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Mucosal Immunol. 2023 Dec 28:S1933-0219(23)00097-1. doi: 10.1016/j.mucimm.2023.12.001. Online ahead of print.

ABSTRACT

Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using Dock8-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell intrinsic DOCK8 was required for maintenance of antigen-specific IgA secreting plasma cells (PCs) in the gut lamina propria. Unexpectedly, DOCK8 was not required for early B cell activation, migration, or IgA class switching. An unbiased interactome screen revealed novel protein partners involved in metabolism and apoptosis. Dock8-deficient IgA⁺ B cells had impaired cellular respiration and failed to engage glycolysis appropriately. These results demonstrate that maintenance of the IgA⁺ PC compartment requires DOCK8 and suggests that gut IgA⁺ PCs have unique metabolic requirements for long-term survival in the lamina propria.

PMID:38159726 | DOI:10.1016/j.mucimm.2023.12.001

Immun Inflamm Dis. 2023 Dec;11(12):e1106. doi: 10.1002/iid3.1106.

ABSTRACT

BACKGROUND: Patients with immunodeficiencies commonly experience diagnostic delays resulting in morbidity. There is an unmet need to identify patients earlier, especially those with high risk for complications. Compared to immunoglobulin quantification and flowcytometric B cell subset analysis, expanded T cell subset analysis is rarely performed in the initial evaluation of patients with suspected immunodeficiency. The simultaneous interpretation of multiple immune variables, including lymphocyte subsets, is challenging.

OBJECTIVE: To evaluate the diagnostic value of cluster analyses of immune variables in patients with suspected immunodeficiency.

METHODS: Retrospective analysis of 38 immune system variables, including seven B cell and sixteen T cell subpopulations, in 107 adult patients (73 with immunodeficiency, 34 without) evaluated at a tertiary outpatient immunology clinic. Correlation analyses of individual variables, k-means cluster analysis with evaluation of the classification into “no immunodeficiency” versus “immunodeficiency” and visual analyses of hierarchical heatmaps were performed.

RESULTS: Binary classification of patients into groups with and without immunodeficiency was correct in 54% of cases with the full data set and increased to 69% and 75% of cases, respectively, when only 16 variables with moderate (p < .05) or 7 variables with strong evidence (p < .01) for a difference between groups were included. In a cluster heatmap with all patients but only moderately differing variables and a heatmap with only immunodeficient patients restricted to T cell variables alone, segregation of most patients with common variable immunodeficiency and combined immunodeficiency was observed.

CONCLUSION: Cluster analyses of immune variables, including detailed lymphocyte flowcytometry with T cell subpopulations, may support clinical decision making for suspected immunodeficiency in daily practice.

PMID:38156376 | DOI:10.1002/iid3.1106

Indian J Cancer. 2023 Apr 17. doi: 10.4103/ijc.IJC_1267_20. Online ahead of print.

ABSTRACT

BACKGROUND: Primary extranodal lymphomas (pENL) are lymphomas with minimal nodal involvement and dominant extranodal disease. We aimed to study the prevalence and clinicopathological characteristics of pENL presenting at our center over 5 years from January 2015 to January 2020.

METHODS: This is a cross-sectional study of pENL patients in which relevant clinical and laboratory data was collected including demography, site, stage, international prognostic index-revised, imaging findings, hematological, and biochemical parameters and comorbidities including underlying immunodeficiency. The paraffin blocks were subjected to routine hematoxylin and eosin stain and immunohistochemistry with standard lymphoma panel.

