Hypersensitivity is an inappropriate excessive immune response to an antigenic stimulus in a pre-sensitized host leading to tissue damage.
It is one of the Immunological disorder along with Autoimmune Diseases, Immunologic deficiency syndromes, Amyloidosis.
The term “allergy” is often equated with hypersensitivity but more accurately should be limited to the IgE-mediated reactions: “Type I: Immediate (Anaphylactic) Hypersensitivity.”
Types Of Hypersensitivity Reactions
Hypersensitivity reactions can be subdivided into four main types. Types I, II, and III are antibody-mediated, whereas type IV is cell-mediated. Type I is IgE mediated whereas all others are IgG-mediated
Type I/ Immediate/ Anaphylactic Hypersensitivity.
An immediate hypersensitivity reaction occurs when an antigen (allergen) binds to IgE on the surface of mast cells with the consequent release of several mediators.
First Exposure:
As the antigen enters the body it is engulfed by macrophages. Macrophase processes the antigens and presents it to the helper T cell. Helper t Call then stimulates B cell which results in Plasma cell formation and IgE production.
The IgE then arms the Basophil and Mast cells this process is called sensitization.
Re-exposures:
In the re-exposure, the antigen firmly binds to the Fc receptor of the antibody present in the surface of the Basophil and Mast cell. It causes degranulation of the basophil and mast cell which releases pharmacologically active mediators within minutes. This is called the Immediate phase.
In the immediate phase symptoms such as edema and erythema (“wheal and flare”) and itching appear rapidly in the body because of these mediators, e.g., histamine, serotonin.
Release of these mediators causes Vasodilation, increase vascular permeability, Increased glandular secretion as in asthma and allergic rhinitis, and contraction of smooth muscle. This causes an immediate reaction of Anaphylaxis/ Anaphylactic shock.
After the Immediate reaction there follows a late phase which begins approximately 6 hours after the immediate reaction. It occurs due to the presence of mediators like Leukotrienes which are synthesized after cell degranulation. These mediators cause an influx of inflammatory cells, such as neutrophils and eosinophils, and symptoms such as erythema and induration occur.
No complements are involved in Type I hypersensitivity reaction.
Atopy
Atopy is the genetically determined state of type-I hypersensitivity to common environmental agents mediated by IgE.
Atopic hypersensitivity disorders exhibit a strong familial predisposition and are associated with elevated IgE levels. Predisposition to atopy is clearly genetic, but symptoms are induced by exposure to specific allergens. These antigens are typically environmental eg. respiratory allergy to pollen, ragweed or house dust even foods. Common clinical manifestations are Hay fever, Asthma, Eczema, Urticaria.
Type II / Cytotoxic Hypersensitivity
Cytotoxic hypersensitivity occurs when the antibody binds with an antigen present in the surface of cells and activates complements. Which eventually forms a Membrane attack complex and damages the cell membrane.
The antibody(IgG or IgM) attaches to the antibody through the Fab regionand acts as a bridge to the complement system through Fc.
Mechanism of Cytoxic Hypersensitivity
- Complement Mediated Cell Lysis.
- Antibody-dependent cell-mediated cytotoxicity (ADCC).
- Phagocytosis by opsonization
- Antibody-dependent cellular dysfunction
1. Complement Mediated Cell Lysis.
An antigen on the cell surface reacts with Antibody (IgG or IgM) and causes activation of the complement system. Formation of membrane attack complex (C5b,6,7,8,9) and it forms drilling holes through the lipid bilayer of the cell membrane. Disruption of cell membrane integrity in RBC, WBC, Glomerular basement membrane. Examples: Transfusion reaction, Erythroblastosis fetalis, Auto-immune Hemolytic anemia, Agranulocytosis, Thrombocytopenia.
2. Antibody-dependent cell-mediated cytotoxicity (ADCC).
Target cells are coated with IgG. Non-sensitized cells having Fc receptor ( Natural Killer cell, Monocyte, Neutrophil, Eosinophil ) appear. Non sensitized cells bind to the target via receptors for the Fc fragment for IgG. Eventually, cell lysis occurs.
Eg: Graft rejection, Lysis of parasites , Lysis of tumor cells.
3. Phagocytosis by opsonization
Opsonization takes place by C3b formation from complement activation and by IgG. Then the target cells are killed by phagocytes.
4. Antibody dependent cellular dysfunction
The antibody binds with Ag present on the cell surface. Then the antibody causes inhibition of cellular function. E.g: Myasthenia Gravis.
Type III/Immune-complex hypersensitivity
Immune complex hypersensitivity occurs when the Antigen-antibody complex induces an inflammatory response. Normally these complexes are removed by the reticuloendothelial system but due to some disorder, they remain and are deposited in the tissue causing various disorders in the body.
In persistent microbial or viral infections, immune complexes may be deposited in organs, e.g., the kidneys, resulting in damage. In autoimmune disorders, “self” antigens may elicit antibodies that bind to organ antigens or deposit in organs as complexes, especially in joints (arthritis), kidneys (nephritis), or blood vessels (vasculitis).
When the immune complexes are deposited there is an activation of complement system. Polymorphonuclear cells are attracted to the site, and inflammation and tissue injury occurs.
There is two typical types of Immune complex hypersensitivity. They are Arthus reaction and serum sickness.
Arthus Reaction
Arthus reaction is characterized by a localized area of tissue necrosis resulting from acute immune complex vasculitis. Antigen, Antibody, and complement are deposited in the vessel wall. There is infiltration by polymorphonuclear cells and intravascular clumping of platelets. This causes vascular occlusion and necrosis of the area.
Dr. Arthus, who first described the inflammatory response that occurs under the following conditions. If animals are given an antigen repeatedly until they have high levels of IgG antibody and that antigen is then injected subcutaneously or intradermally, intense edema and hemorrhage develop, reaching a peak in 3 to 6 hours.
Eg : Farmer’s lung and Erythema nodosum leprosum.
Serum Sickness
Serum Sickness is a systemic immune reaction caused by the deposition of the antigen-antibody complexes throughout the body. After the introduction of antigen ( E.g: horse serum) the antigen is excreted slowly and in response to that body produces antibodies. Thus the antigen and antibody react forming immune complexes that circulate throughout the body causing a systemic inflammatory response.
Typical serum sickness results in fever, urticaria, arthralgia, lymphadenopathy, splenomegaly, and eosinophilia a few days to 2 weeks after injection of the foreign serum or drug.
E.g: A delayed complication of ATS (anti-tetanus serum) and ADS( anti-Diptheria serum), Immune complex glomerulonephritis, Rheumatoid Arthritis.
Type IV/ Delayed (Cell-Mediated) Hypersensitivity
Type IV hypersensitivity is a function of T lymphocyte and not an antibody. Antigen enters into a host who was previously sensitized ( having earlier exposure to the same antigen) which are taken by the antigen-presenting cells (APC). The antigen is processed and presented to Helper T cells. The helper T cell recognizes the antigen in association with class-II MHC protein. The Helper T cell then produces lymphokines, stimulates, and activates macrophase forming Granuloma.
Also recognization of Ag on target cell by Cytotoxic T cell in association with class-I MHC protein. Distruction of target cell by cytoxic T cells.
Eg: Tuberculin test, Contact dermatitis ,Graft rejection.
References : Review of Medical Microbiology and Immunology
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