Pathology
Lecture 9 Immunopathology of Hypersensitivity Reactions I, II, III, and IV
1) Review and understand the basic cellular and humoral elements of the immune
system.
2) Know the definitions of antigen and antibody.
Antigen – Any substance that stimulates the immune system to produce antibodies
(proteins that fight antigens). Antigens are often foreign substances such as bacteria
or viruses that invade the body.
Antibody - A protein produced by a plasma cell in the lymphatic system or bone
marrow. An antibody binds to the specific antigen that has stimulated the immune
system. Once bound, the antigen can be destroyed by other cells of the immune
system.
3) Know the mechanisms involved in IgE mediated immediate hypersensitivity. IgE
is produced by B-cells that have previously been stimulated by the antigen. IgE then
attaches to mast cells and basophils, which release primary and secondary mediators
upon combination with the antigen. Type I (anaphylactic type) immediate
hypersensitivity occurs within minutes of combination of an antigen with an antibody
bound to previously sensitized cell.
4) Know the primary and secondary mast cell mediators involved in type I
hypersensitivity.
Primary
Biogenic
Amines
Chemotactic
Mediators
Enzymes
Proteoglycans
Mediator
Histamines
Adenosine
ECF
NCF
Proteases
Heparin
Reaction/Response
Bronchial constriction, ↑ vascular permeability, ↑ glandular
secretion
Bronchial constriction, inhibits platelet aggregation
Eosinophil Chemotactic Factor
Neutrophil Chemotactic Factor
Generate kinins which activate complement system
Anticoagulant
Secondary
Lipid mediators
Activation of
phospholipase A
→ Arachadonic
Acid
Mediator
Leukotrienes
B4, C4, and D4
Prostaglandins
Cytokines
Reaction/Response
C4, and D4 are potent spasmogenic and vasoactive substances.
B4 is chemotactic for WBC’s including eosinophils
D2 causes intense bronchospasm and ↑ mucus secretion
TNF-α, IL-1, IL-3, IL-4, IL-5, IL-6, and GM-CSF.
IL-4 recruits eosinophils.
5) Understand the mechanisms of type II hypersensitivity due to antibodies
directed towards antigens in tissue or on the surface of cells. Three mechanisms:
a. Complement dependant reactions: antibodies activate complement leading to (1)
C3b deposition and enhanced opsonization and removal by phagocytosis, or (2)
formation of the membrane attack complex (C5-9) and cell lysis. Commonly
involve circulating cells.
b. Antibody-Dependant Cell-Mediated Cytotoxicity (ADCC): utilizes NK
lymphocytes, granulocytes, eosinophils, or macrophages, wherein the Fc receptor
reacts with the Fc portion of the antibody molecule.
c. Antibody-Mediated Cellular Dysfunction. Antibodies bind to antigen and impair
function without evoking secondary reactions. (ex. Grave’s disease)
6) Understand complement activation and its role in complement dependent
reactions of type II hypersensitivity. The complement system consists of about 20
plasma proteins and their products, which can be activated by way of the classic or
alternative pathway to form the membrane attack complex, which lyses targeted cells.
The classic pathway is initiated by reaction with antigen-antibody complexes where a
series of enzymatic cleavages and recombinations form the MAC. The alternative
pathway is initiated directly by nonimmunologic stimuli, such as invading
microorganisms, leading to enzymatic cleavages and ultimately MAC formation.
7) Understand the mechanisms of antibody dependent cell mediated cytotoxicity.
Antibodies react directly with integral surface antigens of targeted cells. The free Fc
portion of the antibody molecule reacts with the Fc receptor of a variety of cytotoxic
leukocytes, most importantly NK cells. Other leukocytes, including monocytes,
neutrophils, and eosinophils, also bear Fc receptors and can participate in ADCC. The
target cells are killed by the Fc receptor-bound cytotoxic leukocytes.
8) Understand the mechanisms involved in antibody mediated cellular dysfunction,
for example myasthenia gravis. Antibodies bind to antigen and impair function
without evoking secondary reactions. In Graves’ disease, thyroid-stimulating
immunoglobulin reacts with the thyroid-stimulating hormone receptor as if it were
TSH however, unlike TSH it is not regulated by feedback inhibition. In myasthenia
gravis, the antibody reacts with the acetylcholine receptor thus inhibiting
acetylcholine binding causing muscle weakness and paralysis. Unlike Graves’ disease
the antibody in myasthenia gravis is a competitive inhibitor and does not activate the
receptor.
9) Understand the mechanisms involved in immune complex hypersensitivity. Type
III (immune complex) hypersensitivity occurs when antigen-antibody complexes
form. When antibody concentrations are high, large complexes precipitate at the site
of inflammation and are removed by phagocytosis. When antigen concentrations are
high, small soluble complexes form and are carried by the blood to cause
inflammation at a distant site (possibly glomerular capillaries in the kidney). If the
complexes become fixed in tissue they bind complement, which is highly chemotactic
for neutrophils. The neutrophils release lysosomal enzymes, resulting in tissue
damage. Hageman factor (factor XII) is also activated resulting in coagulation
(intrinsic pathway) and thrombosis.
10) Know the mechanisms in the arthus reaction and in serum sickness.
a. The Arthus reaction is a localized immune complex reaction that occurs when
exogenous antigen is introduced, either by injection or by organ transplant, in the
presence of an excess of preformed antibodies.
b. Serum sickness is a systemic deposition of antigen-antibody complexes in
multiple sites, especially the heart, joints, and kidneys. In the past, antibody
containing foreign serum (most often horse serum) was administered
therapeutically for passive immunization against microorganisms, but due to the
danger of serum sickness, this is no longer done.
11) Understand the mechanisms involved in acute poststreptococcal
glomerulonephritis. Humoral immune response to microbes can have pathologic
consequences. Following infection with β-hemolytic streptococci, poststreptococcal
glomerulonephritis is caused by antistreptococcal antibodies that form antigenantibody complexes, which deposit in renal glomeruli and produce inflammation of
the nephron, nephritis. This occurs through the alternate pathway wherein only C3
and C5 levels are depressed but C1, C2, and C4 are normal.
12) Understand the mechanisms involved in delayed hypersensitivity (type IV
hypersensitivity). Delayed hypersensitivity reactions involve CD4+ TH 1 cells
reacting with antigens on the surface of antigen presenting cells and undergoing blast
transformation and clonal proliferation. They then produce cytokines including: IFNg, IL-2, and TNF-a.