1. Allergy & Hypersensitivity
There are four types of hypersensitivity reaction mediated by immunological mechanisms that cause tissue damage
Types I–III are antibody-mediated and are distinguished by the different types of antigens recognized and the different classes of antibody involved.
Type I responses are mediated by IgE, which induces mast-cell activation,
types II and III are mediated by IgG, which can engage Fc-receptor and complement-mediated effector mechanisms to varying degrees, depending on the subclass of IgG and the nature of the antigen involved.
Type II responses are directed against cell-surface or matrix antigens.
type III responses are directed against soluble antigens, and the tissue damage involved is caused by responses triggered by immune complexes.
Type IV hypersensitivity reactions are T cell-mediated, commonly called delayed –type hypersensitivity (DTH)and can be subdivided into three groups. In the first group, tissue damage is caused by the activation of macrophages by TH1 cells, which results in an inflammatory response. In the second, damage is caused by the activation by TH2 cells of inflammatory responses in which eosinophils predominate; in the third, damage is caused directly by cytotoxic T cells (CTL).

3. General characteristics of allergic reaction
Sensitization phase: IgE Binds to Fc receptor on mast cell
There are two types of IgE-binding Fc receptor, FcεRI and FcεRII. The first, FcεRI, is a high-affinity receptor of the immunoglobulin superfamily that binds IgE on mast cells, basophils, and activated eosinophils. When the cell-bound IgE antibody is cross-linked by a specific antigen:
Fc eR
Granules
Antigen
Mast cell Fc

4. Activation phase : mast cells begins to release its granules and inflammatory mediators, this depends on the dose of antigen produce a wide variety of biologically active proteins and other chemical mediators. The enzymes and toxic mediators listed in the first two rows are released from the preformed granules. The cytokines, chemokines, and lipid mediators are synthesized after activation

5. Late phase Reaction
Many substances released during mast cell activation and degranulation are responsible for the initiation of profound inflammation response. Which consist of infiltration and accumulation of eosinophils neutrophils basophils , lymphocytes and macrophages. This response often occur within 48 hrs and may persist for several days.

6. Effector phase: the symptoms of allergic reaction are entirely attributed to the inflammatory mediators :

7. Type II hypersensitivity reactions
Antibody-mediated destruction of red blood cells (hemolytic anemia) or platelets (thrombocytopenia) is an uncommon side-effect associated with the intake of certain drugs such as the antibiotic penicillin, the anti-cardiac arrhythmia drug quinidine, or the antihypertensive agent methyldopa. These are examples of type II hypersensitivity reactions in which the drug binds to the cell surface and serves as a target for anti-drug IgG antibodies that cause destruction of the cell. The anti-drug antibodies are made in only a minority of individuals and it is not clear why these individuals make them. The cell-bound antibody triggers clearance of the cell from the circulation, predominantly by tissue macrophages in the spleen, which bear Fcγ receptors.

8. The IgG or IgM antibody can complex with antigens on the surface of cells or extracellular matrix and this complex then may activate complement. Complement activation will result in formation of the Membrane Attack Complex (MAC) and cause osmotic lysis of the target cell as shown in the animation and slide below. B A

9. Type III hypersensitivity reactions
can arise with soluble antigens. The pathology is caused by the deposition of antigen:antibody immune complexes at certain tissue sites. Immune complexes are generated in all antibody responses but their pathogenic potential is determined, in part, by their size and the amount, affinity, and isotype of the responding antibody. Larger aggregates fix complement and are readily cleared from the circulation by the mononuclear phagocytic system. The small complexes that form at antigen excess, however, tend to deposit in blood vessel walls. There they can ligate Fc receptors on leukocytes, leading to leukocyte activation and tissue injury.
A local type III hypersensitivity reaction can be triggered in the skin of sensitized individuals who possess IgG antibodies against the sensitizing antigen. When antigen is injected into the skin, circulating IgG antibody that has diffused into the tissues forms immune complexes locally. The immune complexes bind Fc receptors on mast cells and other leukocytes, which creates a local inflammatory response with increased vascular permeability. The enhanced vascular permeability allows fluid and cells, especially polymorphonuclear leukocytes, to enter the site from the local vessels. This reaction is called an Arthus reaction.
The immune complexes also activate complement, releasing C5a, which contributes to the inflammatory reaction by ligating C5a receptors on leukocytes. This causes their activation and chemotactic attraction to the site of inflammation.

10. The deposition of immune complexes in local tissues causes a local inflammatory response known as an Arthus reaction (type III hypersensitivity reaction) In individuals who have already made IgG antibody against an antigen, the same antigen injected into the skin forms immune complexes with IgG antibody that has diffused out of the capillaries. Because the dose of antigen is low, the immune complexes are only formed close to the site of injection, where they activate mast cells bearing Fcγ receptors (FcγRIII). As a result of mast-cell activation, inflammatory cells invade the site, and blood vessel permeability and blood flow are increased. Platelets also accumulate inside the vessel at the site, ultimately leading to vessel occlusion.

