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Purpose Enteropathy is a non-infectious complication in Common Variable Immune Deficiency (CVID) associated with increased morbidity and mortality. We characterized this group of CVID enteropathy (CVID-E) patients and investigated the effectiveness of immunosuppressive treatments on its clinical course. Method We identified patients with CVID-E in two academic teaching hospitals and obtained informed consents. Using electronic patient health care records, we retrospectively collected clinical information in the national Primary immunodeficiency disorder database until 01-2023. Results We included 39 patients with CVID-E. Bronchiectasis (69.2%) and lymphoproliferation (46.1%) were the most frequent co-occurring symptoms. The most common endoscopy findings concerned inflammation (72.2%) and erythema (69.4%); The most prevalent histopathologic findings were IBD-like inflammation (55.6%), indiscriminate chronic inflammation (47.2%) and indiscriminate active inflammation (38.9%). We assessed 88 events of treatment response in the 25 treated patients. Overall treatment response was poor, however there were 31 events of remission observed, ranging from partial to sustained remission. Of these 26 were the result of tumor necrosis factor inhibitors (TNFi) or thiopurines, either as monotherapy or in combination with other immunosuppressive treatment. 10 patients achieved complete remission. Conclusion In this study, we describe a cohort of CVID-E patients including related comorbidity, clinical course and response to therapy. CVID-E patients frequently develop other, sometimes severe comorbidities. Our study confirms the alleged heterogeneity regarding endoscopic and histopathological findings, and in one third of patients even multiple distinct abnormalities co-occurred in the same biopsy. We found azathioprine and/or TNFi to be the most effective current treatment.

To identify biomarkers and endotypes predictive of treatment response, monitor disease activity, and explore pathways associated with the clinical efficacy of leflunomide and hydroxychloroquine combination therapy (LEF/HCQ) in patients with primary Sjögren's disease (SjD). Serum proteome (Olink Immuno-oncology panel, analyzing 92 proteins) of 29 patients with SjD of the RepurpSS-I study and 8 healthy controls was analyzed at baseline and after 24 weeks of LEF/HCQ. Proteomic changes were correlated to standard and novel clinical endpoints. Transcriptome data of blood mononuclear cells and monocytes were used to assess type I and II IFN scores. At baseline, 29 proteins were differentially expressed between SjD and HC. LEF/HCQ significantly downregulated 22 out of 27 over-expressed proteins, which was not observed in the placebo-arm. Fourteen baseline proteins and the changes of four of these proteins, CXCL10, CXCL11, TNF, and soluble CD70 concentrations, were correlated with clinical response (|r| 0.40-0.62, p<0.05). Principal Component Analysis revealed an IFN-γ-associated set of coherent proteins. At baseline, using only two proteins, CXCL10 and CXCL11 effectively distinguished patients from healthy controls and responders from non-responders (all p<0.05). Finally, in addition to changes in type I IFN signatures, type II IFN signatures were observed in monocytes that were associated with changes in disease activity. These data support a significant role for a type II IFN-associated immune response in SjD pathogenesis, which is targeted by LEF/HCQ. Proteins associated with type II IFN-driven immune responses hold potential to monitor disease activity and predict treatment response.

Bariatric surgery in morbid obesity, either through sleeve gastrectomy (SG) or Roux-Y gastric bypass (RYGB), leads to sustainable weight loss, improvement of metabolic disorders and changes in intestinal microbiota. Yet, the relationship between changes in gut microbiota, weight loss and surgical procedure remains incompletely understood. We determined temporal changes in microbiota composition in 45 obese patients undergoing crash diet followed by SG ( n  = 22) or RYGB ( n  = 23). Intestinal microbiota composition was determined before intervention (baseline, S1), 2 weeks after crash diet (S2), and 1 week (S3), 3 months (S4) and 6 months (S5) after surgery. Relative to S1, the microbial diversity index declined at S2 and S3 ( p  < 0.05), and gradually returned to baseline levels at S5. Rikenellaceae relative abundance increased and Ruminococcaceae and Streptococcaceae abundance decreased at S2 ( p  < 0.05). At S3, Bifidobacteriaceae abundance decreased, whereas those of Streptococcaceae and Enterobacteriaceae increased ( p  < 0.05). Increased weight loss between S3-S5 was not associated with major changes in microbiota composition. No significant differences appeared between both surgical procedures. In conclusion, undergoing a crash diet and bariatric surgery were associated with an immediate but temporary decline in microbial diversity, with immediate and permanent changes in microbiota composition, independent of surgery type.

