Primary Immunodeficiency Disorders Research Articles

Extracellular Vesicles based STAT3 delivery as innovative therapeutic approach to restore STAT3 signaling deficiency

Extracellular Vesicles (EVs) have been proposed as a promising tool for drug delivery because of their natural ability to cross biological barriers, protect their cargo, and target specific cells. Moreover, EVs are not recognized by the immune system as foreign, reducing the risk of an immune response and enhancing biocompatibility. Herein, we proposed an alternative therapeutic strategy to restore STAT3 signaling exploiting STAT3 loaded EVs. This approach could be useful in the treatment of Autosomal Dominant Hyper-IgE Syndrome (AD-HIES), a rare primary immunodeficiency and multisystem disorder due to the presence of mutations in STAT3 gene. These mutations alter the signal transduction of STAT3, thereby impeding Th17 CD4+ cell differentiation that leads to the failure of immune response. We set up a simple and versatile method in which EVs were loaded with fully functional STAT3 protein. Moreover, our method allows to follow the uptake of STAT3 loaded vesicles inside cells due to the presence of EGFP in the EGFP-STAT3 fusion protein construct. Taken together, the data presented in this study could provide the scientific background for the development of new therapeutic strategy aimed to restore STAT3 signaling in STAT3 misfunction associated diseases like AD-HIES. In the future, the administration of fully functional wild type STAT3 to CD4+ T cells of AD-HIES patients might compensate its loss of function and would be beneficial for these patients, lowering the risk of infections, the use of medications, and hospitalizations.

Primary Immunodeficiency Disorders (PIDs) and its Rheumatologic Manifestations Mohammad Imnul Islam

The hallmark of Primary Immunodeficiency Disorders (PIDs) is increased susceptibility to recurrent infections, which are often poorly responsive to therapy, prolonged and life-threatening. The infections can involve bones and joints. PIDs may also predispose to allergic, autoimmune, autoinflammatory and malignant disorders. Arthritis is the most common rheumatological manifestation of PIDs. Recurrent septic arthritis, arthritis with increased susceptibility to infection, skeletal changes, autoimmune disease or systemic lupus erythematosus with negative antinuclear antibody (ANA) are the essential clinical clues that could be considered rheumatologic manifestations of PIDs. This is considerable concern that early detection of PIDs patients invariably improves the quality of life and life expectancy through the prompt implementation of appropriate medical intervention. BANGLADESH J CHILD HEALTH 2022; VOL 46 (2) : 82-85

Increased susceptibility to Mycobacterium avium complex infection in miniature Schnauzer dogs caused by a codon deletion in CARD9

Mammals are generally resistant to Mycobacterium avium complex (MAC) infections. We report here on a primary immunodeficiency disorder causing increased susceptibility to MAC infections in a canine breed. Adult Miniature Schnauzers developing progressive systemic MAC infections were related to a common founder, and pedigree analysis was consistent with an autosomal recessive trait. A genome-wide association study and homozygosity mapping using 8 infected, 9 non-infected relatives, and 160 control Miniature Schnauzers detected an associated region on chromosome 9. Whole genome sequencing of 2 MAC-infected dogs identified a codon deletion in the CARD9 gene (c.493_495del; p.Lys165del). Genotyping of Miniature Schnauzers revealed the presence of this mutant CARD9 allele worldwide, and all tested MAC-infected dogs were homozygous mutants. Peripheral blood mononuclear cells from a dog homozygous for the CARD9 variant exhibited a dysfunctional CARD9 protein with impaired TNF-α production upon stimulation with the fungal polysaccharide β-glucan that activates the CARD9-coupled C-type lectin receptor, Dectin-1. While CARD9-deficient knockout mice are susceptible to experimental challenges by fungi and mycobacteria, Miniature Schnauzer dogs with systemic MAC susceptibility represent the first spontaneous animal model of CARD9 deficiency, which will help to further elucidate host defense mechanisms against mycobacteria and fungi and assess potential therapies for animals and humans.

Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis.

Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia and primary immunodeficiency disorders), but most cases remain idiopathic. To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived, cells, cell cultures and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. We identified bi-allelic pathogenic variants in WFDC2 in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2-deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and thus secretion of mature WFDC2. WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Rubella virus vaccine-induced granulomas: a case in children with ataxia-telangiectasia

Ataxia telangiectasia (AT) is a rare autosomal recessive primary immunodeficiency disorder (PID) resulting from a mutation in the ATM gene, which is involved in DNA repair. We describe the case of a young girl with cutaneous granulomas that developed after childhood vaccinations. Immunohistochemistry revealed granulomas induced by the rubella virus vaccine. This finding raises the question of live rubella vaccine strains safety in immunocompromised children.

