When adaptive immune response occurs in an exaggerated or inappropriate form, the term hypersensitivity is applied. Hypersensitivity reactions are the result of normally beneficial immune responses acting inappropriately and sometimes cause inflammatory reactions and tissue damage.
Many antigens can provoke hypersensitivity. The causes of hypersensitivity reactions vary from one individual to the next. Hypersensitivity is not manifested on the first contact with the antigen but appears on subsequent contact.

CLASSIFICATION
Coombs & Gell classified four types of Hypersensitivity i.e., Types I,II,III,&IV., But in practice these types do not necessarily occur in isolation. The first three are antibody mediated; T cells & macrophages mediate the fourth.

TYPE I –Anaphylactic type
Prototype disorder – Anaphylaxis, some forms of bronchial asthma, hay fever, eczema.
Immune mechanism – Formation of Ig E ( Cytotrophic antibody) leads to release of vaso active amines and other mediators from basophils and mast cells followed by the recruitment of other inflammatory cells.

TYPE II – Cytotoxic type
Prototype disorder- Autoimmune haemolytic anaemia, Erythroblastosis foetalis, Good Pasteur’s syndrome, Pemphigus vulgaris.
Immune mechanism – Formation of Ig G , Ig M, which binds to the antigen on target cell surfaces, leading to phagocytosis of target cells or lysis of target cells by C 8 , C 9 fraction of the activated compliment.

TYPE III – Immune complex disease
Prototype disorder – Arthus reaction, Serum sickness, SLE, Certain forms of acute glomerulonephrites.
Immune mechanism – Antigen –antibody complexes lead to activation of compliment. Attracted neutrophils results in release of lysosomal enzymes & other toxic substances.

TYPE IV – Cell mediated ( delayed) H
Prototype disorder – Tuberculosis, Contact dermatitis, Transplant rejection.
Immune mechanism – Sensitised T lymphocytes produce release of lymphokines and T Cell mediated cyto toxicity.


TYPE I – IMMEDIATE HYPERSENSITIVITY
Type I hypersensitivity is characterized by an allergic reaction that occurs immediately following contact with the antigen, referred to as the allergen.
Atopy is the umbrella term covering asthma, eczema, hay fever, & food allergy.
Coca & Cooke in 1923, described atopy as the clinical presentation of type I hypersensitivity, which include asthma, eczema, urticaria,& food allergy. These usually occur in subjects with a family history of these or similar conditions, & who also show immediate wheal & flare skin reactions to common environmental allergens.

Mechanism:- The initial contact of an allergen with the mucosa is followed by a complex series of events, leading to the production of Ig E. The IgE response is a local event occurring at the site of the allergen’s entry into the body, i.e., at the mucosal surface or the local lymph nodes. Ig E production by the B Cells depends upon allergen presentation by the antigen presenting cells ( A P Cs), & cooperation between the B cells & the TH2 cells. Locally produced IgE first sensitizes local mast cells. Spill over IgE then enters the circulation& binds to specific receptors on both circulating basophils and tissue fixed mast cells throughout the body.

Another important characteristic of IgE is its ability to bind the mast cells & basophils with high affinity through its Fc portion. Thus although the serum half life of free IgE is only a few days, mast cells may remain sensitized by IgE for many months due to the high affinity of binding to the IgE receptor, which protect IgE from destruction by serum proteases

Clinical manifestations:-
A type I reaction may occur as a systemic disorder or as a local reaction. Often the route of antigen exposure determines this. Systemic (parenteral) administration of protein antigens like antisera and drugs like penicillin results in systemic anaphylaxis. Within minutes after re exposure, itching, hives, and skin erythema appear, followed thereafter by striking respiratory difficulty, resulting presumably from the constriction of respiratory bronchioles. Thus the principal organ affected is the lung, more specifically the smooth musculature of the pulmonary blood vessels and the respiratory passages. Pulmonary obstruction is accentuated by hypersecretion of mucus. Laryngeal oedema may cause obstruction of the upper airway. In addition the musculature of the entire gastro intestinal tract may be affected, with resulting diarrhoea, vomiting and abdominal cramps. The patient may go into shock and die within minutes.
Local reactions:- Generally occur on the skin or mucosal surfaces, when these are sites of antigenic exposure. In the skin they may produce urticaria (hives). The common forms of food allergy, hay fever, and certain forms of asthma are examples of localized anaphylactic reactions.

