Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Egypt.
Hypersensitivity BY
Prof. Dr. Mohamed Hamed Mohamed mohamedelariny@yahoo.com +201224067373
2012
Hypersensitivity Allergy It is abnormal antigen-antibody reaction which damage the cells of the body (produced by the normal immune system). Hypersensitivity requires a pre-sensitized (immune) state of the hosts. Allergens: They are antigens which produce a harmful effect and may be bacterial, non bacterial or even simple chemical substance. Mechanisms of hypersensitivity: There are four different mechanisms: -Type I-hypersensitivity. -Type II-hypersensitivity. Immediate Hypersensitivity -Type III-hypersensitivity. -Type IV-hypersensitivity. Delayed Hypersensitivity -All forms of hypersensitivity, except type IV, are mediated by antibodies. Type IV is mediated by T-lymphocytes and macrophages.
Immediate -Immediate onset (up to 12 hours). -Circulating antibodies (humoral). -Passive transfer by serum. -Affect smooth muscle, blood vessels and collagen. -Not affected by the rout of administration. -Types include: Type I,II and III.
Delayed -Delayed onset (after 12 hours). -Cellular immunity (no antibodies). -Passive transfer by cells. -Affect any tissue. - Almost through the skin. -Types include: Type IV.
Types of Immediate Hypersensitivity: 1-Type-I Hypersensitivity (Cytotropic Anaphylaxis). 2-Type-II Hypersensitivity (Cytotoxic) Anaphylaxis. 3-Type-III Hypersensitivity (Aggregate) Anaphylaxis.
1-Type-I Hypersensitivity (Cytotropic Anaphylaxis) Components and cells: i-Allergen: pollen, dust, mite, insects etc selectively activate CD4+Th2 cells and B cells ii-IgE and its production: IgEďźš mainly produced by mucosal B cells in the lamina propria. It has special affinity to the same cells IL-4: is essential to switch B cells to IgE production iii-High affinity receptor of the IgE on mast cell and basophil. iv-Eosinophil
Chemical Mediators: A-Primary Mediators (Preformed mediators in granules): 1-Histamine: dilated blood capillaries, increase the vascular permeability, increase mucus secretion and smooth muscle contraction. 2-Serotinin: as histamine.
3-Eosinophil-chemotactic factor of anaphylaxis (ECF-A): attraction of eosinophils to the site of hypersensitivity reaction.
4-Neutrophil-chemotactic factor of anaphylaxis (NCF-A): neutrophils chemotaxis.
5-Proteases (Tryptase): increase the mucus secretion and ct. degradation (proteolysis).
B-Secondary Mediators (Newly formed mediators): 1-Leukotrienes (B4, C4, D4): similar to histamine but more potent. It induces bronchial smooth muscles contraction (asthma). 2-Prostaglandins (D2): high concentration of PGE inhibits the secretion of histamine. While the low concentration of PGE could promote the release of histamine. Increase vascular permeability (edema), smooth muscles contraction and platelet activation. 3-Platelet activating factor (PAF): platelet aggregations (Microthrombi) and heparin release. 4-Bradykinin: similar to PGE and causes vasodilation. 5-Cytokines: They have numerous effects as i-Activation of endothelium. ii-Eosinophil recruitment.
NB; The complement is not necessary.
Anaphylactic Shock: In Guinea Pig: It dies within 10 minutes due to asphyxia caused by bronchial muscles contraction (Mast cells concentrated around bronchioles) bronchostenosis (Partial).
Lesions: “Acute diffuse alveolar emphysema�. IN Dog: It shows epileptiform fits, coma and death within 1-2 hours of restlessness, diarrhea and vomiting due to falling of blood pressure
Lesions: pooling of blood in the liver and mesenteries due to contraction of venous passages, especially the hepatic vein. In Cattle: It shows cutaneous edema around the eyes, vulva and dyspnea. In Rabbit: It shows constriction of pulmonary artery and dilation of the right heart. In Rat: It shows increase vascular permeability and intestinal hemorrhage.
The lesions of anaphylactic shock can be summarized as 1-Spasm of the smooth muscles of blood vessels and bronchioles. 2-Damaged endothelium of blood vessels with increase permeability. 3-Damaged connective tissue fibers
Atopy (Local anaphylaxis): It is a local anaphylactic reaction of type I hypersensitivity (atopic or allergic dermatitis). It is common in dogs.
2-Type-II Hypersensitivity (Cytotoxic Anaphylaxis) Mechanism of Type II hypersensitivity Antigen or hapten on cell + Antibody (IgG, IgM)
Activate complement Opsonic phagocytosis
Lyse target cell
NK , phagocyte
Stimulate / block
Destroy target cell ADCC
Target cell injury
Change the function of Target cell
There are two mechanisms by which antibody and complement mediate type II hypersensitivity: 1-Antibody reacts with the antigen present on the surface of the cells causing activation of the complement system and resulting in formation of membrane attack complex, resulting cell lysis. 2- The cells become susceptible to phagocytosis (opsonization) by fixation of antibody or C3b fragment to the cell surface.
3-Type-III hypersensitivity (Aggregate Anaphylaxis) The hypersensitivity-III is immune complex-mediated reaction. This complex is deposited either locally or systematically with activation of complement and acute inflammation.
