Publications by authors named "Henny G Otten"

64 Publications

Fructo-Oligosaccharides Modify Human DC Maturation and Peanut-Induced Autologous T-Cell Response of Allergic Patients .

Front Immunol 2020 15;11:600125. Epub 2021 Feb 15.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.

Background: Dendritic cells (DCs) play an important role in antigen presentation, and are an interesting target for immune-modulation in allergies. Short- and long-chain fructo-oligosaccharides (scFOS/lcFOS, FF) have immunomodulatory capacities, and may influence the outcome of DC antigen presentation.

Objective: This study investigated the effect of FF during DC maturation and allergen presentation using cells of peanut-allergic patients in an autologous DC-T cell assay.

Methods: CD14 and CD4 T cells were isolated from peanut-allergic patients. CD14 monocytes were differentiated into immature DCs (imDCs), and matured (matDCs) in the presence or absence of crude peanut-extract (CPE) and/or FF, and co-cultured in an autologous DC-T cell assay. T cell polarization, proliferation and cytokine production were measured.

Results: Expression of maturation surface molecule markers on matDCs was not affected by CPE and/or FF. By contrast, the IL-10 secretion by matDCs increased compared to imDCs, upon exposure to CPE and FF compared to CPE alone. Also the IP-10 secretion increased in CPE/FF-matDCs compared to imDC. CPE-matDCs enhanced IL-13 release in the DC-T-cell assay and Treg polarization in presence or absence of FF. CPE/FF-DCs tended to increase the Treg/Th1 and Treg/Th2 ratios compared to matDCs. The proliferation of both Treg and Th2 cells tended to increase when T cells were co-cultured with CPE-matDCs compared to matDCs, which became significant when CPE-matDCs were also exposed to FF and a same tendency was shown for Th1 proliferation.

Conclusion: Only in the presence of FF, CPE-matDCs produced increased regulatory and Th1-related mediators. CPE-matDCs modified T cell polarization and proliferation, and additional exposure to FF tended to enhance Treg/Th2 and Treg/Th1 ratios instructed by CPE/FF-matDCs. However this effect was not strong enough to suppress CPE-matDCs induced IL-13 release by Th-cells. This indicates the ability of FF to modify DC maturation in the presence of an allergen supporting a more Treg/Th1 prone direction of the successive allergen specific Th2 cell response.
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http://dx.doi.org/10.3389/fimmu.2020.600125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917053PMC
February 2021

High-resolution mapping identifies HLA class II associations with multifocal motor neuropathy.

Neurobiol Aging 2021 Jan 20;101:79-84. Epub 2021 Jan 20.

UMC Utrecht Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery, Utrecht, the Netherlands. Electronic address:

Objective: To gain further insight in the immunopathology underlying multifocal motor neuropathy (MMN) by exploring the association between MMN and the human leukocyte antigen (HLA) class II DRB1, DQB1, and DQA loci in depth and by correlating associated haplotypes to detailed clinical and anti-ganglioside antibody data.

Methods: We performed high-resolution HLA-class II typing for the DRB1, DQB1, and DQA1 loci in 126 well-characterized MMN patients and assessed disease associations with haplotypes. We used a cohort of 1305 random individuals as a reference for haplotype distribution in the Dutch population.

Results: The DRB1*15:01-DQB1*06:02 haplotype (OR 1.6 [95% CI 1.1-2.2], p < 0.05) and the DRB1*12:01-DQB1*03:01 haplotype (OR 2.7 [95% CI 1.2-5.5], p < 0.05) were more frequent in patients with MMN than in controls. These haplotypes were not associated with disease course, response to treatment or anti-ganglioside antibodies.

Conclusions: MMN is associated with the DRB1*15:01-DQB1*06:02 and DRB1*12:01-DQB1*03:01 haplotypes. These HLA molecules or gene variants in their immediate vicinity may promote the specific inflammatory processes underlying MMN.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.014DOI Listing
January 2021

Text Mining of Electronic Health Records Can Accurately Identify and Characterize Patients With Systemic Lupus Erythematosus.

ACR Open Rheumatol 2021 Feb 12;3(2):65-71. Epub 2021 Jan 12.

University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Objective: Electronic health records (EHR) are increasingly being recognized as a major source of data reusable for medical research and quality monitoring, although patient identification and assessment of symptoms (characterization) remain challenging, especially in complex diseases such as systemic lupus erythematosus (SLE). Current coding systems are unable to assess information recorded in the physician's free-text notes. This study shows that text mining can be used as a reliable alternative.

Methods: In a multidisciplinary research team of data scientists and medical experts, a text mining algorithm on 4607 patient records was developed to assess the diagnosis of 14 different immune-mediated inflammatory diseases and the presence of 18 different symptoms in the EHR. The text mining algorithm included key words in the EHR, while mining the context for exclusion phrases. The accuracy of the text mining algorithm was assessed by manually checking the EHR of 100 random patients suspected of having SLE for diagnoses and symptoms and comparing the outcome with the outcome of the text mining algorithm.

Results: After evaluation of 100 patient records, the text mining algorithm had a sensitivity of 96.4% and a specificity of 93.3% in assessing the presence of SLE. The algorithm detected potentially life-threatening symptoms (nephritis, pleuritis) with good sensitivity (80%-82%) and high specificity (97%-97%).

Conclusion: We present a text mining algorithm that can accurately identify and characterize patients with SLE using routinely collected data from the EHR. Our study shows that using text mining, data from the EHR can be reused in research and quality control.
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http://dx.doi.org/10.1002/acr2.11211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882527PMC
February 2021

ARHGDIB and AT1R autoantibodies are differentially related to the development and presence of chronic antibody-mediated rejection and fibrosis in kidney allografts.

Hum Immunol 2021 Feb 6;82(2):89-96. Epub 2021 Jan 6.

Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, Rotterdam, the Netherlands.