TYPE II .HYPERSENSITYVITY
Ig G and Ig M antibodies binding to specific cells or tissues mediate the type II hypersensitivity reactions. The damage caused is thus restricted to the specific cells or tissues bearing the antigens. In general, those antibodies which are directed against the cell surface antigens are usually pathogenetic while those against internal antigens are not so.

Mechanism :-In type II hypersensitivity, antibody directed against cell surface or tissue antigens interacts with complement and a variety of effector cells to bring about damage to the target cells.
Once the antibody has attached itself to the surface of the cell or tissue, it can bind and activate compliment component C1. The consequence of this activation are as follows:-
1. Compliment fragments ( C3a and C5a ) generated by activation of compliment attract macrophages and polymorphs to the site, and also stimulate mast cells and basophils to produce molecules that attract and activate other effector cells.
2. The classical compliment pathway and activation loop leads to the deposition of C3b, C3bi, and C3d on the target cell membrane.
3. The classical compliment pathway and lytic pathway result in the production of C5b-9 membrane attack complex and insertion of the complex into the target cell membrane.

Effector cells, in this case the macrophages, neutrophils, eosinophils, and killer cells ( K cells), bind either to the complexed antibody, via their Fc receptors, or to the membrane – bound C3b, C3bi, C3d via their C3 receptors. Antibodies binding to Fc receptors stimulate phagocytes to produce more leucotrienes and prostaglandins, which are molecules involved in the inflammatory response. Chemokines and chemotactic molecules including C5a, leucotrine B4 ( LTB4) and fibrin peptides may also activate incoming cells. The effector cells firmly bound to the target cells and fully activated, can cause considerable damage.

Examples for type II hypersensitivity reaction:-
Reaction in response to erythrocytes-
Incompatible blood transfusion where the recipient becomes sensitized to the antigens on the surface of the donors erythrocytes.
Haemolytic disease of the newborn where the pregnant woman has become sensitized to the fetal erythrocytes.
Reaction to platelets –Can cause thrombocytopenia
Reactions to neutrophils and lymphocytes are associated with systemic lupus erythematosus.
Reactions against tissue antigens-
A number of autoimmune conditions occur in which antibodies to tissue antigens cause immunopathological damage by activation of type II hypersensitivity mechanisms. Eg. Good Pasteurs Syndrome, Pemphigus and Myesthenia gravis.

Good Pasteur’s Syndrome:-
A number of patients with nephritis are found to have antibodies to a glycoprotein of the glomerular basement membrane. The antibody is usually IgG and in atleast 50% of patients it appears to fix the compliment. The condition usually results in severe necrosis of the glomerulus with fibrin deposition.The assosciation of this type of nephritis with lung haemorrhage was originally noticed by Good Pasture, hence the name.

Pemphigus:-
Pemphigus vulgaris is a serious blistering disease of the skin and mucus membranes. Patients have autoantibodies against desmoglobin-3 a component of desmosomes, which form junctions between epidermal cells. The antibodies disrupt cellular adhesion leading to breakdown of the epidermis.

Myesthenia Gravis:-
A condition in which there is extreme muscular weakness, is associated with antibodies to the acetyl choline receptors present on the surface of muscle membranes.

