| What is type II HS? | Type III hypersensitivity (HS) reactions or immune complex reactions are caused by antibody-antigen complexes (immune complexes) that have not been adequately cleared by innate immune cells
Endogenous or exogenous antigen exposure triggers an
antibody formation.
Exogenous antigens are foreign proteins such as infectious
microbes or pharmaceutical products.
Endogenous antigens are self-antigens against which
autoantibodies are generated (autoimmunity) |
| How is mechanism of Type III HS? | Binding of antibody to antigen and the consequent formation of antigen-antibody complexes led to the activation of classic pathway of complement system. C3b formed during complement activation coats the ICs.
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Erythrocytes and platelets have C3b receptors on their
surface. The C3b coated ICs bind to the erythrocytes and
platelets through the C3b receptors.
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The erythrocytes and platelets carry the ICs to the spleen and liver. The macrophages in liver and spleen, bearing Fc or complement receptors, strip the ICs on the surface of
erythrocytes and platelets and phagocytose the ICs, resulting in the removal of ICs from the circulation.
➢ A healthy immune system will use macrophages in the
spleen and Kupffer cells in the liver to quickly remove
Immune Complexes (IC) from the bloodstream.
➢ Large complexes can be cleared by macrophages but
macrophages have difficulty in the disposal of small IC. |
| How is pathogenicity of IC? | The pathogenicity of IC is partly dependent on the antigenantibody ratio.
When the antibody is in excess, the complexes are insoluble, do not circulate, and are phagocytosed by macrophages in the lymph nodes, liver and spleen.
However, when the antigen is in excess, the aggregates are
smaller. They freely filter out of circulation in organs where
the blood is transformed into fluids such as urine and synovial fluid. Therefore, IC affect glomeruli and joints
Type III HS occurs when there is little antibody and an
excess of antigen, leading to small IC being formed that
do not fix complement and are not cleared from the
circulation
➢ A soluble antigen is recognized by B lymphocytes
but cannot be detected by T lymphocytes until it has
been processed by an APC
➢ The receptors on the surface of B cells (BCRs) can bind
to soluble antigens. |
| How is progress of ICs causing TIIIHS? | ➢ When the antibody response initiates, there is a huge
excess of antigens compared to antibodies (Ag:Ab>>1).
➢ The ICs that are formed are small, soluble, and quickly
cleared
➢ Within 1-2 weeks, as exceedingly more antibodies are
produced, a point is reached when there is only slight
antigen excess, and the ICs interlace and become bigger
and less soluble.
➢ The small complexes that form at slight antigen excess
are viewed as being highly pathogenic and tend to
deposit in small blood vessel walls; in the capillaries
between the endothelial cells and the basement
membrane.
then vasculitis, glomerulonephritis and arthritis are
commonly associated conditions as a result of type III HS
responses. |
| How is pathophysiology of TIII HS? | The cause of damage is a result of the action of cleaved
complement C3a and C5a, which mediate the induction
of granule release from mast cells (from which
histamine can cause urticaria)…and recruitment of inflammatory cells (predominantly
neutrophils ) into the tissue mainly those with lysosomal
action, leading to tissue damage through “frustrated
phagocytosis” by neutrophils and macrophages
Macrophages and neutrophils in particular play a central
role in the inflammatory process by releasing proteins
and small-molecule inflammatory mediators that control
infection but can damage host tissue.
➢ Such reactions progressing to the point of disease
produce IC diseases.
➢ Damage caused are due to innocent bystander lysis
Cause platelet aggregation, clotting factor, microthrombus mostly w/in vessels |
| How is histopathology of TIII HS? | ➢ As observed under methods of histopathology, acute
necrotizing vasculitis within the affected tissues is
observed concomitant to neutrophilic infiltration, along
with notable eosinophilic deposition (fibrinoid necrosis)
➢ Fibrinoid necrosis is a form of necrosis, or tissue
death, in which there is accumulation of amorphous,
basic, proteinaceous material in the tissue matrix
with a staining pattern reminiscent of fibrin
➢ Often, immunofluorescence microscopy can be used to
visualize the ICs. |
| How is presentation of TIII HS? | ➢ The reaction can take hours, days, or even weeks to
develop, depending on whether or not there
is immunologic memory of the precipitating antigen.
