Immunopathology - Hypersensitivity PDF

Immunopathology- Hypersensitivity BSc/MSci BioSciences 2nd Yr Module: Ageing & Degeneration Dr Donald Palmer  Immunopathology The consequence when the immune system causes tissue damage Hypersensitivity Vaccination Transplantation and t...

Immunopathology- Hypersensitivity BSc/MSci BioSciences 2nd Yr Module: Ageing & Degeneration Dr Donald Palmer  Immunopathology The consequence when the immune system causes tissue damage Hypersensitivity Vaccination Transplantation and transfusion How is tolerance generated Mediators of allergic reactions Immunodeficiency Autoimmunity Practical (video) DL  Students should be able to: Describe types of hypersensitivity and their mechanisms. Discuss hypersensitivity responses. Discuss genetic and environmental causes of hypersensitivity. Describe therapeutic strategies. Hypersensitivity  Hypersensitivity It should be remembered that hypersensitivity reactions differ from protective immune reactions only in that they are exaggerated or inappropriate and damaging to the host. The cellular and molecular mechanisms of the two types of reaction are virtually identical. The four types of hypersensitivity reaction  The four types of hypersensitivity reaction (I and II) Type I responses are mediated by IgE, which induces mast-cell activation. Type II responses are mediated by IgG, which can engage Fc-receptor and complement-mediated effector mechanisms, directed against cell-surface or matrix antigens  The four types of hypersensitivity reaction (III) Type III responses are mediated by IgG directed against soluble antigens, and the tissue damage involved is caused by responses (Fc-receptor and complement- mediated effector mechanisms) triggered by immune complexes. The four types of hypersensitivity reaction (IV) Type IV hypersensitivity reactions are T cell- mediated and can be subdivided into three groups. In the first group, tissue damage is caused by the activation of macrophages by TH1 cells, which results in an inflammatory response. In the second, damage is caused by the activation by TH2 cells of inflammatory responses in which eosinophils predominate In the third, damage is caused directly by cytotoxic T cells (CTL). Type I Hypersensitivity (immediate) Type I Hypersensitivity (immediate) Type I Hypersensitivity (immediate) The high affinity Fc epsilonRI receptors are found on mast cells, eosinophils and basophils. Each cell has a high density of these receptors (40-250,000 per cell) so that a wide spectrum of antigen specificities is represented. The cells are activated by the cross-linking of the Fc epsilonRI receptors via antigen binding to the bound IgE molecules. Molecules released by mast cells on activation Eosinophils response in allergic asthma eotaxin Molecules released by Eosinophils on activation Incidence and genetic susceptibility Some 20-30% of the population exhibit type I hypersensitivity or atopic allergy to common environmental substances. There is a genetic component to atopic allergy such that if both your parents exhibit this susceptibility you are more than 2 × more likely to do so and if neither parent has manifest allergies you are less than half as likely to when compared to the population as a whole. Incidence and genetic susceptibility  Genetic susceptibility: The environment also plays a role Both inherited and environmental factors are important determinants in developing atopic allergic disease. Suggestions such as the ‘hygiene hypothesis’ propose that exposure to some infectious agents in early life drives the immune system toward a general state of TH1 responsiveness and non-atopy. In contrast, children with genetic susceptibility to atopy and who live in an environment with low exposure to infections tend to mount TH2 responses, increasing the possibility of developing atopic allergic disease.  