Journal of Clinical Immunology最新文献

Combined immunodeficiency due to CARMIL2 mutations is a rare autosomal recessive primary immunodeficiency characterized by impaired T-cell activation and function, leading to diverse clinical manifestations. Fewer than 50 cases have been reported worldwide. We describe the clinical and genetic features of five patients from Palestine with homozygous CARMIL2 mutations, including the first documented case of recurrent visceral leishmaniasis associated with this gene defect. This retrospective case series was conducted using whole-exome sequencing to confirm the diagnosis. All patients exhibited significant immunologic symptoms, including chronic dermatitis, cutaneous warts, recurrent respiratory infections, and mucocutaneous candidiasis. Two developed cytomegalovirus-related disease. Genetic analysis revealed two novel homozygous variants: NM_001317026.3:c.1865 C > T (p.Ala622Val) in four patients, and c.1973 C > T (p.Ala658Val) in one. Notably, one adult male developed recurrent visceral leishmaniasis, an unusual presentation not previously reported in the context of CARMIL2 deficiency. Consanguinity was identified in two families. All patients required immunomodulatory therapy, and four were evaluated for hematopoietic stem cell transplantation. This case series underscores the clinical heterogeneity of CARMIL2-associated immunodeficiency and highlights the importance of genetic testing in patients with recurrent or atypical infections, particularly in populations with a high prevalence of consanguinity. The novel link to visceral leishmaniasis expands the known phenotypic spectrum of this condition.

Background: IgA vasculitis (IgAV) is an autoimmune disorder characterized by inflammation of the small blood vessels. The pathogenesis of IgAV is believed to involve a complex interplay between immune cells, metabolites, and inflammatory cytokines (ICs).

Methods: We performed two-sample Mendelian randomization (MR) analysis to examine the causal relationship between immune cell traits, metabolites, ICs, and IgAV. Genetic variants associated with exposure, mediators and outcome were extracted from large-scale genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was used as the primary approach, supported by MR Egger, weighted median, simple mode, and weighted mode methods.

Results: In this study, we identified 25 immune cells, 6 metabolites (Threonate, Carnitine C5:1, Chiro-inositol, Carnitine C18:2, 3-formylindole, Cholate to phosphate ratio) and 2 ICs (T - cell surface glycoprotein CD5, Osteoprotegerin) associated with IgAV. Meanwhile, we identified 5 immune cell-metabolites-IgAV pathways (CD28⁺CD45RA^-CD8dim AC-3-formylindole-IgAV; CD28⁺ CD45RA^- CD8dim AC-Cholate to phosphate ratio-IgAV; CD28⁺ CD45RA⁺ CD8br%T cell-3-formylindole-IgAV; CD25 on IgD⁺ CD38^- unswmem-Chiro-inositol- IgAV; HLA DR on CD14⁺ CD16^- monocyte-Chiro-inositol-IgAV; CD39⁺ secreting Treg %secreting Treg-Threonate-IgAV) and 4 immune cells-ICs-IgAV pathways (IgD^- CD38^- AC-Osteoprotegerin-IgAV; CD45 on T-Osteoprotegerin-IgAV; HLA DR on CD14⁺ CD16^- monocyte-CD5-IgAV; HLA DR on CD14⁺CD16^- monocyte-CD5-IgAV).

Conclusions: These results highlight the need for further research to investigate the underlying mechanisms and identify potential therapeutic targets for the treatment of IgAV.

Purpose: Patients with X-linked agammaglobulinemia (XLA) suffer from severe, recurrent infections potentially leading to life-threatening complications. Early diagnosis and timely treatment can prevent infections and secondary complications, emphasizing a role for newborn screening (NBS). NBS for XLA is based on quantification of kappa-deleting recombination excision circles (KRECs). KREC-based screening could result in a large number of false-positive referrals associated with high impact for parents and health care systems, indicating the need for a second tier test.

Methods: KRECs were measured in NBS cards (N = 110,491) with a multiplex TREC/KREC qPCR assay. As second tier test options, an alternative qPCR multiplex assay, epigenetic immune cell counting for relative B-cell quantification and targeted next-generation sequencing with B-cell deficiency gene panel including 73 genes were performed on NBS cards of newborns with low KRECs.

