M. S. Tvorko

Immunopathology

Hypersensitivity Autoimmunity Immunodeficiency

ALLERGYALLERGY

Peter Gell and Robert Coombs developed a classification system for reactions responsible for hypersensitivities in 1963. Their system correlates clinical symptoms with information about immunologic events that occur during hypersensitivity reaction.

The Gell-Coombs classification system divides hypersensitivity into four types:

Type I (Anaphylaxis) Hypersensitivity Type II (Cytotoxic) Hypersensitivity

Type III (Immune Complex) Hypersensitivity

Type IV (Cell-Mediated) Hypersensitivity

Allergic reactions are subdivided into two groups: (1) immediate and (2) delayed reactions, although it is difficult to draw a strict distinction between them. Allergic reactions of immediate action are associated with B-lymphocytes and antibodies circulating in the blood, allergic reactions of delayed action with T-lymphocytes.

Mast cells display a high affinity receptor for IgE

IgE is synthesised in response to certain antigens (allergens)

Allergens are deposited on mucous membranes and taken up and processed by antigen presenting cells (e.g. Dendritic cells or B cells)

Allergen presented to TH2 cells which provide cytokine signals to B cells to produce IgE Ig E binds to mast cells

Cross linking of IgE by subsequent exposure to allergen causes mast cell degranulation

Mast cell degranulation is the major initiation of the acute allergic reactionMast cell mediators include histamine, heparin and other factorsThese cause, mucus secretion, vasodilation and oedema

TYPE I: IMMEDIATE (ANAPHYLACTIC) HYPERSENSITIVITY

Mast cell mediators include pre-formed and newly formed mediators

Pre-formed mediators include : histamine, heparin and neutral protease

Newly formed mediators include leukotrienes, prostaglandin

D2 and platelet activating factor

Skin testing can be useed for identify the allergen responsible for allergies. These tests involve inoculating small amounts of suspect allergen into the skin. Sensitivity to the allergen is shown by a rapid inflammatory reaction characterizide by redness, swelling, and itching at the site of inoculation

Stages of Stages of reaction and reaction and

mechanism mechanism

Prevention Prevention therapytherapy

Allergen penetrates into individual

Avoid meeting allergen

IgE antibody is induced by allergen and binds to mast

cells and basophils

Desensitization

When exposed to the allergen again, the

allergen cross-links the bound IgE,which

induces degra-nulation

Stabilization of mast cells (chromolyn sodium, theocine,

caffeine)

Release of mediators Antagonists of mediators,

Antihistamine drugs

Local manifistations:

rhinitis, asthma, urticaria

Inhibitors of late stage.

Corticosteroides, indometacin

Desensitization. Major manifestations of anaphylaxis occur when large amounts of mediators are suddenly released as a result of a massive dose of antigen abruptly combining with IgE on many mast cells. This is systemic anaphylaxis, which is potentially fatal. Desensitization can prevent systemic anaphylaxis.

Acute desensitization involves the administration of very small amounts of antigen at 15-minute intervals. Antigen-IgE complexes form on a small scale, and not enough mediator is released to produce a major reaction. This permits the administration of a drug or foreign protein to a hypersensitive person, but hypersensitivity is restored days or weeks later.

Chronic desensitization involves the long-term weekly administration of the antigen to which the person is hypersensitive. This stimulates the production of IgG-blocking antibodies in the serum, which can prevent subsequent antigen from reaching IgE on mast cells, thus preventing a reaction.

Type II Mechanism

Antibody mediated hypersensitivity

Antibody directed against membrane and cell surface antigens (autoantibodies)

Antigen-antibody reactions activate complement producing membrane damage

Examples include: transfusion reactions and haemolytic disease of the newborn

Antibodies bind to cell surface Phagocytes bind to the antibody

via their Fc receptor Phagocytosis of target cell Antibody binding also activates

complement via the classical pathway

Complement mediated cell lysis

Type III Hypersensitivity

Immune complex mediated

Excessive formation of immune complexes e.g. persistent low-grade infection, repeated inhalation of antigens

Examples of Type III hypersensitivity include: Farmers lung, immune complex glomerulonephritis

Normally immune complexes are degraded by phagocytosis, particularly in the liver and spleen

Excessive immune complex formation results in deposition in the tissues, particularly arterioles, kidney and joints

