Cellular Immune Activation in Cerebrospinal Fluid From Ugandans With Cryptococcal Meningitis and Immune Reconstitution Inflammatory Syndrome

Abstract

Background Human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) is characterized by high fungal burden and limited leukocyte trafficking to cerebrospinal fluid (CSF). The immunopathogenesis of CM immune reconstitution inflammatory syndrome (IRIS) after initiation of antiretroviral therapy at the site of infection is poorly understood. Methods We characterized the lineage and activation status of mononuclear cells in blood and CSF of HIV-infected patients with noncryptococcal meningitis (NCM) (n = 10), those with CM at day 0 (n = 40) or day 14 (n = 21) of antifungal therapy, and those with CM-IRIS (n = 10). Results At diagnosis, highly activated CD8+ T cells predominated in CSF in both CM and NCM. CM-IRIS was associated with an increasing frequency of CSF CD4+ T cells (increased from 2.2% to 23%; P = .06), a shift in monocyte phenotype from classic to an intermediate/proinflammatory, and increased programmed death ligand 1 expression on natural killer cells (increased from 11.9% to 61.6%, P = .03). CSF cellular responses were distinct from responses in peripheral blood. Conclusions After CM, T cells in CSF tend to evolve with the development of IRIS, with increasing proportions of activated CD4+ T cells, migration of intermediate monocytes to the CSF, and declining fungal burden. These changes provide insight into IRIS pathogenesis and could be exploited to more effectively treat CM and prevent CM-IRIS.

CD4 + T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis

“…In HIVϩ patients, IRIS frequently arises following restoration of T cell-mediated immunity, and in non-HIV individuals, PIIRS is correlated with elevated CSF CD4 ϩ T cell counts. Both are associated with elevated IFN-␥ and often occur despite successful antifungal therapy and clearance supporting the idea that, as in our murine model, immune pathology is Th1 cell driven and is not solely determined by fungal burden (32,33,(36)(37)(38)(39)(40). How the overexuberant Th1 responses develop in these patients is unknown, but they are possibly linked to myeloid cell dysfunction leading to a persistent overly trigger-sensitive (low-threshold) and hyperactivated state (35,39,71).…”

“…Clinical evidence increasingly suggests that the host inflammatory response, rather than pathogen burden, may lead to the development of pathology, neuronal injury, and deteriorating status, especially in IRIS and PIIRS patients (28,30,32,33,(36)(37)(38)(39)(40). Thus, our next goal was to evaluate CNS pathology during the progression of C. neoformans infection and to determine a possible link to the accumulation of a cellular inflammatory response within the CNS.…”

“…T cell inflammatory response in the CNS during cryptococcal meningoencephalitis is highly Th1 polarized, and nearly all CD4 ؉ and CD8 ؉ T cells produce IFN-␥. The subsets of patients with paradoxical inflammatory responses to cryptococcal infection (IRIS and PIIRS) display dominant Th1 T cell polarization with elevated levels of IFN-␥ in the serum and CSF (32,33,(36)(37)(38)(39)(40). Thus, we sought to determine whether murine brain-infiltrating T cells would mimic this phenotype by analyzing T cell cytokine production and expression of polarizing Th-associated transcription factors in the C. neoformans-infected CNS.…”

HIV infection and immune activation

“…Meya et al undertook an analysis of CSF from Ugandan patients with HIV-associated cryptococcal meningitis and demonstrated that CM-IRIS was associated with an increasing frequency of CSF CD4+T cells and NK cells expressing PD-L1 (programmed death ligand 1) and migration of intermediate monocytes to the CSF [55]. Jarvis et al demonstrated that cytokine responses of IFNγ (Th1), IL4 and IL10 (Th2) and IL17 (Th17) in the CSF of patients with HIV-associated CM were linked to increased macrophage activation, more rapid clearance of cryptococci from CSF, and survival at 2 weeks with IL-6 to contribute the most to this protective effect [56].…”

Immunoregulation in Fungal Diseases

“…Interestingly, the authors also noted an increase in the abundance of Treg cells within these individuals, suggesting a role for these regulatory cells in the development or suppression of IRIS [150]. The most precise estimates of IRIS occurrence range from 25%–32.5%, developing on average 8 weeks after the initiation of HAART, with increased expression of pro-inflammatory markers including IFNγ, TNFα, and eotaxin in CM-IRIS patients as compared to individuals simply experiencing a relapse of CM [151,152]. This distinction is critical, as it clearly shows that IRIS is an immunological phenomenon distinct from basic host immune responses to C. neoformans in the CNS.…”