Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none

Abstract

Some individuals who are infected with HIV rapidly deteriorate shortly after starting antiretroviral therapy, despite effective viral suppression. This reaction, referred to as immune reconstitution inflammatory syndrome (IRIS), is characterized by tissue-destructive inflammation and arises as CD4(+) T cells re-emerge. It has been proposed that IRIS is caused by a dysregulation of the expanding population of CD4(+) T cells specific for a co-infecting opportunistic pathogen. Here, we argue that IRIS instead results from hyper-responsiveness of the innate immune system to T cell help, a mechanism that may be shared by the many manifestations of IRIS that occur following the reversal of other types of immunosuppression in pathogen-infected hosts.

Figure 1. Experimental IRIS requires chronic mycobacterial infection of lymphopenic hosts

Immune reconstitution inflammatory syndrome (IRIS) can be experimentally induced in T cell-deficient mice harbouring a chronic Mycobacterium avium infection by injecting purified CD4⁺ T cells into the mice. Importantly, IRIS does not occur in wild-type mice infected before or after CD4⁺ T cell transfer. Furthermore, no IRIS-related symptoms are observed in T cell-deficient mice when T cells are transferred before or soon after the time of infection. IRIS occurs only after transfer of CD4⁺ T cells into lymphopenic mice that were infected with M. avium several months previously.

Figure 2. 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 macro phages 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, macro phages 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 macro phages 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.