The coronavirus disease 19 (COVID-19) is a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that invades lung epithelial cells and can lead to severe respiratory failure. In this study, we evaluated whether Clara cell 16 kDa protein (CC16), a serum marker of lung alveolar cell damage, is predictive for disease severity. Patients suspected of SARS-CoV-2 infection were included in this study. Serum levels of Clara cell 16 kDa protein (CC16), soluble Fas Ligand, cytochrome C, thymus- and activation regulated chemokine (TARC) and of oxidate stress related proteins were analyzed. Clinical patient data were extracted from the Utrecht Patient Oriented Database. COVID-19 positive patients were divided in two groups according to disease severity. The mean day difference between COVID-19 diagnosis date and sampling date was +11 days. Concentrations of TARC were lower in COVID-19 positive versus COVID-19 negative patients (unpaired t-test, p =0.002). In addition, CC16 serum levels were significantly elevated in sera taken from patients that were admitted at the intensive care unit (ICU) ( p =0.0082). In a matched cohort, sera taken prior to ICU admission (-3 days) contained higher CC16 levels (paired t-test, p =0.0072). Multivariable analyses adjusted for known risk factors (age, gender, blood counts, lactate dehydrogenase, c-reactive protein, underlying disease) showed that CC16 levels were independently associated to COVID-19 severity (interquartile-range, odds ratio 1.53, p =0.0102). In conclusion, our findings highlight CC16 as a promising biomarker for early identification of severe COVID19 cases, which could improve patient management and resource allocation.

Mucosal-associated invariant T (MAIT) cells might play a role in B cell hyperactivity and local inflammation in primary Sjögren's syndrome (pSS), just like previously studied mucosa-associated CCR9+ and CXCR5+ T helper cells. Here, we investigated expression of CCR9, CXCR5, IL-18R and IL-7R on MAIT cells in pSS, and assessed the capacity of DMARDs to inhibit the activity of MAIT cells. Circulating CD161+ and IL-18Rα+ TCRVα7.2+ MAIT cells from pSS patients and healthy controls (HC) were assessed using flow cytometry, and expression of CCR9, CXCR5, and IL-7R on MAIT cells was studied. Production of IFN-γ and IL-21 by MAIT cells was measured upon IL-7 stimulation in the presence of leflunomide (LEF) and hydroxychloroquine (HCQ). The numbers of CD161+ and IL-18Rα+ MAIT cells were decreased in pSS patients compared to HC. Relative increased percentages of CD4 MAIT cells in pSS patients caused significantly higher CD4/CD8 ratios in MAIT cells. The numbers of CCR9 and CXCR5-expressing MAIT cells were significantly higher in pSS patients. IL-7R expression was higher in CD8 MAIT cells as compared to all CD8 T cells, and changes in IL-7R expression correlated to several clinical parameters. The elevated production of IL-21 by MAIT cells was significantly inhibited by LEF/HCQ treatment. Circulating CD161+ and IL-18Rα+ MAIT cell numbers are decreased in pSS patients. Given their enriched CCR9/CXCR5 expression this may facilitate migration to inflamed salivary glands known to overexpress CCL25/CXCL13. Given the pivotal role of IL-7 and IL-21 in inflammation in pSS this indicates a potential role for MAIT cells in driving pSS immunopathology.