HYPERSENSITIVITY – TYPE III
Immune complexes are formed every time the antibody meets the antigen, and generally they are removed effectively by the mononuclear phagocyte system, but occasionally they persist and eventually deposit in a range of tissues and organs. The compliment and effector cell mediated damage that follows is known as the type iii hypersensitivity reaction, or immune complex disease.

Types:-
Diseases resulting from immune complex formation can be divided into three groups :-
1. Those due to persistent infection.
2. Those due autoimmune disease.
3. Those caused by inhalation of antigenic material.

Persistent infection – The combined effects of low-grade persistent infection and a weak antibody response lead to chronic immune complex formation, and eventual deposition of complexes in the tissues. Diseases with this etiology include leprosy, malaria, dengue hemorrhagic fever, viral hepatitis and staphylococcal infective endocarditis.

Autoimmune diseases – Immune complex disease is a frequent complication of autoimmune disease, where the continued production of autoantibody to a self-antigen leads to a prolonged immune complex formation. As the number of complexes in the blood increases, the systems that are responsible for the removal of complexes become overloaded, and the complexes are deposited in the tissues. Diseases with this aetiology include rheumatoid arthritis, systemic lupus erythematosis and polymyositis.

Inhalation of antigenic material – Immune complexes may be formed at body surfaces following exposure to extrinsic antigens. Such reactions are seen in the lungs following repeated inhalation of antigenic materials from moulds, plants or animals. This is exemplified in farmer’s lung and pigeon fancier’s lung, where there are circulating antibodies against actinomycetic fungi found in mouldy hay or to pigeon antigens. Both diseases are forms of extrinsic allergic alveolitis, and only occur after repeated exposure to the antigens.

Mechanism:-
1. Immune complexes are capable of triggering a wide variety of inflammatory processes. They interact with the compliment system to generate C3a and C5a ( anaphylatoxins ). These compliment fragments stimulate the release of vasoactive amines, (including histamine and 5- hydroxy tryptamine) and chemotactic factors from mast cells and basophils.
2. Macrophages are stimulated to release cytokines.
3. Complexes interact directly with basophils and platelets to induce
4. the release of vasoactive amines.
5. The vaso active amines released by basophils, platelets and mast cells cause endothelial cell retraction and thus increase vascular permeability, allowing the deposition of immune complexes on the blood vessel wall.

Manifestations:-
There are two patterns of immune complex mediated injury. In the first type, the complexes are deposited in various tissues of the body, thus causing a systematic pattern of injury. In the other, the injury is localized to the site of formation, within a tissue or organ, of the complexes.

Serum sickness type:- ( systemic immune complex disease) :- Induced by injections of foreign antigens, mimics the effect of a persistent infection. Here circulating immune complexes deposit in the blood vessel wall and tissues, leading to increased vascular permeability and thus to inflammatory diseases such as glomerulonephritis and arthritis.

Local immune complex disease (Arthus reaction) :- The arthus reaction may be defined as a localized area of tissue necrosis resulting from acute immune complex vasculitis. The reaction can be produced experimentally by infecting an antigen into the skin of a previously immunized animal. Antibodies against the antigen are therefore already present in the circulation. Because of the large excess of antibodies immune complexes are formed, these are precipitated at the site of injection, especially within vessel walls, where the injected antigen is immediately bound to the circulating antibodies. Intrapulmonary Arthus type reactions seem to be responsible for a number of diseases in humans, including farmer’s lung.

TYPE IV – HYPERSENSITIVITY
Type IV hypersensitivity is mediated by Tcells rather than by antibodies. Two types of reactions mediated by different T cells subsets are involved in type IV hypersensitivity
1. Delayed type hypersensitivity initiated by CD 4 T cells
2. Cellular cytotoxicity, mediated by CD 8 + T cells
In both cases, the reaction is initiated by exposure of sensitized T cells to specific antigenic peptides bound to self-MHC molecules, but the subsequent events are different. In delayed H T4 1 type CD4+ T Cells secrete cytokines, leading to recruitment of other cells, especially macrophages, which are the major effector cells. In cell mediated cytotoxicity, on the other hand, cytotoxic CD8+ T cells themselves assume the effector function.

