or Delayed hypersensitivity Type IV Hypersensitivity It is mediated by cells; circulating antibody and complement are not involved. Many reactions to immunologic insult involve both cellular and humoral components. It is mediated by soluble factors (lymphokines) released by the sensitized T lymphocytes. The lymphokines have biological activities affecting various cell types. Type IV Hypersensitivity Those that may be used as examples of delayed type hypersensitivity response includes: Tuberculin skin reaction Contact sensitivity Granulomatous hypersensitivity Tuberculin-type Hypersensitivity This form of hypersensitivity was originally described by Koch. The skin reaction is frequently used to test for sensitivity to the organisms following previous exposure. This form of hypersensitivity may also be induced by non-microbial antigens, such as beryllium and zirconium. Tuberculin-type Hypersensitivity The tuberculin skin test reaction principally involves monocytes. The tuberculin skin test is an example of the recall response to soluble antigen previously encountered during infection. Tuberculin-type Hypersensitivity Tuberculin-like delayed type hypersensitivity (DTH) reactions are used practically in two ways. First, reaction to soluble antigens from a pathogen demonstrates past infection with that pathogen. Thus tuberculin reactivity confirms past infection with M. tuberculosis, but not necessarily active disease. Tuberculin-type Hypersensitivity Second, DTH responses to frequently encountered microbes are a general measure of cell-mediated immunity. This can be tested with intradermal injection of single antigens from common pathogens, or a multipuncture device which delivers seven common microbial antigens in a standardized fashion. Loss of recall responses to specific antigens occurs in a wide range of diseases and infections which impair T- cell function, and during therapy with corticosteroids or immunosuppressive agents. Contact hypersensitivity Contact hypersensitivity is characterized by an eczematous reaction at the point of contact with the allergen. It is often seen following contact with agents such as nickel, chromate, rubber accelerators and pentadecacatechol. Contact with irritants that damage skin by toxic mechanisms not mediated by hypersensitivity can also produce eczema. Contact hypersensitivity The Langerhans’ cell is the principal antigen-presenting cell Contact hypersensitivity is primarily an epidermal reaction, and the dendritic Langerhans’ cell, located in the suprabasal epidermis, is the principal antigen-presenting cell (APC) involved. Langerhans’ cells are inactivated by ultraviolet B, which can thus prevent or alleviate the effects of contact hypersensitivity. Contact hypersensitivity In vitro, Langerhans’ cells act as APCs and are more potent in this regard than monocytes. Langerhans’ cells take up hapten-modified proteins by micropinocytosis and under the influence of interleukin-1 (IL-1) and tumor necrosis factor (TNF) from keratinocytes and other cells undergo maturation, increase the expression of MHC and co-stimulatory molecules and migrate to draining lymph nodes. Contact hypersensitivity Keratinocytes produce a range of cytokines important to the contact hypersensitivity. IL-3 can activate Langerhans’ cells, co-stimulate proliferative responses, recruit mast cells and induce the secretion of immunosuppressive cytokines. These latter dampen the immune response and induce the clonal anergy in TH1 cells. Contact hypersensitivity Keratinocytes can be activated by a number of stimuli, including allergens and irritants. Activated keratinocytes produce immunostimulatory cytokines such as TNFα and granulocyte- macrophage- colony-stimulating factor (GM-CSF) which activate Langerhans’ cells. Contact hypersensitivity A contact hypersensitivity reaction has two stages: sensitization and allicitation Sensitization produces a population of memory T cells Elicitation involves recruitment of CD4+ lymphocytes and monocytes Sensitization Sensitization takes 10 – 14 days in humans. Once absorbed, the hapten with a protein and is internalized by epidermal Langerhans’ cells, which leave the epidermis and migrates as veiled cells through the afferent lymphatics to the paraoctical areas of regional lymph nodes. Here they present hapten-protien conjugates to CD4+ lymphocytes, producing a population of memory CD4+ T cells. Elicitation Langerhans”cells carrying the hapten carrier complex (1)move from the epidermis to the dermis, where they present the hapten-carrier