Introduction/Definitions:
Hypersensitive reactions are inflammatory reactions within the humoral (Types I-III) or cell-mediated branches of the immune system that lead to extensive tissue damage. Inflammation is a complex process, accompanied by the release of mediators, which, by chemotaxix, attract luekocytes to the point of invasion, create local pain and raise body temperature.
Autograft: tissue transplanted from one site on an individual’s body to another site
Isograft: tissue from an identical twin is used
Allograft: exchanges between genetically different individuals belonging to the same species; the most common types of grafts
Xenograft: a tissue exchange between individuals of a different species.
Note that some diseases such as Rheumatoid arthritis and ankylosing spondylitis are Type II, III & IV hypersensitivities because they are characterized by vasculitis; frequent target is joint lining; antibodies against other antibodies (rheumatoid factor) and T-cell cytokine damage.
IgE-Mediated (Type I) Hypersensitivity:
Pathology: Allergic diseases such as asthma result from Th2-type immune responses against otherwise harmless environmental antigens. Such responses lead to the generation of Th2 T cells, which produce IL-4 and IL-5 and promote the differentiation of B cells into IgE secreting cells.
This IgE binds to Fc receptors on the membranes of blood and tissue. Cross linkage of the receptor bound IgE molecules by subsequent exposure to induces degranulation of and releasing various granules (histamine) that give rise to allergic manifestations. These molecules cause blood vessels to dilate and become leaky, which in turn helps white blood cells, antibodies and to enter sites of infection. The high-affinity receptor for IgE (Fc?RI) is the key molecule in the triggering of IGE-mediated allergic reaction. Mutlivalent allergens bridge the receptor-bound IgE and induce the aggregation of this receptor on the surface of mast cells and basophils, and trigger the subsequent release of mediators such as histamine that are responsible for allergic symptoms. Interfering with the binding of IgE to this receptor is considered to be a strategy for the specific prevention of the IgE mediated allergic reaction. For example, recombinant and synthetic peptides comprising structural elements of human IgE or human Fc?RI have been investigated as competitive inhibitors for the IgE-Fc?RI interaction. Searches have also been made for monoclonal antibodies against IgE or Fc?RI? (the extracellular portion). Takai (Japanese Bioch. Society, 129(1), 2001) report that a Fab fragment of a humainzed antibody against the membrane proximinal IgE-binding domain of human Fc?RI? inhibits the rlease of histamine from human basophils. Interesting this same article reports that secretion of Fabs without the Fc gene was remarkably enhanced compared to that when transfected with the Fc gene.
Clinical manifestations of type I reactions include hay fever and asthma.
Hay Fever (allergic rhinitis): is due to seasonal reaction to inhaled plant pollen or molds, or a chronic, year-round reaction to airborne allergens or inhalants.
Asthma: is a Respiratory disease characterized by episodes of impaired breathing due to severe bronchoconstriction. Symptoms range from bouts of difficult breathing to fatal suffocation.
Atopic Dermatitis/Eczema: (see also skin care)
Eczema results in intensely itchy inflammatory condition of the skin. It usually begins in infancy and is characterized by reddened, encrusted skin lesions on the face, scalp, neck, and inner surfaces of limbs and trunk. It progresses to a dry, scaly, thickened skin condition in adults.
Food and Drug allergy:
Food allergy hypersensitivity involves IgE and degranulation of mast cells, but not all reactions involve this mechanism.
Anaphylaxis: is an Overpowering IgE-Mediated Allergic Reaction. Bee stings and injection of antibiotics or serum are most commonly implicated.
Diagnosis:
–Radioallergosorbent (RAST) test: measures levels of IgE to specific antigens.
–Tryptase test: measures tryptase, an enzyme released by mast cells that increases during an allergic response.
–Differential blood cell count can reveal high levels of basophils and eosinophils.
–Leukocyte histamine-release test: measures the amount of histamine released from the patient’s basophils when exposed to a specific allergen.
–Skin testing: in vivo method to detect precise atopic or anaphylactic sensitivities.
Treatment:
Block the action of lymphocytes, mast cells, or chemical mediators: Almost all current therapeutic efforts against allergic disease have been aimed at the control of the symptoms triggered by mast cell or basophil degranulation.
Treatments typically block the action of lymphocytes, mast cells, or chemical mediators.
