Week 05 (Carcinogenesis-Immunopathology)-RPK-MEDS1075-2118-final-4.pdf

WEEK 5 Dr Roula Kyriacou Course Coordinator & CARCINOGENENESIS-IMMUNOPATHOLOGY Lecturer COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of the R...

WEEK 5 Dr Roula Kyriacou Course Coordinator & CARCINOGENENESIS-IMMUNOPATHOLOGY Lecturer COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of the Royal Melbourne Institute of Technology (RMIT University) pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice LEARNING OBJECTIVES To define and understand the process of carcinogenesis To outline the aetiological factors leading to cancer and to provide examples of carcinogens To distinguish between primary and secondary immunodeficiencies To understand the four types of hypersensitivities, their mechanisms and to provide examples To distinguish between organ-specific and systemic autoimmune disorders CARCINOGENESIS Carcinogenesis is the process of initiation and promotion of cancer A carcinogen is any agent or substance which initiates cancer e.g. chemicals, radiation, viruses Process involves changes in the genome of cells (i.e. mutations), over-expression of genes, or loss of activity of gene products Mutations may be gross defects (e.g. translocations or breaks in chromosome arms) OR They may be a defect involving a single base-pair of DNA (e.g. point mutations; substitutions, deletions) CARCINOGENESIS Four classes of normal regulatory genes are the principle targets of genetic damage growth promoting proto-oncogenes (normally code for proteins involved in the control of normal cell growth & differentiation i.e. they promote cell growth & mitosis) growth-inhibiting tumour suppressor genes (normally discourage cell growth, or temporarily halt cell division to carry out DNA repair) genes that regulate apoptosis (normally allow programmed cell death to occur, preventing further cell growth) genes involved in DNA repair (normally allow repair of DNA following damage/mutations by stimuli) Genetic alterations in the above genes leads to abnormal uncontrolled proliferation of cells (i.e. tumours cells develop with growth & survival advantages over normal cells) Normal cells develop abnormalities in key genes regulating growth and are transformed into neoplastic cells.  Fig. 6.19 (Core Pathology) As a tumour develops, cells undergo further somatic mutation causing mutations in other oncogenes (additional oncogene expression or loss of tumour suppressor genes). A tumour will consist of many different subclones of cells, some with greater growth potential which will eventually dominate. AETIOLOGY OF CANCER Tumours have a multifactorial aetiology in which carcinogens play only one part Body factors (intrinsic factors) are important and environmental factors (extrinsic factors) also play a role in the causation of cancer Genetic makeup, racial background, climactic conditions, environmental agents, diet may all contribute Explains why two people exposed to the same single carcinogen may NOT develop the same cancer  CARCINOGENESIS - INTRINSIC FACTORS 1) Genetic factors e.g. Leukaemia Trisomy 21 as seen in Down’s Syndrome predisposes to leukaemia e.g. Chronic myeloid leukaemia Philadelphia chromosome is seen in 90% cases (reciprocal translocation between chromosome 9 & 22) e.g. Polyposis coli Autosomal dominant trait where hundreds of benign tumours form on the colonic mucosa INTRINSIC FACTORS 2) Racial and geographic factors e.g. Higher incidence of carcinoma of the breast in Australia compared to Japan e.g. Higher incidence of hepatocarcinoma in SE Asia compared to Australia 3) Immunological factors Patients with immunodeficiency (e.g. AIDS) have a higher incidence of some cancers (e.g. Kaposi’s sarcoma, lymphoma) INTRINSIC FACTORS 4) Sex and Hormonal Influences Hormonal stimulation can lead to some cancers e.g. breast (oestrogen stimulation) 5) Age Cancer is more common with increasing age e.g. Carcinoma of the colon INTRINSIC FACTORS 6) Pre-existing Benign Neoplasms Benign tumours that are left untreated for long periods may undergo malignant change due to additional mutations e.g. polyposis coli