TY  - JOUR
A1  - Bumiller-Bini Hoch, Valéria
A1  - Kohler, Ana Flávia
A1  - Augusto, Danillo G.
A1  - Lobo-Alves, Sara Cristina
A1  - Malheiros, Danielle
A1  - Cipolla, Gabriel Adelman
A1  - Winter Boldt, Angelica Beate
A1  - Braun-Prado, Karin
A1  - Wittig, Michael
A1  - Franke, Andre
A1  - Pföhler, Claudia
A1  - Worm, Margitta
A1  - van Beek, Nina
A1  - Goebeler, Matthias
A1  - Sárdy, Miklós
A1  - Ibrahim, Saleh
A1  - Busch, Hauke
A1  - Schmidt, Enno
A1  - Hundt, Jennifer Elisabeth
A1  - Araujo-Souza, Patrícia Savio de
A1  - Petzl-Erler, Maria Luiza
T1  - Genetic associations and differential mRNA expression levels of host genes suggest a viral trigger for endemic pemphigus foliaceus
JF  - Viruses
N2  - The long search for the environmental trigger of the endemic pemphigus foliaceus (EPF, fogo selvagem) has not yet resulted in any tangible findings. Here, we searched for genetic associations and the differential expression of host genes involved in early viral infections and innate antiviral defense. Genetic variants could alter the structure, expression sites, or levels of the gene products, impacting their functions. By analyzing 3063 variants of 166 candidate genes in 227 EPF patients and 194 controls, we found 12 variants within 11 genes associated with differential susceptibility (p < 0.005) to EPF. The products of genes TRIM5, TPCN2, EIF4E, EIF4E3, NUP37, NUP50, NUP88, TPR, USP15, IRF8, and JAK1 are involved in different mechanisms of viral control, for example, the regulation of viral entry into the host cell or recognition of viral nucleic acids and proteins. Only two of nine variants were also associated in an independent German cohort of sporadic PF (75 patients, 150 controls), aligning with our hypothesis that antiviral host genes play a major role in EPF due to a specific virus–human interaction in the endemic region. Moreover, CCL5, P4HB, and APOBEC3G mRNA levels were increased (p < 0.001) in CD4+ T lymphocytes of EPF patients. Because there is limited or no evidence that these genes are involved in autoimmunity, their crucial role in antiviral responses and the associations that we observed support the hypothesis of a viral trigger for EPF, presumably a still unnoticed flavivirus. This work opens new frontiers in searching for the trigger of EPF, with the potential to advance translational research that aims for disease prevention and treatment.
KW  - endemic pemphigus foliaceus
KW  - virus
KW  - genetic association
KW  - differential gene expression
KW  - autoimmune disease
KW  - environmental factors
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270572
SN  - 1999-4915
VL  - 14
IS  - 5
ER  - 
TY  - JOUR
A1  - Twisselmann, Nele
A1  - Pagel, Julia
A1  - Künstner, Axel
A1  - Weckmann, Markus
A1  - Hartz, Annika
A1  - Glaser, Kirsten
A1  - Hilgendorff, Anne
A1  - Göpel, Wolfgang
A1  - Busch, Hauke
A1  - Herting, Egbert
A1  - Weinberg, Jason B.
A1  - Härtel, Christoph
T1  - Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation
JF  - Frontiers in Immunology
N2  - Preterm infants are highly susceptible to sustained lung inflammation, which may be triggered by exposure to multiple environmental cues such as supplemental oxygen (O\(_2\)) and infections. We hypothesized that dysregulated macrophage (MФ) activation is a key feature leading to inflammation-mediated development of bronchopulmonary dysplasia (BPD) in preterm infants. Therefore, we aimed to determine age-dependent differences in immune responses of monocyte-derived MФ comparing cord blood samples derived from preterm (n=14) and term (n=19) infants as well as peripheral blood samples from healthy adults (n=17) after lipopolysaccharide (LPS) exposure. Compared to term and adult MФ, LPS-stimulated preterm MФ showed an enhanced and sustained pro-inflammatory immune response determined by transcriptome analysis, cytokine release inducing a RORC upregulation due to T cell polarization of neonatal T cells, and TLR4 surface expression. In addition, a double-hit model was developed to study pulmonary relevant exposure factors by priming MФ with hyperoxia (O\(_2\) = 65%) or hypoxia (O\(_2\) = 3%) followed by lipopolysaccharide (LPS, 100ng/ml). When primed by 65% O\(_2\), subsequent LPS stimulation in preterm MФ led to an exaggerated pro-inflammatory response (e.g. increased HLA-DR expression and cytokine release) compared to LPS stimulation alone. Both, exposure to 65% or 3% O\(_2\) together with subsequent LPS stimulation, resulted in an exaggerated pro-inflammatory response of preterm MФ determined by transcriptome analysis. Downregulation of two major transcriptional factors, early growth response gene (Egr)-2 and growth factor independence 1 (Gfi1), were identified to play a role in the exaggerated pro-inflammatory response of preterm MФ to LPS insult after priming with 65% or 3% O\(_2\). Preterm MФ responses to LPS and hyperoxia/hypoxia suggest their involvement in excessive inflammation due to age-dependent differences, potentially mediated by downregulation of Egr2 and Gfi1 in the developing lung.
KW  - preterm infants
KW  - sustained inflammation
KW  - macrophages
KW  - hyperoxia
KW  - hypoxia
KW  - infection
KW  - bronchopulmonary dysplasia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250356
SN  - 1664-3224
VL  - 12
ER  -