Hypersensitivity

Reactions (Type 1
and type 2)

Salome Sibashvili
Hypersensitivity

– An exaggerated and/or pathological immune response to foreign or self antigens.

– HSRs are commonly classified into four types
– Type I HSRs (e.g., food and pollen allergies, asthma, anaphylaxis) are immediate
allergic reactions.
– Type II HSRs (e.g., autoimmune hemolytic anemia, Goodpasture syndrome) are
cytotoxic; tissue-specific antibodies cause destruction of cells in these tissues.
– Type III HSRs (e.g., many vasculitides and glomerulonephritides) are immune
complex-mediated; tissue damage is caused by antigen-antibody complex deposition.
– Type IV HSRs (e.g., TB skin tests, contact dermatitis) are delayed and cell-mediated
and are the only HSRs that involve sensitized T lymphocytes rather than antibodies.
IgE

– Monomer
– Binds to mast cells → cross-linking upon allergen exposure → release
of histamine (involved in allergic diseases)
– Binds to basophils
– Allergy: mediation of immediate‑type reaction (type I hypersensitivity -
e.g., anaphylaxis)
– Involved in defense against parasites by stimulating eosinophils
Mast Cells

– Found in tissue (interstitial connective tissue, e.g., submucosa and surrounding

blood vessels)
– Not present in the blood
– Contain basophilic granules and receptors for the Fc part of IgE antibodies
(similarity to basophils)
– Express c-Kit cell surface receptors
– Maturation occurs in target tissue.
Basophil

– Basophilic granules
– Contain histamine and heparin
– Often obscure the nucleus
– Surface receptors for IgE
– Remain in the bloodstream for minutes before migrating into tissue
– Production of leukotrienes→ inflammation and allergic reaction
– Release of histamine and heparin → vasodilation and increased vessel
permeability
– Almost no phagocytic abilities
Type I hypersensitivity Reaction

– Type I hypersensitivity reactions are referred to as “immediate reactions.”

– Antibody-mediated; include anaphylactic and atopic immune responses
– Preformed IgE antibodies coating mast cells and basophils are crosslinked by
contact with free antigen.
– Cell degranulation results in the release of histamine and other inflammatory
mediators.
– Immediate reaction: allergic reaction within minutes of contact with the antigen
– Late-phase reaction: occurs hours after immediate reaction for a duration of
24–72 hours
Pathophysiology
1. IgE is formed as a result of prior sensitization (i.e., previous contact with the antigen)
and coats mast cells and basophils.
2. Subsequent encounter with antigen results in an IgE-mediated reaction by preformed
IgE antibodies: free antigen binds to two adjacent IgE antibodies (crosslinking) →
degranulation of cells
3. Release of histamine and other mediators (e.g., prostaglandin, platelet-activating factor,
leukotrienes, heparin, tryptase), leading to:
o ↑ Smooth muscle contraction → bronchospasm, abdominal cramping
o Peripheral vasodilation and ↑ vascular permeability → hypovolemia, hypotension
o Extravasation of capillary blood → erythema
o Fluid shift into the interstitial space → edema, pulmonary edema
o Pruritus
4. Mast cell secretion of cytokines and other proinflammatory mediators → eosinophil
and neutrophil chemotaxis → late-phase reaction → inflammation and tissue damage
Examples
– Anaphylaxis: pruritus, edema, rash, rhinitis, bronchospasm, and abdominal
cramping
– Angioedema: due to mast cell activation in the dermis and/or subcutaneous
tissue
– Urticaria (hives)
– Atopy- Genetic predisposition to producing IgE antibodies against certain
harmless environmental allergens (e.g., pollen, mites, molds, certain foods)
Associated conditions: asthma, atopic dermatitis, allergic rhinitis, allergic
conjunctivitis, food allergies
– Allergic conjunctivitis
– Allergic rhinitis
– Allergic asthma
– Early symptoms
– •Occur within minutes
– •Degranulation →release of pre-formed mediators (histamine)
– •Synthesis/release of leukotrienes, prostaglandins
– •Edema, redness, itching
– Late symptoms
– •~6 hours later
– •Synthesis/release of cytokines
– •Influx of inflammatory cells ( neutrophils, eosinophils)
– •Induration
Diagnostics

– Skin prick test

– Skin prick test
– Intradermal test -More sensitive than skin prick test; higher risk of false
positives .May lead to anaphylaxis in IgE-mediated HSRs .
– Tryptase - A relatively specific marker of mast cell activation Elevated levels
indicate an increased risk of severe reactions.
– Allergen-specific IgE test (sIgE) - Indicated in patients with known allergic
triggers and clinical symptoms. Preferable to skin testing in patients at high risk
of anaphylaxis. Quantitatively assessed using enzyme-linked immunosorbent
assay (ELISA)
Treatment