The role of non-HLA autoantibodies in chronic-active antibody-mediated rejection (c-aABMR) of kidney transplants is largely unknown. In this study, the presence and clinical relevance of non-HLA autoantibodies using a recently developed multiplex Luminex-based assay were investigated. Patients with a kidney allograft biopsy at least 6 months after transplantation with a diagnosis of c-aABMR (n = 36) or no rejection (n = 21) were included. Pre-transplantation sera and sera at time of biopsy were tested for the presence of 14 relevant autoantibodies. A significantly higher signal for autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) was detected in recipients with c-aABMR as compared to recipients with no rejection. However, ARHGDIB autoantibodies did not associate with graft survival. Levels of autoantibodies against angiotensin II type 1-receptor (AT1R) and peroxisomal trans-2-enoyl-CoA reductase (PECR) were increased in recipients with interstitial fibrosis in their kidney biopsy. Only the signal for AT1R autoantibody showed a linear relationship with the degree of interstitial fibrosis and was associated with graft survival. In conclusion, anti-ARHGDIB autoantibodies are increased when c-aABMR is diagnosed but are not associated with graft survival, while higher levels of AT1R autoantibody are specifically associated with the presence of interstitial fibrosis and graft survival.
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http://dx.doi.org/10.1016/j.humimm.2020.12.003DOI Listing
February 2021

IgE-binding to vicilin-like antimicrobial peptides is associated with systemic reactions to macadamia nut.

Clin Transl Allergy 2020 Dec 2;10(1):55. Epub 2020 Dec 2.

Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Background: Macadamia nut can induce fatal allergic reactions and changes in dietary habits will raise their consumption in industrialised countries. Until now diagnosis of macadamia nut allergy by sIgE solely relies on the macadamia nut extract, but single components are lacking.

Methods: Macadamia nut proteins recognised by IgE from 2 macadamia nut extract positive sera were identified by mass spectrometry (vicilin-like antimicrobial peptides: VLAP). Sensitisation to macadamia nut extract and heterologously expressed isoform VLAP-2-3 was evaluated in 82 nut allergic (NA) and 27 tolerant (NT) patients (no tree nut allergy reported) comprehending 10 macadamia nut allergic (MA) and 18 explicitly reported macadamia nut tolerant patients (MT), using line blots. Co-sensitisation to additional VLAP isoforms and other vicilins was evaluated in 8 MA, 12 MT and 14 NA patients sensitised to VLAP-2-3. Functional properties were determined by indirect basophil activation.

Results: Even though proteins recognised by IgE were identified as VLAP-2-1, 2-2 and 2-3, only peptides specifically belonging to VLAP-2-3 were detected by mass spectrometry. The macadamia nut extract was recognised by 33% of NA patients (27/82) including 3 MA patients and 26% of NT patients (7/27, 3 MT). Similarly, 29% of NA (24/82) patients showed partly strong sIgE-binding to VLAP-2-3 including 3 MA patients with systemic reactions to macadamia nut. Contrary, VLAP-2-3 was recognised by only 2 NT (1 MT) patients (7%) with very low sIgE titres. Simultaneous recognition of the isoforms VLAP-2-1 and 2-2 was observed in all patients positive for VLAP-2-3 with partly reduced sIgE titres in 59% of these patients. Additionally, all three VLAP isoforms were able to repeatedly induce BAT reactivity upon sensitisation with a MA serum.

Conclusion: VLAP proteins are the first described macadamia nut components with serological and functional allergenic properties and they are associated with systemic reactions to macadamia nut.
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http://dx.doi.org/10.1186/s13601-020-00364-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709350PMC
December 2020

Accurate Prediction of Peanut Allergy in One-Third of Adults Using a Validated Ara h 2 Cutoff.

J Allergy Clin Immunol Pract 2021 Apr 26;9(4):1667-1674.e3. Epub 2020 Nov 26.

Department of Dermatology and Allergology, University Medical Center, Utrecht University, Utrecht, the Netherlands; Center of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.

Background: The diagnostic value of peanut components is extensively studied in children, but to a lesser extent in adults with suspected peanut allergy. The use of peanut components in daily practice may reduce the need for double-blind placebo-controlled food challenges (DBPCFCs); however, validation studies are currently lacking.

Objective: To evaluate the diagnostic value of (combined) peanut components and validate a previously found Ara h 2 cutoff level with 100% positive predictive value (PPV) in adults with suspected peanut allergy.

Methods: Adults who underwent a peanut DBPCFC were included: 84 patients from a previous study (2002-2012) and 70 new patients (2012-2019). Specific IgE (sIgE) to peanut extract, Ara h 1, 2, 3, 6, and 8 was measured using ImmunoCAP. Diagnostic value was assessed with an area under the curve (AUC) analysis.

Results: In total, 95 (62%) patients were peanut allergic. sIgE to Ara h 2 and Ara h 6 were the best predictors with an AUC (95% confidence interval) of 0.85 (0.79-0.91) and 0.85 (0.79-0.92), respectively. The Ara h 2 cutoff level with 100% PPV (≥1.75 kU/L) was validated in the 70 new patients. Thirty percent of all included patients could be classified correctly as peanut allergic using this validated cutoff level.

Conclusion: sIgE to Ara h 2 and Ara h 6 have equally high discriminative ability. Peanut allergy can be predicted accurately in one-third of adults using a validated cutoff level of sIgE to Ara h 2.
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http://dx.doi.org/10.1016/j.jaip.2020.11.024DOI Listing
April 2021

ARGX-117, a therapeutic complement inhibiting antibody targeting C2.

J Allergy Clin Immunol 2021 Apr 11;147(4):1420-1429.e7. Epub 2020 Sep 11.

Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Prothix BV, Leiden, The Netherlands. Electronic address:

Background: Activation of the classical and lectin pathway of complement may contribute to tissue damage and organ dysfunction of antibody-mediated diseases and ischemia-reperfusion conditions. Complement factors are being considered as targets for therapeutic intervention.

Objective: We sought to characterize ARGX-117, a humanized inhibitory monoclonal antibody against complement C2.

Methods: The mode-of-action and binding characteristics of ARGX-117 were investigated in detail. Furthermore, its efficacy was analyzed in in vitro complement cytotoxicity assays. Finally, a pharmacokinetic/pharmacodynamic study was conducted in cynomolgus monkeys.

Results: Through binding to the Sushi-2 domain of C2, ARGX-117 prevents the formation of the C3 proconvertase and inhibits classical and lectin pathway activation upstream of C3 activation. As ARGX-117 does not inhibit the alternative pathway, it is expected not to affect the antimicrobial activity of this complement pathway. ARGX-117 prevents complement-mediated cytotoxicity in in vitro models for autoimmune hemolytic anemia and antibody-mediated rejection of organ transplants. ARGX-117 exhibits pH- and calcium-dependent target binding and is Fc-engineered to increase affinity at acidic pH to the neonatal Fc receptor, and to reduce effector functions. In cynomolgus monkeys, ARGX-117 dose-dependently reduces free C2 levels and classical pathway activity. A 2-dose regimen of 80 and 20 mg/kg separated by a week, resulted in profound reduction of classical pathway activity lasting for at least 7 weeks.

