Hypersensitivity

Atopy

• IgE-mediated allergic reactions

• has something to do with the genes the individual has inherited from their parents, such that they now become more predisposed to developing hypersensitivity or allergic reactions to common environmental allergens

Allergy

• Inappropriate immune response

• Once the individual is exposed to certain substances they are allergic to, their immune system responds in an exaggerated way (inappropriate)

Allergen

Substance that triggers allergies

Sensitization/ Immunization Phase

• 1st phase of hypersensitivity reaction

• The initial immunological response to an antigen

• Physical attachment of antibody molecules to antigens of surface cells

Effector Phase

• 2nd phase of hypersensitivity reaction

• Subsequent immunological responses to the same antigens

• Ensues clinical manifestations or immunological response, leading to the different symptoms manifested by patients who are allergic to the different environmental allergens

Effector / Immune Cells

• Cells responsible for the allergic reactions

• PaPProduces antibodies that coats the allergens on its surface

Paul Portier and Charles Richet

• First investigators of hypersensitivity reaction

• Concluded that the localized reaction of the bathers was the result of toxins, the tentacles of the Portuguese Man-of-War

• Coined the term ANAPHYLAXIS, loosely translated from Greek to mean the opposite of prophylaxis, to describe this exaggerated/overreaction

Hypersensitivity reactions

• are immunological responses not controlled by normal regulatory mechanisms

• Typically, it is an exaggerated response to a harmless antigen that results in injury to the tissue, disease, or even death.

• Type I

• Type II

• Type III

Hypersensitivity reactions classified as a humoral response:

Type IV

Hypersensitivity reactions classified as a cell-mediated response:

Type I hypersensitivity reactions

• Also referred to as immediate hypersensitivity or IgE – mediated reactions

• Clinically, manifest as allergies, rhinitis, or anaphylaxis

Cal Wilhelm Prausntitz and Heinz Kustner

• First discovered the antibody associated with Type I hypersensitivity Reaction

• Initially called it serum factor but in 1967, it was identified as IgE

• Passive cutaneous anaphylaxis

IL-4

cytokine responsible for the maturation of the B cell

Type 2 helper T cells (Th2)

The regulation of IgE production usually appears to be a function of a subset of T cells called the?

IL-12 and IL-18

produced by macrophages and may suppress the production of IgE antibodies

IL-13

Differentiation of B cells

IL-5 & IL-9

Development of eosinophils

IL-4 & IL-9

Development of mast cells

IL-4, IL-9, & IL-13

Mucous production

Mast cells and basophils

are effector cells of immediate hypersensitivity reaction.

Mast cells

are the principle (major) effector cells of immediate hypersensitivity

Histamine

• Low-molecular-weight vasoactive amine

• The effect of it depends on which receptors it binds to

H1 Receptors

• Effect is more on respiratory, vascular, and gastrointestinal.

• Contraction of the smooth muscle in bronchioles, blood vessels, and the intestines, and generally induces proinflammatory activity

H2 Receptors

Increases gastric acid production/ secretion, airway mucus production, and permeability of capillaries & venules.

H3 Receptors

The effect is more neurological, because they are found on central and peripheral neural tissues.

H4 Receptors

• Found on different hematopoietic cells, particularly in eosinophils, neutrophils, and basophils.

• Involved in immune regulation, including chemotaxis of mast cells

• Recruitment of eosinophils, neutrophils, and basophils

• Cytokine secretion

Eosinophil Chemotactic Factor of Anaphylaxis (ECF-A)

Causes chemotaxis or attraction of eosinophils to the area and induces expression of eosinophil receptors for C3b.

Allergic Rhinitis

manifest as sneezing, congestion, and watery eyes symptoms that are normally associated with allergies to airborne antigens.

Asthma

occurs when the respiratory passages constrict and the patient wheezes when breathing.

Anaphylaxis

potentially fatal immediate hypersensitivity response presenting with both cardiac and respiratory symptoms.

Cutaneous Testing / Prick Test

• A small drop of material is injected into the skin at a single point

• After 15 minutes, the spot is examined, and the reaction is recorded.

• A positive reaction is formation of a wheal that is 3 mm greater in diameter than the negative control.

• Shows that the patient is allergic to the material that has been injected.

Intradermal Tests

• Use a greater amount of antigen

• More sensitive

• Performed only if prick tests are negative and allergy is still suspected.

