You are on page 1of 9

HYPERSENSITIVITY AND ALLERGY

what are the key features of the 4 hypersensitivity reactions


How do allergens mediate type I (immediate) hypersensitivity reactions
(with examples)
The adaptive immune response
- RESPONSE TO INFECTION: generally beneficial
- But these immune responses can also cause tissue injury and disease:
hypersensitivity diseases
- INAPPROPRIATE RESPONSE TO INNOCUOUS SUBSTANCES :
Allergy/Hypersensitivity
- RESPONSE TO SELF ANTIGENS: autoimmune disease
- RESPONSE TO TRANSPLANTED ORGANS: graft rejection

ALLERGIES
The hallmark of allergic diseases is the production of IgE antibody, which is
dependent on the activation of IL-4producing helper T cells
-

Sensitivity to biological and non-biological materials


Pollens, mites, food, drugs, cosmetics, pollutants
Inconvenient to highly dangerous
Incidence rising?
The typical sequence of events in immediate hypersensitivity consists
of:
o exposure to an antigen,
o activation of lymphocytes (TH2 cells, IL-4producing follicular
helper T [TFH] cells and B cells) specific for the antigen

o production of IgE antibody


o binding of the antibody to Fc receptors of mast cells
Also called SENSITIZATION because IgE-coated mast cells
are ready to be activated on antigen encounter
o triggering of the mast cells by re-exposure to the antigen
o resulting in the release of mediators from the mast cells and the
subsequent pathologic reaction
Allergy is the prototypic TH2-mediated disease.
o Many of the early events and pathologic features of the reaction
are triggered by TH2 cytokines, which may be produced by TFH
cells in lymphoid organs and by classical TH2 cells in tissues.
The clinical and pathologic manifestations of allergy consist of the
vascular and smooth muscle reaction that develops rapidly after
repeated exposure to the allergen (immediate hypersensitivity) and a
delayed late phase inflammatory reaction.
Allergic reactions are manifested in different ways, depending on the
tissues affected, including skin rashes, sinus congestion, bronchial
constriction, abdominal pain, diarrhea, and systemic shock
The development of allergies is the result of complex and poorly
understood gene-environment interactions.
Atopic individuals produce high levels of IgE in response to
environmental allergens, whereas normal individuals generally produce
other Ig isotypes, such as IgM and IgG, and only small amounts of IgE
o IgE antibody is responsible for sensitizing mast cells and provides
recognition of antigen for immediate hyper- sensitivity reactions.
TH2 cells, mast cells, basophils, and eosinophils are the major effector
cells of immediate hypersensitivity reactions and allergic disease.

What causes type I allergic


reactions
-

Allergen + IgE + Mast


cell
Inhaled material
Grass Pollen, House
dust mite
Foods egg
Chemicals nickel
Venoms bee, wasp
Drugs Penicillin

Anaphylaxis (not to be confused withthe 4 hypersensitivity reactions!)


-

Anaphylaxis is a systemic immediate hypersensitivity reaction


characterized by edema in many tissues and a decrease in blood
pressure, secondary to vasodilation.

Result from the systemic presence of antigen introduced by injection, an


insect sting, or absorption accorss and epithelial surface such as gut mucosa

Stage I Generalised itching, Urticaria


Stage II Swelling away from the sting, incontinence
Stage III Difficulty in breathing
Stage IV Fall in blood pressure, loss of consciousness
Anaphylaxis: Systemic allergic reaction to a bee sting (Stage II)

House dust mite (Dermatophagoides pteronyssinus -DerP)


Mast cells
-

Mast cells are activated by cross-linking of FcRI molecules, which


occurs by binding of multivalent antigens to the IgE molecules that are
attached to the Fc receptors
Activation of mast cells results in three types of biologic response:
secretion of the preformed granule contents by exocytosis
(degranulation), synthesis and secretion of lipid mediators, and
synthesis and secretion of cytokines.
Mast cell degranulation is a central component of many allergic
diseases, and the clinical and pathologic manifestations of the diseases
depend on the tissues in which the mast cell mediators have effects as
well as the chronicity of the resulting inflammatory process.
o + leukotrienes synthesized via arachidonic acid pathway!
Location:
o In CT skin, intestinal mucosa
o In mucosal tissue alveoli, intestinal mucosa
Histamine, Serotonin (short-lived) B. Cytokines and Leukotrienes
(sustained)
o Vasoactive: increased local blood flow & vascular permeability
>fluid accumulation; influx blood cells
o Smooth muscle cell contraction > expel
e.g. gut: vomiting, diahorrea; bronchial

constriction:increase mucus & cough


o Cytokines: e.g. IL-4, TNF sustained inflammatory signal

Diagnosis:
-

Skin test wheat and flare


Immunoassay
o Enzyme or Radio labelled anti-IgE + IgE antibody in test sample
+ Allergen coated paper disc
o Radioallegosorbent test (RAST)

