigger a delayed hypersensitivity reaction 48

49 CTL Killing Delayed Hypersensitivity 49

50 Antibody-mediated rejection Preformed antibodies Anti-HLA or anti-abo Rejection occurs immediately ( hyperacute ) Antibodies cause thrombosis Rare these days Newly-made antibodies Appear within days to years Usually directed against graft endothelium Cause damage by: Helping complement kill graft cells Opsonizing graft cells (yummy!) 50

51 Antibody-dependant cell-mediated cytotoxicity (ADCC) Target cell is coated with IgG Effector cell* has receptors for Fc fragment Effector cell binds to target cell Target cell is lysed 51* Macrophage, Neutrophil, or NK Cell

52 Clinical types of Rejection Hyper-acute rejection Within hours Preexisting antidonor antibodies Rare these days Accelerated is similar Acute rejection Starts at about 10 days Cell-mediated Chronic rejection Months to years after transplant Humoral and cellmediated mechanisms Hard to prevent Hard to treat 52

53 Acute cellular (t) Acute humoral 53 Chronic

54 54

55 55

56 Autoimmune Diseases The immune reaction to self-antigens, or autoimmunity, is the cause of certain human diseases. A growing number of entities have been attributed to this process (see table in next slide). 56

57 Organ-Specific Systemic Hashimoto thyroiditis Autoimmune hemolytic anemia Autoimmune atrophic gastritis of pernicious anemia Multiple sclerosis Autoimmune orchitis Goodpasture syndrome Autoimmune thrombocytopenia Systemic lupus erythematosus Rheumatoid arthritis Sjögren syndrome Reiter syndrome Inflammatory myopathies* Systemic sclerosis (scleroderma)* Polyarteritis nodosa* 57 Insulin-dependent diabetes mellitus Myasthenia gravis Graves' disease Primary biliary cirrhosis* Autoimmune (chronic active) hepatitis* Ulcerative colitis *The evidence supporting an autoimmune basis of these disorders is not strong.

58 Autoimmune Diseases The evidence that the diseases listed in the previous table are the result of autoimmune reactions is more persuasive for some than for others. For example, the presence of multiple autoantibodies accounts for many of the clinical and pathologic manifestations of SLE. Moreover, these autoantibodies can be identified within lesions by immunofluorescence and electron-microscopic techniques. 58

59 Autoimmune Diseases 59 In many other disorders, an autoimmune etiology is suspected but is unproven. In some cases of apparent autoimmunity, the response may be directed against an exogenous antigen, such as a microbial protein. Autoimmune diseases range from those in which specific immune responses are directed against one particular organ or cell type, to multisystem diseases. In the systemic diseases, the lesions affect principally the connective tissue and blood vessels of the various organs involved. These diseases are often referred to as "collagen vascular" or "connective tissue" disorders.

60 Autoimmune Diseases: Self-Tolerance Autoimmunity implies loss of self-tolerance. Immunological tolerance is unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that antigen. Self-tolerance refers to a lack of immune responsiveness to one's own tissue antigens. 60

61 Autoimmune Diseases Self-Tolerance During the generation of billions of antigen receptors in developing T and B lymphocytes, receptors are produced that can recognize self-antigens. Several mechanisms work in concert to prevent immune reactions against one's own antigens. These mechanisms are broadly divided into two groups: central tolerance and peripheral tolerance. 61

62 Autoimmune Diseases Self-Tolerance Central tolerance Immature lymphocytes that recognize self-antigens in the central (generative) lymphoid organs are killed by apoptosis. In the B-cell lineage, some of the self-reactive lymphocytes switch to new antigen receptors that are not self-reactive Peripheral tolerance Mature lymphocytes that recognize self-antigens in peripheral tissues undergo one of the following: They become functionally inactive (anergic), Or are suppressed by regulatory T lymphocytes, Or die by apoptosis. 62

63 Autoimmune Diseases Self-Tolerance The variables that lead to a failure of self-tolerance and the development of autoimmunity include: 1. Inheritance of susceptibility genes that may disrupt different tolerance pathways. 2. Infections and tissue alterations that may expose selfantigens and activate APCs and lymphocytes in the tissues, altering the recognition of self-antigens. 63

64 Pathogenesis of autoimmunity Autoimmunity arises from many causes, including: 1) Inheritance of susceptibility genes that may interfere with selftolerance, 2) Environmental triggers (inflammation, other inflammatory stimuli) that promote lymphocyte entry into tissues, 3) Activation of self-reactive lymphocytes, and tissue injury. 64

65 Autoimmune Diseases Systemic Lupus Erythematosus The fundamental defect in SLE is a failure to maintain self-tolerance. A large number of autoantibodies is produced, classically including antinuclear antibodies (ANAs),that can damage tissues either directly or in the form of immune complex deposits. 65

66 Lupus erythematosis pathogenesis Genetic factors B cell reactivity alter the function of T cells, antigen-presenting cells & cytokines production B cells to enhance the function of other cells autoantibody production Organ damage 66

67 Autoimmune Diseases Systemic Lupus Erythematosus 1997 Revised Criteria for Classification of Systemic Lupus Erythematosus Malar rash Oral ulceration Malar rash Photosensitivity 67 Discoid rash Arthritis

