Immune reconstitution inflammatory syndrome (IRIS, or immune reconstitution disease) is a clinical entity characterized by an excessive inflammatory response to a preexisting antigen or pathogen and a paradoxical deterioration in clinical status after initiation of antiretroviral therapy (ART). IRIS may present in 2 different ways: (1) the “paradoxical” worsening of symptoms of a known disease, either at a new body site or at the original body site, or (2) the “unmasking” of an occult opportunistic infection, in which disease that was not clinically apparent prior to ART manifests during ART. The spectrum of clinical events is diverse, with incidence ranging from 10% to 23% of all individuals who started ART and from 8% to 43% of all individuals with an existing opportunistic infection
Figure 1: Model of IRIS.During microbial infection of a T cell-deficient host, the uncoupling of innate and adaptive immune responses sets the stage for excessive inflammation on T cell reconstitution. a | Myeloid cells such as macrophages require two signals to become fully activated. The first involves recognition of microbial products by pattern recognition receptors, which primes the cells for further activation. The second involves interaction with interferon-γ (IFNγ)-producing CD4+ T cells, after which macrophages become fully activated and produce high levels of pro-inflammatory mediators such as tumour necrosis factor (TNF) and interleukin-6 (IL-6). Following bacterial infection of a host with a normal immune system, macrophages take up bacteria and quickly encounter effector CD4+ T cells, resulting in containment of the pathogen. b | On infection of a T cell-deficient host, infected myeloid cells become primed by microbial products but never become fully activated to exert their pro-inflammatory effector functions. As the uncontrolled infection progresses, this can result in disease owing to high levels of pathogen replication. However, over time, as increasing numbers of primed macrophages accumulate in the tissues of the host, this also creates a state of immunological hyper-responsiveness to CD4+ T cell help. When the immunosuppression is removed and antigen-specific CD4+ T cells rapidly reconstitute the infected lymphopenic host, they create a burst of IFNγ-mediated T cell help, and large numbers of primed macrophages now become fully activated en masse. This results in an acute spike in the production of pro-inflammatory mediators, which drives immunopathology during immune reconstitution inflammatory syndrome (IRIS). c | The acute inflammatory response that causes IRIS would normally not be encountered in a T cell-replete host, and thus the rapid kinetics of this activation process may be an important factor driving disease.
