TYPE IVHYPERSENSITIVITYREACTIONSBY:Dr. DINA RASHEEDAssistant Prof.Immunology2012
TYPE IV HYPERSENSITIVITY REACTIONS Immune responses are themselves capable of causing tissue injury and disease. Injurious, or pathologic, immune reactions are called hypersensitivity reactions. This term is derived from the idea that an immune response to an antigen may result in sensitivity to challenge with that antigen and, therefore, hypersensitivity is a reflection of excessive or aberrant immune responses.
TYPE IV HYPERSENSITIVITY REACTIONSHypersensitivity reactions may occur in twosituations: First,responses to foreign antigens may be dysregulated or uncontrolled, resulting in tissue injury. Second, the immune responses may be directed against self (autologous) antigens, as a result of the failure of self-tolerance. Responses against self antigens are termed autoimmunity, and disorders caused by such responses are called autoimmune diseases.
TYPE IV HYPERSENSITIVITYREACTIONSImmediatehypersensitivity,or type I hypersensitivity,is a type of pathologicreaction that is causedby the release ofmediators from mastcells. This reaction mostcommonly is triggeredby the production of IgEantibody againstenvironmental antigensand the binding of IgE tomast cells in varioustissues.
TYPE IV HYPERSENSITIVITYREACTIONS Antibodies directed against cell or tissue antigens can damage these cells or tissues or impair their functions. These diseases are said to be antibody-mediated and represent type II hypersensitivity. Sometimes, antibodies against soluble antigens may form complexes with the antigens, and the immune complexes may deposit in blood vessels in various tissues, causing inflammation and tissue injury. Such diseases are called immune complex diseases and represent type III hypersensitivity.
TYPE IV HYPERSENSITIVITY REACTIONS Finally, some diseases result from the reactions of T-lymphocytes and not antibodies, as in the previous three hypersensitivity reactions. These T cell-mediated diseases represent type IV hypersensitivity. These type IV reactions result from T cell-initiated inflammation. Inflammatory responses result from the manner in which T cells encounter and respond to antigen. The hypersensitivity reactions usually are directed against cellular antigens with restricted tissue distribution. Therefore, T cell-mediated autoimmune diseases tend to be limited to a few organs and usually are not systemic.
TYPE IV HYPERSENSITIVITY REACTIONSFigure 3: Mechanisms of T cell-mediated tissue injury. T cells may cause tissueinjury and disease by two mechanisms: (1) delayed-type hypersensitivityreactions (A), which may be triggered by CD4+ and CD8+ T cells and in whichtissue injury is caused by activated macrophages and inflammatory cells, and(2) direct killing of target cells (B), which is mediated by CD8+ CTLs.
TYPE IV HYPERSENSITIVITY REACTIONS Tissue injury is caused by a delayed-type hypersensitivity reaction mediated by CD4+ T cells or by killing of host cells by CD8+ CTLs. The mechanisms of tissue injury are the same as the mechanisms used by T cells to eliminate cell-associated microbes. CD4+ T cells may react against cell or tissue antigens and secrete cytokines that induce local inflammation and activate macrophages. Different diseases may be associated with activation of TH1 and TH17 cells. TH1 cells are the source of IFN-γ, the principal macrophage- activating cytokine, and TH17 cells are thought to be responsible for recruitment of leukocytes, including neutrophils.
TYPE IV HYPERSENSITIVITY REACTIONS The actual tissue injury in these diseases is caused by the macrophages and neutrophils. CD8+ T cells specific for antigens on host cells may directly kill these cells. In many T cell-mediated autoimmune diseases, both CD4+ T cells and CD8+ T cells specific for self antigens are present, and both contribute to tissue injury. Also, tissue injury with release and alteration of self proteins may result in reactions against these proteins, a phenomenon that has been called "epitope spreading" to indicate that the initial immune response against one or a few self antigen epitopes may expand to include responses against many more self antigens. Chronic inflammatory diseases that are initiated by immune reactions are called immune-mediated inflammatory diseases.
TYPE IV HYPERSENSITIVITY REACTIONS CLINICAL EXAMPLES: Contact dermatitis, is a form of sensitivity to chemicals (e.g., those found in poison ivy) is a T cell-mediated reaction. Tissue injury also may accompany T cell responses to microbes. For instance, in tuberculosis, a T cell-mediated immune response is raised against Mycobacterium tuberculosis, and the response becomes chronic because the infection is difficult to eradicate. The resultant granulomatous inflammation causes injury to normal tissues at the site of infection. Injecting a microbial protein into the skin of an individual who has been immunized against the microbe by prior infection or vaccination, leads to another form of type IV hypersensitivity reaction (DTH), as seen in PPD skin test (Tuberculin test).
This reaction is called delayed-type hypersensitivity (DTH), because itoccurs 24 to 48 hours after an immunized individual is challengedwith a microbial protein (i.e., the reaction is delayed), and because itreflects an increased sensitivity to antigen challenge.The delay occurs because it takes 24 to 48 hours for circulatingeffector T lymphocytes to home to the site of antigen challenge,respond to the antigen at this site, and induce a detectablereaction.DTH reactions are manifested by infiltrates of T cells and bloodmonocytes into the tissues, edema and fibrin deposition caused byincreased vascular permeability in response to cytokines producedby CD4+ T cells, and tissue damage induced by the products ofmacrophages activated by T cells.DTH reactions often are used to determine if people havebeenpreviously exposed to and have responded to an antigen. Forinstance, a DTH reaction to a mycobacterial antigen, PPD(purified protein derivative), is an indicator of a T cell responseto the mycobacteria. This is the basis for the PPD skin test,which frequently is used to detect past or activemycobacterial infection
TYPE IV HYPERSENSITIVITY REACTIONS Excessive polyclonal T cell activation by certain microbial toxins produced by some bacteria and viruses can lead to production of large amounts of inflammatory cytokines, causing a syndrome similar to septic shock. These toxins are called superantigens because they stimulate large numbers of T cells. Superantigens bind to invariant parts of T cell receptors on many different clones of T cells, regardless of antigen specificity, thereby activating these cells.
TYPE IV HYPERSENSITIVITY REACTIONS The therapy for T cell-mediated hypersensitivity disorders is designed to reduce inflammation, using: corticosteroids and antagonists against cytokines such as TNF, and to inhibit T cell responses with immunosuppressive drugs such as cyclosporine. Antagonists of TNF have proved to be beneficial in patients with rheumatoid arthritis and inflammatory bowel disease. Many newer agents are being developed to inhibit T cell responses. These include: agents that block costimulators such as B7 and antagonists against receptors for cytokines such as IL-2. There also is great hope for inducing tolerance in pathogenic T cells, but no successful clinical trials have been reported yet.
TYPE IV HYPERSENSITIVITY REACTIONSThank you for your attention