Clinical Aspects of type 1 hypersensitivity Allergic Rhintis (hay fever) Caused by airborne allergens reacting with IgE- sensitized mast cells in the nasal passages and conjunctiva. Food Allergies Atopic (allergic) Dermatitis (skin) Asthma  Systemic anaphylaxis (or generalised reaction) Ingestion of nuts or seafood, insect bites (venom), and drug injection may all cause life-threatening reactions in highly sensitised individuals. Death in such cases is due to systemic release of vasoactive mediators leading to general vasodilation and smooth muscle contraction resulting in sudden loss of blood pressure, massive oedema and severe bronchiole constriction (systemic anaphylaxis). The dose and route of allergen determine the type of IgE- mediated allergic reaction Possible therapies in allergic reactions The four types of hypersensitivity reaction  Type II Hypersensitivity Syndromes: Immune Mediated Hemolytic Anemia (IMHA) or Autoimmune hemolytic anemia (AIHA) Myasthenia gravis, Goodpasture's disease, Rhesus disease (or haemolytic disease of the newborn) Caused: by specific antibody binding to cells or tissue antigens. The antibodies are of the IgM or IgG classes and cause cell destruction by Fc dependent mechanisms either directly or by recruiting complement via the classical pathway. Schematic illustration of ab-mediated type 2 hypersensitivty reactions A: C’ dependent reaction B: ADCC C: Anti-receptor ab, eg myasthenia gravis Immune Mediated Hemolytic Anemia (IMHA) or Autoimmune hemolytic anemia (AIHA) Lost of rbc due to their destruction Destruction due to Ab binding to rbc, leading to ADCC/MAC Toxin/drugs/antibiotics/virus/parasite bind to the surface of rbc and anti-drug Ab attack cells It can occur inside the blood stream (intravascular hemolysis-Complement mediated) or outside the bloodstream (extravascular hemolysis-ADCC). In most cases in dogs, hemolysis occurs outside the blood stream in the spleen, liver and bone marrow Rbc destruction in IMHA/AIHA Epitopes from drug/toxin binding to rbc and being recognised as non-self Abs generated binds to epitope and recruit the effector mechanisms of c’ mediated lysis and ADCC  rhesus disease Rhesus disease is a cause of haemolysis manifest in the first 24 hours of life due to rhesus incompatibility between mother and baby. It is the result of a mother being rhesus negative and having antibodies produced towards a rhesus positive baby. It occurs after the mother has been sensitised by either a mismatched blood transfusion, or from foetal blood entering her circulation during miscarriage, abortion, placental bleeding, amniocentesis or external cephalic version. Most commonly it occurs at the end of a previous pregnancy during labour and delivery. 1. If the mother is Rh negative and the father is Rh positive, their fetus may be Rh positive or Rh negative. 2. If the fetus is Rh positive, there could be a problem if the fetal Rh-positive blood mixes with the mother’s Rh-negative blood. 3. Left untreated, the mother’s blood will make antibodies () that attack the Rh-positive blood of the fetus. 4. These antibodies can cause health problems for the fetus. These include blood problems or even death.  rhesus disease - prevention The disease is prevented by vaccinating the Rh-negative mother with Rh immune globulin during the mother's pregnancy with an Rh- positive fetus. This prohibits the development of Rh-positive antibodies, or destroys any such antibodies present in the mother's blood, thereby protecting any future Rh-positive fetuses.  Goodpasture's disease Goodpasture's disease (also known as Goodpasture Syndrome, anti-glomerular basement membrane disease, anti-GBM disease) is an uncommon condition which typically causes rapid destruction of the kidneys and bleeding into the lungs. The glomerular basement membrane of this glomerulus is brightly illuminated in yellow by the anti-GBM antibodies that are bound to it. Due to the development of anti-GBM antibodies that bind to the Glomeruli causing tissue damage Treatment is normally immunosuppressive drugs -eg steroids  Myasthenia gravis (MG) MG is a relatively rare autoimmune disorder of peripheral nerves in which antibodies form against acetylcholine (ACh) nicotinic postsynaptic receptors at the myoneural junction. This results in a progressive reduction in muscle strength.  