Conclusions: ARGX-117 is a promising new complement inhibitor that is uniquely positioned to target both the classical and lectin pathways while leaving the alternative pathway intact.
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http://dx.doi.org/10.1016/j.jaci.2020.08.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485568PMC
April 2021

Detection of specific IgE against linear epitopes from Gal d 1 has additional value in diagnosing hen's egg allergy in adults.

Clin Exp Allergy 2020 12 24;50(12):1415-1423. Epub 2020 Sep 24.

Euroimmun AG, Lübeck, Germany.

Background: Although hen's egg allergy is more prevalent in children, up to 0.6% of adults from different European countries suffer from a persistent or newly onset hen's egg allergy, making accurate diagnosis in adults necessary. However, sensitization to hen's egg extracts, components and linear epitopes is solely studied in children.

Methods: Hen's egg allergic (n = 16) and tolerant (n = 19) adults were selected by sensitization towards recombinant components rGal d 1 and/or 3. Sensitization profiles towards egg white and yolk extract and the native components Gal d 1, 2, 3 and 4 were respectively evaluated with the ImmunoCAP or the EUROLINE system. Characterization of linear epitopes was performed with a peptide microarray containing 15mer peptides representing the entire sequence of mature Gal d 1 and 3.

Results: Overall, sIgE titres against hen's egg extracts and single components overlapped largely between allergic and tolerant adults. Although the median sIgE/sIgG4 ratio to Gal d 1 was increased in allergic adults, the range was comparable between both groups. Clinically relevant sensitization to Gal d 1 was confirmed by sIgE-binding to the linear epitopes aa30-41, aa39-50 or aa84-95 in 6/13 allergic adults, mainly suffering from objective symptoms. In comparison, these epitopes were recognized by 1/15 tolerant patient. Only a few linear epitopes were detected for Gal d 3, suggesting a greater importance of conformational epitopes for the recognition of Gal d 3.

Conclusion And Clinical Relevance: Specific IgE-binding to linear epitopes of Gal d 1 is highly specific in identifying hen's egg allergic adults with objective symptoms.
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http://dx.doi.org/10.1111/cea.13730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756380PMC
December 2020

Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

Rheumatology (Oxford) 2021 02;60(2):785-801

Centre for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

Objectives: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD.

Methods: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA.

Results: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction.

Conclusion: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.
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http://dx.doi.org/10.1093/rheumatology/keaa270DOI Listing
February 2021

A Review on the Function and Regulation of ARHGDIB/RhoGDI2 Expression Including the Hypothetical Role of ARHGDIB/RhoGDI2 Autoantibodies in Kidney Transplantation.

Transplant Direct 2020 May 9;6(5):e548. Epub 2020 Apr 9.

Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.

Challenging and still unsolved problems in kidney transplantation are risk stratification and the treatment of humoral rejection. Antibody-mediated rejection is an important cause of early and chronic rejection. The impact of donor-specific HLA antibodies on antibody-mediated rejection-causing graft damage is well known, but the clinical relevance of non-HLA antibodies remains unclear. Recently, in 2 independent studies, a new correlation was found between the presence of non-HLA anti-Rho guanosine diphosphate dissociation inhibitor 2 (ARHGDIB) antibodies and increased graft failure. RhoGDI2, another name for ARHGDIB, is a negative regulator of the Rho guanosine triphosphate (RhoGTP)ases RhoA, Rac1m, and Cdc42, whose main function is regulating the actin network in a variety of cells. RhoGDI2 is mainly expressed intracellularly, and some expression is observed on the cell surface. Currently, there is no mechanism known to explain this correlation. Additionally, the reason why the antibodies are produced is unknown. In this review, we will address these questions, provide an overview of other diseases in which these antibodies are prevalent, and describe the physiological role of RhoGDI2 itself. If the mechanism and impact of RhoGDI2 antibodies in kidney graft failure are known, improved risk stratification can be provided to decrease the rate of donor kidney graft failure.
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http://dx.doi.org/10.1097/TXD.0000000000000993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213606PMC
May 2020

Pretransplant Donor-Specific Anti-HLA Antibodies and the Risk for Rejection-Related Graft Failure of Kidney Allografts.

J Transplant 2020 29;2020:5694670. Epub 2020 Jan 29.

Department of Nephrology & Transplantation, Erasmus Medical Center, Rotterdam, Netherlands.

Background: The presence of donor-specific antibodies (DSAs) against HLA before kidney transplantation has been variably associated with decreased long-term graft survival. Data on the relation of pretransplant DSA with rejection and cause of graft failure in recipients of donor kidneys are scarce.

Methods: Patients transplanted between 1995 and 2005 were included and followed until 2016. Donor-specific antibodies before transplantation were determined retrospectively. For cause, renal transplant biopsies were reviewed.

Results: Pretransplant DSAs were found in 160 cases on a total of 734 transplantations (21.8%). In 80.5% of graft failures, a diagnostic renal biopsy was performed. The presence of pretransplant DSA (DSApos) increased the risk of graft failure within the first 3 months after transplantation (5.2% vs. 9.4%) because of rejection with intragraft thrombosis ( < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos, < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos, < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos.

Conclusions: Pretransplant DSAs are a risk factor for early graft loss and increase the incidence for humoral rejection and graft loss but do not affect the risk for T cell-mediated rejection.
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http://dx.doi.org/10.1155/2020/5694670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008278PMC
January 2020

Response of FcεRI-bearing leucocytes to omalizumab in chronic spontaneous urticaria.

Clin Exp Allergy 2020 03 7;50(3):364-371. Epub 2020 Feb 7.

Division Internal Medicine and Dermatology, Department Dermatology/Allergology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: The pathogenesis of chronic spontaneous urticaria (CSU) and the mechanism of action of omalizumab in CSU remain unclear.

Objective: In this study, we assessed the responsiveness and FcεRI expression of various subsets of leucocytes in patients with CSU treated with omalizumab.