Variants of type IV hypersensitivity reactions
1. Contact H
2. Tuberculin type H .Both occur within 72 hours of antigen challenge
3. Granulomatous H
Develop over a period of 21-28 days. The granulomas are formed by the aggregation and proliferation of macrophages and may persist for weeks. In terms of its clinical consequences, this is by far the most serious type of type IV hypersensitivity response.

Contact H : This is characterized by an eczematous reaction at the point of contact with an allergen. It is often seen following contact with agents such as nickel, chromate, rubber accelerators, penta deca catechol ( found in poison ivy). Langerhans cells and keratinocytes have key roles in contact hypersensitivity. The Langerhans cells are the principal antigen presenting cells. A contact hypersensitivity reaction has two stages, i.e., a sensitization phase and an elicitation phase.
Sensitization takes 10 – 14 days in humans. Once the hapten is absorbed, it combines with a protein and is internalized by epidermal Langerhans cells which leave the epidermis and migrate as veiled cells, afferent lymphatics, to the paracortical areas of regional lymphnodes. Here they present these cells to CD4+ lymphocytes, producing a population of memory CD4+ T cells.
Elicitation phase: Degranulation and cytokine release by mast cells follow soon after contact with an allergen. The earliest histological change, seen after 4-8 hours is the appearance of mononuclear cells around adnexae and blood vessels, with subsequent epidermal infiltration. Macrophages invade the dermis and epidermis by 48 hours. The number of cells infiltrating the epidermis and the dermis reaches the peak in 48-72 hours. Most infiltrating lymphocytes are CD4+ with a few CD8+.

Tuberculin type H : This type of hypersensitivity was originally described by Koch. The tuberculin skin test is an example of the recall response to soluble antigen previously encountered during an infection. Following an intradermal tuberculin challenge in a sensitized individual, antigen specific T cells are activated to secrete cytokines that mediate the hypersensitivity reaction. Macrophages are the main APCs in the tuberculin hypersensitivity reaction. The tuberculin lesion normally resolves within 5-7 days, but if there is persistence of antigen in the tissues, it may develop into a granulomatous reaction.

Granulomatous Hypersensitivity: This is clinically the most important form of type IV hypersensitivity and causes many of the pathological effects in diseases that involve T cell mediated immunity. It usually results from the persistence within macrophages or other particles that the cell is unable to destroy. On occasion it may also be caused by persistent immune complexes, for eg. In allergic alveolitis. Epitheloid cells and giant cells are typical of granulomatous H

Epitheloid cells: These cells are large and flattened with increased endoplasmic rerticulam. They are derived from activated macrophages under the chronic stimulation of cytokines. They continue to secrete TNF and thus potentiate continuing inflammation.

Giant cells : Epitheloid cells may fuse together to form multinucleated giant cells, sometimes referred to as Langerhans giant cells. They have central nuclei but not at the center. There is little endoplasmic retinaculam and the mitochondria and lysosomes appear to be undergoing degeneration.

Granuloma: An immunological granuloma typically has a core of epitheloid cells and macrophages, sometimes with giant cells. In some diseases such as tuberculosis, this central area may have a zone of necrosis, with complete destruction of all the cellular architecture. A cuff of lymphocytes surrounds the macrophage or epitheloid core, and there may also be considerable fibrosis caused by proliferation of fibroblasts and increased collagen synthesis.
Eg . Mitsuda reaction to M. leprae antigens or the Kveim test, where the patients suffering from sarcoidosis react to (unknown) splenic antigens derived from other sarcoid patients.

References:-
Immunology – Roitt- Brostoff-Male
Basic pathology by Kumar , Cotran, Robbins
Text book of Microbiology by Jayaram Panikkar
Boyd’s text book of pathology