Lecture 8 Hypersensitivity Types II-V Type II: Cytotoxic (ITH) Type III: Toxic Complex (ITH) Type IV: T Cell-Mediated (DTH) Type V: Stimulatory

Cytotoxic Hypersensitivity (Type II)

Characteristics of Cytotoxic Hypersensitivity Directed against cell surface or tissue antigen Characterized by complement cascade activation and various effector cells

Complement Formation of membrane attack complex (lytic enzymes) Activated C3 forms opsonin recognized by phagocytes Formation of chemotactic factors Effector cells possess Fc and complement receptors macrophages/monocytes neutrophils NK cells

Examples of Type II Hypersensitivity Blood transfusion reactions Hemolytic disease of the newborn (Rh disease) Autoimmune hemolytic anemias Drug reactions Drug-induced loss of self-tolerance Hyperacute graft rejection Myasthenia gravis (acetylcholine receptor) Sensitivity to tissue antigens Study Guide If all of these reactions require "prior sensitization" before the destructive phase can begin, where is the "prior sensitization"?

ABO Blood Group Antigens NAG Gal NAcGA H Fuc NAG Gal NAG Gal A antigen Fuc B antigen Study Guide What is the hapten? What is the carrier? Precursor oligosaccharide H antigen NAG Gal Gal NAcGA (N-acetylgalactoseamine) Gal (galactose) B Fuc

ABO Blood Group Reactivity blood group genotypes antigens antibodies to (phenotype) ABO in serum A AA, AO A anti-B B BB, BO B anti-A AB AB A and B none O OO H anti-A/B Study Guide What immunoglobulin class(es) are the blood group antibodies? Why are they called "naturally-occurring isohemagglutinins"?

Hemolytic Disease of the Newborn first birth post partum subsequent RhD negative mother RhD positive red cells anti-RhD B cell Study Guide What immunoglobulin class(es)? Why is the second pregnancy at greater risk? Is there a problem in the second pregnancy is the fetus is Rh negative? Why? Lysis Of RBC’s RhD positive fetus RhD positive fetus anti-RhD

Drug-Induced Reactions: Adherence to Blood Components blood cell adsorbed drug or antigen drug metabolite antibody to drug complement Study Guide What is the hapten? What is the carrier? lysis

Toxic Complex Hypersensitivity (Type III) Study Guide What is the difference between Type II and Type III?

Diseases associated with immune complexes Persistent infection microbial antigens deposition of immune complexes in kidneys Autoimmunity self antigens deposition of immune complexes in kidneys, joints, arteries and skin Extrinsic factors environmental antigens deposition of immune complexes in lungs

Inflammatory Mechanisms in Type III Complement activation anaphylatoxins Chemotactic factors Neutrophils attracted difficult to phagocytize tissue-trapped complexes frustrated phagocytosis leads to tissue damage

Disease Models Serum sickness Arthus reaction

Serum Sickness

Arthus Reaction

T-Cell Mediated Hypersensitivity (Type IV / Delayed-Type)

Manifestations of T-Cell Mediated Hypersensitivity Allergic reactions to bacteria, viruses and fungi Contact dermatitis due to chemicals Rejection of tissue transplants

General Characteristics of DTH An exaggerated interaction between antigen and normal CMI-mechanisms Requires prior priming to antigen Memory T-cells recognize antigen together with class II MHC molecules on antigen-presenting cells Blast transformation and proliferation Stimulated T-cells release soluble factors (cytokines) Cytokines attract and activate macrophages and/or eosinophils help cytotoxic T-cells become killer cells, which cause tissue damage

Inducers of Type IV Hypersensitivity

Types of Delayed Hypersensitivity Delayed Reaction maximal reaction time Jones-Mote 24 hours Contact 48-72 hours tuberculin 48-72 hours granulomatous at least 14 days

Jones-Mote Hypersensitivity Now referred to as “cutaneous basophil hypersensitivity” Basophils are prominent as secondary infiltrating cells. Basophilic infiltration of area under epidermis Induced by soluble (weak) antigens Transient dermal response Prominent in reactions to viral antigens, in contact reactions, skin allograft rejections, reactions to tumor cells and in some cases of hypersensitivity pneumonitis (allergic alveolitis) May be important in rejection of blood-feeding ticks on the skin surface

Contact Hypersensitivity Usually maximal at 48 hours Predominantly an epidermal reaction Langerhans cells are the antigen presenting cells a dendritic antigen presenting cell carry antigen to lymph nodes draining skin Associated with hapten-induced eczema nickel salts in jewellry picryl chloride acrylates p-Phenylene diamine in hair dyes chromates chemicals in rubber poison ivy (urushiol) Study Guide What is the circulating equivalent of the Langerhans cell? What is the carrier in hapten-induced eczema?

Poison Ivy contact dermatitis

Tuberculin Hypersensitivity Maximum at 48-72 hours Inflitration of lesion with mononuclear cells First described as a reaction to the lipoprotein antigen of tubercle bacillus Responsible for lesions associated with bacterial allergy cavitation, caseation, general toxemia seen in TB May progress to granulomatous reaction in unresolved infection Study Guide What are the infiltrating mononuclear cells? When does this progress to a granulomatous reaction? How have you heard of tubercule bacillus being used during immunizations?

Granulomatous Hypersensitivity Clinically, the most important form of DTH, since it causes many of the pathological effects in diseases which involve T cell-mediated immunity Maximal at 14 days Continual release of cytokines Leads to accumulation of large numbers of macrophages Granulomas can also arise from persistence of “indigestible” antigen such as talc (absence of lymphocytes in lesion) Study Guide Are you familiar with tuberculosis?

Epitheloid Cell Granuloma Formation Large flattened cells with increased endoplasmic reticulum Multinucleate giant cells with little ER May see necrosis Damage due to killer T-cells recognizing antigen-coated macrophages, cytokine-activated macrophages Attempt by the body to wall-off site of persistent infection

Granuloma Formation

Examples of Microbial-Induced DTH Viruses (destructive skin rashes) smallpox measles herpes simplex Fungi candidiasis dematomycosis coccidioidomycosis histoplasmosis Parasites (against enzymes from the eggs lodged in liver) leishmaniasis schistosomiasis

Type V Stimulatory Hypersensitivity Interaction of autoantibodies with cellular receptors Antibody binding mimics receptor-ligand interaction Examples thyroid stimulating antibody (mimics thyroid stimulating hormone [TSH] of pituitary binds to thyroid cell receptor activation of B-cell by anti-immunoglobulin

Innate Hypersensitivity Reactions Toxic shock syndrome (S. aureus TSS toxin) hypotension, hypoxia, oliguria and microvascular abnormalities excessive release of TNF, IL-1, IL-6 intravascular activation of complement Septicemia - Septic Shock primarily due to lipopolysaccharide Adult respiratory distress syndrome overwhelming accumulation of neutrophils in lung Platelet aggregation/adherence to macrophages by gram-positive bacteria Superantigens Gram positive enterotoxins react directly with T-cell receptors and induce massive cytokine release