Methods: In this prospective cohort study, 30 patients were treated with 6 administrations of 300 mg omalizumab every 4 weeks, followed by a follow-up period of 12 weeks. FcεRI expression and the percentage of basophils, monocytes, and dendritic cell subsets were analysed before and during treatment, and after follow-up. In addition, anti-IgE- and C5a-induced basophil degranulation was measured. The results were correlated with disease activity and response to omalizumab.

Results: In addition to a rapid and significant reduction in FcεRI on basophils, we demonstrated a reduction in FcεRI on plasmacytoid dendritic cells during omalizumab treatment, which persisted until 3 months after discontinuation. FcεRI expression on basophils and its reduction did not correlate with the treatment response. Omalizumab led to an increased percentage of basophils in blood but not of the other FcεRI-bearing leucocytes. Basophil responsiveness was differentially affected; anti-IgE-, but not C5a-induced basophil degranulation increased during the treatment. Apart from clinical non-responders showing a stronger increase in anti-IgE-induced basophil degranulation over a period time, no differences were found in omalizumab responders vs non-responders.

Conclusions/clinical Relevance: FcεRI expression on basophils decreased rapidly, while anti-IgE-induced degranulation significantly increased due to omalizumab treatment in patients with CSU, persisting at least for 3 months after stopping the treatment. None of the markers were able to predict the effectiveness of treatment. Whether basophils play a role in omalizumab responsiveness in CSU remains unclear.
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http://dx.doi.org/10.1111/cea.13566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065003PMC
March 2020

Antibodies Against ARHGDIB and ARHGDIB Gene Expression Associate With Kidney Allograft Outcome.

Transplantation 2020 07;104(7):1462-1471

Department of Microbiology, Immunology and Transplantation, KU Leuven, University of Leuven, Belgium.

Background: The impact of donor-specific anti-HLA antibodies (DSA) on antibody-mediated rejection (AMR) and kidney allograft failure is well established. However, the relevance of non-HLA antibodies remains unclear.

Methods: We investigated 13 pretransplant non-HLA antibodies and their association with histology of AMR (AMRh) and kidney allograft failure. We included single kidney recipients (n = 203) with AMRh, according to the Banff 2017 classification and matched AMRh-free controls (n = 219). Non-HLA antibodies were assessed using multiplex Luminex assay.

Results: Of the selected non-HLA antibodies (against agrin, adipocyte plasma membrane-associated protein, Rho GDP-dissociation inhibitor 2 [ARHGDIB], Rho guanine nucleotide exchange factor 6, angiotensin-II type 1 receptor, endothelin type A receptor, lamin B1, BPI fold-containing family B member 1, peroxisomal trans-2-enoyl-coenzyme A reductase, phospholipase A2 receptor, protein kinase C zeta type, tubulin beta-4B class IVb, vimentin), only antibodies against ARHGDIB (adjusted median fluorescence intensity [aMFI] ≥ 1000), a minor histocompatibility antigen, associated with graft failure, in univariate and multivariate models (hazard ratio = 2.7; 95% confidence interval [CI],1.3-5.4; P = 0.007). There was a 19.5-fold (95% CI, 6.0-63.9; P < 0.0001) increased risk of graft failure in patients positive for both DSA and anti-ARHGDIB antibodies (aMFI ≥ 1000) versus patients negative for both DSA and anti-ARHGDIB antibodies, compared with a 4.4-fold (95% CI, 2.4-8.2; P < 0.0001) increased risk in patients with only DSA, and a 4.1-fold (95% CI, 1.4-11.7; P = 0.009) increased risk in patients with only anti-ARHGDIB antibodies above 2000 aMFI. AMRh associated with increased intrarenal expression of the ARHGDIB gene. In the absence of AMRh and DSA, anti-ARHGDIB antibodies were not clearly associated with graft failure.

Conclusions: The presence of pretransplant anti-ARHGDIB antibodies has an additive effect in patients with DSA on the risk of graft failure via AMRh. Other investigated non-HLA antibodies, including antibodies against angiotensin-II type 1 receptor, did not contribute to risk stratification and could not explain the histology of AMR in the absence of DSA.
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http://dx.doi.org/10.1097/TP.0000000000003005DOI Listing
July 2020

Ara h 7 isoforms share many linear epitopes: Are 3D epitopes crucial to elucidate divergent abilities?

Clin Exp Allergy 2019 11 6;49(11):1512-1519. Epub 2019 Oct 6.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: The peanut allergens Ara h 2, h 6, and h 7 are potent allergens and can trigger severe reactions. Ara h 7 consists of three isoforms differing in their ability to induce basophil degranulation, whereas the ability of Ara h 7.0201 is comparable to Ara h 2 and 6 as shown in previous literature.

Objective: To identify linear epitopes of Ara h 7.0101, Ara h 7.0201 and Ara h 7.0301 recognized by IgE and IgG4 from patients sensitized to Ara h 7 and to investigate their potential to elucidate divergent abilities of the Ara h 7 isoforms in inducing basophil activation.

Methods: Linear epitopes recognized by IgE and IgG4 were mapped by peptide microarray analysis containing 15-mer peptides of Ara h 2.0201, 6, 7.0101, 7.0201 and 7.0301 and 39 peanut allergic patients sensitized to Ara h 7 (discovery). For validation, 20-mer peptides containing the minimal epitope and surrounding amino acids were incubated with 25 sensitized patients and 10 controls (validation).

Results: Three out of 14 linear epitopes were unique for each isoform (Ara h 7.0101: aa 97-109; Ara h 7.0201: aa 122-133; Ara h 7.0301: aa 65-74) but scarcely recognized by IgE. The main linear IgE epitope (aa 51-57) located in the long flexible loop of all Ara h 7 isoforms was bound by antibodies from 31% of the patients (discovery and validation cohort). Regarding IgG4, 55% of the patients recognized an epitope present on all isoforms (aa 55-65), whereas epitope aa 129-137, only present on Ara h 7.0101/0.0301, was recognized by 38% of the patients. Recognition was highly individual, although 20% of the patients recognized any linear epitope neither by IgE nor by IgG4 despite a low mean z-score of ≥ 1.7. Remarkably, only 50% of the patients recognized one or more epitopes by IgE.

Conclusion & Clinical Relevance: Ara h 7 isoforms share many linear epitopes being easily accessible for antibody binding. Unique epitopes, essential to elucidate divergent potencies, were scarcely recognized, suggesting a crucial involvement of conformational epitopes.
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http://dx.doi.org/10.1111/cea.13496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900131PMC
November 2019

Sesame oleosins are minor allergens.