– Severe reactions: emergency resuscitation

– Moderate reactions (more pronounced urticaria/angioedema, fever,
arrhythmia, bronchospasm): antihistamines with or without glucocorticoids.
– Mild reactions (mild urticaria/angioedema, GI symptoms, tremor, palpitations,
headache, cough): expectant management with or without antihistamines
– Emergency self‑management- Epinephrine autoinjectors, antihistamines,
corticosteroids.
Allergen immunotherapy
(desensitization)
– Indication- Documented IgE-mediated allergy (e.g., allergic rhinitis, allergic
asthma, allergy to wasp or bee venom). Significant symptoms and inadequate
relief from symptomatic therapy and exposure prophylaxis. Significant
symptoms despite symptomatic therapy and avoidance of the allergen.
– Method- Only available for some allergens but can be quite effective
Application of specific antigen in subclinical dose (subcutaneous, mucosal). Slow
escalation of dose . Goal: ↑ production of IgG antibodies instead of excessive
IgE production (isotype switching) . Duration of treatment: at least 3 years
Type II Hypersensitivity Reaction

– Type II hypersensitivity reactions, or “cytotoxic reactions,” are antibody-

mediated and responsible for a number of autoimmune disorders.
– IgG and IgM antibodies specific for cell surface or extracellular matrix antigens
can cause tissue injury by activating the complement system, by recruiting
inflammatory cells, and by interfering with normal cellular functions.
Pathophysiology

– IgM and IgG mistakenly bind to surface antigens of the cells in the body, which
results in
1. Cellular destruction- Antibody-dependent cell-mediated cytotoxicity (NK cells
or macrophages) . Target cell opsonization → phagocytosis and/or
complement activation
2. Inflammation- Fc-receptor mediated immune cell activation. Antibodies bind
to cellular surfaces → activation of the complement system
3. Impaired cellular function- Antibodies bind to cell surface receptors →
inhibition or activation of downstream signaling pathways → impaired cellular
function
Complement-dependent reactions

– The first cytotoxic mechanism of type II hypersensitivity is activation of

the complement system
– IgG or IgM antibodies bind to antigen and activate complement proteins
– The process gets started when C1, the first of the complement proteins, which
binds the Fc portion of the antibody.
– C1 then engages other members of the complement family - C2 through C9,
some of which are activated by being cleaved or chopped by an enzyme.
– The cleaved fragments C3a, C4a, and C5a act as chemotactic factors, meaning
they attract certain cells, in this case neutrophils, they degranulate (peroxidase,
myeloperoxidase and proteinase) all help generate little oxygen radicals that are
highly cytotoxic to cells and can cause tissue damage.
– The second cytotoxic mechanism requires us to follow the complement
system through to the end, that said, C5b, and C6-C8, and a bunch of C9 come
together to form the membrane attack complex, or MAC.
– The MAC “attacks” the cell by inserting itself into the cell membrane, punching
a hole or creating a channel that allows fluid and molecules to flow in and out
of the cell
– Due to the osmotic difference, fluid rushes into the cell, and the cell swells and
eventually bursts, called cell lysis, and it dies.
– The third cytotoxic mechanism of type II hypersensitivity happens when IgG
antibodies coat a blood cell and are bound by C3b
– the cell has been opsonized, which means it’s targeted for phagocytosis which is
where they get engulfed and destroyed
by phagocytes like macrophages and neutrophils.
– Once opsonized, the antigen-antibody complex and the cell it's attached to
encounters a phagocyte in the body’s blood filtration organ—the spleen, and
the phagocytes target cells by binding to the Fc tail of the antibody, or the C3b
bound to the IgG, then engulfs and destroys the cell.
Complement-Independent reactions

– First mechanism is called antibody-dependent cell-mediated cytotoxicity or

ADCC
– the bound antigen-antibody complex gets recognized by natural killer cells
– The natural killer cell recognizes the Fc tail of the antibody and releases toxic
granules
– These granules contain perforins which just like the MAC, form pores in the cell,
the pore allows entry of enzymes called granzymes as well as granulysin which
work together to cause cell death
– Second mechanism called antibody-mediated cellular dysfunction.
– Sometimes when an antibody binds to its antigen, it just, sort of gets in the way.
When this happens it can change the way the cell is supposed to function.
– This is the case in the autoimmune disease Myasthenia gravis where antibodies
specific for the acetylcholine receptor in muscles simply blocks the binding
of acetylcholine which causes the muscles to not get stimulated and
progressively weaken over time.
Examples

– Rheumatic fever
– •Strep antibodies cross-react with cardiac myocytes
– Exposure to wrong blood type
– •RBC lysis by circulating IgG
– •Erythroblastosis fetalis
– Autoimmune hemolytic anemia
– •Methyldopa and penicillin: drugs bind to surface of RBCs
– •Mycoplasma pneumonia: Induces RBC antibodies
Examples

– Pemphigus vulgaris
– •Antibodies against desmosomes in epidermis
– Goodpasture syndrome
– •Nephritic syndrome and pulmonary hemorrhage
– •Type IV collagen antibodies
– Myasthenia gravis
– •Antibodies against Ach receptors
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