Mannose-binding lectin promoter polymorphisms and gene variants in pulmonary tuberculosis patients from Cantabria (northern Spain)

Mannose-binding lectin is a central molecule of the innate immune system. Mannose-binding lectin 2 promoter polymorphisms and structural variants have been associated with susceptibility to tuberculosis. However, contradictory results among different populations have been reported, resulting in no convincing evidence of association between mannose-binding lectin 2 and susceptibility to tuberculosis. For this reason, we conducted a study in a well genetically conserved Spanish population in order to shed light on this controversial association. We analysed the six promoter and structural mannose-binding lectin 2 gene variants in 107 patients with pulmonary tuberculosis and 441 healthy controls. Only D variant and HYPD haplotype were significantly more frequents in controls which would indicate that this allele could confer protection against pulmonary tuberculosis, but this difference disappeared after statistical correction. Neither the rest of alleles nor the haplotypes were significantly associated with the disease. These results would indicate that mannose-binding lectin promoter polymorphisms and gene variants would not be associated with an increased risk to pulmonary tuberculosis. Despite the slight trend of the D allele and HYPD haplotype in conferring protection against pulmonary tuberculosis, susceptibility to this disease would probably be due to other genetic factors, at least in our population

Whole-Genome Sequence of Serratia liquefaciens HUMV-21, a Cytotoxic, Quorum-Sensing, and Biofilm-Producing Clinical Isolate

A clinical isolate of Serratia liquefaciens (strain HUMV-21) was obtained from a skin ulcer of an adult patient. We report here its complete genome assembly using PacBio single-molecule real-time (SMRT) sequencing, which resulted in a single circular chromosome with 5.3 Mb. About 5,844 protein-coding genes are predicted from this assembly

Mannose-binding lectin gene variants and infections in patients receiving autologous stem cell transplantation

BACKGROUND: Serious infections are common in patients undergoing autologous stem cell transplantation (ASCT) mainly because of the effects of immunosuppression. The innate immune system plays an important role in the defense against different infections. Mannose binding lectin (MBL) is a central molecule of the innate immune system. There are several promoter polymorphisms and structural variants of the MBL2 gene that encodes for this protein. These variants produce low levels of MBL and have been associated with an increased risk for infections. METHODS: Prospective cohort study. The incidence, severity of infections and mortality in 72 consecutive patients with hematologic diseases who underwent ASCT between February 2006 and June 2008 in a tertiary referral center were analyzed according to their MBL2 genotype. INNO-LiPA MBL2 was used for MBL2 gene amplification and genotyping. Relative risks (RR) (IC95%) as measure of association were calculated. Multivariate analysis was performed using logistic regression. RESULTS: A statistically significant higher number of fungal infections was found in patients with MBL2 variants causing low MBL levels (21.1%versus1.9%, p=0.016). In this MBL2 variant group infection was more frequently the cause of mortality than in the MBL2 wild-type group (p=0.05). Although not statistically significant, there was a higher incidence of major infections in the MBL2 variant group as well as a higher number of infections caused by gram-positive bacteria. CONCLUSIONS: Low-producer MBL2 genotypes were associated with an increased number of fungal infections in ASCT patients, which would suggest that MBL has a protective role against such infections. ASCT patients with MBL2 variant genotypes are more likely to die as a result of an infection