Clin Transl Allergy 2019 28;9:32. Epub 2019 Jun 28.

1Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: In daily practice, one-third of sesame allergic patients, confirmed by clinical history or food challenge, do not show any detectable specific IgE using current diagnostics. Currently used sesame extracts are water-based and therefore lacking hydrophobic proteins like oleosins. Oleosins, the stabilizer of lipid droplets in plants, are described as allergens in sesame, peanut and hazelnut. In this study, we examine the role of oleosins in sesame allergy and their potential cross-reactivity between sesame and (pea)nuts.

Methods: Specific IgE and IgG sensitisation to native and heterologously expressed sesame components and oleosins from other nuts, free of seed storage proteins, was assessed by line blot and sera from 17 sesame allergic patients without detectable specific IgE sensitisation to sesame, and compared to 18 sesame allergic and 13 tolerant patients with specific IgE sensitisation to sesame.

Results: Sesame allergic patients without sensitisation showed no specific IgE to the tested sesame oleosins or components. Low levels of specific IgE to sesame oleosins were detected in 17% of sesame allergic and 15% of tolerant patients with sIgE sensitisation. Oleosins were recognised by serum IgG from multiple patients confirming immune reactivity and excluding technical issues leading to lack of specific IgE-binding to oleosins.

Conclusion: Sesame oleosins are minor allergens and appear to have no additonal value in diagnosing sesame allergy in adults based on sIgE and sIgG detection. There is a high need for additional diagnostic tools in those patients to minimize the number of required food challenges.
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http://dx.doi.org/10.1186/s13601-019-0271-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599271PMC
June 2019

Antibodies against ARHGDIB are associated with long-term kidney graft loss.

Am J Transplant 2019 12 3;19(12):3335-3344. Epub 2019 Jul 3.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

The clinical significance of non-HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large-scale studies incorporating analysis of multiple non-HLA antibodies simultaneously. We developed a multiplex non-HLA antibody assay against 14 proteins highly expressed in the kidney. In this study, the presence of pretransplant non-HLA antibodies was correlated to renal allograft survival in a nationwide cohort of 4770 recipients transplanted between 1995 and 2006. Autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) were significantly associated with graft loss in recipients transplanted with a deceased-donor kidney (N = 3276) but not in recipients of a living-donor kidney (N = 1496). At 10 years after deceased-donor transplantation, recipients with anti-ARHGDIB antibodies (94/3276 = 2.9%) had a 13% lower death-censored covariate-adjusted graft survival compared to the anti-ARHGDIB-negative (3182/3276 = 97.1%) population (hazard ratio 1.82; 95% confidence interval, 1.32-2.53; P = .0003). These antibodies occur independently from donor-specific anti-HLA antibodies (DSA) or other non-HLA antibodies investigated. No significant relations with graft loss were found for the other 13 non-HLA antibodies. We suggest that pretransplant risk assessment can be improved by measuring anti-ARHGDIB antibodies in all patients awaiting deceased-donor transplantation.
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http://dx.doi.org/10.1111/ajt.15493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899679PMC
December 2019

Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients.

Am J Transplant 2019 10 1;19(10):2926-2933. Epub 2019 Jul 1.

Eurotransplant Reference Laboratory, Leiden University Medical Center, Leiden, the Netherlands.

Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, as determined by extensive laboratory testing. AM patients have superior long-term graft survival compared with highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants in 1995-2005, we selected deceased donor single transplants with a minimum of 1 HLA mismatch and determined the cumulative 6-month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of 1 HLA-B plus 1 HLA-DR, or 2 HLA-DR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to nonsensitized patients, independent of other risk factors for rejection. In contrast to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low-risk transplants for highly sensitized patients with rejection rates similar to those of nonimmunized individuals.
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http://dx.doi.org/10.1111/ajt.15486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790659PMC
October 2019

Results and reflections from the PROfiling Consortium on Antibody Repertoire and Effector functions in kidney transplantation: A mini-review.

HLA 2019 08 18;94(2):129-140. Epub 2019 Jun 18.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Kidney transplantation is the best treatment option for patients with end-stage renal disease (ESRD). The waiting time for a deceased donor kidney in the Netherlands is approximately 3 years. Mortality among patients on the waiting list is high. The aim of the PROCARE consortium (PROfiling Consortium on Antibody Repertoire and Effector functions) was to decrease the waiting time by providing a matching algorithm yielding a prolonged graft survival and less HLA-immunization compared with the currently used Eurotransplant Kidney allocation system. In this study, 6097 kidney transplants carried out between January 1995 and December 2005 were re-examined with modern laboratory techniques and insights that were not available during that time period. In this way, we could identify potential new parameters that can be used to improve the matching algorithm and prolong graft survival. All eight University Medical Centers in the Netherlands participated in this multicenter study. To improve the matching algorithm, we used as central hypothesis that the combined presence of class-I and -II single-antigen bead (SAB)-defined donor-specific HLA antibodies (DSA) prior to transplantation, non-HLA antibodies, the number of B- and/or T-cell epitopes recognized on donor HLA, and specific polymorphisms in effector mechanisms of IgG were associated with an increased risk for graft failure. The purpose of this article is to relate the results obtained from the PROCARE consortium study to other studies published in recent years. The clinical relevance of SAB-defined DSA, complement-fixing DSA, non-HLA antibodies, and the effector functions of (non)-HLA-antibodies will be discussed.
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http://dx.doi.org/10.1111/tan.13581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6772180PMC
August 2019

Galectin-9 and CXCL10 as Biomarkers for Disease Activity in Juvenile Dermatomyositis: A Longitudinal Cohort Study and Multicohort Validation.

Arthritis Rheumatol 2019 08 12;71(8):1377-1390. Epub 2019 Mar 12.

University Medical Centre Utrecht, Utrecht, The Netherlands.

Objective: Objective evaluation of disease activity is challenging in patients with juvenile dermatomyositis (DM) due to a lack of reliable biomarkers, but it is crucial to avoid both under- and overtreatment of patients. Recently, we identified 2 proteins, galectin-9 and CXCL10, whose levels are highly correlated with the extent of juvenile DM disease activity. This study was undertaken to validate galectin-9 and CXCL10 as biomarkers for disease activity in juvenile DM, and to assess their disease specificity and potency in predicting the occurrence of flares.