Diffuse cerebral microhemorrhages in Wiskott-Aldrich syndrome – A rare radiological manifestation of a rare immunodeficiency disorder

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder with the characteristic triad of immunodeficiency, thrombocytopenia, and eczema. It results from a genetic mutation in the gene encoding WAS protein. We present a case of a 4-year-old male child who presented with two episodes of generalised tonic clonic seizures (GTCS) type convulsions. Magnetic resonance imaging (MRI) brain with contrast revealed diffuse cerebral microhemorrhages in supratentorial and infratentorial brain parenchyma which is a rare manifestation and not adequately documented in literature to the best of our knowledge.

The Scope and Impact of Viral Infections in Common Variable Immunodeficiency (CVID) and CVID-like Disorders: A Literature Review.

Common Variable Immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disorder characterised by impaired antibody production, leading to recurrent infections and an increased susceptibility to viral pathogens. This literature review aims to provide a comprehensive overview of CVID's relationship with viral infections, encompassing disease pathogenesis, key presenting features, specific monogenic susceptibilities, the impact of COVID-19, and existing treatment options. The pathogenesis of CVID involves complex immunological dysregulation, including defects in B cell development, antibody class switching, and plasma cell differentiation. These abnormalities contribute to an impaired humoral immune response against viral agents, predisposing individuals with CVID to a broad range of viral infections. Genetic factors play a prominent role in CVID, and monogenic drivers of CVID-like disease are increasingly identified through advanced genomic studies. Some monogenic causes of the CVID-like phenotype appear to cause specific viral susceptibilities, and these are explored in the review. The emergence of the COVID-19 pandemic highlighted CVID patients' heightened predisposition to severe outcomes with viral infections. This review explores the clinical manifestations, outcomes, and potential therapeutic approaches for COVID-19 in CVID patients. It assesses the efficacy of prophylactic measures for COVID-19, including vaccination and immunoglobulin replacement therapy, as well as trialled therapies.

Increased mortality in infants with abnormal T-cell receptor excision circles.

T-Cell Receptor Excision Circles based newborn screening (TREC-NBS) allows for early detection of T-cell lymphopenia in infants with primary immunodeficiency disorders (PIDD). The utility of abnormal TREC-NBS in infants without PIDD is not well studied. We sought to evaluate the association of abnormal TREC-NBS with mortality. 365,207 TREC-NBS from October 2011 to December 2014 were reviewed. 467 newborns had abnormal screens and did not meet the criteria for a PIDD diagnosis. Cases were matched to controls (1:3) based on gestational age, birth weight, neonatal intensive care unit status (NICU), and race. Data were obtained through NBS, birth and death certificates records from the Michigan Department of Health and Human Services (MDHHS) databases. Infants with abnormal TREC-NBS had higher mortality even when PIDD was ruled-out. Transient abnormal TREC-NBS was not associated with higher mortality, but unresolved or late abnormal TREC-NBS was associated with higher mortality. Infants with late abnormal TREC-NBS had severe prematurity, lower birth weight, lower Apgar scores, and higher percentage of congenital anomalies. Infants with abnormal TREC-NBS may be at a higher risk of morbidity and mortality and should be carefully followed, especially if discharged home before a repeat screen can be completed. This study explores the risk factors and mortality for newborns with secondary T-cell lymphopenia captured on T-Cell Receptor Excision Circles based newborn screening (TREC-NBS). Abnormal TREC-NBS allows for prompt life-saving interventions for primary immunological conditions such as Severe Combined Immunodeficiency (SCID), but can also be associated with non-immunologic conditions. Unresolved and late abnormal TREC-NBS is associated with higher mortality even without primary immunodeficiency, likely detected in infants with more severe prematurity, lower birth weight, and congenital anomalies. TREC-NBS positive infants with secondary T-cell lymphopenia require special attention and close monitoring.

Wiskott-Aldrich syndrome: A new synonym mutation in the WAS gene.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency disorder. Mutations in the WAS gene are considered to be the primary cause of WAS. In this work, we report a boy who presented with intracranial hemorrhage (ICH) as an initial symptom and detects a novel pathogenic synonymous mutation in his WAS gene. His mother was a carrier of the mutant gene. The mutation, located at position c.273 (c.273 G>A) in exon 2, is a synonym mutation and predicted to affect protein expression by disrupting gene splicing. This study summarizes the diagnosis and treatment process of the patient and expands the genetic spectrum of WAS.

General Population Awareness of Primary Immune Deficiency Disease in Children in the Arar Region, Saudi Arabia.

