MICR2209 Introduction to Immunopathology Dr Allison Imrie 1
Allergy and Hypersensitivity Adaptive immune responses can sometimes be elicited by antigens not associated with infectious agents, and this can cause disease Hypersensitivity is a term used to denote excessive or aberrant immune responses Responses to foreign antigen may be dysregulated or uncontrolled, resulting in tissue injury Immune response may be directed against self antigens: autoimmunity. Such disorders are called autoimmune diseases Allergy is the most common form of hypersensitivity 2
Type I hypersensitivity Immediate hypersensitivity is a rapid, IgEand mast cell-mediated vascular and smooth muscle reaction Responses involve mast cell degranuulation induced by interaction of antigen with IgE bound on cell surface via FcεRI 3
Measuring IgE in serum can be used diagnostically as its level increases in certain disease states (as shown in the panels). These conditions are known as allergic but IgE will also increase with helminthic worm infections. It is measured in international units where 1 IU=2.4 nanograms. Type I hypersensitivity 4
Symptoms experienced by the patient can be very different depending on whether the allergen is injected, inhaled, or eaten, and depending also on the dose of the allergen. 5
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This slide shows a selection of allergens associated with allergic diseases. They include fungi, cockroaches, house dust mites and pollen. Allergens are usually proteins and the allergen sources shown here are likely to contain many individual proteins which will be allergenic in susceptible individuals. Pollen Type I - Allergens Fecal pellets 7
Type II Hypersensitivity Haemolytic disease of the newborn Pemphigus Myasthenia Gravis 8
Type II hypersensitivity is also known as Antibody Dependent Cellular Cytotoxicity (ADCC). Involves IgG or IgM binding to antigens located on cell surfaces. The binding of antibody to the cell surface activates complement or effector cells via Fc receptors. The end result in either situation is death of the cell bearing the antigen. Cells involved in the killing are neutrophils, eosinophils, macrophages, monocytes and NK cells, all of which possess a cell surface receptor which binds to the Fc region of IgG bound to the antigen in question - without this they will not be able to participate in Type II reactions. 9
Type II Hypersensitivity 10
Type II Hypersensitivity 11
Type II Hypersensitivity 12
Type II Hypersensitivity Haemolytic Disease of the Newborn Red blood cells from a RhD positive fetus leak into maternal circulation usually during birth and stimulate an immune response if mother is RhD negative. This is not a problem with the first pregnancy but could be in subsequent pregnancies as the maternal Ab cross the placenta. The antibodies react with the fetus RBC and cause tissue damage enlargement of the liver, elevated bilirubin, petechial haemorrhaging. Now rare due to injection of anti-rhd immediately post-partum of first child which destroys RhD positive RBC 13
Type II Hypersensitivity In myasthenia gravis, autoantibodies against the α chain of the nicotinic acetylcholine receptor, which is present on skeletal muscle cells at neuromuscular junctions, can block neuromuscular transmission. The antibodies are believed to drive the internalization and intracellular degradation of acetylcholine receptors. Patients with myasthenia gravis develop potentially fatal progressive weakness as a result of their autoimmune disease. As the number of receptors on the muscle is decreased, the muscle becomes less responsive to acetylcholine. In normal circumstances, acetylcholine released from stimulated motor neurons at the neuromuscular junction binds to acetylcholine receptors on skeletal muscle cells, triggering muscle contraction (left panel). 14
Type II Hypersensitivity Autoantibodies to Cells and Host Proteins Pemphigus is an autoimmune disease caused by autoantibodies to an intracellular adhesion molecule, desmoglein, involved in formation of tight junctions Cellular adhesion is disrupted, leading to breakdown of epidermis 15
Type III Hypersensitivity Immune complexes are formed when antibody binds with antigen; usually removed by macrophages after complement activation Persisting immune complexes can be deposited in a range of tissues and organs. The effector cell-mediated damage that can occur is known as immune complex disease, or type III hypersensitivity Systemic Lupus Erythmatosus 16
Type III Hypersensitivity Immune complexes may not be cleared because the antigen is present in high concentration (self antigen) or is persistently being produced e.g. due to chronic infection or occupational exposure. They can activate complement and stimulate inflammatory reactions and in addition, because of their size, get trapped by small blood vessels in important organs. Here they will also activate complement and tissue damage will result. 17
Type III Hypersensitivity Figure 13-27 part 2 of 2 18
Type IV Hypersensitivity Contact Sensitivity Granuloma - TB Turberculin test 19
Type IV Hypersensitivity Type IV hypersensitivity reactions are T cell-mediated and pathology may involve: Tissue damage caused by the activation of macrophages by TH1 cells, which results in an inflammatory response (e.g.,granuloma) Damage caused by the activation of TH1 cells, cytotoxic CD8 T cells and macrophages (e.g,contact sensitivity) Damage is caused directly by cytotoxic T cells (CTL) (e.g, tuberculin response) 20
Type IV Hypersensitivity Figure 12-24 Hypersensitivity reactions are mediated by T cells. This table shows three routes by which antigens involved in Type IV hypersensitivity might gain entry to the host. In delayed type hypersensitivity, antigen is injected into the host, in contact hypersensitivity, antigen is absorbed into the skin of the host and in gluten sensitive enteropathy, antigen is ingested. 21
Type IV Hypersensitivity Characteristics of Type IV Reactions 22
Type IV Hypersensitivity 1. Contact hypersensitivity 2. Tuberculin reaction Elicitation of a delayed-type hypersensitivity response to a contact-sensitizing agent. The contact-sensitizing agent is a small highly reactive molecule that can easily penetrate intact skin. It binds covalently as a hapten to a variety of endogenous proteins, which are taken up and processed by Langerhans' cells, the major antigen-presenting cells of skin. These present haptenated peptides to effector TH1 cells (which must have been previously primed in lymph nodes and then have traveled back to the skin). These then secrete cytokines such as IFN-γ that stimulate keratinocytes to secrete further cytokines and chemokines. These in turn attract monocytes and induce their maturation into activated tissue macrophages, which contribute inflammatory lesions. 23
Type IV Hypersensitivity Figure 12-25 Delayed type hypersensitivity (DTH) The first phase involves uptake, processing, and presentation of the antigen by local antigenpresenting cells. In the second phase, TH1 cells that were primed by a previous exposure to the antigen migrate into the site of injection and become activated. Because these specific cells are rare, and because there is little inflammation to attract cells into the site, it can take several hours for a T cell of the correct specificity to arrive. These cells release mediators that activate local endothelial cells, recruiting an inflammatory cell infiltrate dominated by macrophages and causing the accumulation of fluid and protein. At this point, the lesion becomes apparent. 24
Type IV Hypersensitivity Tuberculin reaction Tuberculin Reaction Histology: Infiltrate of leukocytes Positive PPD test: >10 mm induration (PPD=purified protein derivative) Local responses to antigen can indicate the presence of active immunity. Active immunity is often studied in vivo, especially in humans, by injecting antigens locally in the skin. If a reaction appears, this indicates the presence of antibodies or immune lymphocytes that are specific for that antigen; the tuberculin test is an example of this. When people have had tuberculosis they develop cell-mediated immunity that can be detected as a local response when their skin is injected with a small amount of tuberculin, an extract of Mycobacterium tuberculosis, the pathogen that causes tuberculosis. The response typically appears a day or two after the injection and consists of a raised, red, and hard (or indurated) area in the skin, which then disappears as the antigen is degraded 25