AUTOIMMUNE DISEASES
What are the main features of autoimmune diseases?
Outline the tissue damage (pathology) associated with RA, Diabetes
and Goodpastures, SLE.
How do genetics and environment influence the development of
autoimmune conditions?
AUTOIMMUNITY reaction against self antigens
- Failure of the normal mechanisms of self-tolerace results in reactions
against ones own cells and tissues
- At least 2-5% of the population has autoimmune diseases
- Autoimmune diseases are chronic
- Antibody-mediated diseases are produced either by anti- bodies that
bind to antigens on particular cells or in extracellular tissues or by
antigen-antibody complexes that form in the circulation and are
deposited in vessel walls
- In organ-specific autoimmune disease, exemplified by Hashimotos
thyroiditis, Graves disease and type 1 diabetes, the target
autoantigens and lesions are restricted to a particular organ. In
nonorgan-specific (systemic) autoimmune diseases, such as SLE
and RA, the autoantibodies have widespread reactivity and the lesions
involve deposition of circulating immune complexes.
- Patients quite often develop more than one autoimmune disease.
Effector mechanisms of antibody-mediated disease.
1) Antibodies opsonize cells and may activate complement, generating
complement products that also opsonize cells, leading to phagocytosis
of the cells through phagocyte Fc receptors or C3b receptors.
2) Antibodies recruit leukocytes by binding to Fc receptors or by
activating complement and thereby releasing byproducts that are
chemotactic for leukocytes.
3) Antibodies specific for cell surface receptors for hormones or
neurotransmitters may
a. stimulate the activity of the receptors even in the absence of the
hormone, as in Graves diseases (hyperthyroidism)
b. inhibit binding of the neurotransmitter to its receptor, as in
myasthenia gravis

Autoimmune diseases are multifactorial


-

Autoimmune diseases generally involve multiple genetic contributions,


including polymorphisms associated with HLA, autoantigens, PRRs,
cytokines, cytokine receptors, co-stimulatory and signaling molecules,
and transcription factors.
Seventy-five percent of autoimmune disease occurs in females, most
commonly between puberty and the menopause.
Changes in disease severity can occur during pregnancy.
Feedback control of lymphocytes through the cytokinehypothalamus
pituitaryadrenal loop may be defective in rheumatoid arthritis and
some other autoimmune diseases.
Twin studies reinforce the importance of genetic contributions but also
indicate a strong environmental influence.
Both microbial and nonmicrobial environmental factors are implicated.

Genetic
- eg Ankylosing spondylitis HLA-B27 (RR 87)
- MS HLA-DR2 (RR5)
- IDDM HLA-DR3/DR4 heterozygote (RR14-25)
- RA HLA-DR4 (RR4.2-7)
Hormonal/sex eg female:male
- AS 0.3
- MS 10
- RA 3
- SLE 10-20
Environmental co-factors
- eg Goodpastures (autoabs to type IV collagen Type II
hypersensitivity)
o Present in basement membranes throughout the body including
lungs, kidney and inner ear
o All patients get glomerulonephritis,only 40% get lung
hemorrhage, none get ear problems
- Disease Pattern explained by autoantigen availability
o Glomeruli filter plasma therefore BM accessible
o Cochlear BM not accessible to autoabs
o In lung, BM seperates alveolar epithelium from capillary
endothelium- so
o 40% lung disease caused by damage due to smoking

Unidentified triggers
- viral?? Bacterial??
- Various proposed mechanisms for the induction of autoimmunity by
infectious agents.
- Eg. Rheumatic Fever- streptococcal M-antigen Abs cross-reactive
with myosin heart muscle
Systemic lupus erythematosus (Type III hypersensitivity)
-

Skin rash caused by complexes of DNA and anti- DNA antibodies


becoming localized in the skin to cause inflammation
Genetic and environmental factors contribute to a breakdown of
tolerance in self-reactive B and T lymphocytes
Chronic, remitting and relapsing, multisydrome autoimmune diseases
Affects mainly women 1 in 700 US woman
Rashes, arithritis, glomerulonephrititis + hemolytic anemia,
thrombocytopenia and CNS involvement can be observed

Type I Diabetes
-

Chronic inflammatory infiltration and destruction of the insulinproducing B cell of the pancreatic islets of Langerhans
Type IV hypersensitivity

Rheumatoid arthritis (Type II, III & IV


hypersensitivity)
-

Female:male ratio 3:1


Affects 2% of the population
Crippling disease
Killing disease
High social costs: divorce, loss of work
Cost to UK economy 1 billion annually
Cellular involvement:
o T cells
o B cells (Abs, RF, IC)
o Monocytes
o macrophages
o fibroblasts
o neutrophils
Main feature of RA is joint erosion leading
to deformity and disability

Autoimmune Diseases
- Central Tolerance not 100% foolproof
- Autoreactive T and B cells controlled by peripheral tolerance
mechanisms
- Autoimmune diseases can result when peripheral tolerance fails
- Central tolerance does not delete ALL potentially dangerous
lymphocytes
PERIPHERAL TOLERANCE a state of tolerance acquired by mature
lymphocytes in the peripheral tissues, as opposed to central tolerance, which
is acquired by immature lymphocytes during their development.
The importance of maintaining peripheral tolerance
- self reactive lymphocytes can escape -ve selection in the thymus

(central tolerance) due to low affinity to self MHC/antigen and the


exclusive expression of some proteins in the periphery.
these upon recognition of specific autoantigens can cause direct and/or
indirect tissue damage
autoimmune diseases such as RA, type I Diabetes and lupus

Mechanisms of maintenance of peripheral tolerance


- Deletion/Apoptosis
- Anergy (unresponsive)
o Lack of 2nd signal or co-stimulation
- Immunological Ignorance No contact with self Ag
o eg. Type IV collagen in lung Goodpastures syndrome, antigens
of the eye and testis
- Immune Deviation Th1(generally bad for autoimmune disease) to Th2
(bad for allergy/asthma) bias
- Active Suppression (Immune Regulation) - Regulatory T cells