Background Primary immunodeficiency disorders (PIDD) are of various types and severities, and they are associated with a delay in diagnosis. Early diagnosis of PIDD helps to improve the quality of life of affected children and prevent permanent consequences such as organ damage. Hence, awareness of PIDD is a must in the community to aid in early detection. Objectives The study aims to investigate the general population's awareness of PIDD in children in Arar, Northern Saudi Arabia. Methods A cross-sectional design was utilized to determine the awareness of PIDD in children in Arar, Northern Saudi Arabia. The participants were selected through an online self-administered questionnaire. The collected data was analyzed using descriptive and inferential statistics. Results A total of528 participants were involved in the current study. The majority of the sample population falls within the 20-30 age range. 9.1% of respondents know a child with primary immunodeficiency. Additionally, participants were aware of certain symptoms, such as delayed growth and chronic diarrhea, with rates of 47.0% and 34.1%, respectively. On the other hand, symptoms like otitis media and sinusitis have lower awareness rates of 25.8% and 33.3%, respectively. Conclusion This study can help in developing targeted awareness campaigns and educational programs to improve the understanding of primary immune deficiency disease among the general population in Saudi Arabia. This, in turn, can lead to earlier diagnosis and better management of the disease in children, ultimately improving their quality of life.

MULTIPLE GIANT CHALAZIA IN HYPERIMMUNOGLOBULINEMIA E SYNDROME: A CASE REPORT

Introduction : Hyperimmunoglobulinemia E syndrome (HIES) is a rare primary immunodeficiency disorder that manifests as elevated level of serum immunoglobulin E (IgE) higher than 1.000 IU/mL and multisystem disorder characterized by recurrent skin and pulmonary abscesses caused by autosomal dominant or recessive disorder with gene mutation. We present a case of multiple giant chalazion ina patient with HIES.
 Case Illustration : A 15-year-old boy was referred to Ophthalmology Department with multiple giant lumps on the left eyelid for the last 2 weeks. He had a history of recurrent multiple lumps on the left lower eyelid in the last 1 year. He was diagnosed with HIES since 8 years ago. He had normal visual acuity of both eyes. Multiple giant chalazion were observed on the left upper and lower eyelid. The patient also presented with scalp and neck infection. Laboratory studies showed elevated total serum IgE level of 53,032 IU/mL and eosinophilia.
 Discussion : Ocular manifestations in HIES patients are not common. Some cases reported chalazia, keratoconus, and blepharitis. Surgical incision drainage was performed in our patient. Medications and surgical intervention had produced only transient improvement. The patient was treated conservatively. Riskof chalazia recurrence remains unknown as reported cases presented with diverse clinical presentation and follow-up serum IgE evaluation is not routinely performed.
 Conclusion : Recurrent multiple giant chalazia may occur as an ophthalmic feature of HIES. HIES should be considered and investigated in patients presenting with recurrent giant chalazia.

MULTIPLE GIANT CHALAZIA IN HYPERIMMUNOGLOBULINEMIA E SYNDROME: A CASE REPORT

Abstract
 Introduction : Hyperimmunoglobulinemia E syndrome (HIES) is a rare primary immunodeficiency disorder that manifests as elevated level of serum immunoglobulin E (IgE) higher than 1.000 IU/mL and multisystem disorder characterized by recurrent skin and pulmonary abscesses caused by autosomal dominant or recessive disorder with gene mutation. We present a case of multiple giant chalazion ina patient with HIES.
 Case Illustration : A 15-year-old boy was referred to Ophthalmology Department with multiple giant lumps on the left eyelid for the last 2 weeks. He had a history of recurrent multiple lumps on the left lower eyelid in the last 1 year. He was diagnosed with HIES since 8 years ago. He had normal visual acuity of both eyes. Multiple giant chalazion were observed on the left upper and lower eyelid. The patient also presented with scalp and neck infection. Laboratory studies showed elevated total serum IgE level of 53,032 IU/mL and eosinophilia.
 Discussion : Ocular manifestations in HIES patients are not common. Some cases reported chalazia, keratoconus, and blepharitis. Surgical incision drainage was performed in our patient. Medications and surgical intervention had produced only transient improvement. The patient was treated conservatively. Riskof chalazia recurrence remains unknown as reported cases presented with diverse clinical presentation and follow-up serum IgE evaluation is not routinely performed.
 Conclusion : Recurrent multiple giant chalazia may occur as an ophthalmic feature of HIES. HIES should be considered and investigated in patients presenting with recurrent giant chalazia.