e.g. adenomatous polyp CARCINOGENESIS - EXTRINSIC FACTORS 1) Chemical agents Percival Pott (1775) described the association between soot exposure and carcinoma of the scrotum in chimney sweeps - polycyclic aromatic compounds are carcinogenic CH 3 NH 2 2-naphthylamine CH 3 7,12-dimethylbenzanthracene (DMBA) O C2 H5 O C NH 2 N N N (CH3) 2 Urethane “Butter Yellow” 2) PHYSICAL AGENTS a) Ionizing radiation UV light, X-rays, g-rays, products of radioactive decay b) Trauma Chronic injury and tissue damage, not single episode of trauma c) Inert substances in body Plastic films, glass, fibres, methylcellulose, metal foils and wires, asbestos fibres 3) BIOLOGICAL AGENTS a) Parasites e.g. Schistosoma spp cause a chronic infection of the bladder and predispose to carcinoma Carcinoma of the urinary bladder 3) BIOLOGICAL AGENTS b) Fungi and bacteria e.g. Aspergillus flavus is a fungus that produces aflatoxin (carcinogen) in starchy foods (e.g. peanuts) → Primary hepatocarcinoma e.g. Helicobacter pylori → Carcinoma of stomach 3) BIOLOGICAL AGENTS c) Viruses The only biological agents that can directly cause tumours Hepatitis B Virus → hepatocarcinoma Human Herpes Virus-8 → Kaposi’s sarcoma Epstein Barr Virus → Burkitt’s lymphoma Human Papilloma Virus → cervical cancer IMMUNOPATHOLOGY Disorders due to an abnormality in immune system function Subdivided into: 1) Immunodeficiencies (1° or 2°) Inadequate immune response → increased susceptibility to infections & tumours 2) Hypersensitivities Excessive immune response → tissue damage 3) Autoimmune diseases Inappropriate immune response → tissue damage PRIMARY IMMUNODEFICIENCY Present at birth due to genetic/congenital disorder a) Agammaglobulinaemia = Bruton’s disease X-linked disorder Low/absent B-cells ( antibody production) Normal T-cell function Severe bacterial infections Streptococcal infection in affected child PRIMARY IMMUNODEFICIENCY b) Congenital thymic aplasia = Di George syndrome Developmental disorder → absent thymus/functional tissue Often no parathyroids → hypocalcaemia Absent T-cells, no cellular immunity Near normal B-cell function Severe viral, fungal & protozoal infections Herpes virus infection in affected child PRIMARY IMMUNODEFICIENCY c) Combined immunodeficiency = Swiss-type syndrome Developmental disorder Absent lymphocyte stem cells in bone marrow Absent B-cells & T-cells (i.e. no humoral or cellular immunity) Overwhelming, recurrent infections of various types Children in “bubbles” “Bubble boy” SECONDARY IMMUNODEFICIENCY a) Miscellaneous immunodeficiencies Due to: Ageing Infections Neoplasms Immunosuppressive drugs Radiation  SECONDARY IMMUNODEFICIENCY a) Miscellaneous immunodeficiencies Ageing:  production of bone marrow stem cells Erysipelas (Streptococcus infection)  SECONDARY IMMUNODEFICIENCY a) Miscellaneous immunodeficiencies Infections: Depress immunity non-specifically Haemophilus influenzae Influenza virus particles bacteria  SECONDARY IMMUNODEFICIENCY a) Miscellaneous immunodeficiencies Neoplasms: Depress immunity e.g. Thymoma, Hodgkin’s disease Hodgkin’s disease of spleen  SECONDARY IMMUNODEFICIENCY a) Miscellaneous immunodeficiencies Immunosuppressive drugs: Specifically lower immunity e.g. in transplantation Transplanted organ rejection  SECONDARY IMMUNODEFICIENCY a) Miscellaneous immunodeficiencies Radiation: Lymphocyte depletion due to radiation therapy, nuclear blasts Effects of radiation exposure SECONDARY IMMUNODEFICIENCY b) Acquired Immune Deficiency Syndrome (AIDS) First described in 1981 Infection with the Human Immunodeficiency Virus (HIV), a member of lentivirus subfamily of retroviruses May be congenital or acquired Two major targets: immune system & CNS Virus infects CD4+ cells (e.g. T lymphocytes, macrophages, microglia) Leads to severe impairment of cell-mediated immunity SECONDARY IMMUNODEFICIENCY AIDS = clinical syndrome characterized by high viral replication & profound immune cell loss ( 200 CD4+ cells/ml) AIDS defining conditions: Opportunistic infections, secondary neoplasms and neurologic disorders (AIDS-associated dementia, aseptic meningitis, peripheral neuropathies) Opportunistic infections