➢ Typically, clinical features emerge a week following initial antigen challenge, when the deposited IC can precipitate an inflammatory response
➢ The severity may be dependent on the quantity &
distribution of IC
– Widespread inflammation wherever complexes
deposits through blood
– Localized inflammation if at the site of antigen entry.
➢ The principal feature that separates type III reactions
from other hypersensitivity reactions is that in type III
reaction, the antigen-antibody complexes are pre-formed
in the circulation before their deposition in tissues |
| What is serum sickness? | ➢ Serum Sickness (SS) is the systemic forms of type III HS
reactions.
➢ A disease which is now of pure historic interest but was a
common occurrence in patients receiving repeated
injections of anti-diphteric horse serum (or anti-Tetanos).
This class of drugs provide so-called passive
immunization.
➢ This illness was so named because it frequently followed
the administration of this therapeutic horse antiserum.
➢ In the preantibiotic era, antiserum made by immunizing
horses was often used to treat pneumococcal
pneumonia; the specific anti-pneumococcal antibodies in
the horse serum would help the patient to clear the
infection |
| How does sermus sickness occur? | ➢ SS can be developed as a result of exposure
to antibodies derived from animals.
➢ These sera or antitoxins are generally administered to
prevent or treat an infection or envenimation
➢ SS is a reaction to a large doses of proteins in antiserum
derived from a non-human animal source, occurring 4–
10 days after exposure; an interval that corresponds to
the time required to mount a primary immune
response that switches from IgM to IgG antibody against
the foreign antigens in horse serum.
➢ The body produces antibodies, which combine with
these proteins to form IC
➢ The formation of ICs causes clearance of the
foreign antigen and so serum sickness is usually a selflimiting disease.
➢ SS is characterized by the deposition of these antigenantibody complexes in blood vessel walls, especially in the kidneys and joints |
| What does serum sickness result in? | ➢ The antigen-antibody complexes precipitate, enter the
walls of blood vessels, and activate the complement
cascade, initiating an inflammatory response and
consuming much of the available C3.
➢ This results in hypocomplementemia, a low C3 level in
serum
➢ The result is a leukocytoclastic vasculitis
➢ They can also cause more reactions resulting in typical
symptoms of SS.
Symptoms
➢ The precise manifestations of SS depend on:
– Quantity of ICs
– Size of complexes (determine the site of deposition) |
| What are tissue and organ effects of serum sickness? | ➢ IC deposition occurred in a variety of tissues and organs
leading to:
– generalized vasculitis (rashes)
– itching
– joint pain (arthralgia), especially finger and toe joints
– fever, as high as 104°F and usually appears before rash
– lymphadenopathy (swelling of lymph nodes), particularly
near the site of injection, head and neck
– malaise
– hypotension
– splenomegaly
– glomerulonephritis
– proteinuria
– hematuria
– shock |
| How is dx of serum sickness? | ➢ Serum sickness after a second dose of antigen follows
the kinetics of a secondary antibody response and the
onset of disease occurs typically within a day or two.
➢ Diagnosis is based on history given by patient, including
recent medications.
➢ True SS is a delayed hypersensitivity reaction, triggered by:
Antiserum – rabies and tetanus
Snake anti-venom, Rituximab is a chimeric murine/human monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells.
➢ Allergenic extracts, hormones and vaccines can also
cause serum sickness.
➢ Certain medicines (such as penicillin, cefaclor, and sulfa)
can cause a similar reaction. |
| How is tx of serum sickness? | ➢ With discontinuation of offending agent, symptoms
usually disappear within 4–5 days.
➢ Corticosteroids, antihistamines, and analgesics are the
main line of treatment.
