Publications

Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.

OBJECTIVE

The aim of our study was to investigate whether current eGFR equations in clinical use might systematically over-estimate the kidney function, and thus misclassify CKD status, of Black Americans with HIV. Specifically, we evaluated the impact of removing the race coefficient from the MDRD and CKD-EPI equations on comparisons between Black and White HIV-infected veterans related to: 1) the prevalence of reduced eGFR; 2) the distribution of eGFR values; and 3) the relationship between eGFR and all-cause mortality.

DESIGN

Retrospective cohort study.

SETTING

The Department of Veterans Affairs (VA) HIV Clinical Case Registry (CCR), which actively monitors all HIV-infected persons receiving care in the VA nationally.

PATIENT/PARTICIPANTS

21,905 treatment-naïve HIV-infected veterans.

MAIN OUTCOME MEASURES

Estimated glomerular filtration rate (eGFR) using the abbreviated Modification of Diet in Renal Disease (MDRD) formula with and without (MDRD-RCR) the race coefficient and all-cause mortality.

RESULTS

Persons with eGFR <45 mL/min/1.73m(2) had a higher risk of death compared with those with eGFR >80 mL/min/1.73m(2) among both Blacks (HR=2.8, 95%CI: 2.4-3.3) and Whites (HR=1.9, 95%CI: 1.4-2.6), but the association appeared to be stronger in Blacks (P=.038, test for interaction). Blacks with eGFR 45-60 mL/min/1.73m(2) also had a higher risk of death (HR=1.7, 95%CI: 1.4-2.1) but Whites did not (HR=.86, 95%CI: .67-1.10; test for interaction: P<.0001). Racial differences were substantially attenuated when eGFR was re-calculated without the race coefficient.

CONCLUSIONS

Our findings suggest that clinicians may want to consider estimating glomerular filtration rate without the race coefficient in Blacks with HIV.

BACKGROUND

Epithelial barrier dysfunction and increased permeability may contribute to antigen sensitization and disease progression in asthma. Claudin-18.1 is the only known lung-specific tight junction protein, but its contribution to airway barrier function or asthma is unclear.

OBJECTIVES

We sought to test the hypotheses that claudin-18 is a determinant of airway epithelial barrier function that is downregulated by IL-13 and that claudin-18 deficiency results in increased aeroantigen sensitization and airway hyperresponsiveness.

METHODS

Claudin-18.1 mRNA levels were measured in airway epithelial brushings from healthy controls and patients with asthma. In patients with asthma, claudin-18 levels were compared with a three-gene-mean marker of T2 inflammation. Airway epithelial permeability changes due to claudin-18 deficiency were measured in 16HBE cells and claudin-18 null mice. The effect of IL-13 on claudin expression was determined in primary human airway epithelial cells and in mice. Airway hyperresponsiveness and serum IgE levels were compared in claudin-18 null and wild-type mice following aspergillus sensitization.

RESULTS

Epithelial brushings from patients with asthma (n = 67) had significantly lower claudin-18 mRNA levels than did those from healthy controls (n = 42). Claudin-18 levels were lowest among T2-high patients with asthma. Loss of claudin-18 was sufficient to impair epithelial barrier function in 16HBE cells and in mouse airways. IL-13 decreased claudin-18 expression in primary human cells and in mice. Claudin-18 null mice had significantly higher serum IgE levels and increased airway responsiveness following intranasal aspergillus sensitization.

CONCLUSIONS

These data support the hypothesis that claudin-18 is an essential contributor to the airway epithelial barrier to aeroantigens. Furthermore, T2 inflammation suppresses claudin-18 expression, potentially promoting sensitization and airway hyperresponsiveness.