Immune Assessment of BNT162b2 m-RNA-Spike Based Vaccine Response in Adults

Vaccine efficacy is based on clinical data. Currently, the assessment of immune response after SARS-CoV-2 vaccination is scarce. A total of 52 healthcare workers were immunized with the same lot of BNT162b2 vaccine. The immunological response against the vaccine was tested using a T-specific assay based on the expression of CD25 and CD134 after stimulation with anti-N, -S, and -M specific peptides of SARS-CoV-2. Moreover, IgG anti-S2 and -RBD antibodies were detected using ELISA. Furthermore, the cell subsets involved in the response to the vaccine were measured in peripheral blood by flow cytometry. Humoral-specific responses against the vaccine were detected in 94% and 100% after the first and second doses, respectively. Therefore, anti-S T-specific responses were observed in 57% and 90% of the subjects after the first and second doses of the vaccine, respectively. Thirty days after the second dose, significant increases in T helper 1 memory cells (p < 0.001), peripheral memory T follicular helper (pTFH) cells (p < 0.032), and switched memory (p = 0.005) were observed. This study describes the specific humoral and cellular immune responses after vaccination with the new mRNA-based BNT162b2 vaccine. A mobilization of TFH into the circulation occurs, reflecting a specific activation of the immune system.Funding: This work was partially supported by the Cantabrian Government, grant number 2020UIC22-PUB-001, and from Instituto de Salud Carlos III, grant number COV20/00170

Cranial and extracranial giant cell arteritis do not exhibit differences in the IL6 -174 G/C gene polymorphism

Since interleukin-6 (IL-6) is a pivotal proinflammatory cytokine implicated in the pathogenesis of giant cell arteritis (GCA), we aimed to determine the potential association of the functional IL6 -174 G/C polymorphism with GCA as well as if the single base change variation at the promoter region in the human IL-6 gene may account for differences in the clinical spectrum of GCA between cranial and extracranial large vessel vasculitis (LVV)-GCA

HLA association with the susceptibility to anti-synthetase syndrome

Objective To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). Methods We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. Results A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P = 1.56E?09, odds ratio?OR [95% confidence interval?CI] = 2.54 [1.84?3.50] and 21.4% versus 5.5%, P = 18.95E?18, OR [95% CI] = 4.73 [3.18?7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P = 0.0003, OR [95% CI] = 0.48 [0.31?0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P = 0.001, OR [95% CI] = 2.54 [1.39?4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. Conclusions Our results support the association of the HLA complex with the susceptibility to ASS

Novel frameshift variants expand the map of the genetic defects in IRF2BP2

BackgroundAt present, the knowledge about disease-causing mutations in IRF2BP2 is very limited because only a few patients affected by this condition have been reported. As previous studies have described, the haploinsufficiency of this interferon transcriptional corepressors leads to the development of CVID. Very recently, a more accurate phenotype produced by truncating variants in this gene has been defined, manifesting CVID with gastrointestinal inflammatory symptoms and autoimmune manifestations.MethodsWe analyzed 5 index cases with suspected primary immunodeficiency by high throughput sequencing. They were submitted for a genetic test with a panel of genes associated with immune system diseases, including IRF2BP2. The screening of SNVs, indels and CNVs fulfilling the criteria with very low allelic frequency and high protein impact, revealed five novel variants in IRF2BP2. In addition, we isolated both wild-type and mutated allele of the cDNA from one of the families.ResultsIn this study, we report five novel loss-of-function (LoF) mutations in IRF2BP2 that likely cause primary immunodeficiency, with CVID as more frequent phenotype, variable expression of inflammatory gastrointestinal features, and one patient with predisposition of viral infection. All identified variants were frameshift changes, and one of them was a large deletion located on chromosome 1q42, which includes the whole sequence of IRF2BP2, among other genes. Both de novo and dominant modes of inheritance were observed in the families here presented, as well as incomplete penetrance.ConclusionsWe describe novel variants in a delimited low-complex region, which may be considered a hotspot in IRF2BP2. Moreover, this is the first time that a large CNV in IRF2BP2 has been reported to cause CVID. The distinct mechanisms than LoF in IRF2BP2 could cause different phenotype compared with the mainly described. Further investigations are necessary to comprehend the regulatory mechanisms of IRF2BP2, which could be under variable expression of the disease

Cranial and extracranial large-vessel giant cell arteritis share a genetic pattern of interferon-gamma pathway

OBJECTIVES: Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA. METHODS: Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls. CONCLUSIONS: Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway

The presence of both HLA-DRB1[*]04:01 and HLA-B[*]15:01 increases the susceptibility to cranial and extracranial giant cell arteritis.

