Understanding Mechanisms Underlying the Pathology of Immune Reconstitution Inflammatory Syndrome (IRIS) by Using Animal Models

Abstract

Purpose of Review Despite the increasing number of clinical reports on immune reconstitution inflammatory syndrome (IRIS), mechanistic understanding of IRIS is still largely limited. The main focus of this review is to summarize animal studies, which were performed to better understand the cellular and molecular mechanisms underlying the pathology of IRIS. Recent Findings Three IRIS animal models have been reported. They are Mycobacterial IRIS (M-IRIS), cryptococcal IRIS (C-IRIS) and Pneumocystis-IRIS. M-IRIS animal model suggested that, rather than lymphopenia itself, the failure to clear the pathogen by T cells results in excessive priming of the innate immune system. If this happens before T cell reconstitution, hosts likely suffer IRIS upon T cell reconstitution. Interestingly, T cells specific to self-antigens, not only pathogen-specific, could drive IRIS as well. Summary The mechanism to develop IRIS is quite complicated, including multiple layers of host immune responses; the innate immune system that detects pathogens and prime host immunity, and the adaptive immune system that is reconstituted but hyper-activated particularly through CD4+ T cells. Animal models of IRIS, although there are still small numbers of studies available, have already provided significant insights on the mechanistic understanding of IRIS.

Th1-Dependent Cryptococcus-Associated Immune Reconstitution Inflammatory Syndrome Model With Brain Damage

“…Our histology data also indicated minimal lung injury in C-IRIS mice, despite cellular infiltration including macrophages, neutrophils, and dendritic cells in the lung. In contrast to Cn , it is of note that Mycobacterium avium elicits strong innate immune responses and was used in a Mycobacterium -associated IRIS model ( 1 , 44 , 45 ), particularly exhibiting inflamed lung even before T cell reconstitution ( 46 ). In contrast, human C-IRIS is known to affect any organs, including the CNS ( 47 ).…”

“…Immune reconstitution inflammatory syndrome (IRIS) is a pathological condition whereby a recovering immune system paradoxically worsens the patient’s condition by responding excessively to a previously acquired infection ( 1 , 2 ). IRIS has been reported in patients, who are recovering from an immunocompromised condition and pre-infected with fungi such as Cryptococcus, Candida, Aspergillus , as well as mycobacteria and viruses ( 3 – 5 ).…”

Niflumic Acid Reverses Airway Mucus Excess and Improves Survival in the Rat Model of Steroid-Induced Pneumocystis Pneumonia

“…Therefore, the pathology features and response to NFA therapy determined here may not necessarily extrapolate to other types of PcP. For example, PcP in patients with immune reconstitution inflammatory syndrome (IRIS) display high lymphocyte counts after antiretroviral-therapy-related T-cell recovery (Eddens and Kolls, 2015; Gopal et al, 2017; Aggarwal et al, 2018). A progressive increase in CLCA1 as in this model may more likely occur in the setting of the slowly developing PcP of untreated AIDS or in cancer patients receiving steroids, than in the context of recovering CD4+ T-cell counts able to trigger a strong cellular immune response, or of other underlying etiologies.…”

Predictors of glucose metabolism and blood pressure among Ethiopian individuals with HIV/AIDS after one‐year of antiretroviral therapy

“…Immune reconstitution during the few months after ART initiation may lead to increased secretion of TNF‐α which may induce insulin resistance by various mechanisms involving insulin receptor signalling cascade [26–28]. This has been shown in experimental [29] and longitudinal studies [27].…”