Diseases of Immunity (1)

Hypersensitivity Reactions Normally, a balanced system optimizes the eradication of infecting organisms without serious injury to host tissues. However, immune responses may be inadequately controlled or inappropriately targeted to host tissues, and in these situations, the normally beneficial response will cause of disease.

Hypersensitivity Reactions The term hypersensitivity is used to describe immune responses which are damaging rather than helpful to the host. WHY? This term originated from the idea that individuals who mount immune responses against an antigen are said to be "sensitized" to that antigen, and therefore, pathologic or excessive reactions are manifestations of "hypersensitivity."

CAUSES OF HYPERSENSITIVITY REACTIONS Autoimmunity. Reactions against microbes. Reactions against environmental antigens.

Hypersensitivity Reactions Classification: Type I “Allergy & anaphylaxis” Type II “Antibody dependant” Type III “Immune complex - mediated” Type IV “Cell-mediated (delayed type)” N.B: First 3 types are antibody-mediated injury & the last type is cell-mediated injury

Type I Hypersensitivity ANAPHYLACTIC REACTION ALLERGIC REACTION ANAPHYLACTIC REACTION

Type I Hypersensitivity Definition : It is rapidly developing immunologic reaction occurring within minutes after the interaction of an antigen (allergen) with IgE antibodies bound to surface of mast cells or basophils in individuals previously sensitized to the antigen

Type I Hypersensitivity Antigen is usually exogenous , environmental and is called allergen Allergens may be introduced by inhalation, ingestion, touch, or by intravenous injection. The reaction is mediated by IgE produced by previously sensitized B lymphocytes.. IgE binds to the main effector cells ; the mast cell (in tissues) or basophils (in blood). The initiated reaction passes through 2 phases an early one and a late one.

Type I Hypersensitivity: Phases As Seen in the localized reactions Initial response: Characterized by; Vasodilatation, Vascular leakage, and Smooth muscle spasm Increased glandular secretions These changes become evident within 5 to 30 minutes after exposure to an allergen and subside in 60 minute. It is mainly mediated by histamine released by MAST CELLS.

Type I Hypersensitivity: Phases Late-phase reaction: Develop in 2 to 8 hours later without additional exposure to antigen and lasts for several days. Characterized by intense infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells, and tissue destruction. Occurs under effect of esinophils and neutrophils chemotactic factors released by mast cells.

Type I Hypersensitivity: Clinical Manifestations The resultant reaction can occur as a systemic disorder or as a local reaction depending on the route of entry of allergen

Type I Hypersensitivity clinical presentation Local reactions: Antigen is confined to a particular site Skin contact  Localized cutaneous swellings (urticaria, hives) and eczema, Ingestion  Allergic gastroenteritis (food allergy)  diarrhoea Inhalation  bronchospasm  allergic rhinitis, and bronchial asthma .

Type I Hypersensitivity: Clinical Manifestations Systemic Anaphylaxis: This usually follows an intravenous injection of an antigen to which the host has already became sensitized for.  systemic vasodilatation  “anaphylactic shock” is produced and even death within minutes Example: IV administration of Penicillin, Bee venom. NOTE: The immune response in the late-phase inflammatory reaction, plays an important protective role in parasitic infections.

Type II Hypersensitivity reaction

Type II Hypersensitivity Antibody-mediated diseases; Target antigens are present on the surface of cells or other tissue components The antigens may be intrinsic to the cell membrane, or they may take the form of an exogenous antigen, such as a drug metabolite, adsorbed on the cell surface The antibodies unite with the antigens MAINLY in the bloodstream, This union sets off the complement system, and destruction of the local tissue cells ensues.

Type II Hypersensitivity Mechanism A, Opsonization B, Inflammation C, Antireceptor antibodies

Opsonization and phagocytosis When circulating cells, such as erythrocytes or platelets, carry abnormal antigen on their surface, they become coated (opsonized) with autoantibodies, become targets for phagocytosis by neutrophils and macrophages . Opsonized cells are usually eliminated in the spleen.

