HYPERSENSITIVITY REACTIONS AND AUTOIMMUNITY

BSc in Public Health

11th &12th week

2014

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

HYPERSENSITIVITY REACTIONS

Type I. „immediate”

Type II. Type III. Type IV.„late”

Antibody mediated T cell mediated

TYPES OF ANTIBODY MEDIATED HYPERSENSITIVITY REACTIONS

FcRIα)

TYPE I HYPERSENSITIVITY

REACTIONALLERGY

SENSITISATION PROCESS

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

Pruritus

TYPES OF ALLERGIC REACTIONS

chromosome 11q

FcεRβ chain gene

chromosome 11q

IL-3-5 IL-9, IL-13 GMCSF

HLAII DRB1*015

allergy Inproper

immunregulation Th1/Th2 inbalance

regulation of IgE synthesis

high eosinophil counts

Environmental factors

lack of tolerance

Genetic factors

GENETIC/ENVIRONMENTAL PREDISPOSITION TO ALLERGY

Prick test

TYPE II HYPERSENSITIVITYIgG 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

Killing of target cell by effector-macrophage orNK-cell

Killing of targetcell by complement-mediated lysis

complement activation

IgG

IgG

Receptor-specific autoantibodyinterferes withsignal transduction

NKMf

C '

ADCC

MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS

Extensive tissue damage

FcR

C3R

C3b C3b

C3b

C3b C3b C3b

Binding Opsonization Internalization Enzyme release

Opsonized surface Binding Frustrated Enzyme release phagocytosis

FRUSTRATED PHAGOCYTOSIS MEDIATED BY IgG TYPE ANTIBODIES

DRUG INDUCED ANEMIA

MYASTHENIA GRAVIS

Autoantibodies against ACh receptors in neuromuscular junction inhibiting transmission

of nerve impulses to muscles

progressive muscle weakness

GRAVES DISEASE

Autoantibodies against TSH receptors on thyroid cells causing stimulation and overproduction of thyroid hormones

hyperthyroidism, goiter, protrusion of eyeballs

TYPE III HYPERSENSITIVITY

Antibodies binding to soluble antigens forming small circulating immune complexes which are

deposited in various tissuesDepends on:

Size of immune complexes

Antigen-antibody ratio

Affinity of antibody

Isotype of antibody

• 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 III HYPERSENSITIVITY

T CELL MEDIATED PROCESS

TYPE IV HYPERSENSITIVITY REACTION

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)

Introduction of Ag Ag = antigen:

Purified protein derivate (PPD) isolated from mycobacteria

SCREENING PREVIOUS IMMUNIZATION

(MEMORY T CELL RESPONSE)

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

Insulin

b cell d cella cell a cell b cell d cell

Pancreatic islet cells

AUTOREACTIVE CYTOTOXIC T CELLS KILL INSULIN SECRETING β-CELLS

glucagon somatostatin108 insulin secreting cells

MECHANISM OF AUTOIMMUNE INSULIN-DEPENDENT DIABETES (type IV)