Hypersensitivity (Type IV)

Chapter 26 Hypersensitivity (Type IV)





Delayed hypersensitivity


Delayed-type hypersensitivity (DTH) is a T cell-mediated inflammatory response in which the stimulation of antigen-specific effector T cells leads to macrophage activation and localized inflammation and edema within tissues. This effector T cell response is essential for the control of intracellular and other pathogens. If the response is excessive, however, it can damage host tissues.


The T cell response may be directed against exogenous agents, such as microbial antigens and sensitizing chemicals, or against self-antigens. Typically T cells are sensitized to the foreign antigen during infection with the pathogen or by absorption of a contact sensitizing agent across the skin.



Subsequent exposure of the sensitized individual to the exogenous antigen, either injected intradermally or applied to the epidermis, results in the recruitment of antigen-specific T cells to the site and the development of a local inflammatory response over 24–72 hours.


If the foreign antigen persists in the tissues, chronic activation of T cells and macrophages may lead to granuloma formation and tissue damage.


If the antigen is an organ-specific self antigen, autoreactive T cells may produce localized cellular inflammation and autoimmune disease, such as type I diabetes mellitus.


According to the Coombs and Gell classification, type IV or DTH reactions take more than 12 hours to develop and involve cell-mediated immune reactions rather than antibody responses to antigens. Some other hypersensitivity reactions may straddle this definition because they have:



For example, the late-phase IgE-mediated reaction may peak 12–24 hours after contact with allergen, and TH2 cells and eosinophils contribute to the inflammation as well as IgE (see Chapter 23).


In contrast to other forms of hypersensitivity, type IV hypersensitivity is transferred from one animal to another by T cells, particularly CD4 TH1 cells in mice, rather than by serum. Therefore DTH can develop in antibody-deficient humans, but is lost as CD4 T cells fall in HIV infection and AIDS.


Type IV hypersensitivity reflects the presence of antigen-specific CD4 T cells and is associated with protective immunity against intracellular and other pathogens. However, there is not a complete correlation between type IV hypersensitivity and protective immunity, and progressive infections can develop despite the presence of strong DTH reactivity.




Contact hypersensitivity


Contact hypersensitivity is characterized by an eczematous skin reaction at the site of contact with an allergen (Fig. 26.2). Sensitizing agents for humans include metal ions, such as nickel and chromium, many industrial chemicals including those in rubber and leather and natural products present in dyes, drugs, fragrances and plants, such as pentadecacatechol, the sensitizing chemical in poison ivy. This is distinct from the non-immune-mediated inflammatory response to irritants.



Sensitizing agents behave as haptens. Haptens are:



Some contact allergens are modified by detoxifying enzymes encountered in the skin to form highly reactive metabolites that bind to self-proteins.


Potent haptens, such as dinitrochlorobenzene (DNCB), sensitize nearly all individuals and are used in animal models of allergic contact dermatitis.



A contact hypersensitivity reaction has two stages – sensitization and elicitation



Dendritic cells and keratinocytes have key roles in the sensitization phase


Antigen presenting cells (APC) in the skin include Langerhans’ cell (LCs), located in the suprabasal epidermis, and dermal dendritic cells (dDCs). Contact hypersensitivity is primarily an epidermal reaction, and epidermal LCs were considered to be the APC responsible for initiating contact sensitivity (Fig. 26.3). More recent studies have established that dDCs are essential for stimulating hapten-specific T cells.



Langerhans’ cells (see Chapter 2) are specialized DCs which extend dendritic processes throughout the epidermis, allowing them to sample environmental antigens. LCs express MHC class II, CD1 and the C-type lectin, langerin (CD207), which is responsible for the development of Birbeck granules, the cell membrane-derived organelle characteristic of LCs (see Fig. 26.3). The majority of dermal DCs are Langerin, but there is a small population of Langerin+ dDCs, which are distinct from LCs, but also migrate rapidly to draining lymph nodes on exposure to sensitizers and activate hapten-specific CD8+ T cells. Both LCs and dDCs take up hapten-modified proteins by micropinocytosis but they also absorb lipid-soluble haptens, which modify cytoplasmic proteins. Under the influence of IL-1 and TNF secreted by keratinocytes and other cells, these DCs undergo maturation and increase expression of MHC and co-stimulatory molecules. Both LCs and dDCs are inactivated by ultraviolet B, which can therefore prevent or alleviate the effects of contact hypersensitivity.




Sensitization stimulates a population of memory T cells


Sensitization takes 10–14 days in humans. Hapten-bearing LCs and dDCs bearing modified proteins migrate as veiled cells through the afferent lymphatics to the paracortical areas of regional lymph nodes, where they activate CD4+ and CD8+ T cells.


MHC class I-restricted CD8+ T cells are important in contact hypersensitivity responses in humans and mice and are the major effector cells for many allergens. For example, lipid-soluble urushiol from poison ivy enters the cytoplasm of APCs and haptened cytoplasmic proteins are processed through the MHC class I pathway, leading to the activation of allergen-specific CD8+ T cells. Hapten-specific CD4 T cells are also activated hapten–peptide conjugates in association with MHC class II molecules and become effector/memory CD4+ T cells, which contribute to the skin inflammation, or regulatory CD4+ T cells (Fig. 26.4).



Activated T cells change the pattern of adhesion molecules on their surface by downregulating the chemokine receptor, CCR7, and CD62L.



The expression of leukocyte functional antigen-1 (LFA-1), very late antigen-4 (VLA-4), and the chemokine receptors CXCR3 and CCR5 is increased. As a result the activated/memory T cells remain within the circulation rather than trafficking through lymphoid tissue, and are able to bind to adhesion molecules on the endothelium of inflamed tissues.



Elicitation involves recruitment of CD4+ and CD8+ lymphocytes and monocytes


The application of a contact allergen leads to:




There is induction of mRNA for TNF, IL-1β, and GM–CSF in Langerhans’ cells within 30 minutes of exposure to allergen, and increased transcription of mRNA for IL-1α, macrophage inflammatory protein-2 (CXCL2), and interferon-induced protein-10 (CXCL10) by keratinocytes.


TNF and IL-1 are potent inducers of endothelial cell adhesion molecules, including:




VCAM-1 and ICAM-1 are the receptors for VLA-4 and LFA-1, respectively, on the surface of effector/memory T cells and contribute to their recruitment across the endothelium. These locally released cytokines and chemokines also produce a gradient signal for the movement of mononuclear cells towards the dermoepidermal junction and epidermis.

Stay updated, free articles. Join our Telegram channel

Jun 18, 2016 | Posted by in IMMUNOLOGY | Comments Off on Hypersensitivity (Type IV)

Full access? Get Clinical Tree

Get Clinical Tree app for offline access