RESULTS: Of 341 lymphomas, 73 (21.4%) were pENL with commonest site being gastrointestinal tract (31.5%) followed by head and neck (23.2%) and soft tissues (9.6%). Diffuse large B-cell lymphoma (DLBCL) (39.7%) was the commonest histological type (germinal center type-48%, nongerminal center-52%) followed by marginal zone lymphomas (MZL) (23.3%) and primary CNS lymphoma (8.2%). Primary breast lymphoma, primary bone marrow lymphoma, and follicular lymphoma constituted 4.1, 5.4, and 4.1% of pENL, respectively. There was a case of high grade B cell lymphoma of ileum with features intermediate between DLBCL and Burkitt. Other unusual pENL were anaplastic DLBCL of tonsils, DLBCLs of bone marrow with M band, MZL of base of tongue, Richter’s transformation of tonsillar small lymphocytic lymphoma, and follicular lymphoma presenting as pericardial mass. Of 12 cases of T-non-Hodgkin lymphoma, commonest were mycosis fungoides (4/12) followed by mediastinal T-lymphoblastic lymphoma (2/12) and peripheral T-cell lymphoma (2/12).

CONCLUSION: pENL has unique clinical presentation depending on the location with site-specific distribution of histological subtypes.

PMID:38155455 | DOI:10.4103/ijc.IJC_1267_20

Int Arch Allergy Immunol. 2023 Dec 28:1-10. doi: 10.1159/000535258. Online ahead of print.

ABSTRACT

INTRODUCTION: Inborn errors of immunity (IEIs) are inherited disorders that present with increased susceptibility to infections as well as noninfectious complications. Due to the aberrant immune functions of patients with IEI, autoimmune cytopenia (AIC) may be the initial finding, which makes diagnosis a challenge. We aimed to evaluate the clinical course, laboratory findings, and treatment response of AIC in children with IEI.

METHODS: Data of children with autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenic purpura (ITP) were obtained from a retrospective chart review of IEI patients diagnosed and followed in our center. Demographic and clinical features and therapeutic outcomes were evaluated. Immunologic findings were compared between patients with AIHA, ITP, and Evans syndrome (ES). The patients were also divided into two subgroups based on the presence or absence of immune dysregulation diseases (IDDs), and all data were compared between these two groups.

RESULTS: Out of 562 patients with IEI, 6% (n: 34) had AIC which were ITP (23.5%), AIHA (35.5%), and ES (41.2%). AIC was the initial finding in 50% of these 34 patients. Patients with ES had a higher mean percentage of CD8+ T lymphocytes than ITP patients (40.77 ± 20.21% vs. 22.33 ± 12.48%, p = 0.011). Patients with IDDs were more likely to develop ES (p = 0.004), lymphoproliferation (p = 0.005), and resistance to first-line therapy (p = 0.021) than other IEI groups.

CONCLUSION: This study shows that AIC may be the initial finding of IEI, particularly when lymphoproliferation and resistance to first-line therapy co-occur. Therefore, detailed investigation should be offered to all patients to avoid diagnostic delay.

PMID:38154455 | DOI:10.1159/000535258

EClinicalMedicine. 2023 Dec 22;67:102393. doi: 10.1016/j.eclinm.2023.102393. eCollection 2024 Jan.

ABSTRACT

BACKGROUND: Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed.

METHODS: We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints.

FINDINGS: 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA: (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01).

INTERPRETATION: Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure.

FUNDING: There was no external funding source for this study.

PMID:38152413 | PMC:PMC10751840 | DOI:10.1016/j.eclinm.2023.102393

J Leukoc Biol. 2023 Dec 27:qiad128. doi: 10.1093/jleuko/qiad128. Online ahead of print.

ABSTRACT

We have developed a new format of a chimeric antigen receptor for αβ T cells, in which the single-chain variable fragment recognizing the tumor antigen is directly fused to the T cell receptor, called T cell receptor fusion construct (TRuC). Here, we express an anti-CD19 εTRuC in primary γδ T cells that were expanded using zoledronate (Zol) or concanavalin A. We show that the resulting εTRuC γδ T cells were reprogrammed to better recognize CD19-positive B cell tumors and-in case of the Zol-expanded cells-a CD19-expressing colon adenocarcinoma-derived cell line in vitro. This resulted in enhanced tumor killing, upregulation of the activation marker CD25, and secretion of cytokines. We found that the transduction efficiency of the concanavalin A-expanded cells was better than the one of the Zol-expanded ones. Our in vitro cytotoxicity data suggest that the Vδ2 T cells were better killers than the Vδ1 T cells. Finally, addition of vitamin C promoted the recovery of larger γδ T cell numbers after lentiviral transduction, as used for the expression of the εTRuC. In conclusion, the generation and use of γδ εTRuC T cells might be a new approach for cancer immunotherapy.