➢ The choice depends on the severity of the reaction
Prevention
➢ Avoidance of antitoxins that may cause serum sickness is
the best way to prevent serum sickness. Although,
sometimes, the benefits outweigh the risks in the case of
a life-threatening bite or sting
➢ Prophylactic antihistamines or corticosteroids may be
used concomitant with the antitoxin.
➢ Skin testing may be done beforehand in order to identify
individuals who may be at risk of a reaction. |
| What are serum sickness like reactions? | ➢ The term serum sickness-like reaction (SSLR) is
occasionally used to refer to similar illnesses that arise
from the introduction of certain non-protein substances.
Serum sickness–like reactions are specific drug reactions
that are not associated with circulating immune
complexes.
The mechanism of many of the drugs responsible for
serum sickness–like reaction is not well known.
➢ A similar type of immunopathological response (Type III
reactions) is also seen in other situations; |
| How is infectious vasculitis? | ➢ When an adaptive antibody response fails to clear an
infectious agent, for example in subacute bacterial
endocarditis or chronic viral hepatitis.
➢ In this situation, the multiplying bacteria or viruses are
continuously generating new antigen in the presence of a
persistent antibody response that fails to eliminate the
organism.
➢ ICs disease ensues, with injury to small blood vessels in
many tissues and organs, including the skin, kidneys, and
nervesOther causes of infectious vasculitis;
Post streptococcal glomerulonephritis (in fighting a strep
infection, the patient makes an antibody that reacts
against the strep but also cross-reacts with some antigen
in the glomerulus; ICs lodge there and cause nephritis),
Hepatitis, Meningitis, Mononucleosis, Malaria, Lyme
arthritis, Trypanosomiasis,… |
| How do ICs form autoimmune diseases? | ➢ ICs also form in Autoimmune diseases where, because
the antigen persists, the deposition of ICs (complexes of
Ab with self-proteins, glycoproteins, or even with DNA)
continues, and serious disease can result.
➢ In SLE, complexes of DNA and anti-DNA antibodies
accumulate in synovial membranes, causing arthritis , or
accumulate on the basement membrane of the kidney,
causing progressive kidney damage.
➢ IC deposition is also a prominent feature of several other
autoimmune diseases, including rheumatoid arthritis,
scleroderma and Sjögren’s syndrome
➢ Immune Complex formation in vasculitis
Anytime you see a vasculitis, think of Type III
hypersensitivity reaction |
| How is leukocytoclastic vasculitis in TIIIHS? | ➢ Leukocytoclastic vasculitis (LCV), also known as
hypersensitivity vasculitis and hypersensitivity angiitis, is
a histopathologic term commonly used to denote a
small-vessel vasculitis
➢ Histologically, LCV is characterized by leukocytoclasis,
which refers to vascular damage caused by nuclear debris
from infiltrating neutrophils.
➢ LCV classically presents as palpable purpura. Less
common clinical findings include urticarial plaques,
vesicles, bullae, and pustules.
➢ Cutaneous lesions of LCV are often asymptomatic, but
may be associated with pruritus or pain |
| What are features of LCCV? | ➢ Features of palpable purpura in LCV are as follows:
– Lesions are usually round and 1-3 mm
– They may coalesce to form plaques; in some instances,
they may form bullae and ulcerate
– Palpable purpura is most common on dependent areas,
such as the lower legs; areas of tight-fitting clothing; and
areas of trauma; however, any surface can be involved.
– In some cases, the purpuric lesions are barely palpable.
➢ Urticarial lesions may develop in some patients with LCV.
In rare cases, this type of lesion predates the purpuric
lesions.
➢ The urticarial lesions associated with LCV differ from
those of classic urticaria; |
| What causes LCV? | ➢ LCV may be secondary to medications, underlying
infection, drugs; food or food additives; collagen-vascular
disorders, or malignancy. Cases of LCV have been
reported following COVID-19 vaccination.
➢ However, approximately half of cases are idiopathic.
