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Turk J Med Sci. 2023 Jul 23;53(5):1512-1522. doi: 10.55730/1300-0144.5719. eCollection 2023.

ABSTRACT

BACKGROUND/AIM: Dental caries is a frequently occurring and multifactorial chronic disease in children resulting from the interaction of cariogenic bacteria and host susceptibility. The aim of this study was to elucidate the impacts of primary immunodeficiency disorders (PIDs) on microbiota of dental caries in children by 16S rRNA gene-based metagenomic analysis.

MATERIALS AND METHODS: Enrolled in this study were 15 children with primary PID with caries (PID group) and 15 healthy children with caries as a control (CG). The DMFT index, saliva flow rate, and buffering capacity of each participant were assessed before the metagenomic analyses were conducted. For taxonomic profiling, the reads were obtained by high-throughput sequencing of the V3-V4 hypervariable region of 16S rRNA.

RESULTS: The DMFT score, saliva flow rate, and buffering capacity of the groups were similar. The flow rate and buffering capacity had no correlation with the number of species with 95% confidence. The metagenomic analysis resulted in the identification of 2440 bacterial species in all of the samples. Among the 50 most prevalent species present at ≥1% relative abundance, Prevotella melaninogenica and Prevotella salivae were differentially more abundant in the PID group. The PID group and CG showed similar species richness and evenness, but 4 of the 5 samples with the highest Shannon-Weiner and Inverse Simpson indices belonged to the PID group. The Spearman test results for correlation of the species in the PID subgroups showed that Prevotella oris had a positively correlated relationship with both Scardovia wiggsiae and Saccharibacteria genera incertae sedis.

CONCLUSION: This study provided insight into the caries microbiota of children with immunodeficiency diseases. Differentially abundant species, novel bacterial associations, and unique bacterial species were disclosed in the PID samples, indicating the role of the immune system in altering the caries microbiota. The prominent bacterial species and associations in the PID group should be suspected in regard to their link with present or future diseases.

PMID:38813004 | PMC:PMC10763755 | DOI:10.55730/1300-0144.5719

Cent Eur J Immunol. 2024;49(1):26-36. doi: 10.5114/ceji.2024.136371. Epub 2024 Mar 22.

ABSTRACT

The flow cytometry method could support physicians’ decisions in the diagnosis and treatment monitoring of immunodeficient patients. Most clinical recommendations are focused on the search for alterations in T- and B-lymphocyte subsets, less commonly natural killer (NK) cells and granulocytes. While reference values for clinically meaningful lymphocyte subsets have been published ubiquitously among numerous countries, we have not found significant data for a population of adult Polish habitats; thus we determined reference values for T, B, and NK subsets according to sex and age. The female group showed a higher percentage of lymphocytes (CD45⁺⁺), T helper lymphocytes with a higher absolute count, as well as CD4/CD8 ratio, marginal zone-like B cells, class-switched B cells, and CD21^low B cells than the male group. The male group was found to have elevated percentages of naïve B lymphocytes, transitional B cells, and plasmablasts. A weak positive correlation with age was found among double positive T lymphocytes, natural killer T cells (NKT) lymphocytes, and CD21^low B cells. A negative correlation with age for double negative T lymphocytes, marginal zone-like B cells, and plasmablasts was noted. The results indicated the importance of creating distinct reference ranges regarding sex and age concerning immunophenotype.

PMID:38812608 | PMC:PMC11130990 | DOI:10.5114/ceji.2024.136371

Front Pediatr. 2024 May 9;12:1326489. doi: 10.3389/fped.2024.1326489. eCollection 2024.

ABSTRACT

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHLH) is an inherited life-threatening disease. Five types are identified, with the addition of congenital immunodeficiency syndromes in which HLH is a typical manifestation. The literature on this disease is very scarce in the Middle East, with only a few scattered reports.

METHODS: We report detailed demographic, clinical, and genomic data from 28 patients diagnosed with primary and familial HLH over the last decade in Qatar. An evaluation was performed of allele frequencies of deleterious variants from 12 primary and familial HLH causative genes on the Qatar Genome Programme (QGP) cohort of 14,669 Qatari individuals.

RESULTS: The genetic diagnosis was obtained in 15 patients, and four novel mutations in Perforin 1 (PRF1), UNC13D, LYST, and RAB27A genes were found. We identified 22,945 low/high/moderate/modifier impact variants significantly enriched in the QGP in those 12 genes. The variants rs1271079313 in PRF1 and rs753966933 in RAB27A found in our patient cohort were significantly more prevalent in the QGP compared to the Genome Aggregation Database (gnomAD) database, with a high carrier frequency in the Qatari population.

CONCLUSIONS: We established the first primary and familial HLH Registry in the Gulf Region and identified novel possibly pathogenic variants present at higher frequency in the Qatari population, which could be used for screening purposes. Raising awareness about primary and familial HLH and implementing screening activities in the Qatari highly inbred population could stem into more comprehensive premarital and prenatal evaluations and faster diagnosis.

