Although the exact mechanism involved in the development of immune reconstitution inflammatory syndrome (IRIS) is not clearly understood, the explanation presented in this discussion is based on current theories.
As a background to understanding inflammatory responses, it is first important to appreciate that there are four defined CD4+ T cell subsets that provide a homeostatic balance between pro and anti inflammatory responses that occur in a healthy functioning immune system. The four CD4+ T cell subsets we will discuss are the Th1, Th17, Treg and the Th2 subset.
Initially, naive CD4+ T cells (termed Th0) encounter processed antigen by dendritic cells through the MHC class II and T cell receptor in the T cell zone of secondary lymphoid tissues, such as the lymph nodes. Depending on the type of cytokine released by the dendritic cell upon this interaction, the Th0 CD4 cells differentiate into either Th1, Th2, Th17 or Treg phenotypes.
Interleukin-12 released by the dendritic cells will cause the Th0 CD4 cells to differentiate into Th1 functional cells. These cells secrete IFN-? which promotes pro-inflammatory responses and will mobilize the maturation of CD8+ cytotoxic T cells and stimulate NK cells.
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When a combination of Transforming Growth Factor (TGF ?) and IL-6 are released together by the dendritic cell, the Th0 CD4 cells differentiate into Th17 functional cells. These cells secrete IL-17, which also induces pro-inflammatory cytokines and tips the balance towards inflammatory immune responses.
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When the dendritic cells only release TGF- β, the Th0 CD4 cells differentiate into T regulatory (Treg) cells. These cells secrete IL-10 and TGF- β. IL-10 antagonises pro-inflammatory immune responses by suppressing Th1 and Th17 T cell development.
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When the dendritic cells release IL-4 after Th0 binding, the cells differentiate into Th2 cells. These cells secrete IL-4 and IL-10 which antagonise pro-inflammatory responses by suppressing Th1 and Th17 T cell development. Th2 T cells also provide cytokine stimulation to promote the maturation of B cells to plasma cells and the production of antibodies.
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Homeostatic balance of pro- and anti-inflammatory immune responses.
In adaptive immune responses to pathogens, there is a critical balance between pro- and anti-inflammatory immune responses. Uncontrolled pro-inflammatory immune responses can result in damage to host tissues, whereas anti-inflammatory immune responses initiated prematurely can result in survival of the pathogen, which is deleterious for the host. Th1 and Th17 CD4+ T cell subsets result in pro-inflammatory responses and Treg and Th2 CD4+ T cell subsets result in anti-inflammatory responses. It is thought that in a natural healthy immune response, there is a homeostatic balance between these subsets, resulting in the elimination of the pathogen, but also reducing the risk of tissue damage in the process. Inability to clear pathogen, or an overload of antigen, is either a result of this balance or a cause of an imbalance.
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What happens when IRIS occurs?
Currently, it is thought that IRIS is a result of an imbalance towards pro-inflammatory immune responses during the immune reconstitution phase that occurs shortly after initiation of ARV therapy. There is a preferential differentiation of pro-inflammatory CD4+ T cell subsets.
If we break down the sequence of events: when a person becomes infected with HIV, the virus replicates preferentially in secondary lymphoid tissue.
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This results in an accumulation of viral gp120, which interacts with CD4 receptors expressed on CD4+ T cells and promotes retention of CD4+ T cells in the lymph node by interference with lymph node homing and exit receptor regulation. When ARV therapy is initiated, the drugs act by inhibiting viral replication and allow the release of sequestrated CD4+ T cells. Thus, the first phase of immune reconstitution following ARV therapy is the redistribution of sequestered CD4+ T cells from the lymph nodes to peripheral blood and tissues. It has been shown that the majority of these cells are Th1 and Th17 memory cells and the second phase is the resulting imbalance towards inflammatory responses due to these cells initiating uncontrolled pro-inflammation.
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