PMID:38149982 | DOI:10.1093/jleuko/qiad128

Pediatr Transplant. 2023 Dec 26:e14678. doi: 10.1111/petr.14678. Online ahead of print.

ABSTRACT

BACKGROUND: This prospective study aimed to comprehensively understand the changes in intestinal flora at different stages after hematopoietic stem cell transplantation (HSCT) in pediatric patients and to analyze the effect of intestinal flora on acute graft versus host disease (aGVHD), especially on gastrointestinal graft versus host disease (GI GVHD).

METHODS: A total of 32 children with primary diseases of primary immunodeficiency disease (PID) and thalassemia were included. 16S sequencing was used to characterize the microbiota layout at three time points peri-transplant including pre-transplant, Day +3, and Day +30.

RESULTS: By comparing the intestinal flora of children with GI GVHD and those without GI GVHD, it suggests that in children with GI GVHD, the distribution of intestinal flora after transplantation was more variable and more chaotic (chao1 index, Friedman test, p = .029). Besides, Veillonella and Ruminococcaceae were more abundant before transplantation, Bifidobacteriaceae and Bacillales were more abundant after transplantation. Comparing children with PID and thalassemia, it was found that the destruction of gut microbiota diversity was more significant in children with thalassemia after transplantation. The comparison of children with 0-I° aGVHD and II-III° aGVHD indicates that children with II-III° aGVHD had more Bilophila before transplantation than children with 0-I° aGVHD. Additionally, exploratory analyses to evaluate correlations between clinical characteristics (medications, immune cell recovery, etc.) and microbiome features were also performed.

CONCLUSIONS: This study has synthetically shown the distribution of intestinal flora after allo-HSCT, and some characteristic bacteria at different stages that may serve as potential biomarkers were screened out additionally, perhaps providing clues for the prevention and treatment of the disease.

PMID:38148707 | DOI:10.1111/petr.14678

Cureus. 2023 Nov 25;15(11):e49393. doi: 10.7759/cureus.49393. eCollection 2023 Nov.

ABSTRACT

Background Herpes zoster (HZ) is a viral disease, which is more common among the elderly and immunodeficient individuals, among which approximately 22% of cases might progress to post-herpetic neuralgia (PHN). Hence, this study aimed to assess the knowledge, attitude and practice (KAP) towards HZ and its vaccination among primary health care physicians in Makkah, Saudi Arabia, 2023. Methodology This analytical cross-sectional study used an online pre-validated questionnaire and was conducted from July to August 2023. The target population included physicians working in primary healthcare (PHC) daily clinics in Makkah. Results A total of 153 participants were included in the current study. Of which 90 (58.8%) were females and 120 (78.4%) participants had chicken pox history. Around 123 (80.4%) had previously heard about shingles. The most reported source of information was physicians (63%) followed by the Internet (12.2%). Risk factors for shingles were found to be immunodeficiency (95.1%) and age (78%). Most (88.2%) participants had previously heard about the shingles vaccine and 99 (64.7%) reported that the shingles vaccine is needed even if the patient had chicken pox in the past. Most participants (82.4%) knew that the vaccine should be given to adults aged more than 50 years. About 69 (45.1%) thought that they were extremely likely to get the shingles vaccine if the doctor recommended it. Barriers to shingles vaccination among study participants included participant’s perception that they were not at risk of getting shingles (33%) and concerns about vaccines’ side effects (27.5%). The average knowledge score about shingles was found to be 9.51 ± 3.14 and the average knowledge score about shingles vaccine was found to be 5.43 ± 1.46. Gender was significantly associated with knowledge score about the vaccine (p-value= 0.028) where females had higher knowledge scores about shingles vaccine as compared to males. Qualification level and current Saudi Commission for Health Specialties (SCFHS) classification were found to be significantly associated with knowledge scores about shingles (p-value = 0.002 and 0.003, respectively). Conclusion A good level of KAP about shingles and its vaccine was found among the study participants. However, few knowledge gaps in methods of protection were assessed. Female gender, married participants and higher SCFHS qualification level were positively associated with higher levels of knowledge and awareness as compared to other groups.