complex to memory CD4+ T cells (2) Activated CD4+ T cells released IFNγ, which induces expression of ICAM-1 (3) and later MHC class II molecules (4) on the surface of keratinocytes and on the endothelial cells of dermal capillaries and activates keratinocytes such as IL-,1 IL-6 and GM-CSF Elicitation (5) Non antigen specific CD4+ T cells are attracted to the site by cytokinesis (6) and may bind to keratinocytes via ICAM-1 and class II molecules. Activates macrophages are also attracted to the skin, but this occurs later. Thereafter the reaction stars to downregulate. This doenregulation may be influenced by eicosanoids such as PGE, produced by activated keratinocytes and macrophages (7) has been shown to induce a specific inhibitor of IL-1 activity GRANULOMATOUS HYPERSENSITIVTY Granulomatous hypersensitivity is clinically the most important form of TYPE IV hypersensitivity, and causes many of the pathological effects in disease that involves T cells mediated immunity. It usually results from the persistence within macrophages of intracellular microorganisms or other particles that the cells is unable to destroy. This process results in epithelioid cell granuloma formation. This histological appearance of the granuloma reaction is quite different from that of the GRANULOMATOUS HYPERSENSITIVTY However, they often result from sensitization to similar microbial antigens. Immunological granuloma formation also occurs in the sensitivity reactions to zirconium and beryllium, and in sarcoidosis, although in the latter the antigen is unknown. Foreign body granuloma formation occur with talc, silica and a variety of other particulate agents. In this case macrophages are unable to digest the inorganic matter. These non immunological granulomas may be distinguished by the absence of lymphocytes in the lesion. GRANULOMATOUS HYPERSENSITIVTY An immunological granuloma typically has a core of epithelioid 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 cellular architecture. The macrophage/epithelioid core is surrounded by a cuff of lymphocytes, and there may also be considerable fibrosis caused by proliferation of fibroblasts and increased collagen DELAYED HYPERSENSITIVITY REACTIONS Type Reaction Clinical Histology Antigen time appearance
contact 48-72 hr Eczema Lymphocytes, Epidermal e.g.
later nickel, rubber, macrophages, poison ivy oedema of epidermidis tuberculin 48-72 hr Local induration Lymphocytes, Intradermal e.g. monocytes, tuberculin macrophages granuloma 21-28 days Hardening e.g. Macrophages, Persistent Ag or skin or lungs epithelioid cells, Ag/Ab giant cells, complexes or fibrosis non- immunoglobin e.g. talc Type V Hypersensitivity Receptor mediated hypersensitivity Type V Hypersensitivity This reaction occur when IgG class antibodies directed towards cell surfaces antigens have either a stimulating or inhibitory effect on their target. Cells are signaled by agents such as hormones, mainly amino acid- based hormones: These hormones cannot pass through plasma membranes because they are Type V Hypersensitivity Type V hypersensitivity has been added as a distinction from Type II. This additional class of reaction refers to stimulatory hypersensitivity where, instead of binding to cell surface components and destroying the cells, IgG receptors thus either prevents ligand binding, or mimics the effect of the endogenous ligand, thus impairing Type V Hypersensitivity This is a useful distinction to Type II reactions where the cytotoxic binding of antibody causes cell death. Stimulatory hypersensitivity occurs when the autoantibodies cause inappropriate stimulation of the cell. Allergic Contact Dermatitis from a Henna Tattoo Colby C. Evans, M.D. John D. Fleming, M.B., B.S New England Journal of Medicine August 2008 Allergic Contact Dermatitis from a Henna Tattoo
Temporary henna tattooing is a custom
at weddings in much of the world. The dyeing agent (hennotannic acid) rarely leads to skin sensitization. However, tattoo henna is often mixed with paraphenylenediamine (PPD) to hasten drying and darken the color. PPD is a common allergen that is also found in permanent hair dyes. Allergic Contact Dermatitis from a Henna Tattoo
Allergens that cause reactions in
patients who are sensitive to PPD include sunscreens containing aminobenzoic acid, certain local anesthetics, and sulfonamides. The patient was treated high-potency topical corticosteroids, and the lesions resolved, although with extensive postinflammatory hyperpigmentation. Allergic Contact Dermatitis from a Henna Tattoo