PMID:38808104 | PMC:PMC11130942 | DOI:10.3389/fped.2024.1326489

J Clin Immunol. 2024 May 28;44(6):138. doi: 10.1007/s10875-024-01736-3.

ABSTRACT

BACKGROUND: Inborn Errors of Immunity (IEI) comprise several genetic anomalies that affect different components of the innate and adaptive responses, predisposing to infectious diseases, autoimmunity and malignancy. Different studies, mostly in adults, have reported a higher prevalence of cancer in IEI patients. However, in part due to the rarity of most of these IEI subtypes (classified in ten categories by the Primary Immunodeficiency Committee of the International Union of Immunological Societies), it is difficult to assess the risk in a large number of patients, especially during childhood.

OBJECTIVE: To document the cancer prevalence in a pediatric cohort from a single referral institution, assessing their risk, together with the type of neoplasia within each IEI subgroup.

METHOD: An extensive review of clinical records from 1989 to 2022 of IEI patients who at some point developed cancer before the age of sixteen.

RESULTS: Of a total of 1642 patients with IEI diagnosis, 34 developed cancer before 16 years of age, showing a prevalence (2.1%) significantly higher than that of the general age matched population (0.22). Hematologic neoplasms (mostly lymphomas) were the most frequent malignancies.

CONCLUSION: This study represents one of the few reports focused exclusively in pediatric IEI cases, describing not only the increased risk of developing malignancy compared with the age matched general population (a fact that must be taken into account by immunologists during follow-up) but also the association of the different neoplasms with particular IEI subtypes, thus disclosing the possible mechanisms involved.

PMID:38805138 | DOI:10.1007/s10875-024-01736-3

J Allergy Clin Immunol Glob. 2024 Apr 23;3(3):100267. doi: 10.1016/j.jacig.2024.100267. eCollection 2024 Aug.

ABSTRACT

BACKGROUND: Forkhead box protein N1 (FOXN1) transcription factor plays an essential role in the development of thymic epithelial cells, required for T-cell differentiation, maturation, and function. Biallelic pathogenic variants in FOXN1 cause severe combined immunodeficiency (SCID). More recently, heterozygous variants in FOXN1, identified by restricted gene panels, were also implicated with causing a less severe and variable immunodeficiency.

OBJECTIVE: We undertook longitudinal follow-up and advanced genetic investigations, including whole exome sequencing and whole genome sequencing, of newborns with a heterozygous variant in FOXN1.

METHODS: Five patients (3 female, 2 male) have been followed since they were first detected with low T-cell receptor excision circles during newborn screening for SCID. Patients underwent immune evaluation as well as genetic testing, including a primary immunodeficiency panel, whole exome sequencing, and whole genome sequencing in some cases.

RESULTS: Median follow-up time was 6.5 years. Initial investigations revealed low CD3⁺ T lymphocytes in all patients. One patient presented with extremely low lymphocyte counts and depressed phytohemagglutinin responses leading to a tentative diagnosis of SCID. Over a period of 2 years, CD3⁺ T-cell counts rose, although in some patients it remained borderline low. One of 5 children continues to experience recurrent upper respiratory infections and asthma episodes. The remaining are asymptomatic except for eczema in 2 of 5 cases. Lymphocyte proliferation responses to phytohemagglutinin were initially low in 3 patients but normalized by age 10 months. In 3 of 5 cases, T lymphocyte counts remain low/borderline low.

CONCLUSION: In cases of monoallelic FOXN1 variants, using whole exome sequencing and whole genome sequencing to rule out possible other significant pathogenic variants allowed us to proceed with confidence in a conservative manner, even in extreme cases consistent with newborn screen-positive early presentation of SCID.

PMID:38800615 | PMC:PMC11127205 | DOI:10.1016/j.jacig.2024.100267

Cureus. 2024 Apr 25;16(4):e58989. doi: 10.7759/cureus.58989. eCollection 2024 Apr.

ABSTRACT

Common variable immunodeficiency (CVID) is a primary immunodeficiency with the involvement of B cells, T cells, and antigen-presenting cells. Patients with CVID are more susceptible to malignancies and bacterial infections in the gastrointestinal and respiratory tracts. We discuss a case of a 50-year-old male who presented to the emergency department with a history of intermittent abdominal pain, diarrhea, night sweats, fever, nausea, and weight loss of 40 pounds over six months. A CT of the abdomen revealed splenomegaly with several infiltrated solid nodules as well as enlarged mediastinal, hilar, periesophageal, cervical, and left supraclavicular lymph nodes, findings suggestive of lymphoma. The diagnosis of nodular lymphocyte-predominant Hodgkin lymphoma was confirmed by immunohistology, which revealed that CD20 and CD3 were both positive in small lymphocytes. Immunoglobulin (Ig) levels were low for IgG and IgM, findings highly suggestive of CVID. We want to shed light on the importance of performing the clinical workup for CVID when Hodgkin lymphoma and recurrent infections are present, as the immunodeficiency remains underdiagnosed and underreported.

PMID:38800171 | PMC:PMC11127610 | DOI:10.7759/cureus.58989

Front Immunol. 2024 May 10;15:1405022. doi: 10.3389/fimmu.2024.1405022. eCollection 2024.

