HYPERSENSITIVITY REACTIONS AND AUTOIMMUNITY BSc in Public Health 11th &12th week 2014

HYPERSENSITIVITY REACTIONS Innocous materials can cause hypersensitivity in certain individuals leading to unwanted inflammation  damaged cells and tissues Non-proper reaction of the immune system to foreign substances Mainly harmless substances – after second or multiple exposure Type I. „immediate” Type II. Type III. Type IV. „late” Antibody mediated T cell mediated

TYPES OF ANTIBODY MEDIATED HYPERSENSITIVITY REACTIONS FcRIα)

TYPE I HYPERSENSITIVITY REACTION ALLERGY

SENSITISATION PROCESS Once sensitized (immunized), every following exposure to the allergen elicits the allergic reactions.

TYPES OF ALLERGIC REACTIONS Pruritus

GENETIC/ENVIRONMENTAL PREDISPOSITION TO ALLERGY Genetic factors chromosome 11q FcεRβ chain gene IL-3-5 IL-9, IL-13 GMCSF HLAII DRB1*015 Inproper immunregulation Th1/Th2 inbalance regulation of IgE synthesis high eosinophil counts allergy Environmental factors lack of tolerance

Prick test

Type II hypersensitivity IgG type antibodies bound to cell surface or tissue antigens cells expressing the antigen become sensitive to complement mediated lysis or to opsonized phagocytosis frustrated phagocytosis  tissue damage the antibody inhibits or stimulates target cell function no tissue damage

MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS

FRUSTRATED PHAGOCYTOSIS MEDIATED BY IgG TYPE ANTIBODIES Binding Opsonization Internalization Enzyme release Extensive tissue damage Opsonized surface Binding Frustrated Enzyme release phagocytosis

DRUG INDUCED ANEMIA

MYASTHENIA GRAVIS GRAVES DISEASE Autoantibodies against TSH receptors on thyroid cells causing stimulation and overproduction of thyroid hormones Autoantibodies against ACh receptors in neuromuscular junction inhibiting transmission of nerve impulses to muscles progressive muscle weakness hyperthyroidism, goiter, protrusion of eyeballs

TYPE III HYPERSENSITIVITY Antibodies binding to soluble antigens forming small circulating immune complexes which are deposited in various tissues Depends on: Size of immune complexes Antigen-antibody ratio Affinity of antibody Isotype of antibody

TYPE III HYPERSENSITIVITY symptoms caused by type III hypersensitivity reactions depend on the site of immune complex deposition serum sickness – intravenous immunecomplexes (horse antiserum against snake/spider venom) Arthus reaction – localized, skin Farmer’s lung – localized, lungs

TYPE IV HYPERSENSITIVITY REACTION T CELL MEDIATED PROCESS

TYPE IV (DELAYED-TYPE) HYPERSENSITIVITY

TYPE IV (DELAYED-TYPE) HYPERSENSITIVITY

TYPE IV (DELAYED-TYPE) HYPERSENSITIVITY

DELAYED-TYPE HYPERSENSITIVITY (DTH) (e.g. tuberculin skin test)

TUBERCULIN SKIN TEST (MANTOUX TEST) SCREENING PREVIOUS IMMUNIZATION (MEMORY T CELL RESPONSE) Introduction of Ag Ag = antigen: Purified protein derivate (PPD) isolated from mycobacteria

CONTACT DERMATITIS mediated by both helper and cytotoxic T cells recognizing peptide antigens originated from skin proteins that were modified by the contact sensitizing agents (e.g. cathecol of poison ivy, nickel)

CELIAC DISEASE gluten is recognized as non-self antigen by T cells inflammation of the gut wall in the presence of gluten tissue damage cause villous atrophy  malabsorption gluten-free diet can solve the problem

AUTOIMMUNITY Recognition of self-antigens by the cells of the adaptive immunity (B and T cells) normally induce tolerance Tolerance is achieved by different mechanisms in the body: elimination of auto-reactive (self-recognizing) lymphocytes in the bone marrow and thymus (the process is more strict regarding T cells) limited access of lymphocytes to some tissues (CNS, eyes, testicles) suppression by regulator T cells (CD4+ subtype) induction of anergy (e.g. in the absence of costimulation) normal tissue cells are not expressing MHC class II and/or costimulatory molecules If any of these malfunction, activation of auto-reactive lymphocytes may provoke severe immune response against self tissues

AUTOIMMUNE DISEASES The immune response against self-tissues is the same as against pathogens Continuous presence of self-antigens maintain activation of auto-reactive cells  chronic inflammation Tissue destruction surpasses tissue regeneration Autoimmune responses can be categorized into type II, III or IV hypersensitivity reactions (the innocuous agent is the self-antigen in these cases)

GOODPASTURE SYNDROME (type II) auto-antibody production against type IV collagen of the basement membrane causing inflammation and tissue damage in the kidneys and lungs localized / tissue-specific autoimmune disease

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) (type III) characteristic dermal lesion in SLE patients: the malar rash or butterfly rash fluorescent microscopic figure of immunecomplex depositions at the dermal-epidermal junction

RENAL FAILURE IN IMMUNECOMPLEX DISEASES Glomerulus of a healthy individual. Relatively wide spaces between capillary loops. One of the feared complications of the systemic autoimmune diseases is renal failure. This is most likely to occur in SLE. Here is a glomerulus in which the capillary loops are markedly pink and thickened such that capillary lumens are hard to see. This is lupus nephritis.

REUMATHOID ARTHRITIS (type III and IV) cellular immune response against the synovial membranes of joints CD4+ and CD8+ T cells B cells/plasma cells neutrophils macrophages Rheumatoid factor: anti-IgG-Fc specific antibodies

MECHANISM OF AUTOIMMUNE INSULIN-DEPENDENT DIABETES (type IV) AUTOREACTIVE CYTOTOXIC T CELLS KILL INSULIN SECRETING β-CELLS Insulin b cell d cell a cell 108 insulin secreting cells glucagon somatostatin Pancreatic islet cells