Results: In total, 136/110,491 newborns had KRECs below cut-off. With the alternative qPCR multiplex assay, 16/110 of these newborns (14.5%) had KRECs above cut-off and would not have been referred. With epigenetic immune cell counting, 16.5% (17/103) had relative B-cell counts in the range of healthy controls. Targeted NGS showed promising results as 87 out of 103 (84%) newborns with low KRECs did not show any pathogenic/likely pathogenic variants and would not have been referred for follow-up diagnostics.

Conclusion: Several second tier tests can potentially reduce the number of false-positive referrals in NBS for XLA. NGS seems to be the most effective technique in NBS for XLA and other forms of agammaglobulinemia. Our results show promising first steps towards the implementation of NBS for XLA.

Fungal infections contribute to a significant disease burden in patients with chronic granulomatous disease (CGD). While the presentation may differ depending on genotype and environmental exposure to fungus, associated mortality rates are universally high. This is a retrospective study wherein medical records of patients diagnosed with CGD from 1994 to 2022 at our center in North India were reviewed. We categorized patients into 2 groups: patients with proven invasive fungal infection and patients with probable invasive fungal infections. We analyzed demographic details, clinical details, and the overall outcome of these patients. We identified 40 patients (40.4%) with fungal infections in our cohort of 99 patients with CGD. Twenty-one patients had proven invasive fungal infection, and 19 had probable invasive fungal infection. Pneumonia was the most common presentation in our cohort (n = 35; 87.5%). Two patients had isolated osteomyelitis, 1 had brain abscess, and 2 had candidemia. Aspergillus sp. was isolated most frequently (n = 27), followed by Candida sp. (n = 5), Mucorales sp. (n = 2), Paecilomyces sp. (n = 1) and Fusarium dimerum (n = 1). Aspergillus fumigatus (n = 11) was the most identified species of Aspergillus. Eleven patients had bacterial co-infection. Twenty-one patients (52.5%) died in this cohort. Risk factors for mortality identified are X-linked CGD (p = 0.027), bacterial coinfection (p = 0.003) and infection in infancy (p = 0.045). Aspergillus sp. is the most common offending fungus, and pneumonia is the most common manifestation of fungal infection in our patients with CGD. Infants, males, and patients with bacterial coinfection should be treated more aggressively amongst patients with CGD with fungal infection.

Background: Non-Aspergillus invasive fungal infections (NAFI) are increasingly reported in patients with Chronic Granulomatous Disease (CGD), but precise clinical descriptions remain scarce.

Objective and methods: We conducted a retrospective analysis of NAFI cases among CGD patients in the French National Registry of Primary Immunodeficiencies (CEREDIH) and in a comprehensive literature review.

Results: We identified 16 proven NAFI (9 molds, 6 yeasts and 1 Pneumocystis) among 263 CGD patients from CEREDIH and included an additional 106 probable/proven NAFI from a literature review (75 molds, 29 yeasts, 1 Pneumocystis, 1 dimorphic). Mold NAFI occurred at a median age of 17 years [IQR 9-23], and were mostly located to the lungs (79%, 65/82). Mold NAFI were breakthrough in 59% of patients (35/59), and 24% were receiving immunosuppressive treatments (13/54, mostly high-dose corticosteroids, n = 11). Lung surgical biopsies yielded the highest diagnostic rate (39/39) compared to less invasive methods (BAL 8/18 and transthoracic punctures 8/12). Nine patients with mold NAFI, including 3 refractory cases, were cured after Hematopoietic Stem Cell Transplantation (HSCT). Overall mortality for mold NAFI was 25% (20/81). Yeast infections occurred at a median age of 5 years [IQR 0-13], and 36% were receiving immunosuppressive treatments (5/14, mostly anti-TNF agents, n = 4). Infections were frequently located to lymph nodes or lungs, and 64% (21/33) were disseminated. Two yeast NAFI were cured after HSCT. Mortality was 26% (7/27).

Conclusion: NAFI in CGD patients are frequently severe, often occur despite prophylaxis and under additional immunosuppression, commonly require invasive procedures for diagnosis, and may be effectively managed with HSCT.

Purpose: Bone marrow failure (BMF) in idiopathic aplastic anemia (AA) and hypoplastic myelodysplastic neoplasms (MDS-h) results from the destruction of hematopoietic progenitors by autoreactive T cells; however, the molecular events driving the pathogenesis of these disorders remain unclear. We therefore applied whole-exome sequencing (WES) in AA and MDS-h patients to identify acquired and inherited gene variants presumed to have functional consequences for BMF. We also used transcriptome profiling to investigate the molecular mechanisms underlying the aberrant T cell response.