Objectives: To determine if patients with the predominant extracranial large-vessel-vasculitis (LVV) pattern of giant cell arteritis (GCA) have a distinctive HLA-B association, different from that reported in biopsy-proven cranial GCA patients. In a further step we assessed if the combination of HLA-B and HLA-DRB1 alleles confers an increased risk for GCA susceptibility, either for the cranial and extracranial LVV phenotypes. Methods: A total of 184 patients with biopsy-proven cranial GCA, 105 with LVV-GCA and 486 healthy controls were included in our study. We compared HLA-B phenotype frequencies between the three groups. Results: HLA-B*15 phenotype was significantly increased in patients with classic cranial GCA compared to controls (14.7% versus 5.8%, respectively; p<0.01; OR [95% CI] =2.81 [1.54-5.11]). It was mainly due to the HLA-B*15:01 allele (12.5% versus 4.0%, respectively; p<0.01; OR [95% CI] =3.51 [1.77-6.99]) and remained statistically significant after Bonferroni correction. Similar HLA-B*15 association was observed in patients with the LVV-GCA (11.4% versus 5.8%, p=0.04, OR [95% CI] =2.11 [1.04-4.30]). This association was also mainly due to the HLA-B*15:01 allele (10.5% versus 4.0%, respectively; p=0.0054; OR [95% CI] =2.88 [1.19-6.59]). Noteworthy, the presence of HLA-B*15:01 together with HLA-DRB1*04:01 led to an increased risk of developing both cranial and extracranial LVV-GCA. Conclusions: Susceptibility to GCA is strongly related to the HLA region, regardless of the clinical phenotype of expression of the disease.This work was partially supported by RETICS Programs, RD08/0075 (RIER), RD12/0009/0013 and RD16/0012 from ‘‘Instituto de Salud Carlos III’’ (ISCIII) (Spain). However, this research did not receive any specific grant from funding agencies in the commercial or not-for-profit sectors

Association of HLA-B*41:02 with Henoch-Schönlein Purpura (IgA Vasculitis) in Spanish individuals irrespective of the HLA-DRB1 status

INTRODUCTION: A study was conducted to determine whether the human leukocyte antigen (HLA) B alleles are implicated in the susceptibility to Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies. METHODS: The study population was composed of 349 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria, and 335 sex and ethnically matched controls. HLA-B phenotypes were determined by sequencing-based typing (SBT) and analyzed by chi-square or Fisher exact test. RESULTS: A statistically significant increase of HLA-B*41:02 allele in HSP patients when compared with controls was found (8.3% versus 1.5% respectively; P = 0.0001; OR (odds ratio) =5.76 [2.15-19.3]). These results remained statistically significant after adjusting for Bonferroni correction (P = 0.0028). An internal validation also confirmed the susceptibility effect on HSP associated with HLA-B*41:02 (OR = 5.70 [1.98-16.44]). Since a former study described an association between HLA-DRB1*01:03 and HSP susceptibility, we also evaluated the implication of HLA-B*41:02 independently of HLA-DRB1*01:03. Interestingly, the association remained statistically significant (P = 0.0004, OR = 4.97 [1.8-16.9]). No HLA-B association with specific HSP clinical features was found. CONCLUSIONS: Our study indicates that HLA-B*41:02 is associated with the susceptibility to HSP in Spanish patients irrespective of HLA-DRB1 status.This study was supported by a grant from ‘Fondo de Investigaciones Sanitarias’ PI12/00193 (Spain). RLM is a recipient of a Sara Borrell postdoctoral fellowship from the Instituto de Salud Carlos III at the Spanish Ministry of Health (Spain) (CD12/00425). FG and BU are supported by funds from the RETICS Program (RIER) (RD12/0009/0013).Ye