Unit 3 - Immunological factors in disease
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Lecture 5 -
Allergy
Allergic diseases are a common & increasing cause of illness
Affecting 15-20% of the populations
Atopy is the tendency to produce an exaggerated IgE
immune response to harmless environmental substances
Pathology of allergy
Normally the immune system does not make detectable
response to many environmental substances like food and
inhaled particles to which it is exposed on a daily basis
In allergy: exposure to allergen leads to production of
specific IgE Abs that bound to surface mast cells
Upon re-exposure, the allergen binds to membrane bound
IgE which activates the mast cell
•
This leads to release mediators causing either:
1-early phase response (sneezing and rhinorrhea)
2- Late phase response which occur after 4-8 hours
characterized by persistence swelling and inflammation
- Long standing or recurrent allergic inflammation may
give rise to a chronic inflammatory response
Factors influencing susceptibility to allergic diseases
Hygiene hypothesis: infections in early life bias the
immune system against the development of allergy
Positive family history
Genetic factor (genes that control cytokins production and
IgE level)
Presenting problems in allergy
A general approach to the allergic patient
Common presentation of allergic diseases
- Urticaria - Angioedema
- Atopic dermatitis - Allergic conjunctivitis
- Allergic rhinitis (hay fever) - Asthma
- Food allergy (egg) - Drug allergy
- Allergy to insect venom - Anaphylaxis
Clinical assessment
It is important to identify what the patient means by allergy.
Up to 20% of the UK population describe themselves as
having a food allergy
< 1% have an IgE mediated HS reaction
Enquire about allergic symptoms (past, present)
Family history of allergic diseases
Identify potential allergens in the home and workplace
Investigations
1) Skin prick test : read after 10 mins and a positive result
is indicated by a local wheal and flare response ≥ 2 mm
larger than negative control
2) Specific IgE test (RAST)radio allergo sorbent test:
quantitation IgE specific to allegen
3) Supervised exposure to allergen (challenge test):
bronchial provocation test and done in special center
4) Mast cell tryptase : measurement of this enzyme in the
serum , peaks at 1-2 hrs remaining elevated for 24 hrs
Nonspecific markers of atopic diseases
A. Total serum IgE: is elevated in atopic diseases , parasites
and helminthes infection, lymphoma
- Significant allergic diseases can occur despite a normal
total IgE level
B. Peripheral blood eosinophilia : is common in atopic
individuals and >20%
Treatment
Avoidance of allergen
Antihistamines block histamine H1 receptors. S.e.
sedation
corticosteroids: down- regulates proinflammatory
cytokines production
Sodium cromoglicate : stabilizes mast cell membrane and
inhibit the release of vasoactive mediators. It is used
prophylaxis
Ag –specific immunotherapy: by sequential
administration of escalating amount of diluted allergen
over a prolonged period of time
Omalizumab: monoclonal Ab against IgE
Preloaded self-injectable adrenaline : used in anaphylaxis
Anaphylaxis
It is a life threatening, systemic allergic reaction caused
by release of histamine and other mediators.
It is either
IgE mediated mast cell degranulation (Causes)
1) Food (Fish, egg, peanut)
2) 2-insect stings (Bee, Wasp)
3) 3-chemicals (penicillin, latex)
Non –IgE mediated mast cell degranulation
(anaphylactoid) (Causes)
1) Drugs (Aspirin, radiocontrast media)
2) Physical (Exercise, cold)
3) Idiopathic
Clinical assessment (manifestation)
1) Flushing and sweating
2) Wheeze due to bronchoconstrictions
Unit 3 - Immunological factors in disease
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3) Hypotension
4) Urticaria
5) Cardiac arrhythmia
6) Angioedema of lips and mucous membrane
7) Laryngeal obstruction (strider)
8) Diarrhoea and abdominal pain
9) Loss of consciousness
Differential diagnosis
1) Causes of loss of consciousness ( myocardial infarction,
vasovagal syncope)
2) Causes of respiratory distress (status asthmaticus )
3) Causes of laryngeal obstructions (C1 inhibitor deficiency)
4) Causes of generalized flushing ( Carcinoid Syndrome)
5) Other causes (phaeochromocytoma)
Investigations
Serum mast cell tryptase
Specific IgE is important in anaphylaxis
Treatment
Prevention further exposure to allergen
Ensuring patent airway patency
Administration of oxygen
Restoration of blood pressure (laying the patient flat and
iv fluids)
Prompt administration of adrenaline that reverse the
action of histamine, given im ( adult dose 0.3 ml , 300
micrograms 1:1000 solution and repeated at 5-10 minutes
intervals if the initial response is inadequate
Intravenous antihistamine (chlorphenamine 10-20 mg im
or slow iv injection)
Corticosteroids (100-300 mg) prevent late –phase
symptoms in severly affected patients
Nebulised β2 –agonists may also be indicated
Angioedema
•
Is the episodic, localized, non –pitting swelling of
submucous or subcutaneous tissues.