Myasthenia gravis (MG) Thymic abnormalities are clearly associated with MG but the nature of the association is uncertain. Ten percent of patients with myasthenia gravis have a thymic tumor and 70% have hyperplastic changes (germinal centers) that indicate an active immune response. Given the immunologic function of the thymus and the improvement in the clinical condition of patients following thymectomy, the thymus is suspected to be the site of autoantibody formation. However, the stimulus that initiates the autoimmune process has not been identified. The four types of hypersensitivity reaction Type III Hypersensitivity Syndromes: Arthus reaction, Caused: by immune complexes essentially of IgG antibodies with soluble antigens. It is now thought that this form of hypersensitivity has a lot in common with type I except that the antibody involved is IgG and therefore not prebound to mast cells, so that only preformed complexes can bind to the low affinity FcgammaRIII. Activation of C’ and accumulation of PMNs important components  The Arthus reaction The Arthus reaction is the name given to a local type III hypersensitivity reaction. Because the FcgammaRIII is a low affinity receptor and because the threshold for activation via this receptor is considerably higher than for the IgE receptor the reaction is slow compared with a type I reaction, typically maximal at 4-8hrs, and consequently more diffuse.  The Arthus reaction The condition extrinsic allergic alveolitis occurs when inhaled antigen complexes with specific IgG in the alveoli, triggering a type III reaction in the lung, for example in 'pigeon fanciers lung' where the antigen is pigeon proteins inhaled via dried faeces. Complement is not required for the Arthus reaction, but may modify the symptoms.  Type IV Hypersensitivity (Delayed type hypersensitivity: DTH) Syndromes: Contact dermatitis, Tubercular lesions Caused: This is the only class of hypersensitive reactions to be triggered by antigen-specific T cells  Type IV Hypersensitivity (DTH) Results when an APC, picked up antigen, processed it and displayed appropriate peptide fragments bound to class II MHC to a specific TH1 cell. Activation of the T cell produces cytokines, chemokines for macrophages, other T cells and, to a lesser extent, neutrophils as well as TNF and IFN. The consequences are a cellular infiltrate in which mononuclear cells (T cells and macrophages) tend to predominate. It is usually maximal in 48-72 hours.  Delayed hypersensitivity reactions Clinical Type Reaction time Histology Antigen and site appearance epidermal lymphocytes, (organic followed by chemicals, contact 48-72 hr eczema macrophage; poison ivy, edema of heavy metals, epidermis etc.) intradermal lymphocytes, (tuberculin, tuberculin 48-72 hr local induration monocytes, lepromin, macrophages etc.) persistent antigen macrophages, or foreign epitheloid and body granuloma 21-28 days hardening giant cells, presence fibrosis (tuberculosis, leprosy, etc.) TH1 influence of the immune response Elicitation of a delayed-type hypersensitivity response to a contact-sensitizing agent  Granulomas Inert foreign body materials, (talc crystals) and Intracellular microorganisms mycobacteria that are capable of inducing a cell-mediated immune response. Macrophages present it to T cells. Activated T cells produce IL-2 , IFN-gamma which causes activated macrophages to aggregate into nodules (granulomas). The continued release of cytokines results in sustained recruitment and activation of lymphocytes and macrophages and the maintenance of these immune mediated granulomas TY Summary PE MECHANISM EXAMPLES NAME TIME Ag induces cross-linking of IgE Systemic anaphylaxis, Local IgE-mediated 2-30 I bound to mast cells with release of anaphylaxis, Hay fever, Asthma, hypersens’ mins vasoactive mediators Eczema Antibody- Ab directed against cell-surface Blood transfusion reactions, mediated 5- II antigens mediates cell destruction Haemolytic disease of the newborn cytotoxic 8hrs via ADCC or complement Autoimmune Haemolytic anaemia hypersens’ Immune- Ag-Ab complexes deposited at Arthus reaction (Localised); complex 2- various sites induces mast cell III Systemic reactions disseminated mediated 8hrs degranulation via FcgammaRIII, rash, arthritis, glomerulonephritis hypersens’ PMN degranulation damages tissue Memory TH1 cells release cell-mediated 24- Contact dermatitis, Tubercular IV cytokines that recruit and activate hypersens’ 72hrs lesions macrophages