Case 48: Drug-Induced Serum Sickness Flashcards
what happens during a type III hypersensitivity reaction?
IgG forms immune complexes with the antigen in excess
some immune
complexes are too small to precipitate – when this happens,
such soluble immune complexes can produce pathological damage to
blood vessels
the small immune complexes are taken up by endothelial cells in various parts of the
body and become deposited in tissues
complement is activated which leads to tissue damage and inflammatory responses which are triggered by immune complexes deposited in tissues
what are some examples of type III hypersensitivity reactions?
serum sickness
SLE
what is the Arthus reaction?
the subcutaneous injection of large doses of antigen evokes a brisk IgG
response
the activation of complement by the IgG:antigen complexes generates
the complement component C3a and C5a
local endothelial cells are activated by the interactions in blood vessels between
the immune complexes, complement, and circulating leukocytes and platelets = up regulate their expression of adhesion molecules to facilitate emigration of WBC
platelets also accumulate = blood clots
C3a = a potent stimulator of histamine release from
mast cells
C5a = one of the most active chemokines produced by the body
what are the steps that happen during an Arhaus reaction?
- locally injected antigen in immune individual who already has IgG antibody against this antigen
- local immune complex formation
- activation of complement releases inflammatory mediators C5a, C3a, and C4a
C5a also induces mast cell degranulation
- local inflammation, increased fluid and protein release, phagcytosis, and blood vessel occlusion
what are the different parts of the body that can be effected by a type III hypersensitivity reaction?
IV high dose –> vasculitis, nephritis or arthritis if the immune complexes are deposited in the blood vessel walls, renal glomeruli or joint spaces, respectively
subcutaneous antigen = Arthus reaction which effects the perivascular area
inhaled antigen = Farmer’s lung which affects the alveolar/capillary interface
how do you treat serum sickness?
corticosteroid prednisone
what is the most common cause of serum sickness today?
antibiotics like penicillin which acts as a hapten
these drugs bind to host
proteins that serve as carriers and thus can elicit a rapid and strong IgG antibody
response
how is serum sickness different than other types of hypersensitivity?
a reaction can appear on first encounter with the antigen, if that is long-lived
and given in a sufficiently large dose
Hives (urticaria) and edema about the mouth and eyelids were the first
symptoms of serum sickness developed by Gregory. What caused these early
symptoms?
The symptoms were caused by the activation of complement-generated C3a, which
releases histamine from mast cells and causes hives.
The swelling around the mouth
and eyelids is a form of angioedema.
At one point Gregory became confused and disoriented and did not recognize
his parents. His cerebrospinal fluid was normal and a CT scan of his brain was
normal. However, an electroencephalogram displayed an abnormal pattern of brain
waves. What produced these clinical and laboratory findings?
Gregory almost certainly had developed vasculitis in the small blood vessels of his
brain, and this compromised oxygen delivery to his brain.
What other manifestations of vasculitis were noted in Gregory?
He had red cells and albumin in his urine, which indicated an inflammation of the
small blood vessels in his kidney glomeruli.
He also developed purpura in his feet
and ankles. Purpura (which is the Latin word for purple) indicates hemorrhage from
small blood vessels in the skin that are inflamed and have become plugged with clots.
A skin biopsy of one lesion showed the deposition of IgG and C3 around the small
blood vessels, suggesting that an immune reaction was taking place.
Gregory had enlarged lymph nodes everywhere and his spleen was also
enlarged. If you had a biopsy of a node what would you expect to see?
You would expect to see massive follicular hyperplasia, polyclonal B-cell activation,
and many mature plasma cells in the medulla. The massive B-cell activation in the
lymph nodes leads to an overflow of plasma cells from the medulla of the nodes into
the efferent lymph. It is otherwise very, very rare to find plasma cells in the blood, as
were found in Gregory’s blood. They find their way to the bloodstream via the thoracic
duct. The enlargement of the spleen was almost certainly due to hyperplasia
of the white pulp. Some plasma cells probably enter the blood from the hyperplastic
follicles in the spleen.
Gregory had a brisk ‘acute-phase response’. What is this, and what causes it?
The acute-phase reaction is caused by interleukin (IL)-1 and to a greater extent by
IL-6, which are released from monocytes that have been activated by the uptake of
immune complexes.
The acute-phase response consists of marked changes in protein
synthesis by the liver.
The synthesis of albumin drops sharply, as does the synthesis
of transferrin. The synthesis of fibrinogen, C-reactive protein, amyloid A, and
several glycoproteins is rapidly upregulated.
The precise advantage to the host of the
acute-phase reaction is not well understood, but it is presumably a part of innate
immunity, which aids host resistance to pathogens before the adaptive immune system
becomes engaged.
Penicillin can cause more than one type of hypersensitivity reaction. What
laboratory test gave the best evidence that Gregory was suffering from a disease
caused by immune complexes?
His serum C1q level was decreased.
This almost always indicates complement consumption
by immune complexes via the classical pathway.
In hereditary angioedema
the C1q level is normal; in this disease, complement is activated
because of a defect in an inhibitor and not by the formation of immune complexes
The level of C3 in Gregory’s serum was also lowered, a further indication of complement
consumption.
When Gregory returned for a follow-up clinic visit, a skin test for immediate
hypersensitivity was performed by intradermal injection of penicillin. He did not
respond. Does this mean that an incorrect diagnosis was made and that he did not
have serum sickness due to penicillin?
No!
The skin test is positive when there are IgE antibodies bound to the mast cells in
the skin. Gregory did not have IgE antibodies against penicillin, as confirmed by the
negative RAST test.
Serum sickness is caused by complement-fixing IgG antibodies.