•
It may occur alone or in conjunction with urticaria
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It is a result of mast cell degranulation which may be
spontaneous or triggered by an allergic IgE mediated
response.
•
It is caused by drugs (aspirin, ACE inhibitors, NSAID,
radiocontrast media, antibiotics)
Clinical presentations
Localized soft tissue oedema (face, extremities, genetalia)
Respiratory tract obstruction (larynx, tongue)
Oedema of the intestine (abdominal pain , distention)
It is usually accompanied by urtcaria
It is discriminate from hereditary angioedema is not
associated with urticaria, does not respond to
antihistamine therapy.
Investigations
- Full blood count - CRP
- Thyroid function test - Liver function test
- Skin prick test - Specific IgE test
- C3, C4, C1 inhibitor level
Treatment
Oral antihistamines
Urgent medical attention when there is tongue or throat
swelling and fatal airway obstructions.
Specific allergies
Insect venom allergy
Local reactions to insect stings may cause extensive
swellings around the site lasting 7 days
Peanut allergy
Is most common food related allergy. It is rarely resolve
and lifelong avoidance is recommended
C1 inhibitor deficiency
Hereditary angioedema (HAE)
(inherited C1 inhibitor deficiency)
It is AD disorder due to decreased production of C1
inhibitor protein
C1 inhibitor is complement regulatory protein that inhibit
classical pathway of the complement
It is also a regulatory protein for the kinin cascade
It may be spontaneous or triggered by local trauma or
infection
Edema of the face, extremities, upper airway (laryngeal
obstructions) and GIT
Episodes of HAE are self- limitings and usually resolve
within 48 hours.
Acute episodes are accompanied by low C4 levels
Diagnosis by low level of C1 inhibitor
Treatment with infusion of purified C1 inhibitor
preparations and fresh frozen plasma
Acquired C1 inhibitor deficiency
Clinically indistinguishable from HAE
Associated with autoimmune & lymphoprolifrative disease
Treatment of underlying disorder may induce remission of
angioedem
Unit 3 - Immunological factors in disease
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Transplantation and graft rejection
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It is a definitive treatment of end stage organ disease
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Major complications is graft rejection and infection
The complications depend on:
1) Type of organ transplanted
2) Genetic disparity
3) Primary disease
4) Drug therapy used
Transplant rejection
Solid organ transplantation stimulates an aggressive
immune response by the recipient, unless the transplant is
between monozygotic twins
The most important genetic determinant is the difference
between donor and recipient HLA proteins
Compatibility at all HLA loci decrease acute rejection
improves graft survival and allows the use of less intense
immunosuppressive protocols.
Types of rejection
1) Hyperacute rejection
Results in rapid and irreversible destruction of the graft
It is mediated by pre-existing recipient Abs against donor
( ABO, HLA) which is arise due to previous exposure to
transplantation, blood transfusion and pregnancy
It is type II HS reaction, end with thrombosis and necrosis
No treatment
2)
Acute rejection
Occur after 5-30 days
Treatment by increasing immunosuppressive drugs
a. Acute vascular rejection: it is due to Abs formation and
T, B lymphocytes activation, causing vasculitis
b. Acute cellular rejection: it is due to T cell infiltration
and activation (CD4 and CD8) ,type IV Hs
3) Chronic allograft failure (rejection)
Associated with Proliferation of transplant vascular
smooth muscle, interstitial fibrosis and scaring
Occur > 30 days
Due to immune and non-immune mechanisms
(hypertension, hyperlipidaemia and chronic drug toxicity)
Rx: decrease drug toxicity, control HT and
hyperlipidaemia
Investigations
HLA typing
Anti HLA Abs screenings
Donor-recipient cross matching
C4d staining that deposit in graft capillaries that useful in
early diagnosis of vascular rejection
Immunosuppressive drugs
1) Anti- prolifrative agents(azathioprine):
Inhibit DNA synthesis and block lymphocytes
proliferations
s.e. increased infection, leucopenia, hepatotoxicity
2) Calcineurin inhibitors(Ciclosporin):
Inhibit T cell signaling and block lymphocytes
proliferations
s.e. increased infection,nephrotoxicity ,HT
3) corticosteroids: decrease phagocytosis, decrease
lymphocytes activation and proliferation, decrease
cytokine production
s.e. increased infection
4) Anti T cell Abs (CD3)
Deplete T cells s.e. increased infection
Complications of immunosuppressant drugs
1) Infection with opportunistic pathogens
CMV---- Rx by ganciclovir
Pneumocystis----- Rx by trimethoprim
2)
Malignancy
Increased with virus associated tumor
EBV---- lymphoma
Human herpes v 8----Kaposi’s sarcoma
Increased lung, breast and colon cancer
Living organ donation
Shortage of organ donors is a problem
Cadaver ( RTA, brain- stem death)
Their relatives
The sale of organs is illegal