Complexes induce platelet aggregation and complement activation

Attempted phagocytosis causes enzyme release and results in tissue damage

Type III Hypersensitivity

RF is capable of self-

associating into immune

complexes

These immune complexes

may fix complement and

activate additional

inflammatory processes

Small immune complexes may

directly activate

macrophages to produce

proinflammatory cytokines

by binding to macrophage-

surface receptors

RF is capable of self-

associating into immune

complexes

These immune complexes

may fix complement and

activate additional

inflammatory processes

Small immune complexes may

directly activate

macrophages to produce

proinflammatory cytokines

by binding to macrophage-

surface receptors

Type IV Hypersensitivity

Delayed type hypersensitivity Takes more than 12 hrs to develop after

antigenic challenge Examples include: contact dermatitis and

tuberculin reaction Antigens include large molecules or small

molecules (haptens) linked to carrier molecules

APC resident in the skin process antigen and migrate to regional lymph nodes where they activate T cells

Sensitised T cells migrate back to the the skin where they produce cytokines which attract macrophages which cause tissue damage

Type IV Mechanism

Type IV Reaction – Contact Dermatitis

Autoimmunity

Autoimmunity is a reaction of the immune system to the bodies own tissues

Self molecules are recognised as antigens due to a breakdown of self-tolerance

Antibodies (autoantibodies) react against these components

Includes organ-specific and non-organ specific diseases

CLASSIFICATION OF AUTOIMMUNE DISEASES

Organ Specific• Insulin dependent diabetes mellitus (IDDM) / Type I)• Grave’s disease• Goodpasture’s syndrome• Myasthenia gravis

Systemic• Systemic lupus erythematosus• Rheumatoid arthritis• Multiple sclerosis• Sjogren’s syndrome

ANA (antinuclear antibodies): SLE Anti-ds DNA: SLE Anti-histone: drug-induced SLE Anti-IgM (rheumatoid factor): part of RA Anti-neutrophil: vasculitis Anti-centromere: CREST - scleroderma Anti-mitochondrial: primary biliary cirrhosis Anti-basement membrane: Goodpasture’s (renal, lung) Anti-epithelial cell: pemphigus vulgaris Anti-gliadin (not an autoantibody): celiac disease,

dermatitis herpetiformis

Autoantibodies

Systemic Lupus Erythematosus Chronic, systemic inflammatory disease caused by

immune complex formation.

The word "systemic" means the disease can affect many parts of the body.

Pathophysiology associated with clinical features secondary to immune complexes depositing in tissues resulting in inflammation.

Parts of the body affected include: the joints, skin, kidneys, heart, lungs, blood vessels, and brain.

SLE Butterfly Rash The source of the name

"lupus" is unclear. All explanations originate with the characteristic butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks.

Stranger still, is the account that the term "Lupus" didn't come from latin at all, but from the term for a French style of mask which women reportedly wore to conceal the rash on their faces

Effector mechanisms Autoantibodies to many autoantigens Most common autoantibody is to ds-DNA Immune complex deposition on basement

membranes with complement activation and inflammation

Laboratory diagnosis Anti-nuclear antibody (ANA)

HEp-2 cells Homogeneous pattern and titer > 1:160

Anti ds-DNA Crithidia lucilliae

C3 level

RHEUMATOID ARTHRITIS (RA)

Characterized by inflammation of synovial membrane of joints and articular surfaces of cartilage and bone

Vasculitis is a systemic complication

Affects 3% to 5% of U.S. population

Female to male ratio of 3:1

HLA DR4 is genetic risk factor

Effector mechanism• CD4 T cells, activated B cells, macrophages and plasma

cells• 85% of patients have rheumatoid factor

Rheumatoid factor• IgM, IgG and IgA specific for IgG• Immune complex formation exacerbates inflammation

Laboratory diagnosis• Rheumatoid factor• Anti-cyclic citrulinated peptide• C-reactive protein (CRP)

Rheumatoid arthtritisRheumatoid arthtritis

Grave’s diseaseGrave’s disease

Myasthenia gravis

Multiple sclerosisMultiple sclerosis

Types of Transplants Autograft

Self tissue transferred from one site to another

Isograft Genetically identical

individuals

Allograft Different members of

the same species

Xenograft Different species

Hyperacute Rejection

Summary 3 major types of graft rejection

Immune response to MHC antigen is the strongest force in rejection

Graft rejection occurs in two stages

Immunosuppressive therapies used to suppress graft rejection