Methods: Levels of galectin-9 and CXCL10 were measured by multiplex immunoassay in serum samples from 125 unique patients with juvenile DM in 3 international cross-sectional cohorts and a local longitudinal cohort. The disease specificity of both proteins was examined in 50 adult patients with DM or nonspecific myositis (NSM) and 61 patients with other systemic autoimmune diseases.

Results: Both cross-sectionally and longitudinally, galectin-9 and CXCL10 outperformed the currently used laboratory marker, creatine kinase (CK), in distinguishing between juvenile DM patients with active disease and those in remission (area under the receiver operating characteristic curve [AUC] 0.86-0.90 for galectin-9 and CXCL10; AUC 0.66-0.68 for CK). The sensitivity and specificity for active disease in juvenile DM was 0.84 and 0.92, respectively, for galectin-9 and 0.87 and 1.00, respectively, for CXCL10. In 10 patients with juvenile DM who experienced a flare and were prospectively followed up, continuously elevated or rising biomarker levels suggested an imminent flare up to several months before the onset of symptoms, even in the absence of elevated CK levels. Galectin-9 and CXCL10 distinguished between active disease and remission in adult patients with DM or NSM (P = 0.0126 for galectin-9 and P < 0.0001 for CXCL10) and were suited for measurement in minimally invasive dried blood spots (healthy controls versus juvenile DM, P = 0.0040 for galectin-9 and P < 0.0001 for CXCL10).

Conclusion: In this study, galectin-9 and CXCL10 were validated as sensitive and reliable biomarkers for disease activity in juvenile DM. Implementation of these biomarkers into clinical practice as tools to monitor disease activity and guide treatment might facilitate personalized treatment strategies.
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http://dx.doi.org/10.1002/art.40881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973145PMC
August 2019

Development and Validation of a Multiplex Non-HLA Antibody Assay for the Screening of Kidney Transplant Recipients.

Front Immunol 2018 19;9:3002. Epub 2018 Dec 19.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.

The best treatment for patients with end-stage renal disease is kidney transplantation. Although graft survival rates have improved in the last decades, patients still may lose their grafts partly due to the detrimental effects of donor-specific antibodies (DSA) against human leukocyte antigens (HLA) and to a lesser extent also by antibodies directed against non-HLA antigens expressed on the donor endothelium. Assays to detect anti-HLA antibodies are already in use for many years and have been proven useful for transplant risk stratification. Currently, there is a need for assays to additionally detect multiple non-HLA antibodies simultaneously in order to study their clinical relevance in solid organ transplantation. This study describes the development, technical details and validation of a high-throughput multiplex assay for the detection of antibodies against 14 non-HLA antigens coupled directly to MagPlex microspheres or indirectly via a HaloTag. The non-HLA antigens have been selected based on a literature search in patients with kidney disease or following transplantation. Due to the flexibility of the assay, this approach can be used to include alternative antigens and can also be used for screening of other organ transplant recipients, such as heart and lung.
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http://dx.doi.org/10.3389/fimmu.2018.03002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315148PMC
October 2019

Can alternative epitope mapping approaches increase the impact of B-cell epitopes in food allergy diagnostics?

Clin Exp Allergy 2019 01 31;49(1):17-26. Epub 2018 Oct 31.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

In vitro allergy diagnostics are currently based on the detection of specific IgE binding on intact allergens or a mixture thereof. This approach has drawbacks as it may yield false-negative and/or false-positive results. Thus, we reviewed the impact of known B-cell epitopes of food allergens to predict transience or persistence, tolerance or allergy and the severity of an allergic reaction and to examine new epitope mapping strategies meant to improve serum-based allergy diagnostics. Recent epitope mapping approaches have been worthwhile in epitope identification and may increase the specificity of allergy diagnostics by using epitopes predominately recognized by allergic patients in some cases. However, these approaches did not lead to discrimination between clinically relevant and irrelevant epitopes so far, since the polyclonal serum IgE-binding epitope spectrum seems to be too individual, independent of the disease status of the patients. New epitope mapping strategies are necessary to overcome these obstacles. The use of patient-derived monoclonal antibodies instead of patient sera for functional characterization of clinically relevant and irrelevant epitope combinations, distinguished by their ability to induce degranulation, might be a promising approach to gain more insight into the allergic reaction and to improve serum-based allergy diagnostics.
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http://dx.doi.org/10.1111/cea.13291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380004PMC
January 2019

Toward a Sensible Single-antigen Bead Cutoff Based on Kidney Graft Survival.

Transplantation 2019 04;103(4):789-797

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: There is no consensus in the literature on the interpretation of single-antigen bead positive for a specific HLA antibody.

Methods: To inform the debate, we studied the relationship between various single-antigen bead positivity algorithms and the impact of resulting donor-specific HLA antibody (DSA) positivity on long-term kidney graft survival in 3237 deceased-donor transplants.

Results: First, we showed that the interassay variability can be greatly reduced when working with signal-to-background ratios instead of absolute median fluorescence intensities (MFIs). Next, we determined pretransplant DSA using various MFI cutoffs, signal-to-background ratios, and combinations thereof. The impact of the various cutoffs was studied by comparing the graft survival between the DSA-positive and DSA-negative groups. We did not observe a strong impact of various cutoff levels on 10-year graft survival. A stronger relationship between the cutoff level and 1-year graft survival for DSA-positive transplants was found when using signal-to-background ratios, most pronounced for the bead of the same HLA locus with lowest MFI taken as background.

Conclusions: With respect to pretransplant risk stratification, we propose a signal-to-background ratio-6 (using the bead of the same HLA-locus with lowest MFI as background) cutoff of 15 combined with an MFI cutoff of 500, resulting in 8% and 21% lower 1- and 10-year graft survivals, respectively, for 8% DSA-positive transplants.
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http://dx.doi.org/10.1097/TP.0000000000002357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430591PMC
April 2019

Pretransplant C3d-Fixing Donor-Specific Anti-HLA Antibodies Are Not Associated with Increased Risk for Kidney Graft Failure.

J Am Soc Nephrol 2018 09 26;29(9):2279-2285. Epub 2018 Jul 26.

Laboratory of Translational Immunology.

