People with Primary Progressive Multiple Sclerosis Have a Lower Number of Central Memory T Cells and HLA-DR+ Tregs.

The importance of circulating immune cells to primary progressive multiple sclerosis (PPMS) pathophysiology is still controversial because most immunotherapies were shown to be ineffective in treating people with PPMS (pwPPMS). Yet, although controversial, data exist describing peripheral immune system alterations in pwPPMS. This study aims to investigate which alterations might be present in pwPPMS free of disease-modifying drugs (DMD) in comparison to age- and sex-matched healthy controls. A multicentric cross-sectional study was performed using 23 pwPPMS and 23 healthy controls. The phenotype of conventional CD4+ and CD8+ T cells, regulatory T cells (Tregs), B cells, natural killer (NK) T cells and NK cells was assessed. Lower numbers of central memory CD4+ and CD8+ T cells and activated HLA-DR+ Tregs were observed in pwPPMS. Regarding NK and NKT cells, pwPPMS presented higher percentages of CD56dimCD57+ NK cells expressing NKp46 and of NKT cells expressing KIR2DL2/3 and NKp30. Higher disease severity scores and an increasing time since diagnosis was correlated with lower numbers of inhibitory NK cells subsets. Our findings contribute to reinforcing the hypotheses that alterations in peripheral immune cells are present in pwPPMS and that changes in NK cell populations are the strongest correlate of disease severity.

Hypoxia inducible-factor 1 alpha regulates neutrophil recruitment during fungal-elicited granulomatous inflammation.

Chronic pulmonary aspergillosis (CPA) is a devastating disease with increasing prevalence worldwide. The characteristic granulomatous-like inflammation poses as the major setback to effective antifungal therapies by limiting drug access to fungi. These inflammatory lung structures are reported to be severely hypoxic; nevertheless, the underlying mechanisms whereby these processes contribute to fungal persistence remain largely unknown. Hypoxia-inducible factor 1 alpha (HIF-1α), besides being the major cellular response regulator to hypoxia, is a known central immune modulator. Here, we used a model of Aspergillus fumigatus airway infection in myeloid-restricted HIF-1α knock-out (mHif1α-/- ) mice to replicate the complex structures resembling fungal granulomas and evaluate the contribution of HIF-1α to antifungal immunity and disease development. We found that fungal-elicited granulomas in mHif1α-/- mice had significantly smaller areas, along with extensive hyphal growth and increased lung fungal burden. This phenotype was associated with defective neutrophil recruitment and an increased neutrophil death, therefore highlighting a central role for HIF-1α-mediated regulation of neutrophil function in the pathogenesis of chronic fungal infection. These results hold the promise of an improved capacity to manage the progression of chronic fungal disease and open new avenues for additional therapeutic targets and niches of intervention.