Pathogenesis:
Types of immune complex reaction: 1-Local form: Arthus reaction : 2-Systemic or general form: Serum sickness :
Local Form: Arthus reaction: It is immediate hypersensitivity characterized by vasculitis.
Pathogenesis: The subcutaneously injected antigen into sensitized animal diffuses away from the site of injection into the small blood vessel-walls and formed immune complex beneath the endothelial cells and leads to release complement (C3a and C5a) attract the neutrophils to the site of injection. The neutrophils release lysosomal enzymes causing damage of the wall of b.vs. Edema, hemorrhages, thrombosis and necrosis.
NB: If the neutrophil is blocked, the reaction does not occur. Microscopic Lesions: i-Vasculitis with necrotic vessel-wall (small b.vs. and capillaries) and massive aggregation of neutrophils with serofibrinous inflammation (fibrinoid necrosis). ii-Hemorrhage and edema (due to increase the permeability). iii-Thrombosis and infarction.
Systemic or general form: Serum sickness : It has two types. i-Acute Serum Sickness ii-Chronic Serum Sickness
Acute serum sickness: It develops without previous sensitization to the responsible antigen. A large single dose of antigen is injected as horse serum. A part of this antigen acts as preparatory dose and to produce specific antibodies and the second part acts as eliciting to and combined with produced antibodies forming Ag-Ab complex in the blood circulation. Large blood vessels, endocardium and renal glomeruli are affected.
Chronic serum sickness: It results of repeated intravenous exposure to antigen which results in immune complex formation in blood.
Delayed Hypersensitivity Type-IV Hypersensitivity Cell-mediated Hypersensitivity Types of delayed hypersensitivity: 1-Bacterial hypersensitivity. 3-Transplant rejection. 5-Drug hypersensitivity.
2-Contact dermatitis hypersensitivity. 4-Fleea-bite dermatitis.
Bacterial hypersensitivity: Numerous bacterial infection causes delayed hypersensitivity as tuberculosis, brucellosis and glanders. It is manifested by erythema and edema to necrosis.
Koch phenomenon It is the reaction caused by tubercle bacilli in normal and immunized guinea pigs. The normal one develops hard nodules at the site of injection within 2 weeks. These nodules are ulcerated and the animals die from generalized tuberculosis within 2 months. The tuberculous guinea pig develops inflammatory edema and necrosis at the site of injection within 1-2 days. The necrotic area sloughs and heals with scar formation, and the animal does not die. Microscopically, granulomatous reaction is seen (Macrophages, lymphocytes and epithelioid cells besides fibrous tissue capsule).
Transplant rejection: The immunologic reactivity against transplanted cells may be directed against many antigens on the surface membrane of cells such as i-Antigens on erythrocytes ii-Antigens on surface of nucleated cells as MHC class I. Graft rejection occurs when the recipient's immune system recognizes the graft as foreign, and destroys it. There are several different kinds of grafts: Autograft: tissue transferred from one site in the body to another in the same individual. Isograft: tissue transferred between genetically identical individuals Allograft: tissue transferred between genetically different individuals of the same species Xenograft: tissue transferred between different species
Autografts and isografts are usually accepted (because graft and host are genetically identical). Allografts are often rejected as foreign. Xenografts have the most genetic disparity, and are often vigorously rejected. "Graft rejection" usually refers to allograft rejection (because autografts and isografts don't induce rejection, and xenografts are rare events).
Mechanism of transplant rejection
i-Direct pathway of graft rejection (recognition): It is mediated by CD8 cytotoxic T lymphocytes which cause cell injury and tissue damage
ii-Indirect pathway of graft rejection (recognition): It mediated by recipient's T lymphocytes that recognize antigen on the graft presented by the antigen presenting cells of the recipient. It is depend on the activation of CD4 lymphocytes and attracted by mediators (cytokines or lymphokines) which released from T-cells (delayed hypersensitivity).
Major histocompatibility complex (HLA): It is a collection of genes on chromosome 6. Class I genes: for recognition so it present on all nucleated cells. Class II genes: for body defense so it present on macrophages, dendritic cells, T and B lymphocytes. Class III genes: encode products of complement protein and TNF. Koch Phenomenon: It is the reaction caused by tubercle bacilli in normal and immunized guinea pigs. Koch blue bodies: It is lymphoid form of the theileria in lymph nodes and spleen. Koch Postulate: It is a diagnostic test for reappearance the symptoms of a disease by experimental animals.
Types
Classificat ions
Differences between types of hypersensitivity reactions
Type II
Immediate
Type I
Type III
Type IV
Delaye d
Mechanis m
Ig
Mediators Compl Histamine -ement
Target tissue
Examples
Cytotropic
IgE
+ ve
None
Smooth muscle Collagen, b. vs.
Anaphylactic shock
Cytotoxic
IgG, M
+ ve
+ ve
RBCs, WBCs. Platelets
Eq inf anemia B. transfusion
Aggregate
IgG, M
None
+ ve
Arthus ph, Serum sickness
None
None
None
b. vs., endocardiu m, glomeruli All tissue
Cell mediated
Koch ph, transplantati on