IntroductionIncreased CCL5 expression and CD8 T cells have been shown to be pivotal regulators of immunopathology in primary Sjögren’s syndrome (pSS) and pSS-like disease. Increased CCL5 expression by CCR9+ CD4 T cells has previously been implicated as a contributor to immunopathology in pSS. The role of CD8 T cells and in particular CCR9+ CD8 T cells and their potential to secrete CCL5 has not previously been studied in pSS. In this study we investigated both CCR9 and CCL5 expression by CD8 T cells in pSS patients compared to healthy controls (HC).MethodsCCR9 expression on CD8 T cells from peripheral blood was compared between patients with pSS and HC by flow cytometry. Intracellular CCL5 expression by naive, memory and effector CCR9- and CCR9+ CD8 T cells was assessed. In addition, the capacity and pace of CCL5 release upon T cell activation was determined for all subsets and compared with CD4 T cells.ResultsThe frequency of circulating CCR9+ CD8 T cells in pSS patients is increased compared to HC. Antigen-experienced CD8 T cells, especially CCR9+ effector CD8 T cells, express the highest CCL5 levels, and release the highest levels of CCL5 upon activation. Memory and effector CD8 T cells of pSS patients express significantly less CCL5 and subsequently release less CCL5 upon stimulation compared to HC. CCR9+ CD8 T cells rapidly release CCL5 and significantly more than CCR9+ CD4 T cells.ConclusionCCR9+ CD8 T cells express more CCL5 than CCR9- CD8 T cells. CCL5 is rapidly released upon activation, resulting in reduced intracellular expression. Reduced CCL5 expression by an elevated number of antigen-experienced CCR9-expressing CD8 T cells in pSS patients points towards increased release in vivo . This suggests that CCL5 release by CCR9+ CD8 T cells contributes to immunopathology in pSS.

In Behçet's disease (BD), an auto-inflammatory vasculitis, an unbalanced gut microbiota can contribute to pro-inflammatory reactions. In separate studies, distinct pro- and anti-inflammatory bacteria associated with BD have been identified. To establish disease-associated determinants, we performed gut microbiome profiling in BD patients from the Netherlands ( = 19) and Italy ( = 13), matched healthy controls (HC) from the Netherlands ( = 17) and Italy ( = 15) and oral microbiome profiling in Dutch BD patients ( = 18) and HC ( = 15) by 16S rRNA gene sequencing. In addition, we used fecal IgA-SEQ analysis to identify specific IgA coated bacterial taxa in Dutch BD patients ( = 13) and HC ( = 8). In BD stool samples alpha-diversity was conserved, whereas beta-diversity analysis showed no clustering based on disease, but a significant segregation by country of origin. Yet, a significant decrease of unclassified and genera was associated with BD patients compared to HC. Subdivided by country, the Italian cohort displays a significant decrease of unclassified and genera, in the Dutch cohort this decrease is only a trend. Increased IgA-coating of spp., spp. and species was found in stool from BD patients. Moreover, oral Dutch BD microbiome displayed increased abundance of and families. BD patients show decreased fecal abundance of and and increased oral abundance of and . In addition, increased fecal IgA coating of and may reflect retention of anti-inflammatory species and neutralization of pathosymbionts in BD, respectively. Additional studies are warranted to relate intestinal microbes with the significance of ethnicity, diet, medication and response with distinct pro- and inflammatory pathways in BD patients.