Also see debility, emaciation, continual Candida albicans - Oral thrush dry cough, sore throat, pale furry tongue, purple skin lesions AIDS Opportunistic infections Candida albicans - Oral thrush Pneumocystis jirovecii (carinii ) - Pneumonia Day 6 Day 10 AIDS Opportunistic infections Toxoplasma gondii - CNS infection Cryptosporidium - GIT infection Cytomegalovirus (CMV) - pulmonary, GIT infection Atypical Mycobacterium - GIT infection AIDS Neoplasms - Lymphoma - Kaposi’s sarcoma HYPERSENSITIVITIES The hypersensitivities/allergies occur as result of an excessive immune response → tissue damage Genetic aetiology, environmental triggers often implicated Four types, all antibody (Ab) mediated except one Type I: Immediate (or anaphylactic) Type II: Antibody mediated Type III: Immune complex mediated Type IV: T cell mediated (Delayed) TYPE I IMMEDIATE HYPERSENSITIVITY Due to sensitized mast cells and IgE e.g. bronchial asthma, bee stings, hay fever, urticaria (hives) 1st encounter with allergen (sensitizing antigen e.g. pollen, house dust, dander, food) - stimulates the formation of IgE Ab instead of IgG or IgA - no reaction (IgE inactivates Ag but excess attaches onto mast cell surface) TYPE I IMMEDIATE HYPERSENSITIVITY Allergen IgE Antibody Sensitized mast cell First exposure to allergen TYPE I IMMEDIATE HYPERSENSITIVITY 2nd & subsequent encounters with allergen causes degranulation of mast cells → mediators of AI released (histamine, serotonin etc.) → anaphylaxis (local or generalised effects) Bronchoconstriction, inflammation, oedema, vasodilatation &  vascular permeability Most severe form of anaphylaxis is anaphylactic shock (due to intense bronchoconstriction & profound vasodilatation) e.g. penicillin allergy TYPE I IMMEDIATE HYPERSENSITIVITY Degranulation of IgE-Allergen mast cell reaction Second exposure to allergen TYPE I IMMEDIATE HYPERSENSITIVITY Allergy to bee stings causes blistering  TYPE I IMMEDIATE HYPERSENSITIVITY Allergy to pollen causes hay fever (allergic rhinitis) TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Due to IgG or IgM Abs causing direct cell damage & lysis e.g. Erythroblastosis foetalis (haemolytic disease of the newborn) & incompatible ABO blood transfusion reactions Abs may be directed against a cell surface component (receptor) or against a small molecule that has attached itself to the cell surface (e.g. drugs/antibiotics may attach to cells of genetically predisposed people) Alternatively, antibodies may stimulate or inhibit a receptor e.g. Thyrotoxicosis, Myasthenia gravis TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Complement, Phagocytosis, Killer T-cells IgG or IgM Antibody Lysis of cell cell with ‘foreign’ surface component Lysis of cells due to ‘foreign’ cell surface component – cytotoxic hypersensitivity TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Typical example is Erythroblastosis foetalis (haemolytic disease of the newborn) Rh (D) blood groups: ~85% Caucasians are Rh +ve (DD or Dd) 15% are Rh -ve (dd) Problem arises in Rh-ve mothers carrying Rh+ve babies in 2nd and subsequent pregnancies TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY + Rh -ve mother Small trickle of + foetal blood cells into maternal circulation + + + + + + + + Rh +ve foetus + + + + + During 1st pregnancy TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Many foetal blood cells (Rh +ve) in maternal Rh -ve mother circulation + + + + + + Immune response + + + + + + (formation of + + + + + Anti-Rh Abs) + + + Rh +ve foetus At 1st baby’s delivery  TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Small trickle of Rh -ve mother foetal blood cells + in maternal + circulation stimulate + + + + immunity and more + + + + Rh +ve foetus + Abs form + + + + During 2nd pregnancy (mother is sensitized)  TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Antibodies of mother Rh -ve mother enter foetal blood + + and destroy baby’s Rh +ve blood cells + + + + + + + + Rh +ve foetus + + + + + During 2nd pregnancy TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Immunoprophylaxis is carried out on all Rh-ve mothers close to the time of delivery