68 Autoimmune Diseases Systemic Lupus Erythematosus 1997 Revised Criteria for Classification of Systemic Lupus Erythematosus Serositis Neurologic disorder Renal disorders 68

69 Autoimmune Diseases Systemic Lupus Erythematosus 1997 Revised Criteria for Classification of Systemic Lupus Erythematosus Hematologic disorder Hemolytic anemia: with reticulocytosis, Leukopenia: < cells per liter (4000 cells per mm 3 ) total on two or more occasions Lymphopenia: < cells per liter (1500 cells per mm 3 ) on two or more occasions Thrombocytopenia: < cells per liter ( cells per mm 3 ) in the absence of offending drugs Immunologic disorder Anti-DNA antibody to native DNA in abnormal titer Anti-Sm: presence of antibody to Sm nuclear antigen Positive finding of antiphospholipid antibodies 69

70 Autoimmune Diseases Systemic Lupus Erythematosus 1997 Revised Criteria for Classification of Systemic Lupus Erythematosus 11. Antinuclear antibody: An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome. 70

71 71

72 Immune Deficiencies: Basic Concepts Immune deficiencies primary (inherited) secondary (to infection, immunosuppression, etc.) Patients more susceptible to infections and cancer Type of infection varies: Ig, C or phagocytic cell defect: bacterial infection T cell defect: viral and fungal infections 72

73 Primary Immune Deficiency Diseases: Basic Concepts Rare! Genetic Can affect any part of immune system: Adaptive (humoral or cellular) Innate (C, phagocytes, NK cells) Typical patient: infant with recurrent infections Primary importance for our class: boards 73

74 SCID SCID X-linked agammaglobulinemia DiGeorge syndrome SCID Hyper-IgM syndrome IgA deficiency 74

75 Primary immune deficiencies X-Linked Agammaglobulinemia Common Variable Immunodeficiency (CVID) Hyper-IgM Syndrome Selective IgA Deficiency Combined T-cell and B-cell (antibody) deficiencies 75

76 X-linked Agammaglobulinemia Pre-B cells can t differentiate into B cells Patients have no immunoglobulin Affects males Presents at 6 months of age (maternal Ig gone) Recurrent bacterial infections Treatment: intravenous pooled human Ig 76

77 Common variable immunodeficiency Group of disorders characterized by defective antibody production Affects males and females equally Presents in teens or twenties Basis of Ig deficiency is variable (hence the name) and often unknown Patients more susceptible to infections, but also to autoimmune disorders and lymphoma! 77

78 Severe Combined Immunodeficiency 78

79 Examples of Infections in Immunodeficiencies Pathogen Type T-Cell-Defect B-Cell Defect Bacteria Bacterial sepsis Streptococci, staphylococci, Haemophilus Granulocyte Defect Staphylococci, Pseudomonas Complement Defect Neisserial infections, other pyogenic bacterial infections Viruses Cytomegalovirus, Epstein-Barr virus, severe varicella, chronic infections with respiratory and intestinal viruses Enteroviral encephalitis Fungi and parasites Candida, Pneumocystis carinii Severe intestinal giardiasis Candida, Nocardia, Aspergillus Special features Aggressive disease with Recurrent opportunistic pathogens, failure sinopulmonary to clear infections infections, sepsis, chronic meningitis 79

80 A good way to study immune deficiencies Disease Transmission Defect Clinical stuff XLA X-linked No mature B cells; no Ig Infant with recurrent bacterial infections CVID IgA deficiency Hyper-IgM DiGeorge SCID 80

81 AIDS(SECONDARY IDS) Etiology: HIV Pathogenesis: Infection, Latency, Progressive T-Cell loss Morphology: MANY Clinical Expressions: Infections, Neoplasms, Progressive Immune Failure, Death, HIV+, HIV-RNA (Viral Load) 81

82 Epidemiology Homosexual: (40%, and declining) Intravenous drug usage (25%) Heterosexual sex (10% and rising) 82

83 Reverse transcriptase The enzyme reverse transcriptase (RT) is used by retroviruses to transcribe their single-stranded RNA genome into single-stranded DNA and to subsequently construct a complementary strand of DNA, providing a DNA double helix capable of integration into host cell chromosomes. 83

84 Pathogenesis Attaching Budding 84

85 Pathogenesis Early budding Late budding Mature new virions 85

86 General immune abnormalities Lymphopenia Decreased t-cell function B-cell activation, polyclonal Altered monocyte/macrophage function 86

87 AIDS related Infections 87 Protozoal/Helminthic: Cryptosporidium, PCP (Pneumocystis Carinii Pneumonia), Toxoplasmosis Fungal: Candida, and the usual 3 Bacterial: TB, Nocardia, Salmonella Viral: CMV, HSV, VZ (Herpes Family)

88 88 PCP

89 89 CRYPTOSPORIDIUM

90 90 Caseating granuloma

91 Cancers related to AIDS Kaposi sarcoma B-cell lymphomas CNS lymphomas Cervix cancer, squamous cell 91

92 92