Immune reconstitution inflammatory syndrome associated with pulmonary pathogens

Abstract

Immune reconstitution inflammatory syndrome (IRIS) is an exaggerated immune response to a variety of pathogens in response to antiretroviral therapy-mediated recovery of the immune system in HIV-infected patients. Although IRIS can occur in many organs, pulmonary IRIS, associated with opportunistic infections such as Mycobacterium tuberculosis and Pneumocystis jirovecii, is particularly associated with high morbidity and mortality. The pathology of IRIS is associated with a variety of innate and adaptive immune factors, including CD4⁺ T-cells, CD8⁺ T-cells, γδ T-cells, natural killer cells, macrophages, the complement system and surfactant proteins, Toll-like receptors and pro-inflammatory cytokines and chemokines. Although there are numerous reports about the immune factors involved in IRIS, the mechanisms involved in the development of pulmonary IRIS are poorly understood. Here, we propose that studies using gene-deficient murine and nonhuman primate models will help to identify the specific molecular targets associated with the development of IRIS. An improved understanding of the mechanisms involved in the pathology of pulmonary IRIS will help to identify potential biomarkers and therapeutic targets in this syndrome.

FIGURE 1

Immune reconstitution inflammatory syndrome (IRIS) associated with Mycobacterium tuberculosis (TB) infection. a) In healthy individuals in response to M. tuberculosis infection, macrophages and dendritic cells induce polarising cytokines including interleukin (IL)-6, IL-12 and IL-23. These cytokines polarise T-cells which in turn activate macrophages to kill M. tuberculosis. b) In HIV-infected patients there is no M. tuberculosis control because of lack of effective T-cell responses. IRIS develops in HIV-infected patients with pre-antiretroviral therapy (ART) risk factors, such as low CD4⁺ cells, high HIV viral load, high M. tuberculosis antigen load and a short interval between M. tuberculosis treatment and ART. A variety of innate and adaptive immune cells, pro-inflammatory cytokines, chemokines and matrix metalloproteinases (MMPs) are involved in the exaggerated inflammatory response seen in IRIS. IFN: interferon; Th: T-helper cell; NK: natural killer; TLR: Toll-like receptor; CXCL: C-X-C motif chemokine ligand; TNF: tumour necrosis factor; CRP: C-reactive protein.