This week's blogpost comes from Lucy Bell, an Innate2Adaptive alumnus who reviews an interesting recent publication which adds insight to our understanding of immune reconstitution inflammatory syndrome.

I was interested by this recent paper by Scriven et al. in the Journal of Acquired Immunodeficiency Syndromes, entitled “The CSF Immune Response in HIV-1–Associated Cryptococcal Meningitis: Macrophage Activation, Correlates of Disease Severity, and Effect of Antiretroviral Therapy”. As the title suggests, the authors analysed the immune response within the cerebrospinal fluid (CSF) of HIV-1 positive patients with cryptococcal meningitis. They approach this by a combination of flow-cytometry based cellular assessments and multiplex cytokine measurements, and integrate this with data analysis techniques including principal component analysis (PCA) to explore the factors driving variation within their dataset.

Cryptococcal meningitis is a central nervous system infection caused by the environmentally prevalent fungus Cryptococcus neoformans, which does not cause disease in immunocompetent individuals. However, it acts as an opportunistic pathogen to cause meningitis in immunosuppressed patients, such as in advanced HIV disease (AIDS).

The part of the study that piqued my interest was their assessment of patients presenting with what the authors term ‘ART (antiretroviral therapy)-associated cryptococcal meningitis’: that is, patients who develop the infection within a short period of time after commencing ART. This likely includes patients with immune reconstitution inflammatory syndrome (IRIS), a clinical term for when patients who commence ART then either develop increased severity of an existing opportunistic infection (‘paradoxical’ IRIS), or present with a new opportunistic infection (‘unmasking’ IRIS). The pathology of IRIS is likely complex, but revolves around ART-triggered recovery of the immune response in a previously immunosuppressed tissue environment with high microbial loads, and consequent potential immunopathology.

The patient group of most interest in this paper were those who had commenced or switched to 2nd line ART in the 12 weeks prior to presentation. This definition may include individuals with unmasking IRIS (although the authors use a strict provisional case definition for cryptococcal IRIS which only one of the patient group fulfils). The authors find that this group of patients clustered separately on both PCA and non-hierarchal cluster analysis, and that the factors which distinguish the group were higher and lower CSF proportions of CD4+ T-cells & CD8+ T-cells respectively, as well as higher expression of CD206 on monocyte/macrophage cell types.

CD206 (also known as mannose receptor) is a marker of ‘alternative activation’ of macrophages,  driven by stimulation with interleukin-4 and interleukin-13 produced by T-helper 2 (Th2) CD4+ T-cells, as opposed to classical activation driven by interferon gamma produced by T helper 1 (Th1) cells. This marries somewhat with previous work from the same group, which found high levels of activated macrophages and Th2 cytokines in the CSF of patients with possible paradoxical cryptococcal IRIS. The authors hypothesise that the shift in macrophage phenotype could be driven directly by reduction in the HIV viral load, which has been shown in other models to be inversely correlated with CD206 expression. However, they do not speculate further on the precise host:pathogen interactions which might drive this.

We have also noted evidence of Th2 immune responses in patients with IRIS (unmasking TB-IRIS in our case) which poses the question of whether dysregulated Th2 responses might be a common process driving immune reconstitution-associated immunopathology across different opportunistic infections, and if so, how does commencing ART trigger this? Further studies such as the one in this paper utilising specimens from the site of disease, as well as the opportunity to assess immune responses in vivo with increasing levels of dimensionality via -omics technologies, should allow us to further explore these and related questions.

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