11. serum sickness
A systemic type III hypersensitivity reaction, known as serum sickness can result from the injection of large quantities of a poorly catabolized foreign antigen. This illness was so named because it frequently followed the administration of therapeutic horse antiserum. In the preantibiotic era, antiserum made by immunizing horses was often used to treat pneumococcal pneumonia; the specific anti-pneumococcal antibodies in the horse serum would help the patient to clear the infection. In much the same way, antivenin (serum from horses immunized with snake venoms) is still used today as a source of neutralizing antibodies to treat people suffering from the bites of poisonous snakes.
Serum sickness occurs 7–10 days after the injection of the horse serum, an interval that corresponds to the time required to mount a primary immune response that switches from IgM to IgG antibody against the foreign antigens in horse serum.
The onset of disease coincides with the development of antibodies against the abundant soluble proteins in the foreign serum; these antibodies form immune complexes with their antigens throughout the body. These immune complexes fix complement and can bind to and activate leukocytes bearing Fc and complement receptors; these in turn cause widespread tissue injury. The formation of immune complexes causes clearance of the foreign antigen and so serum sickness is usually a self-limiting disease.
Serum sickness after a second dose of antigen follows the kinetics of a secondary antibody response and the onset of disease occurs typically within a day or two. Serum sickness is nowadays seen after the use of anti-lymphocyte globulin, employed as an immunosuppressive agent in transplant recipients.

12. Delayed-type hypersensitivity or type IV hypersensitivity reaction
Unlike the immediate hypersensitivity reactions described so far, which are mediated by antibodies, delayed-type hypersensitivity or type IV hypersensitivity reactions are mediated by antigen-specific effector T cells.
tuberculin test is used to determine whether an individual has previously been infected with Mycobacterium tuberculosis. Small amounts of tuberculin—a complex mixture of peptides and carbohydrates derived from M. tuberculosis—are injected intradermally. In individuals who have previously been exposed to the bacterium, either by infection with the pathogen or by immunization with BCG, an attenuated form of M. tuberculosis, a local T cell-mediated inflammatory reaction evolves over 24–72 hours.
The response is mediated by TH1 cells, which enter the site of antigen injection, recognize complexes of peptide:MHC class II molecules on antigen-presenting cells, and release inflammatory cytokines, such as IFN-γ and TNF-β. The cytokines stimulate the expression of adhesion molecules on endothelium and increase local blood vessel permeability, allowing plasma and accessory cells to enter the site; this causes a visible swelling.

13. Very similar reactions are observed in several cutaneous hypersensitivity responses. These can be elicited by either CD4 or CD8 T cells, depending on the pathway by which the antigen is processed. Typical antigens that cause cutaneous hypersensitivity responses are highly reactive small molecules that can easily penetrate intact skin, especially if they cause itching that leads to scratching. These chemicals then react with self proteins, creating protein-hapten complexes that can be processed to hapten-peptide complexes, which can bind to MHC molecules that are recognized by T cells as foreign antigens.
There are two phases to a cutaneous hypersensitivity response—sensitization and elicitation. During the sensitization phase, cutaneous Langerhans' cells take up and process antigen, and migrate to regional lymph nodes, where they activate T cells with the consequent production of memory T cells, which end up in the dermis. In the elicitation phase, further exposure to the sensitizing chemical leads to antigen presentation to memory T cells in the dermis, with release of T-cell cytokines such as IFN-γ and IL-17. This stimulates the keratinocytes of the epidermis to release cytokines such as IL-1, IL-6, TNF-α and GM-CSF, and CXC chemokines including IL-8, interferon-inducible protein (IP)-9, IP-10, and MIG (monokine induced by IFN-γ). These cytokines and chemokines enhance the inflammatory response by inducing the migration of monocytes into the lesion and their maturation into macrophages, and by attracting more T cells.

14. The contact-sensitizing agent is a small highly reactive molecule that can easily penetrate intact skin. It binds covalently as a hapten to a variety of endogenous proteins, which are taken up and processed by Langerhans' cells, the major antigen-presenting cells of skin. These present haptenated peptides to effector TH1 cells (which must have been previously primed in lymph nodes and then have traveled back to the skin). These then secrete cytokines such as IFN-γ that stimulate keratinocytes to secrete further cytokines and chemokines. These in turn attract monocytes and induce their maturation into activated tissue macrophages, which contribute to the inflammatory lesions depicted

15. The stages of a delayed-type hypersensitivity reaction The first phase involves uptake, processing, and presentation of the antigen by local antigen-presenting cells. In the second phase, TH1 cells that were primed by a previous exposure to the antigen migrate into the site of injection and become activated. Because these specific cells are rare, and because there is little inflammation to attract cells into the site, it can take several hours for a T cell of the correct specificity to arrive. These cells release mediators that activate local endothelial cells, recruiting an inflammatory cell infiltrate dominated by macrophages and causing the accumulation of fluid and protein. At this point, the lesion becomes apparent.

16. The delayed-type (type IV) hypersensitivity response is directed by chemokines and cytokines released by TH1 cells stimulated by antigen
Antigen in the local tissues is processed by antigen-presenting cells and presented on MHC class II molecules. Antigen-specific TH1 cells that recognize the antigen locally at the site of injection release chemokines and cytokines that recruit macrophages to the site of antigen deposition.