of the first and each subsequent birth Human immunoglobulin against Rh factor is injected into mother (destroying foetal cells) Prevents formation of anti-Rh Abs (prevents sensitization and prevents erythroblastosis) TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Stimulatory or inhibitory hypersensitivity Antibodies can form to a cell surface receptor stimulating the cell into activity OR making the cell inactive by blocking a receptor Both cause tissue damage due to inflammation e.g. Graves’ disease, Myasthenia gravis TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Antibody to cell receptor Adverse effects Secretion or inhibition Receptor-Antibody Interaction TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Graves’ disease (thyrotoxicosis) Formation of thyroid-stimulating Abs (TSI) bind to TSH receptor leading to: - excessive secretion of thyroid hormones (T3, T4) - hyperplasia of thyroid follicular epithelium → goitre, increased metabolism, decrease in weight, exophthalmos TYPE II ANTIBODY MEDIATED HYPERSENSITIVITY Myasthenia gravis Abs form against acetylcholine receptors of skeletal muscle cells, blocking action of acetylcholine Fatigue, weakness of muscles Ocular, facial muscles involved early, ptosis, difficulty in speaking, chewing, swallowing TYPE III IMMUNE COMPLEX MEDIATED HYPERSENSITIVITY Soluble antigen combines with specific Abs to form immune (Ag-Ab) complexes These circulate around body and localize in walls of vessels, leading to thrombosis, inflammation, tissue damage, necrosis e.g. serum sickness, glomerulonephritis TYPE III IMMUNE COMPLEX MEDIATED HYPERSENSITIVITY Microthrombi Platelet } aggregation Vasoactive Amine Release Attraction of Neutrophils Anaphylatoxin Cell Damage Immune complex } Complement Histamine activation Release Immune complexes lodge in vascular walls Microthrombus formation & C’ injure tissue TYPE III IMMUNE COMPLEX MEDIATED HYPERSENSITIVITY Serum sickness Horse-derived antitoxin administered to treat advanced toxaemias e.g. tetanus Formation of immune complexes (systemic) → Arthritis, vasculitis, Arthus phenomenon renal failure, carditis, - reaction in skin oedema, fever, often fatal TYPE III IMMUNE COMPLEX MEDIATED HYPERSENSITIVITY Glomerulonephritis Following streptococcal infection, soluble Ag still present, immune complexes form, filtered by glomeruli of the kidney (localized) → Acute vasculitis, albuminuria, haematuria, oedema Resolution usually in children Renal failure may occur TYPE IV T CELL MEDIATED (DELAYED) HYPERSENSITIVITY No antibodies involved Sensitized T-cells, killer cells, activated macrophages and secretion of cytokines cause tissue damage e.g. tuberculin reaction, contact dermatitis, graft rejection Delayed reaction (develops in sensitized individual 24-48 hours after contact with antigen) Granuloma formation may be seen TYPE IV T CELL MEDIATED (DELAYED) HYPERSENSITIVITY Activated Sensitized T-cell macrophage MIF contacting Ag MAF SRF IL CF MF Secretion of cytokines Killing Killer Altered T-cell body cell TYPE IV T CELL MEDIATED (DELAYED) HYPERSENSITIVITY e.g. Tuberculin reaction (Mantoux test) Tuberculin (protein extract of M. tuberculosis) is administered intradermally; +ve reaction > 72hrs TYPE IV T CELL MEDIATED (DELAYED) HYPERSENSITIVITY e.g. Contact dermatitis Due to nickel plated buckle, nickel plated stud, perfume, rubber soles TYPE IV T CELL MEDIATED (DELAYED) HYPERSENSITIVITY e.g. Mosquito bites, transplanted organ rejection AUTOIMMUNE DISEASES Inappropriate immune response → tissue damage Recognition of self fails and immune system reacts against components of the body which act as antigens i.e. Autoantigens Autoantigens stimulate a humoral response against them, giving rise to autoantibodies OR they stimulate a T cell mediated immune response (sensitized T-cells react with & destroy tissues) AUTOIMMUNE DISEASES 1) Organ Specific Diseases Autoantibodies form against tissue (glandular tissues/epithelia/blood cells) → tissue damage, chronic inflammation e.g. Hashimoto’s disease (chronic autoimmune thyroiditis) Autoantibodies against thyroid gland (anti-thyroid specific antibodies) ed