Complement-fixing antibodies against donor HLA are considered a contraindication for kidney transplant. A modification of the IgG single-antigen bead (SAB) assay allows detection of anti-HLA antibodies that bind C3d. Because early humoral graft rejection is considered to be complement mediated, this SAB-based technique may provide a valuable tool in the pretransplant risk stratification of kidney transplant recipients. Previously, we established that pretransplant donor-specific anti-HLA antibodies (DSAs) are associated with increased risk for long-term graft failure in complement-dependent cytotoxicity crossmatch-negative transplants. In this study, we further characterized the DSA-positive serum samples using the C3d SAB assay. Among 567 pretransplant DSA-positive serum samples, 97 (17%) contained at least one C3d-fixing DSA, whereas 470 (83%) had non-C3d-fixing DSA. At 10 years after transplant, patients with C3d-fixing antibodies had a death-censored, covariate-adjusted graft survival of 60%, whereas patients with non-C3d-fixing DSA had a graft survival of 64% (hazard ratio, 1.02; 95% confidence interval, 0.70 to 1.48 for C3d-fixing DSA compared with non-C3d-fixing DSA; =0.93). Patients without DSA had a 10-year graft survival of 78%. The C3d-fixing ability of pretransplant DSA is not associated with increased risk for graft failure.
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http://dx.doi.org/10.1681/ASN.2018020205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115667PMC
September 2018

Non-Digestible Oligosaccharides Can Suppress Basophil Degranulation in Whole Blood of Peanut-Allergic Patients.

Front Immunol 2018 11;9:1265. Epub 2018 Jun 11.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.

Background: Dietary non-digestible oligosaccharides (NDOs) have a protective effect against allergic manifestations in children at risk. Dietary intervention with NDOs promotes the colonization of beneficial bacteria in the gut and enhances serum galectin-9 levels in mice and atopic children. Next to this, NDOs also directly affect immune cells and low amounts may reach the blood. We investigated whether pre-incubation of whole blood from peanut-allergic patients with NDOs or galectin-9 can affect basophil degranulation.

Methods: Heparinized blood samples from 15 peanut-allergic adult patients were pre-incubated with a mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS), scFOS/lcFOS, or galectin-9 (1 or 5 µg/mL) at 37°C in the presence of IL-3 (0.75 ng/mL). After 2, 6, or 24 h, a basophil activation test was performed. Expression of FcεRI on basophils, plasma cytokine, and chemokine concentrations before degranulation were determined after 24 h.

Results: Pre-incubation with scGOS/lcFOS, scFOS/lcFOS, or galectin-9 reduced anti-IgE-mediated basophil degranulation. scFOS/lcFOS or 5 µg/mL galectin-9 also decreased peanut-specific basophil degranulation by approximately 20%, mainly in whole blood from female patients. Inhibitory effects were not related to diminished FcεRI expression on basophils. Galectin-9 was increased in plasma after pre-incubation with scGOS/lcFOS, and both NDOs and 5 µg/mL galectin-9 increased MCP-1 production.

Conclusion And Clinical Relevance: The prebiotic mixture scFOS/lcFOS and galectin-9 can contribute to decreased degranulation of basophils in peanut-allergic patients. The exact mechanism needs to be elucidated, but these NDOs might be useful in reducing allergic symptoms.
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http://dx.doi.org/10.3389/fimmu.2018.01265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004414PMC
August 2019

Association Between Promoter Polymorphisms in CD46 and CD59 in Kidney Donors and Transplant Outcome.

Front Immunol 2018 14;9:972. Epub 2018 May 14.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Complement regulating proteins, including CD46, CD55, and CD59, protect cells against self-damage. Because of their expression on the donor endothelium, they are hypothesized to be involved in accommodation. Polymorphisms in their promoter regions may affect their expression. The aim of this study was to investigate if donor polymorphisms in complement regulating proteins influence kidney transplant outcomes. We included 306 kidney transplantations between 2005 and 2010. Five polymorphisms in the promoters of CD46, CD55, and CD59 were genotyped. A CD59 promoter polymorphism (rs147788946) in donors was associated with a lower 1-year rejection-free survival [adjusted hazard ratio (aHR) 2.18, 95% CI 1.12-4.24] and a trend toward impaired 5-year graft survival ( = 0.08). Patients receiving a kidney with at least one G allele for the CD46 promoter polymorphism rs2796267 (A/G) showed a lower rejection-free survival, though this became borderline significant after adjustment for potential confounders (aHR 1.87, 95% CI 0.96-3.65). A second CD46 promoter polymorphism (rs2796268, A/G), was also associated with a lower freedom from acute rejection in the presence of at least one G allele (aHR 1.95, 95% CI 1.03-3.68). Finally, the combined presence of both favorable genotypes of rs2796267 and rs147788946 had an additional protective effect both on acute rejection ( = 0.006) and graft survival ( = 0.03). These findings could help to identify patients who could benefit from intensified immunosuppressive therapy or novel complement inhibitory therapeutics.
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http://dx.doi.org/10.3389/fimmu.2018.00972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960667PMC
July 2019

Exposure of Intestinal Epithelial Cells to Short- and Long-Chain Fructo-Oligosaccharides and CpG Oligodeoxynucleotides Enhances Peanut-Specific T Helper 1 Polarization.

Front Immunol 2018 11;9:923. Epub 2018 May 11.

Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.

Background: Non-digestible oligosaccharides promote colonization of beneficial gut bacteria and have direct immunomodulatory effects. Apical exposure of intestinal epithelial cells (IECs) to short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS) in a transwell co-culture model enhanced the CpG-induced (TLR-9 ligand) T helper 1 (Th1) phenotype and regulatory IL-10 response of underlying peripheral mononuclear cells (PBMCs) of healthy donors. scGOS is derived from lactose and may pose risks in severe cow's milk allergic patients, and scFOS/lcFOS may be an alternative. The goal of this study was to determine the immunomodulatory effects of scGOS/lcFOS and scFOS/lcFOS in an allergen-specific transwell co-culture model using PBMCs from peanut-allergic patients.

Methods: IECs cultured on transwell filters were apically exposed to CpG, either or not in combination with oligosaccharides. These IECs were co-cultured with basolateral PBMCs of peanut-allergic patients that were either activated with aCD3/28 or peanut extract. Basolateral cytokine production and T-cell polarization were measured and the contribution of galectin-9 and the dectin-1 receptor in immune modulation were assessed.

