Hypersensitivity Reaction Type 4

  Type 4 hypersensitivity reactions are cell mediated hypersensitivity reactions that result in damage to host cells and tissues. These reactions are initiated by T-cells. The main T-cell types involved are T-helper type 1 cells, Th17 cells and killer or cytotoxic T-cells.

Antigens are presented to these cells by APCs such as dendritic cells. The damage to hosts is caused by activated macrophages and other leukocytes such as neutrophils and natural killer cells.

  Antigens triggering these reactions can be foreign agents that alter self antigens once inside the body.

  • These are basically chemicals that covalently bind to normal glycoproteins present on skin cells.
  • Example of such chemical is Urushiol.
  • It is present in the surface oils of the leaves of poison ivy that cause contact hypersensitivity.

These antigens can also be auto antigens that are recognized by autoreactive T-cells.

  • Autoreactive T-cells can be present in case of failure of self tolerance mechanisms.
  • Antigens derived from intracellular pathogens can also trigger type 4 hypersensitivity reactions.
  • Mostly these microbes are those that escape elimination by immune mechanisms and cause prolonged infections. For example Mycobacterium (Tuberculin test)

Type 4 Hypersensitivity

Like all hypersensitivity reactions type 4 hypersensitivity also develops into two stages. Sensitization stage and Effector stage.

Sensitization stage

  • Sensitization stage refers to the first or primary contact with the antigen.
  • During sensitization stage T-cells are sensitized and antigen specific memory T-cells are generated.
  • Sensitization in type 4 hypersensitivity occurs in a period of 7 to 10 days.

Effector stage

  • Effector stage refers to the secondary or subsequent contact with the antigen.
  • During the effector stage the host tissue damage takes place.
  • This damage is apparent only after 1 to 2 days of second exposure.
This delay in the manifestation of type 4 hypersensitivity reactions is the hallmark of these reactions. This delay is due to the time taken by T-cells for activation differentiation, cytokine and chemokines secretion, Also the recruitment of macrophages and other leukocytes to the site of antigen exposure takes time. For this reason type 4 hypersensitivity reactions are also known as delayed type hypersensitivity (DTH).

Mechanism of Type 4 Hypersensitivity Reactions

Type 4 hypersensitivity reactions are initiated by T-cells. There are two main t-cell subtypes

  • CD4 positive T-cells that differentiate into T helper cells and
  • CD8 positive T-cells that differentiate into cytotoxic or killer T-cells.

Which T-cell will initiate the reaction depends on how the antigens are presented to these naive T-cells.

  • If peptide fragments derived from antigens are presented in complex with MHC 2 molecules CD4 positive or helper T-cells are activated.
  • On the other hand if antigens are presented in complex with MHC1 molecules CD8 positive or cytotoxic T-cells are activated.

Contact sensitivity caused by poison ivy involves CD8 positive T-cells. These cytotoxic T-cells are sensitized during primary contact with the antigen and on secondary contact activated cytotoxic T-cells use their cytotoxic mechanisms to damage the skin cells and cause local inflammation.

Sensitization Stage Reactions

Suppose an intracellular pathogen enters the body for the first time. They infect the local host cells at the site of entry. These antigens are taken up by dendritic cells, which process them and display them as peptide MHC 2 complex on their surface.

These dendritic cells migrate to nearby lymph node and interact with naive CD4 positive T-cells. In the presence of cytokines secreted by dendritic cells and resident macrophages, CD4 positive T-cells get activated and become T-helper type one cells(Th1).

These cells undergo proliferation and differentiation to form effector T-helper type one(Th1) cells and antigen specific memory T-cells.

Next they migrate to the site of infection and works towards the elimination of the pathogens by cell mediated responses.

All these events during the sensitization stage require at least 1 to 2 weeks. Now the person is sensitized and antigen specific memory T-cells are present in the body.

Effector Stage Reactions

  When the individual is exposed to the same antigen for the second time effector stage results. This time antigen specific memory T-cells are already present.
Dendritic cells take up these pathogens process them and present them in complex with MHC 2 molecules.

  The resident macrophages also get activated by pathogen and they start releasing cytokines such as interleukin (IL12).

Memory T-cells interact with the antigens presented by dendritic cells and in the presence of cytokines released by activated macrophages they proliferate and differentiate into effector T helper type one cells.

These cells further release cytokines such as interferon gamma(IFN-γ), tumor necrosis factor beta(TNF-β) and interleukin 2 (IL2). These accumulated cytokines at the site of infection.

Now recruit monocytes from circulation to the site. Monocytes differentiate into macrophages when they migrate from blood to tissues. These macrophages also get activated and they further secrete cytokines and chemokines that recruit more monocytes, neutrophils, natural killer cells to the site of infection.

All these activated effector cells release inflammatory mediators that damaged host cells at the site of infection. Together the immune cells and the mediators released by them result in the extensive amplification of the response.

The events of effector stage takes 1 to 2 days and only after that the damage to the host is evident.
As the reaction fully develop the majority of participating cells are macrophages and other innate immune cells. Only about 5% cells are antigen specific Th1 cells.

T-helper type 1 (Th-1) cells are the important initiators of type 4 hypersensitivity reactions. Activated macrophages are the principal effector cells of these reactions. The damage is caused to the host because of heightened phagocytic activity and nonspecific destruction of host cells by neutrophils, natural killer cells etc. 

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