Novel CARMIL2 (RLTPR) Mutation Presenting with Hyper-IgE and Eosinophilia: A Case Report.

BACKGROUND: Inborn errors of immunity are a growing group of disorders with a wide spectrum of genotypic and phenotypic profiles. CARMIL2 (previously named RLTPR) deficiency is a recently described cause of immune dysregulation, mainly presenting with allergy, mucocutaneous infections, and inflammatory bowel disease. CARMIL2 deficiency is categorized under diseases of immune dysregulation with susceptibility to lymphoproliferative conditions. CASE PRESENTATION: Here we describe a 29-years-old male from a consanguineous family, with food and sting allergy, allergic rhinitis, facial molluscum contagiosum (viral infection of the skin in the form of umbilicated papules), eosinophilia and highly elevated serum IgE level. Whole exome sequencing revealed numerous homozygous variants, including a CARMIL2 nonsense mutation, a gene regulating actin polymerization, and promoting cell protrusion formation. CONCLUSION: The selective role of CARMIL2 in T cell activation and maturation through cyto-skeletal organization is proposed to be the cause of immune dysregulation in individuals with CARMIL2 deficiency. CARMIL2 has an important role in immune pathways regulation, through cell maturation and differentiation, giving rise to a balance between Th1, Th2, and Th17 immune response. This case can improve the understanding of the different impacts of CARMIL2 mutations on immune pathways and further guide the diagnosis of patients with similar phenotypes.

Case Report of a Novel NFkB Mutation in a Lymphoproliferative Disorder Patient.

BACKGROUND: Lymphoproliferative disorders include a heterogeneous list of conditions that commonly involve dysregulation of lymphocyte proliferation resulting in lymphadenopathy and bone marrow infiltration. These disorders have various presentations, most notably autoimmune manifestations, organomegaly, lymphadenopathy, dysgammaglobulinemia, and increased risk of chronic infections. CASE PRESENTATION: A young boy presented with symptoms overlapping different lymphoproliferative disorders, including episodes of chronic respiratory tract infections, dysgammaglobulinemia, lymphadenopathy-associated with splenomegaly as well as skin rashes. Genetic studies revealed multiple heterozygous variants, including a novel mutation in the NFκB1 gene. CONCLUSION: This novel mutation can reveal new aspects in the pathogenesis of lymphoproliferative disorders and propose new treatments for them.

Novel Variants of DOCK8 Deficiency in a Case Series of Iranian Patients.

BACKGROUND: Dedicator of Cytokinesis 8 (DOCK8) deficiency, the most frequent cause of autosomal recessive hyper immunoglobulin (Ig)E syndrome, is a rare combined immunodeficiency. OBJECTIVE: In this study, we report seven patients, with consanguineous parents, with five novel variants within the DOCK8 gene. METHODS: For genetic analysis, we performed Whole Exome Sequencing (WES) or targeted sequencing by means of Next-generation sequencing (NGS) for some of the patients. For others, Sanger sequencing, Fluorescence-activated cell sorting (FACS), or polymerase chain reaction (PCR) were used. RESULTS: We report five novel variants within the DOCK8 gene: three deletions (deletion of exons 4-12, 24-30, and 22-27), one frameshift (LRG_196:g.189315dup;p.(Leu1052Profs*7)), and a splice region variant (LRG_196t1:c.741+5G>T). Patients presented with skin lesions, food allergy, candidiasis, otitis, recurrent respiratory infections, short stature, aortic aneurism, gynecomastia, and coarse facial features. Patients had leukocytosis, eosinophilia, lymphopenia, and monocytosis, elevated IgE, IgG, IgA, reduced IgM and IgA levels. Patients had a low percentage of CD3+ and CD4+ cells and a high percentage of CD19+, CD27+CD19+, and recent thymic emigrants T cells. The percentage of natural killer cells was increased in one of the patients while it was decreased in another patient. One patient died due to disseminated intravascular coagulation after hematopoietic stem cell transplantation. CONCLUSION: We reported novel variants within the DOCK8 gene and highlighted the risk of aneurysms in these patients, which have been rarely reported in these patients.

Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation.

Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3 encoding Ikaros and Aiolos have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NK cells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of proinflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic and transcriptional dysregulation.

BCGitis as the primary manifestation of chronic granulomatous disease.

Patients with primary immunodeficiency disease (PID) are not only vulnerable to mycobacterial disease, but are also more likely to develop adverse events following BCG vaccination. These events can range from regional disease (BCGitis) to disseminated disease (BCGosis). Chronic granulomatous disease (CGD), which is characterized by impaired leukocyte phagocytic function, is one of the many inherited PIDs that increase the body's susceptibility to recurrent bacterial and fungal infections. Here, we report a 6-year-old boy with no significant past medical history who presented with progressive lymphadenopathy six years after BCG vaccination. He was later diagnosed with CGD on further evaluation.

The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity.

The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1-/- mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity.

