HYPERSENSITIVITY REACTIONS Innocous materials can cause hypersensitivity in certain individuals unwanted inflammation damaged cells and tissues Non-proper reaction of the immune system to foreign substances Mainly harmless substances – after second or multiple times The effector mechanisms and tissue destruction in hypersensitivity reactions are identical to those seen in autoimmune diseases.

ANTIBODY MEDIATED HYPERSENSITIVITY REACTIONS IgE Mast cell IgG – immune complex FcγR+ cells NK, macrophage IgG – immune complex FcγR+ cells Complement Hay fever Asthma Systemic anaphylaxis Certain drug allergies (penicillin) Serum sickness Arthus reaction 1-2 min4-8 h 2-8 h

Type II hypersensitivity IgG type antibodies bound to the cell surface or to tissue antigens cells expressing the antigen become sensitive to complement mediated lysis or to opsonized phagocytosis frustrated phagocytosiss  tissue demage the antibody inhibits or stimulates target cell function – no tissue damage (e.g. M. gravis – receptor blocker antibodies)

MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS Hemolytic anemia of newborns Erythroblastosis fetalis Drug induced Hemolytic anemia Trombocytopenia Penicillin-based antibiotics Anti-arythmic drug quinidin Myastenia gravis

Penicillin-induced hypersensitivity

The tissue, which can not be phagocytosed, is damaged Absorbed antigen (drug) FRUSTRATED PHAGOCYTOSIS MEDIATED BY IgG TYPE ANTIBODIES Binding Opsonization Internalization Enzyme release Opsonized surface Binding Frustrated Enzyme release phagocytosis

TYPE III HYPERSENSITIVITY Antibodies binding to soluble antigens Small circulating immune complexes Depends on: Size of immune complexes Antigen-antibody ratio Affinity of antibody Isotype of antibody

Size of immune complexes formed during immune responses

The pathology is determined by the site of immune complex deposition

Arthus reaction hard swelling, erythema

THE PROCESS OF TISSUE DAMAGE CAUSED BY IMMUNE COMPLEXES Immune complexes activate the complement system, neutrophils, bazophil granulocytes and thrombocytes Blood vessel wall permeability Frustrated phagocytosis

Serum sickness Mechanisms of tissue demage is independent on the site of deposition Steps of tissue demage – Formation immune complexes in the blood – Deposition depends on the size, composition and cytophylic properties of the antibody (IgM, IgG, IgA) – FcγRIII has a pivotal role – Permeability of endothelium – Tissue demage Increased permeability of blood vessels Reqruitment of neutrophils – enzymes, chemoattractans, dilatators, prostaglandins fibrosis Consequences of tissue demage depends on the site of deposition – Acute serum disease – 7 – 10 days Polyclonal antibodies against snake venom produced in horses Immune suppresszive anti-lymphocyte globulin Bacterial trombolytic streptokinase – treatment of miocardial infarction Subacute bacterial endocarditis – pathogens are not eliminated Chronic viral hepatitis

Serum therapy against diphtheria Corynebacterium diphtheriae Klebs-Löffler bacillus (1883) Edwin Klebs Emil von Behring Nobel prize 1901 Tom (1894, London)

Skin symptoms of serum sickness

Serum sickness

TYPE IV HYPERSENSITIVITY REACTION T CELL MEDIATED PROCESS

Type IV hypersensitivity reaction Chemokines, cytokines, cytotoxins

Tuberculin skin test Ag = antigen Mycobacterium protein (PPD) Introduction of Ag

Delayed-type hypersensitivity (DTH) (e.g., tuberculin skin test) T H 1 from a previous immunization (memory)

*a contact-sensitizing agent is usually a small molecule that penetrates the skin then binds to self-proteins, making them “look” foreign Contact Dermatitis

Delayed-type hypersensitivity is mediated by T cells