Enterococcus faecium, an ubiquous colonizer of humans and animals, has evolved in the last 15 years from an avirulent commensal to the third most frequently isolated nosocomial pathogen among intensive care unit patients in the United States. E. faecium combines multidrug resistance with the potential of horizontal resistance gene transfer to even more pathogenic bacteria. Little is known about the evolution and virulence of E. faecium, and genomic studies are hampered by the absence of a completely annotated genome sequence. To further unravel its evolution, we used a mixed whole-genome microarray and hybridized 97 E. faecium isolates from different backgrounds (hospital outbreaks (n = 18), documented infections (n = 34) and asymptomatic carriage of hospitalized patients (n = 15), and healthy persons (n = 15) and animals (n = 21)). Supported by Bayesian posterior probabilities (PP = 1.0), a specific clade containing all outbreak-associated strains and 63% of clinical isolates was identified. Sequencing of 146 of 437 clade-specific inserts revealed mobile elements (n = 74), including insertion sequence (IS) elements (n = 42), phage genes (n = 6) and plasmid sequences (n = 26), hypothetical (n = 58) and membrane proteins (n = 10), and antibiotic resistance (n = 9) and regulatory genes (n = 11), mainly located on two contigs of the unfinished E. faecium DO genome. Split decomposition analysis, varying guanine cytosine content, and aberrant codon adaptation indices all supported acquisition of these genes through horizontal gene transfer with IS16 as the predicted most prominent insert (98% sensitive, 100% specific). These findings suggest that acquisition of IS elements has facilitated niche adaptation of a distinct E. faecium subpopulation by increasing its genome plasticity. Increased genome plasticity was supported by higher diversity indices (ratio of average genetic similarities of pulsed-field gel electrophoresis and multi locus sequence typing) for clade-specific isolates. Interestingly, the previously described multi locus sequence typing-based clonal complex 17 largely overlapped with this clade. The present data imply that the global emergence of E. faecium, as observed since 1990, represents the evolution of a subspecies with a presumably better adaptation than other E. faecium isolates to the constraints of a hospital environment.

Nowadays, Enterococcus faecium is one of the leading nosocomial pathogens worldwide. Strains causing clinical infections or hospital outbreaks are enriched in the enterococcal surface protein (Esp) encoding ICEEfm1 mobile genetic element. Previous studies showed that Esp is involved in biofilm formation, endocarditis and urinary tract infections. In this study, we characterized the role of the putative AraC type of regulator (locus tag EfmE1162_2351), which we renamed ebrB and which is, based on the currently available whole genome sequences, always located upstream of the esp gene, and studied its role in Esp surface exposure during growth. A markerless deletion mutant of ebrB resulted in reduced esp expression and complete abolishment of Esp surface exposure, while Esp cell-surface exposure was restored when this mutant was complemented with an intact copy of ebrB. This demonstrates a role for EbrB in esp expression. However, during growth, ebrB expression levels did not change over time, while an increase in esp expression at both RNA and protein level was observed during mid-log and late-log phase. These results indicate the existence of a secondary regulation system for esp, which might be an unknown quorum sensing system as the enhanced esp expression seems to be cell density dependent. Furthermore, we determined that esp is part of an operon of at least 3 genes putatively involved in biofilm formation. A semi-static biofilm model revealed reduced biofilm formation for the EbrB deficient mutant, while dynamics of biofilm formation using a flow cell system revealed delayed biofilm formation in the ebrB mutant. In a mouse intestinal colonization model the ebrB mutant was less able to colonize the gut compared to wild-type strain, especially in the small intestine. These data indicate that EbrB positively regulates the esp operon and is implicated in biofilm formation and intestinal colonization.

Common Variable Immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are primary antibody deficiencies characterized by hypogammaglobulinemia and recurrent infections, which can lead to structural airway disease (AD) and interstitial lung disease (ILD). We investigated associations between serum IgA, oropharyngeal microbiota composition and severity of lung disease in these patients. In this cross-sectional multicentre study we analyzed oropharyngeal microbiota composition of 86 CVID patients, 12 XLA patients and 49 healthy controls (HC) using next-generation sequencing of the 16S rRNA gene. qPCR was used to estimate bacterial load. IgA was measured in serum. High resolution CT scans were scored for severity of AD and ILD. Oropharyngeal bacterial load was increased in CVID patients with low IgA ( = 0.013) and XLA ( = 0.029) compared to HC. IgA status was associated with distinct beta (between-sample) diversity ( = 0.039), enrichment of ( , and more severe radiographic lung disease ( = 0.003), independently of recent antibiotic use. AD scores were positively associated with , and , and ILD scores with and negatively with . In clinically stable patients with CVID and XLA, radiographic lung disease was associated with IgA deficiency and expansion of distinct oropharyngeal bacterial taxa. Our findings highlight IgA as a potential driver of upper respiratory tract microbiota homeostasis.