• A positive reaction is formation of a wheal that is 3 mm greater

In vitro skin tests

Involve measurement of either total IgE (RIST) or antigen-specific IgE.

Radioimmunosorbent Test (RIST)

Measures total IgE by capturing the antibody with solid phase anti-IgE.

Radioallergosorbent Test (RAST)

Measures antigen-specific IgE by using solid phase antigen to capture patient antibodies.

Type II hypersensitivity reactions

• Production of IgG and IgM antibodies that target cell surface antigens is the cause of the ensuing pathology

• Occur in response to antigens on transplacented cells, host cells during autoimmune disorders, or foreign antigens that bind to a host cell

Medication-induced hemolytic anemia

↓RBCs because there is ↑destruction or lysis of RBCs via complement mediated or ADCC mediated

Medication-induced thrombocytopenia

↓platelets because of increased destruction

Medication-induced neutropenia

↑destruction of neutrophils thus ↓ circulating levels of neutrophils.

Graves’ disease

• There is an antibody — Thyroid Stimulating Immunoglobulin (TSI) which competes with TSH in binding with thyroid stimulating hormone receptors

• When thyroid stimulating immunoglobulins bind to TSH receptors, this causes increased production of T3 and T4 because there is no negative feedback in this mechanism, leading to hyperthyroidism.

Myasthenia gravis

• there are autoimmune antibodies against the acetylcholine receptors.

• Acetylcholine has nowhere to bind to and cannot cause its post-neuronal effect leading to hypotonia, droopy eyelids, and any other manifestations

Pernicious anemia

• Normally, parietal cells of gastric mucosa is responsible for the production of intrinsic factor. However, in this condition, there are antibodies against intrinsic factor

• Decreased absorption of vitamin B12 would affect DNA synthesis, eventually leading to anemia.

Hemolytic disease of the newborn (HDN)

Occurs when a mother, whose red blood cells do not express the Rh antigen (Rh negative), is carrying a fetus that is Rh positive.

Goodpasture’s syndrome

Antibodies bind to antigens present on the kidney and lung basement membranes

isohemagglutinins

natural IgM antibodies that are generated without exposure to the “A” or “B” antigens.

Direct Antiglobulin Testing (DAT)

• Detects presence of antibodies to that certain antigen

• Performed to detect transfusion reactions, hemolytic disease of the newborn, and autoimmune hemolytic anemia.

• Polyspecific antihuman globulin

Indirect (AHG) Coombs’ Test

Used in the crossmatching of blood to prevent a transfusion reaction

Type III hypersensitivity reactions

• IgG and IgM antibodies target soluble antigens, such that large immune complexes form

• Immune complex deposition and subsequent host responses to the deposited complexes bring about the pathology observed

Arthus Reactions

localized immune complex disease

Serum sickness

cryoglobulins (Abs) binds to the antigen causing cyanosis or oxygen deprivation in the cells, seen as pallor or numbness.

Rheumatoid Arthritis (RA)

antibodies specific to a certain rheumatoid factor deposits in the joints causing painful or stiffening of the joints.

Systematic lupus erythematosus (SLE)

• An autoimmune disorder characterized by the production of numerous autoantibodies

• When these autoantibodies bind to soluble antigens, immune complexes form that become deposited and trapped in various tissues

Post streptococcal glomerulonephritis

• Is a kidney disease that results from the deposition of immune complexes in the kidneys (renal glomeruli)

• Occurs 1 to 3 weeks following some infections with group A streptococcus, S. pyogenes

Farmer’s lung

Occupational disease that occurs in farmers exposed to hay or grass contaminated with Thermophilic actinomycetes.

• Agglutination reactions using antigen-coated carrier particles

• Enzyme immunoassays

• Fluorescent staining of tissue sections

• Measuring complement levels

Testing for type III hypersensitivity

Type IV hypersensitivity reactions

• Cell mediated

• The effector phase is often referred to as delayed type hypersensitivity (DTH) response.

Mantoux test / TB test / PPD testing

• used to determine whether an individual has been infected with M. tuberculosis.

• Inject a small amount of PPD derivative tuberculin in the forearm of the patient and after 48-72 hours, if the patient has the tuberculosis antigen, (+) reaction = raised, indurated lesion

Cytotoxic T-cell mediated type IV hypersensitivity

Usually seen in type 1 diabetes wherein cytotoxic T cells causes destruction of Beta cells of the pancreas