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

APRIL gene polymorphism and serum sAPRIL levels in children with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multi-factor autoimmune disorder with diverse clinical manifestations and unclear pathogenesis. Genetic components play important roles in the incidence and development of SLE. Among these, APRIL as a cytokine has roles in the stimulation and antibody production in B cells. APRIL was hypothesized to be associated with SLE. The aim of this study was to assess the involvement of the APRIL gene in SLE susceptibility in Iranian patients. A single-nucleotide polymorphism (SNP) for rs11552708 of APRIL gene was analyzed by real-time PCR in 60 SLE Iranian children and 64 healthy controls. DNA samples of patients and healthy controls were extracted from peripheral blood leukocytes by phenol-chloroform. Serum samples obtained from 45 children with SLE and 45 healthy controls were assayed by enzyme-linked immunosorbent assay (ELISA). The G/G genotype (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.22-2.07; P = 0.68) and G allele (OR 0.81, 95% CI 0.25-2.56; P = 0.89) frequencies of polymorphism at codon 67 (67G) do not differ significantly in the SLE patients compared with those in the healthy controls. The serum APRIL levels in the SLE patients (mean ± SD = 29.27 ng/ml ± 20.77, range from 0 to 55.33 ng/ml) were significantly higher than those in the healthy controls (P = 0.02). Our results demonstrated that rs11552708 of the APRIL gene is not associated with SLE susceptibility in Iranian children. Likewise, these findings suggest that APRIL antagonist could be a potential therapeutic target to control SLE in children.

Association of interleukin-6 single nucleotide polymorphisms with juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. Genetics and inflammatory elements seem to act as major underlying factors in its pathogenesis. The aim of this study is to identify the associations between interleukin-6 (IL-6) gene polymorphisms and individuals' vulnerability to JIA in a group of Iranian pediatric patients. Fifty-four patients with JIA were enrolled in this investigation and compared with 139 healthy individuals. Using polymerase chain reaction with sequence-specific primers, cytokine genotyping was performed. The allele and genotype frequencies of two single nucleotide polymorphisms (SNPs) within the IL-6 gene at -174 and +565 positions were assessed. A significant positive association was observed for IL -6 -174 G allele in the patient group (p = 0.02). Furthermore, a positive association was observed in patients with JIA for the GG genotype at the same position (p < 0.01), thus revealing a predisposing effect in JIA patients. On the other hand, a significant negative association was found for IL-6 -174 CG genotype (p < 0.01) in the case group. No significant difference was discovered in both the allelic and genotypic frequencies of IL-6 +565 position between patients and controls. Additionally, haplotype analysis divulged over representation of IL-6 GG haplotype in patient group (p < 0.01) as well as IL-6 CG haplotype in healthy controls (p < 0.01). Certain allele, genotype, and haplotype in IL-6 gene were over expressed in patients with JIA, which probably could render individuals more susceptible to this disease.

Specific immunotherapy in ovarian cancer: a systematic review.

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Several approaches of active and passive immunotherapy for EOC have been studied. The aim of this systematic review was to assess the clinical efficacy of specific immunotherapy in patients with EOC. We found 4524 references in seven databases and we included ten controlled clinical trials with 2285 patients with EOC reporting five active immunotherapeutic agents and three passive immunotherapies. Meta-analysis of six studies showed that overall there was not any significant difference in overall survival and recurrence-free survival between patients undergoing specific immunotherapy and those in control group. Most of the studies we evaluated reported a positive outcome from treatment with specific immunotherapy, although this was not significant.

Single nucleotide polymorphisms of TNF-Α gene in febrile seizures.

Febrile seizures (FS) is the most common seizure disorder during childhood. This study was performed in 78 patients with FS and 137 control subjects to assess polymorphisms of the TNF-α gene at positions -308 and -238, using the polymerase chain reaction and the sequence specific primers method. The highest positive allelic association that made the patients susceptible to FS was seen for TNF-α -238/G (p<0.0001). The GG genotype at TNF-α -238 was significantly higher in the patients with FS, compared to the controls (p=0.0001). Also, GA genotype at the same position was significantly lower in patients than in controls (P=0.0001). The GG haplotype had a significant positive association at TNF-α (308, 238) while GA haplotype showed a negative association (P<0.001). Our data support the idea that TNF-α single-nucleotide polymorphisms play a role in the pathogenesis of FS.

Association of IL6 single nucleotide polymorphisms with febrile seizures.

Febrile seizures (FSs) are the most common convulsive event in children. Inflammatory elements and genetics have major roles in their pathogenesis. As of the importance of interleukin-6 (IL-6) in FS, this study was performed to assess IL6 single nucleotide polymorphisms (SNPs) in a group of patients with FS. IL6 gene (-174 and +565) SNPs were studied on genomic DNAs of 90 children with FS, using PCR-SSP method. The results were compared to 139 healthy individuals. The presence of the G allele or the GG genotype at +565 position reduced risk of FS, while the A allele at +565 position of the promoter regions was a constituted risk factor for developing FS. This study could support the idea that IL6 SNPs play a role in the pathogenesis of FS.