metabolism, → loss of gland, replacement by lymphocytes, weight gain, thyroid resembles lymph node oedema, dry skin, puffy face, goitre – Goitre seen with hypofunction = hypothyroidism treat with thyroxine ORGAN SPECIFIC AUTOIMMUNE DISEASES e.g. Chronic auto-immune atrophic gastritis Autoantibodies against parietal cells → atrophy and fibrosis of acid-secreting gastric mucosa Autoantibodies may also be produced against intrinsic factor → pernicious anaemia Atrophy of mucosa, loss of folds, achlorhydria, dyspepsia ORGAN SPECIFIC AUTOIMMUNE DISEASES e.g. Rheumatic heart disease Infection with Group A Streptococcus pyogenes Excess Abs form, react with & destroy CTs - Aschoff nodule (Aschoff body) - pancarditis AUTOIMMUNE DISEASES Autoantibodies may form to a cell receptor causing lysis, or stimulating the cell into activity or making the cell inactive by blocking a receptor → leads to an autoimmune disease via a Type II hypersensitivity reaction Hence Graves’ disease, Myasthenia gravis are considered autoimmune disorders AUTOIMMUNE DISEASES 2) Systemic Diseases Many tissues, organs affected especially connective tissue (muscles, joints, loose connective tissues) Damage by multiple autoantibodies and also by cell mediated immune response Chronic inflammation, debilitating or fatal disease results SYSTEMIC AUTOIMMUNE DISEASES e.g. Systemic lupus erythematosus (SLE) Autoantibodies present in tissue fluids (Antinuclear antibodies or ANAs) Multiple autoantigens: e.g. nuclear DNA, nucleoproteins (histones), non-histone proteins bound to RNA Synovial joints, skin, kidneys, brain, connective tissues are major targets Characteristic rash (e.g. malar rash) Joint & muscle involvement with arthritis (e.g. polyathralgia) SYSTEMIC AUTOIMMUNE DISEASES e.g. Rheumatoid arthritis Damage to bone, joints & CT (polyarthritis) Subcutaneous and visceral lesions may be seen (rheumatoid nodules) Autoantigen is an abnormal IgG, to which another antibody is formed = rheumatoid factor (IgM & less frequently IgG) Immune complexes (IgG/IgM) deposit in tissues, esp. in joints T cell-mediated immunity also causes tissue damage See degenerating collagen, chronic inflammation, polyarthritis SUMMARY Carcinogenesis refers to the initiation and promotion of cancer & involves genetic alterations in four classes of genes Gene mutations may be caused by carcinogens (chemicals, radiation, viruses) Aetiology is multifactorial in which carcinogens play only one part, interaction of intrinsic and extrinsic factors is important SUMMARY Primary immunodeficiencies: 1) Agammaglobulinaemia -  B cells 2) Thymic aplasia -  T cells 3) Combined immunodeficiency -  T & B cells Secondary immunodeficiencies: 1) Miscellaneous causes such as ageing, infections, tumours, drugs, radiation exposure 2) Infection with HIV → AIDS SUMMARY Type I Immediate hypersensitivity due to sensitized mast cells,  IgE → AI & tissue damage Type II Antibody Mediated hypersensitivity due to IgG or IgM Abs causing cell lysis, or stimulation or inhibition → tissue damage Type III Immune Complex Mediated hypersensitivity due to immune complex deposition→ tissue damage Type IV T Cell Mediated (Delayed) hypersensitivity due to sensitized lymphocytes & activated macrophages → tissue damage SUMMARY Autoimmune disorders involve failure of self recognition and reaction of immune system against components of the body Autoantigens and auto-antibodies involved in tissue damage; cell mediated immune mechanisms also important Organ specific diseases are confined to a single tissue or a small group of related tissues e.g. Hashimoto’s disease of thyroid; Chronic autoimmune gastritis; RHD Systemic autoimmune diseases affect many tissues of the body e.g. SLE; Rheumatoid arthritis RECOMMENDED READING/VIEWING: WEEK 5 Kumar et al., Robbins Basic Pathology 10th ed: Chapter 6 (p. 200-241) - Carcinogenesis Chapter 5 (p. 121-188) - Immunopathology Stevens et al., Steven’s Core Pathology 3rd ed: Chapter 5 (p. 83-96) - Carcinogenesis Chapter 7 (p. 97-106) - Immunopathology Additional Modules on Canvas: Learning Module 7 - Neoplasia Learning Module 8 - Carcinogenesis & Immunopathology