➢ The most common drugs that cause LCV are antibiotics,
particularly beta-lactam drugs, nonsteroidal antiinflammatory drugs, and diuretics.
➢ However, almost all drugs are potential causes.
➢ Foreign proteins such as streptokinase, those found in
vaccines, and those used in monoclonal antibody therapy
can be associated with a SS syndrome with LCV
Infections include RT infections, HIV, HepC, bacterial endocariditis |
| How is pathophysiology of LCV? | ➢ IC deposition, with resultant neutrophil chemotaxis and
release of proteolytic enzymes and free oxygen radicals,
is a key component in the pathophysiology of LCV.
➢ However, the exact mechanisms remain unknown
➢ Systemic symptoms noted with leukocytoclastic
vasculitis may include low-grade fevers, malaise,
weight loss, myalgias, and arthralgias
➢ LCV may be localized to the skin or may be associated
with systemic involvement. Internal disease most often
manifests in the joints, the gastrointestinal (GI) tract, and
the kidneys
➢ LCV may be acute or chronic. Patients with chronic
disease may experience persistent lesions or intermittent
recurrence
➢ Hypersensitivity vasculitis occurs in 10-30 persons per
million persons per year. |
| What is Henoch-Schönlein Purpura (HSP)? | ➢ Henoch-Schönlein purpura (HSP), a specific subtype of
LCV , is characterized by predominant IgA-mediated
vessel injury
➢ It is an acute IgA–mediated disorder characterized by a
generalized vasculitis involving the small vessels of the
skin, the gastrointestinal (GI) tract, the kidneys, the
joints, and, rarely, the lungs and the central nervous
system (CNS)
The typical prodrome of HSP includes the following:
– Headache
– Anorexia
– Fever
Then Rash (90-100% in legs hallmark), Abdominal pain and vomiting (35-85%), Joint pain (60-84% Knees), Subcutaneous edema (20-50%) |
| What are clinical features of HSP? | ➢ IC glomerulonephritis, as seen in Henoch-Schönlein
purpura is an example of IgA involvement in a
nephropathy.
➢ The reaction can take hours, days, or even weeks to
develop, depending on whether or not there is
immunlogic memory of the precipitating antigen.
➢ Typically, clinical features emerge a week following initial antigen challenge, when the deposited ICs can
precipitate an inflammatory response.
➢ The classic clinical findings of palpable purpura in HSP are often preceded by viral respiratory illness.
➢ HSP is more common in children but can also occur in
adults. Children may develop systemic disease with GI,
joint, and/or kidney involvement.
➢ In adults, arthritis and kidney disease occur more
frequently. HSP in adults, especially older men, may be
associated with malignancy |
| How are demographics of LCV? Hx? | ➢ Leukocytoclastic vasculitis affects men and women in
approximately equal proportions.
➢ Leukocytoclastic vasculitis may occur at any age. HenochSchönlein purpura is more common in children under 10 years of age.
Hx (preceding fever, arthralgia, arthritis, myalgia, abdo pain, diarrhea, melena, hematochezia, cough, hemoptysis, sinusitis...)
Investigation (Symptoms of the rash itself are usually minimal, but the presence of any accompanying systemic features such as fever, arthralgia, myalgia, nausea, vomiting, headache and photophobia should prompt immediate investigation for a serious systemic cause.) |
| What are labs for LCV? | ➢ The evaluation of a patient with leukocytoclastic
vasculitis (LCV) serves two purposes.
– The first is determining the presence of systemic disease.
– The second is identifying an associated disorder, which can provide prognostic information.
➢ No standard protocol has been established…
Procedures
➢ Although small vessel vasculitis is a clinical diagnosis, a skin biopsy will confirm it.
➢ A skin biopsy of a relatively new lesion should be performed in most adult patients with suspected leukocytoclastic vasculitis (LCV).
➢ If the cause of LCV is relatively clear, biopsy may not be necessary.