Type II Hypersensitivity Mechanism Clinical examples; Incompatible transfusion reactions (mismatched blood transfusion reaction) Erythroblastosis fetalis “Rhesus antigen incompatibility” Autoimmune haemolytic anemia, or thrombocytopenia Certain drug reactions “penicillin  hemolysis”

acute inflammation in tissues, Complement and Fc receptor-mediated inflammation: Antibodies bound to cellular antigens activate the complement system by the "classical" pathway leading to: acute inflammation in tissues, Examples: vasculitis.

Antibody-Mediated Cellular Dysfunction Antibodies directed against cell surface receptors impair or dysregulate their function without causing cell injury or inflammation Example: Myasthenia gravis Autoantibodies against acetylcholine receptors in the motor end plates of skeletal muscles impair neuromuscular transmission and therefore cause muscle weakness.

Type III Hypersensitivity reaction

Type III Hypersensitivity Immune Complex - Mediated Type III hypersensitivity is mediated by the deposition of antigen-antibody complexes formed in blood vessels. The antigens may be Exogenous antigens, such as bacteria, or viruses Endogenous antigens, such as DNA. Immune complexes deposit in blood vessels in various tissue beds ,they have the ability to fix complement and trigger the subsequent injurious inflammatory reaction (either systemic or Localized )

Mechanism OF Systemic Immune Complex Disease: 1- antigen-antibody complex formation. 2-deposition of complexes in blood vessels 3- stimulation of inflammatory reaction of blood vessels NECROTIZING VASCULITIS

Systemic Immune Complex Disease Mechanism Favoured sites of immune complex deposition are; Renal glomeruli, Joints, Skin, Heart, Serosal surfaces, Small blood vessels

Type III Hypersensitivity Examples Autoimmune diseases as: Systemic lupus erythematosis Scleroderma Sjogren syndrome

Type IV Hypersensitivity reaction

Type IV Hypersensitivity (Cell Mediated) Two types of T-cell reactions are capable of causing tissue injury and disease: (1) delayed-type hypersensitivity (DTH), initiated by TH1-type CD4+ T cells (2) direct cell cytotoxicity, mediated by cytotoxic CD8+ T cells that are responsible for tissue damage.

1-Delayed-Type Hypersensitivity It is responsible for mediating immune reaction in case of; Defence against variety of intracellular persistent or non-degradable antigens, such as tubercle bacilli. pathogens, including mycobacteria, fungi, and certain parasites, It may also be involved in transplant rejection. Tumour immunity NOTE: In AIDS  loss of CD4+ T lymphocytes  increased susceptibility for developing TB & fungal infection.

Delayed-Type Hypersensitivity Sequence of Cellular Events On subsequent exposure of an individual previously sensitised, the memory TH1 cells interact with the antigen on the surface of APC . APC become activated, they produce IL-12 that activate CD+4 cells. In turn CD+4 cells will secrete: IFN-γ that activates macrophages to produce substances that cause tissue damage and promote fibrosis, TNF promotes inflammation. When macrophages become activated they transform into epithelioid cells And they occasionally fuse  multinucleated giant cells.

Delayed-Type Hypersensitivity Morphology DTH is characterized histologically by the formation of Granuloma (a specific form of chronic inflammation) It refers to microscopic aggregate of epithelioid cells, usually surrounded by a collar of lymphocytes with or without the formation of multinucleated giant cells.

Granuloma Epithelioid cells are transformed macrophages that have abundant large and pink cytoplasm (epithelium like)

Example for DTH Tuberculin reaction A classic example of DTH elicited by antigen challenge in an individual already sensitized to the tubercle bacillus by a previous infection. Between 8 and 12 hours after intracutaneous injection of tuberculin (a protein extract of the tubercle bacillus), a local area of erythema and induration appears, reaching a peak (typically 1-2 cm in diameter) in 24 to 72 hours (hence the adjective, delayed) and thereafter slowly subsiding.

2- Direct cell cytotoxicity In this variant of type IV hypersensitivity, sensitized CD8+ T cells kill antigen-bearing target cells These effector cells are called cytotoxic T lymphocytes (CTLs) They mediate their action through class I MHC molecule, where they directly lyse infected cells or stimulates their apoptosis. It plays an important role in graft rejection, resistance to virus infections, and possibly tumor immunity