Skew Immune Response away from TH2 Response: a more fundamental approach to disease therapy might be to prevent the initial generation of the Th2 like immune response against the allergen, or to induce a Th1 like response against the allergen since Th1 and Th2 immune responses are typically mutually inhibitory.
–Desensitization: controlled exposure to the antigen through ingestion, sublingual absorption, or injection to reset the allergic reaction has sometimes been used.
Antibody-Mediated Cytotoxic (Type II) Hypersensitivity (Reactions that Lyse Foreign Cells):
Type II hypersensitivity reactions involve antibody-mediated destruction of cells. Antibody can activate the creating pores in the membrane of a foreign cell, or it can mediate cell destruction by . Antibody bound to a foreign cell can also serve as an opsonin, enabling phagocytic cells with Cc or C3b receptors to bind and phagocytose the antibody-coated cell.
Type II hypersensitivities are a complex group of syndromes that involve complement-assisted destruction (lysis) of cells by antibodies (IgG and IgM) directed against those cells’ surface antigens.
Rh Incompatability: occurs when a motherʼs immune system detects the foreign Rh factors on fetal RBCs and is sensitized to them by producing antibodies and memory B cells
Transfusion reactions are Type II Reactions. For example, if a type A person is transfused with blood containing type B cells, anti-B iso-hemagglutinins bind to the B blood cells and mediate their destruction by means of complement mediated lysis.
Autoimmne diseases (Inappropriate response to self):
–Myasthenia gravis: See autoimmune disorders
Antibodies against the acetylcholine receptors on the nerve-muscle junction alter function
–Graves’ Disease:
Antibodies against thyroid-stimulating hormone receptors
–Multiple Sclerosis: (also type III hypersensitivity)
T cells and antibodies sensitized to myelin sheath destroy neurons.
Immune Complex Mediated (Type III) Hypersensitivity (Immune Complex Reactions):
The reaction of antibody with antigen generates immune complexes which usually facilitates the clearance of antigen by phagocytic cells. In some cases, however, large amounts of immune complexes lead to tissue damaging type III hypersensitive reactions. Much of the tissue damage in type III reactions occurs from release of lytic enzymes by neutrophils as they attempt to phagocytose immune complexes.
Acute post-streptococcal glomerulonephritis (APSGN): occurs when particular types of Group A Step cause disease, such as sore throat or skin infection. Antibody/streptococcal antigen complexes settle into the basement membranes of the kidney. Complement activation leads to infiltration of neutrophils and kidney damage occurs.
Systemic lupus erythematosus (SLE): involves inflammation of many organs; antibodies against red and white blood cells, platelets, clotting factors, nucleus DNA
Type IV Hypersensitivities: Cell-Mediated (Delayed) Reactions:
Type IV hypersensitivities involves primarily the T-cell branch of the immune system. It results when T cells respond to antigens displayed on self tissues or transplanted foreign cells. It is traditionally known as delayed hypersensitivity because symptoms arise one to several days following the second contact with antigen.
Contact Dermatitis: is caused by exposure to resins in poison ivy and poison oak, haptens in household and personal articles, and certain drugs. It requires a sensitizing dose followed by a provocative dose.
Allergen penetrates the outer skin layers which are processed by skin dendritic cells and presented to T cells, subsequent exposures attract lymphocytes and macrophages and c ells release enzymes and cytokines that damage the epidermis in the immediate vicinity.
Tuberculosis Infection: Diagnosis includes a tuberculin reaction
Transplantation or grafting of organs and tissues (Host versus Graft Rejection): is a common medical procedure, but it is plagued with the natural tendency of lymphocytes to seek out and destroy foreign antigens.
When a donor tissue (graft) displays surface molecules of a different MHC class, the T cells of the recipient will react to it as a foreign substance. Cytotoxic T cells of a host recognize foreign class I MHC markers on the surface of grafted cells. Helper and cytotoxic T cells bind to the grafted tissue and secrete lymphokines that begin the rejection process within 2 weeks of transplantation. Antibodies formed against the transplanted tissue contribute to damage.
Graft versus host disease (GVHD) (Graft Rejection of Host):
Some grafted tissues (bone marrow) contain indigenous populations of passenger lymphocytes
These lymphocytes make it quite possible for the graft to reject the host
Autoimmune Diseases:
–Type I Diabetes:
T cells attack insulin-producing cells.
–Multiple Sclerosis: (also type II hypersensitivity)
T cells and antibodies sensitized to myelin sheath destroy neurons.