Methods: WES was performed on DNA from 42 patients at diagnosis. Transcriptome profiling of CD3⁺ cells was conducted in 21 patients and 10 healthy donors. Peripheral blood cell populations were analyzed by flow cytometry.

Results: Pathogenic/likely pathogenic (P/LP) somatic gene variants were detected in 79% of patients and were functionally associated with BMF-relevant processes such as antigen processing/presentation, T cell-mediated immunity, and DNA repair. P/LP germline gene variants were found in all patients, almost half of whom harbored variants associated with inborn errors of immunity. Patient T cells displayed expression signatures of increased inflammation, apoptosis, hypoxia response, and decreased oxidative phosphorylation. Dysregulated long noncoding RNAs were predicted to primarily regulate the differentiation of T helper 17 cells. Patients also showed significantly lower frequencies of immature progenitors and natural killer cells compared with controls.

Conclusion: Patients with idiopathic AA and MDS-h carried multiple germline immune-related gene variants that may increase susceptibility to immune-mediated BMF. Furthermore, patient T cells exhibited altered energy metabolism, which may represent a therapeutic target for modulating immune responses in autoimmune diseases.

The cellular basis of COVID-19 severity in patients with deficiencies in type I IFN immunity remains unclear. In this study, we differentiated cardiomyocytes and macrophages from IFNAR1 competent (IFNAR1^comp) and deficient (IFNAR1^def) induced pluripotent stem cells (iPSCs), and analyzed virus replication and cytokine production after exposure to SARS-CoV-2. Cardiomyocytes expressed the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) and showed abundant SARS-CoV-2 replication, which was higher in IFNAR1^def than IFNAR1^comp cells. Treatment with exogenous IFNα mitigated infection in IFNAR1^comp, but not in IFNAR1^def cardiomyocytes. In contrast, macrophages did not express ACE2 and did not support SARS-CoV-2 replication, but produced pro-inflammatory cytokines upon virus exposure, which was impaired in IFNAR1^def macrophages. In conclusion, type I IFNs decrease SARS-CoV-2 replication in human iPSC-derived cardiomyocytes, while they increase cytokine responses of macrophages.

Background: Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked(IPEX) syndrome caused by FOXP3 mutations is rare. FOXP3 is a transcription factor required for the regulatory T cell (Treg) development/function.

Aim: We aimed to characterize the clinical, immunologic, and genetic features of a single-center cohort of IPEX syndrome.

Patients and methods: We present the clinical/immunological/genetic features of 12 patients with IPEX syndrome. We used whole exome and Sanger sequencing for the diagnosis/familial segregation. We performed immunophenotyping and measured Treg percentage and FOXP3 expression in peripheral blood by flow cytometric analysis.

Results: Median age at diagnosis was 2.5 years (range: 0.3-22 years). Common clinical manifestations were infections (n = 9, 75%), allergies (n = 8, 67%), autoimmunity (n = 7, 58%), enteropathy (n = 7, 58%), and lymphoproliferation (n = 3, 25%). Atypical initial presentations included class IV lupus nephritis, a SCID-like immunophenotype (CD3⁺ T cells: 4% [100/µL]; CD4⁺ T cells: 3%, CD8⁺ T cells: 1%, CD19⁺ B cells: 81%, CD16/56⁺ NK cells: 13%), and isolated hypogammaglobulinemia persisting for years during follow-up. At the time of diagnosis, three (25%) patients had leukopenia, six (50%) had lymphopenia and two (17%) had neutropenia. Eosinophilia was observed in 42% of patients (25% mild, 17% moderate). Six different variants in FOXP3 were characterized in 12 patients from nine unrelated families. Four (33%) patients underwent hematopoietic stem cell transplantation (HSCT). Overall, three (25%) patients died due to infections. One patient died due to HSCT-related catheter complications, one patient died in an accident. Among the transplanted patients, two are alive and well. Among the non-transplanted patients, five are alive and are being followed up at our center. Treg (CD4⁺CD127^-/lowCD25⁺Foxp3⁺) percentage was low in eight patients compared to healthy controls (p < 0.001). FOXP3 expression was low in all the patients compared to healthy controls.

Conclusion: Atypical presentations make the diagnosis of IPEX syndrome challenging. This study expands the current knowledge of IPEX syndrome by describing a single-center cohort with certain atypical manifestations and by confirming previously reported rare phenotypes. Elucidating the genetic basis of immunodeficiency diseases contributes to improving diagnostic approaches and patient management.