Immune Complex–Mediated

(Type III) Hypersensitivity

NAME – HARMEET KAUR

M.Sc. BIOTECHNOLOGY
3RD SEMESTER
ROLL No. - 14
• The reaction of antibody with antigen generates immunecomplexes. Generally, these
complexes facilitate the clearance of antigen by phagocytic cells and red blood cells .
• In some cases, however, the presence of large numbers and networks of immune complexes
can lead to tissue-damaging type III hypersensitivity reactions.
• The magnitude of the reaction depends on the number and size of immune complexes,
their distribution within the body, and the ability of the phagocyte system to clear the
complexes and thus minimize the tissue damage.
• The deposition of these complexes initiates a reaction that results in the recruitment of
complement components and neutrophils to the site, with resultant tissue injury.
• In particular, complex deposition is frequently observed on blood-vessel walls, in the
synovial membrane of joints, on the glomerular basement membrane of the kidney, and on
the choroid plexus of the brain.
• The deposition of these complexes initiates a reaction that results in the recruitment of
neutrophils to the site. The tissue there is injured as a consequence of granular release from
the neutrophil.
Immune complex‐mediated (type III) hypersensitivity – underlying pathogenic
mechanisms.
• The union of such antigens and antibodies to form a complex within the body may well give rise to acute
inflammatory reactions through a variety of mechanisms.
• For a start, intravascular complexes can aggregate platelets with two consequences: they provide a source of
vasoactive amines and may also form microthrombi that can lead to local ischemia (reduced blood supply
and thus reduced oxygen to the tissues).
• Immune complexes can also stimulate macrophages, through their Fcγ receptors, to generate the release of
proinflammatory cytokines IL‐1β and TNF, reactive oxygen intermediates, and nitric oxide
• Complexes that are insoluble often cannot be digested after phagocytosis by macrophages and so provide a
persistent activating stimulus. If complement is activated, the generation of the C5a chemotactic factor will
lead to an influx of neutrophils which phagocytose (or try to phagocytose) the immune complexes; this in
turn results in the extracellular release of the neutrophil granule contents, particularly when the complex is
deposited on a basement membrane and cannot be phagocytosed (so‐called “frustrated phagocytosis”).
• The proteolytic enzymes (including neutral proteases and collagenase), kinin‐forming enzymes, polycationic
proteins, and reactive oxygen and nitrogen intermediates that are released will, of course, damage local
tissues and intensify the inflammatory responses. The anaphylatoxins C3a and C5a produced following
complement activation will cause release of mast cell mediators, resulting in vascular permeability changes.
Immune complex‐mediated (type III) hypersensitivity – underlying pathogenic mechanisms. ROI, reactive oxygen
intermediates ; NO, nitric oxide.
Type III Reactions Can Be Localized
Injection of an antigen intradermally or subcutaneously into an animal that has high levels of circulating antibody specific for
that antigen leads to formation of localized immune complexes, which mediate an acute Arthus reaction within 4–8 h.

The Arthus reaction

Maurice Arthus found that injection of soluble antigen intradermally into hyperimmunized rabbits with high levels of
precipitating antibody produced an erythematous and edematous reaction that reached a peak at 3–8 hours and then
usually resolved. The lesion was characterized by an intense infiltration with neutrophils. The injected antigen precipitates
with antibody often within the venule, too fast for the classical complement system to prevent it.
Reactions to inhaled antigens
Intrapulmonary Arthus‐type reactions to exogenous inhaled antigen are responsible for a number of type III hypersensitivity
disorders. The severe respiratory difficulties associated with farmer’s lung occur within 6–8 hours of exposure to the
thermophilic actinomycetes that grow in the moldy hay. Inhalation of bacterial spores in dust from the hay introduces
antigen into the lungs and an immune complex‐mediated hypersensitivity reaction occurs.
Reactions to resident infections or to self antigens
Type III reactions are often provoked by the local release of antigen from infectious organisms within the body; for example,
living filarial worms, such as Wuchereria bancrofti, are relatively harmless, but the dead parasite found in lymphatic vessels
initiates an inflammatory reaction thought to be responsible for the obstruction of lymph flow and the ensuing, rather
monstrous, elephantiasis. Microbial cell death following chemotherapy may cause an abrupt release of microbial antigens
and, in individuals with high antibody levels, produce quite dramatic immune complex‐mediated reactions, such as erythema
nodosum leprosum in the skin of dapsone‐treated lepromatous leprosy patients.
Development of a localized
Arthus reaction (type III
hypersensitive reaction).
Complement activation
initiated by immune
complexes (classical pathway)
produces complement
intermediates
that (1) mediate mast-cell
degranulation, (2)
chemotactically attract
neutrophils, and (3) stimulate
release of lytic enzymes from
neutrophils
trying to phagocytose C3b-
coated immune complexes.
Type III Reactions Can Also Be Generalized
When large amounts of antigen enter the bloodstream and bind to antibody, circulating immune complexes can form. If
antigen is in excess, small complexes form; because these are not easily cleared by the phagocytic cells, they can cause tissue-
damaging type III reactions at various sites. Typically, within days or weeks after exposure to foreign serum antigens, an
individual begins to manifest a combination of symptoms that are called serum sickness. These symptoms include fever,
weakness, generalized vasculitis (rashes) with edema and erythema, lymphadenopathy, arthritis, and sometimes
glomerulonephritis. The precise manifestations of serum sickness depend on the quantity of immune complexes formed as
well as the overall size of the complexes, which determine the site of their deposition. As mentioned above, the sites of
deposition vary but, in general, complexes accumulate in tissues where filtration of plasma occurs. This explains the high
incidence of glomerulonephritis (complex deposition in the kidney) and vasculitis (deposition in the arteries) and arthritis
(deposition in the synovial joints) caused by serum sickness.
Formation of circulating immune complexes contributes to the pathogenesis of a number of conditions other than serum
sickness. These include the following:
• Autoimmune Diseases Infectious Diseases
Systemic lupus erythematosus Poststreptococcal glomerulonephritis
Rheumatoid arthritis Meningitis
Goodpasture’s syndrome Hepatitis
• Drug Reactions Malaria
Allergies to penicillin and sulfonamides
Deposition of immune complexes in the kidney glomerulus. (1) Complexes induce release of vasoactive mediators from
basophils and platelets that cause (2) separation of endothelial cells. (3) Attachment of larger complexes to exposed basement
membrane, with smaller complexes passing through to the epithelial side. (4) Complexes induce platelet aggregation. (5)
Chemotactically attracted neutrophils release granule contents in “frustrated phagocytosis” to damage basement membrane and cause
leakage of serum proteins. Complex deposition is favored in the glomerular capillary because it is a major filtration site and has a high
hydrodynamic pressure. Deposition is greatly reduced in animals depleted of platelets or treated with vasoactive amine antagonists.