PMID:38146551 | PMC:PMC10749668 | DOI:10.7759/cureus.49393

Pediatr Allergy Immunol. 2023 Dec;34(12):e14066. doi: 10.1111/pai.14066.

ABSTRACT

BACKGROUND: Whole-exome sequencing (WES) provides a powerful diagnostic tool for identifying primary immunodeficiency diseases (PIDs). This study explores the utility of this approach in uncovering previously undiagnosed PIDs in children with community-acquired sepsis (CAS), with a medical history of recurrent infections or a family history of PIDs.

METHODS: We performed WES on DNA samples extracted from the blood of the 34 enrolled patients, followed by bioinformatic analysis for variant calling, annotation, and prioritization. We also performed a segregation analysis in available family members to confirm the inheritance patterns and assessed the potential impact of the identified variants on protein function.

RESULTS: From 34 patients enrolled in the study, 29 patients (85%) with previously undiagnosed genetic diseases, including 28 patients with PIDs and one patient with interstitial lung and liver disease, were identified. We identified two patients with severe combined immunodeficiency (SCID), patients with combined immunodeficiency (CID), six patients with combined immunodeficiency with syndromic features (CID-SF), four patients with defects in intrinsic and innate immunity, four patients with congenital defects of phagocyte function (CPDF), and six patients with the disease of immune dysregulation. Autoinflammatory disorders and predominantly antibody deficiency were diagnosed in one patient each.

CONCLUSION: Our findings demonstrate the potential of WES in identifying undiagnosed PIDs in children with CAS. Implementing WES in the clinical evaluation of CAS patients with a warning sign for PIDs can aid in their timely diagnosis and potentially lead to improved patient care.

PMID:38146112 | DOI:10.1111/pai.14066

J Clin Med. 2023 Dec 13;12(24):7651. doi: 10.3390/jcm12247651.

ABSTRACT

Myelodysplastic neoplasm (MDS) is a heterogeneous group of myeloid neoplasms affected by germline and somatic genetic alterations. The incidence of MDS increases with age but rarely occurs at a young age. We investigated the germline and somatic genetic alterations of Korean patients with young-onset MDS (<40 years). Among the thirty-one patients, five (16.1%) had causative germline variants predisposing them to myeloid neoplasms (three with GATA2 variants and one each with PGM3 and ETV variants). We found that PGM3 deficiency, a subtype of severe immunodeficiency, predisposes patients to MDS. Somatic mutations were identified in 14 patients (45.2%), with lower rates in patients aged < 20 years (11.1%). Nine (29%) patients had U2AF1 S34F/Y mutations, and patients with U2AF1 mutations showed significantly worse progression-free survival (p < 0.001) and overall survival (p = 0.006) than those without U2AF1 mutations. A UBA1 M41T mutation that causes VEXAS syndrome was identified in a male patient. In conclusion, a germline predisposition to myeloid neoplasms occurred in ~16% of young-onset MDS patients and was largely associated with primary immunodeficiencies, including GATA2 deficiency. Furthermore, the high frequency of somatic U2AF1 mutations in patients with young-onset MDS suggests the presence of a distinct MDS subtype.

PMID:38137719 | DOI:10.3390/jcm12247651