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Type IV hypersensitivity

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TYPE IV/DELAYED TYPE HYPERSENSITIVITY

Author: Sanketh DS, MDS

INTRODUCTION

The immune system protects the human body against disease by dispatching a bunch of immune cells whenever the body encounters foreign material or antigens. These immune cells elicit an inflammatory response in order to remove or eliminate the foreign antigen without causing much damage to the host. However, under certain conditions, the host may elicit an exaggerated or an inappropriate immune response to a foreign antigen causing much damage to host tissues. This exaggerated or inappropriate immune response is termed hypersensitivity.  There are four types of hypersensitivity reactions them being Type I, Type II, Type III and Type IV hypersensitivity.

Type IV hypersensitivity reaction is a T-cell mediated response primarily caused by CD4+ T cells, though these reactions can also be caused by CD 8+ T cells. Type IV hypersensitivity is also called delayed type hypersensitivity due to its delayed onset of reaction.

PATHOPHYSIOLOGY

Type IV hypersensitivity starts with a sensitization phase, where an individual is first sensitized to an external agent or antigen. During this phase the exogenous antigen is picked up by an antigen presenting cell (APC) usually Langerhans cell also called a dendritic cell.  The Langerhans cell swims to a nearby lymph node and presents it to a CD4+ T cell via the MHC II molecule. On presentation of the antigen, the CD4+ T cell recognises the antigen through its T cell receptor and could differentiate into different T helper cell subtypes depending on certain cytokines present in the environment. In type IV hypersensitivity reactions, the differentiation is usually skewed towards the TH1 subset of CD 4+ T cells. Langerhans cell produces cytokine IL-12, which helps this process. Sometimes, the APC could also produce cytokines like IL-1 and IL-6, which along with TGF-β causes the CD4+ T cell to differentiate into the TH17 subset.  

Subsequent exposure to the antigen forms the effector phase of the reaction and the manifestations usually peak at around 48-72 hours of the second exposure (hence called delayed hypersensitivity reaction). The antigens are again picked up by the APC, and this time presented to the TH1 cell which kicks of a cascade of reactions. On recognition of the antigen, the TH1 cell produces cytokine IFN-γ. IFN-γ activates macrophages making them super active and alert. These activated macrophages have better antigen presenting abilities, increased MHC II expressions and improved phagocytosing capabilities. Activated macrophages produce pro-inflammatory cytokines like IL-1 and TNF-α, which cause leukocytes to leak out of nearby blood vessels. Leaking monocytes differentiate to macrophages which are again activated by IFN-γ. Activated macrophages also produce IL-12 which could cause activation of more TH1 cells. Accumulating macrophages in the site of infection release various lytic enzymes and free radicals to help remove the offending agent, in the process also causing tissue damage. If at all TH17 cells are activated, they release cytokines like IL-17, IL-22 and other chemokines, which help in recruiting neutrophils to the site of infection/insult.

However, there are occasions when the offending agent is not removed and persists despite the inflammation. This is usually the case with chronic granulomatous infections like tuberculosis, sarcoidosis and some fungal infections.  In such cases, the persisting antigen causes a continuous loop of  TH1 cells activating macrophages via IFN-γ and macrophages activating TH1 cells via IL-12. Constant activation of macrophages by IFN-γ causes macrophages to transform into epitheloid cells (resemble epithelial cells, hence the name). It may also cause fusion of adjacent epitheloid cells to form multinucleate giant cells like Langhans giant cells and foreign body giant cells. The epitheloid cells and giant cells are surrounded by lymphocytes and fibrosis. This mass is called a granuloma!

Type IV hypersensitivity reactions could also be mediated by CD8+ T cells. Autoimmune diseases like Type I diabetes and rheumatoid arthritis, graft rejections and viral infections have CD8+ T cell mediated tissue damage. CD8+ T cells damage cells expressing the offending antigen and are hence called cytotoxic T lymphocytes (CTL). Now, it has to be remembered that all nucleated cells express MHC I molecules. So, for example, in a viral infection the affected keratinocyte may express the viral antigen through its MHC I molecule. This antigen presented through MHC I is recognized by a CTL via its T cell receptor. On recognition, the CTL releases enzymes called perforins that create pores in the cell and then release granzymes into the infected cell causing apoptosis!

REFERENCES

Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran – Pathologic Basis of Disease. 8th ed. Saunders Elsevier; 2010.

Abbas AK, Litchman AH, Pillai S. Cellular and Molecular Immunology. 8th ed. Saunders; 2015.

Kindt TJ, Goldsby RA, Osborne BA, Kuby J.  Kuby immunology. 6th ed. New York: W.H. Freeman; 2007.

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