ABSTRACT

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a rare autosomal recessive disorder, manifests with hypoglobulinemia and chromosomal instability accompanied by DNA hypomethylation. Pathological variants in the DNMT3B, ZBTB24, CDCA7, or HELLS genes underlie its etiology. Activated lymphocytes from patients often display distinctive multiradial chromosomes fused via pericentromeric regions. Recent studies have provided deeper insights into how pathological variants in ICF-related proteins cause DNA hypomethylation and chromosome instability. However, the understanding of the molecular pathogenesis underlying immunodeficiency is still in its nascent stages. In the past half-decade, the roles of CDCA7, HELLS, and ZBTB24 in classical non-homologous end joining during double-strand DNA break repair and immunoglobulin class-switch recombination (CSR) have been unveiled. Nevertheless, given the decreased all classes of immunoglobulins in most patients, CSR deficiency alone cannot fully account for the immunodeficiency. The latest finding showing dysregulation of immunoglobulin signaling may provide a clue to understanding the immunodeficiency mechanism. While less common, a subgroup of patients exhibits T-cell abnormalities alongside B-cell anomalies, including reduced regulatory T-cells and increased effector memory T- and follicular helper T-cells. The dysregulation of immunoglobulin signaling in B-cells, the imbalance in T-cell subsets, and/or satellite RNA-mediated activation of innate immune response potentially explain autoimmune manifestations in a subset of patients. These findings emphasize the pivotal roles of ICF-related proteins in both B- and T-cell functions. ICF syndrome studies have illuminated many fundamental mechanisms. Further investigations will certainly continue to unveil additional mechanisms and their interplay.

PMID:38799442 | PMC:PMC11116680 | DOI:10.3389/fimmu.2024.1405022

Front Immunol. 2024 May 10;15:1405317. doi: 10.3389/fimmu.2024.1405317. eCollection 2024.

ABSTRACT

INTRODUCTION: Lanadelumab is a first-line long-term prophylaxis (LTP) in hereditary angioedema (HAE). Real-life data on its long-term efficacy and safety are limited. It is unknown whether patients using lanadelumab need short-term prophylaxis (STP).

OBJECTIVES: To provide 4-year follow-up data for our first 34 patients treating with lanadelumab.

METHODS: Patients were assessed for their current injection interval, attacks, treatment satisfaction, disease control (AECT), quality of life impairment (AE-QoL), events that can induce attacks, and the use of STP since the start of their treatment with lanadelumab.

RESULTS: Of 34 patients who started lanadelumab treatment, 32 were still using it after 4 years, with a median injection interval of 33 (range 14-90) days. HAE patients (n=28) reported longer intervals, i.e. 35 (14-90) days, than patients with angioedema due to acquired C1 inhibitor deficiency (n=4, 23 (14-31) days). With their current injection intervals, used for a mean duration of 29 ± 17 months, patients reported a yearly attack rate of 0.3 ± 0.1. More than 70% of patients were attack-free since starting their current injection interval. All patients reported well-controlled disease, i.e. ≥10 points in the AECT; 21 patients had complete control (16 points). AE-QoL scores improved further compared to our initial report, most prominently in the fears/shame domain (-6 points). Treatment satisfaction was very high. No angioedema occurred after 146 of 147 potentially attack-inducing medical procedures without STP.

CONCLUSIONS: Our results demonstrate the long-term efficacy and safety of lanadelumab in real-life and question the need for STP in patients who use effective LTP.

PMID:38799421 | PMC:PMC11116806 | DOI:10.3389/fimmu.2024.1405317

Clin Immunol. 2024 May 23:110263. doi: 10.1016/j.clim.2024.110263. Online ahead of print.

ABSTRACT

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity.

METHODS: A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT.

RESULTS: The median age at transplant was 11.0 months (4.6-61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40-100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2-13.6), 0.9 × 10⁹/L 0.6-1.2), and 0.5 × 10⁹/L (0.2-0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0-14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4-11.5). The 10-year overall probability of survival is 84.3%.

CONCLUSION: Monitoring IRC is important in ensuring adequate disease-free survival.

PMID:38795901 | DOI:10.1016/j.clim.2024.110263

Vet Clin North Am Equine Pract. 2024 May 23:S0749-0739(24)00031-2. doi: 10.1016/j.cveq.2024.04.005. Online ahead of print.

ABSTRACT

Equine common variable immunodeficiency (CVID) is a rare, late-onset, nonfamilial humoral deficiency characterized by B-cell depletion and/or dysfunction resulting in inadequate antibody production and predisposition to recurrent infections. Serum immunoglobulin concentration and peripheral blood lymphocyte immunophenotyping are required to diagnose and characterize CVID in horses. Early recognition of the disease by the equine practitioner is paramount to managing the quality of life for these patients, for whom specific treatment is not yet available and long-term prognosis remains poor. An approach to the diagnosis, identification of complicating factors, and management of horses with CVID are discussed.

PMID:38789347 | DOI:10.1016/j.cveq.2024.04.005