➢ Muscle, nerve, or visceral organ biopsy may be warranted in patients with severe vasculitic syndromes. |
| What are histologic findings for LCV? | ➢ Skin biopsy reveals the presence of vascular and
perivascular infiltration of polymorphonuclear leukocytes
with formation of nuclear dust (leukocytoclasis),
extravasation of erythrocytes, and fibrinoid necrosis of
the vessel walls.
➢ This process is dynamic, and biopsy of a lesion performed too early or too late in the evolution of LCV may not reveal these findings
➢ Immunofluorescent staining may reveal immunoglobulins
(eg, immunoglobulin G, immunoglobulin M) and
complement components (eg, C3, C4) deposited on the
skin basement membrane, suggesting immune complex
deposition.
➢ In Henoch-Schönlein purpura, IgA-predominant deposits
may be found. |
| How is prognosis and tx of LCV? | ➢ The prognosis of small vessel vasculitis ranges from a single event lasting a few weeks to a chronic or recurrent condition.
➢ The prognosis of cutaneous vasculitis depends on the underlying syndrome or the presence of end-organ dysfunction.
➢ In the absence of internal involvement, the prognosis is excellent, with the majority of cases resolving within weeks to months. Approximately 10% of patients will have chronic or recurrent disease
➢ Cases that primarily involve the skin should be treated with nontoxic modalities whenever possible, avoiding the use of systemic corticosteroids and immunosuppressive agents.
➢ When vasculitis is drug induced or related to an infection, no specific treatment is required other than cessation of the drug or treatment of the infection.
➢ The medications range from NSAIDs to immunosuppressants, including prednisone, azathioprine and methotrexate |
| What are arthus reactions? | ➢ The Arthus reaction(a local forms of IC diseases) involves the in situ formation of antigen/antibody complexes after the intradermal injection (or S/C) of an antigen.
➢ If the animal/patient was previously sensitized (has circulating antibody), an Arthus reaction occurs within 4h to 8h
➢ When antigen is injected into the skin, circulating
IgG antibody that has diffused into the tissues forms ICs
locally.
➢ Typical of most mechanisms of the type III HS, Arthus
manifests as local vasculitis due to deposition of IgGbased ICs in dermal blood vessels
➢ The ICs bind Fc receptors on mast cells and other
leukocytes, which creates a local inflammatory response
with increased vascular permeability |
| What is end result of arthus reaction? | Further aggregation of immune complex-related processes
induce a local fibrinoid necrosis with ischemia-aggravating
thrombosis in the tissue vessel walls.
➢ The end result is a localized area of redness and
induration that typically lasts a day or so; Arthus
reaction.
➢ Platelet aggregation, especially in microvasculature, can
cause localized clot formation, leading to blotchy
hemorrhage
➢ After an insect bite, a sensitive individual may have a
rapid, localized type I reaction at the site.
➢ Often, some 4-8 h later, a typical Arthus reaction also
develops at the site, with pronounced erythema and
edema (localized vasculitis).
Reported for vaccines of Diphtheria and tetanus, severe pain, swelling, induration, edema, hemorrhage necrosis |
| What is farmer's lung? | Some inhaled allergens provoke IgG rather
than IgE antibody responses, perhaps because they are
present at relatively high levels in inhaled air.
➢ When a person is reexposed to high doses of such
inhaled antigens, immune complexes form in the alveolar
wall of the lung.
➢ This leads to the accumulation of fluid, protein, and cells in the alveolar wall, slowing blood-gas interchange and
compromising lung function.
➢ This type of reaction occurs in certain occupations such
as farming, where there is repeated exposure to mold
spores in the dust from moldy hay, straw, or grain
As a result, farmers inhale both dust particles and mold
spores.
➢ In fact, a farmer can inhale up to 750,000 of these spores per minute!!! |
| What are types of farmer's lung? | ➢“Bird fancier’s lung” (BFL) from inhalation of a complex
mixture of proteins from avian serum, feces, and feathers.
➢Pigeons, parakeets, and other small cage birds are usually involved, but the disease may also occur in individuals using featherdown duvets and pillows |