Results: IECs exposed to CpG increased IFN-γ, IL-10, and galectin-9 production by aCD3/28-stimulated PBMCs, whereas IL-13 decreased. Both scGOS/lcFOS and scFOS/lcFOS further enhanced IFN-γ and IL-10, while suppressing IL-13 and TNF-α. In the peanut-specific model, only scFOS/lcFOS further increased IFN-γ and IL-10 production, coinciding with enhanced Th1-frequency. Expression of CRTH2 reduced after CpG exposure, and was further reduced by scFOS/lcFOS. Galectin-9 inhibitor TIM-3-Fc abrogated the additional effect of scFOS/lcFOS on peanut-specific IFN-γ production, while neutralization of the dectin-1 receptor was not effective.

Conclusion: Epithelial exposure to scFOS/lcFOS enhanced the CpG-induced Th1 and regulatory IL-10 response in a peanut-specific co-culture model. These effects suggest scFOS/lcFOS as candidate for dietary adjunct in allergen-specific immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2018.00923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958185PMC
June 2019

PIRCHE-II Is Related to Graft Failure after Kidney Transplantation.

Front Immunol 2018 5;9:321. Epub 2018 Mar 5.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor-recipient couples that were transplanted between 1995 and 2005. For these donors-recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04-1.23,  = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10-1.34,  < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival.
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http://dx.doi.org/10.3389/fimmu.2018.00321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844930PMC
March 2019

Reduced Expression of Membrane Complement Regulatory Protein CD59 on Leukocytes following Lung Transplantation.

Front Immunol 2017 22;8:2008. Epub 2018 Jan 22.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Cellular protection against undesired effects of complement activation is provided by expression of membrane-bound complement regulatory proteins including CD59. This protein prevents membrane attack complex formation and is considered to be involved in graft accommodation. Also, CD59 downregulates CD4+ and CD8+ T-cell activation and proliferation. It is unknown whether CD59 expression is affected by transplantation. The aim of this study was to evaluate the quantitative CD59 antigen expression on distinct leukocyte subsets following lung transplantation ( = 26) and to investigate whether this differs from pretransplantation ( = 9). The results show that CD59 expression on leukocytes is significantly lower posttransplantation compared with healthy controls ( = 0.002) and pretransplantation ( < 0.0001). Moreover, the CD59 expression diminishes posttransplantation on all distinct lymphocyte subsets ( < 0.02). This effect appeared to be specific for CD59 since the expression of other surface markers remained stable or inclined following transplantation. The highest antigen expression posttransplantation was observed on CD4+ T cells and monocytes ( ≤ 0.002). These findings show that CD59 expression on leukocytes diminishes posttransplantation, which could result in decreased resistance against complement and enhanced T-cell activation. If such reduction in CD59 expression also occurs on endothelial cells from the transplanted organ, this could lead to a change into a prothrombotic and proinflammatory phenotype.
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http://dx.doi.org/10.3389/fimmu.2017.02008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786830PMC
January 2018

Serum intestinal fatty acid-binding protein in the noninvasive diagnosis of celiac disease.

APMIS 2018 Mar 31;126(3):186-190. Epub 2018 Jan 31.

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

Current diagnostic guidelines for celiac disease (CD) in pediatric patients require a duodenal biopsy if the IgA anti-tissue transglutaminase (tTG) is below 10x the upper limit of normal (ULN). Additional markers may enable a noninvasive diagnosis in this group. Serum intestinal-fatty acid-binding protein (I-FABP), a marker for intestinal epithelial damage, could be useful in this respect. A total of 95 children with a clinical suspicion of CD and tTG 1-10x ULN were investigated. All had a duodenal biopsy and analysis of serum I-FABP. A control group of 161 children with familial short stature and normal tTG was included. I-FABP levels in the 71 patients with tTG 1-10x ULN and biopsy-proven CD (median 725 pg/mL) were not significantly different (p = 0.13) from the levels in the 24 patients with a tTG 1-10x ULN but a normal biopsy (median 497 pg/mL). However, when combining tTG and I-FABP levels, 11/24 patients could have been diagnosed noninvasively if tTG is ≥ 50 U/mL and I-FABP ≥880 pg/mL or in 12/19 patients if tTG is ≥ 60 U/mL and I-FABP ≥ 620 pg/mL. Therefore, addition of I-FABP to the diagnostic procedure of CD may provide a noninvasive diagnosis in patients with a tTG ≥ 50 U/mL.
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http://dx.doi.org/10.1111/apm.12800DOI Listing
March 2018

Sensitization to PR-10 proteins is indicative of distinctive sensitization patterns in adults with a suspected food allergy.

Clin Transl Allergy 2017 23;7:42. Epub 2017 Nov 23.

Department of Dermatology and Allergology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Background: The extent of co-sensitization within and between food protein families in an adult population is largely unknown. This study aimed to identify the most frequently recognized components in the PR-10 and storage protein family, as well as patterns in (co-)sensitization, in a birch-endemic area.

Methods: Results of ImmunoCAP ISAC, performed during routine care in Dutch adult outpatients suspected of food allergy, were collected.

Results: A total of 305 patients were selected, aged 16-79 years (median 32 years). Sensitization to one or more PR-10 proteins was most frequent (74% of all subjects), followed by 35% to storage protein and 15% to nsLTPs. Within the PR-10 family, subjects were most often sensitized to Bet v 1 (73% of 305), Cor a 1.04 (72%) and Mal d 1 (68%). Sensitization to PR-10s from soy, celery and kiwi occurred distinctively less often (< 55% of Bet v 1 sensitized subjects) compared to other food PR-10s (all > 70%). Subjects sensitized to these 'less common PR-10 proteins' were sensitized to more food and inhalant components on the ISAC, compared to subjects sensitized to 'common PR-10 proteins' (median 22 vs 13 out of 112,  < 0.0001). Seven subjects demonstrated sensitization to food PR-10 proteins, without concomitant sensitization to pollen PR-10s. Within the storage proteins, sensitization to multiple peanut allergens was most common (on average 3 out of 4).

Conclusions: Sensitization to PR-10 food proteins could occur without concomitant sensitization to common PR-10 from pollen in a subset of subjects. Less commonly recognized PR-10 proteins appear to be an indication of polysensitization.
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http://dx.doi.org/10.1186/s13601-017-0177-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700688PMC
November 2017