Primary immunodeficiency disorders imitating inflammatory bowel diseases: clinical aspects and problems of the differential diagnosis

From the beginning of 2000s, there has been a significant increase in the incidence of inflammatory bowel diseases (IBD) and primary immunodeficiency disorders (PIDs) in adults and children in many countries around the world. The aim of the review is to summarize the state-of-the-art on diverse clinical types of PIDs with gastrointestinal manifestations and their differential diagnostic algorithms.
 Atypical PIDs with “blunted” clinical manifestations are challenging for the timely diagnosis. Some types of PIDs with gastrointestinal involvement are also difficult to differentiate with classical IBDs. Molecular genetic studies have allowed for selection of a specific group of monogenic IBD-like diseases, represented mainly by PIDs. The authors discuss current classification of PIDs and their main clinical types imitating IBD, with important clinical and laboratory aspects. High level of information and awareness of practicing specialists working with IBD patients would be helpful in the selection of a patient cohort with possible PIDs and in the performance of extended laboratory assessment or referring for genetic tests. Timely diagnosis of PIDs would ensure quick administration of target therapy or hematopoietic stem cell transplantation, which in most cases would allow for the achievement of the disease remission, improvement of quality and duration of life.

Effect of allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease in children: A multicentre, retrospective cohort study in China

Chronic granulomatous disease (CGD) in children is a rare primary immunodeficiency disorder that can lead to life-threatening infections and inflammatory complications. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly being used to treat severe CGD in children. We conducted a multicenter retrospective analysis of children with CGD who were treated with allo-HSCT at four pediatric hematopoietic stem cell transplant centers in China from September 2005 to December 2019. The study included a total of 171 patients (169 males and 2 females). The median age at the time of transplantation was 6.1 (0–16.4) years. Among them, 154 patients had X-linked recessive inheritance caused by CYBB gene mutations, 12 patients were autosomal recessive, 1 patient had DNAH11 and HYDIN gene mutations, and 4 patients had no gene mutations. The median follow-up period was 36.3 (1.9–79) months. All participating patients were applied to myeloablative conditioning (MAC) regimens. The rates of OS, EFS, and GEFS within three years were 87.5%, 85.3%, and 75.2%, respectively. The total graft failure and the total mortality rate were 5.3% and 11.1%. The cumulative incidence of acute GVHD was 53.8% and the incidence of chronic GVHD was 12.9%, The incidence of chronic GVHD was higher for patients who received unrelated donor cord blood stem cell transplantation (UD-CB) (P = 0.001). Chronic GVHD and coinfections are the risk factors for OS and EFS in patients with CGD after receiving allo-HSCT. UD-CB is a risk factor for EFS and the presence of pneumonia before transplantation is a risk factor for OS. In conclusion, through this study, we have demonstrated that allo-HSCT has excellent efficacy in the treatment of CGD in children, especially, RD-haplo is associated with a lower rate of graft failure incidence and mortality than the treatment modalities of other donor type. Therefore, allo-HSCT is strongly recommended when a well-matched donor is available. If a well-matched donor is not available, the HLA-mismatched donor should be carefully evaluated, and the conditioning regimen modified accordingly.

Hyper-IgE syndrome: a case report

Introduction and importance: Hyper-IgE syndrome (HIES), also known as Job syndrome, is a rare primary immunodeficiency disorder characterized by elevated serum IgE levels, recurrent infections, and various clinical features. Early diagnosis, prompt management of infections, and supportive care are essential in improving outcomes for individuals with HIES. Genetic testing, including STAT3 gene sequencing, plays a crucial role in confirming the diagnosis. Further research is needed to enhance our understanding of HIES and develop targeted therapies to improve the quality of life for affected individuals. Case presentation: This case report presents the clinical features and management of a 37-year-old male with HIES, diagnosed at the age of 2 due to recurrent cold abscesses caused by Staphylococcal infections. Clinical discussion: The patient exhibited typical symptoms of HIES, including recurrent eczema, frequent bacterial infections, mucocutaneous candidiasis, and various physical abnormalities. Diagnostic markers such as elevated IgE levels and eosinophilia supported the HIES diagnosis, which was further confirmed by the identification of a STAT3 gene mutation. Treatment primarily involved supportive measures and antibiotics for infections. The patient’s blood test results and imaging findings revealed abnormalities such as low red blood cell count, elevated erythrocyte sedimentation rate, and pulmonary nodules. Conclusion: This case report highlights the importance of early diagnosis, prompt management of infections, and the need for ongoing research to improve our understanding and treatment of HIES.

A Review of Primary Immuno-deficiency Disorders Predisposing to Cancer

Introduction: Primary immunodeficiencies are relatively rare and heterogeneous disorders in which one or more component of immune system have genetic defect. The majority of the patients suffer from frequent infections with different microorganisms according to the type of disorder they have. Some people with primary immunodeficiency are susceptible to malignant diseases. The type of malignancy depends on the type of primary immunodeficiency, age of the patient and the type of virus infection. Many advances have been made in understanding of molecular mechanisms in humeral and cellular immune defects. Furthermore، our knowledge has been increased about the incidence of infections and tumors in primary immunodeficiency and this helps us in early diagnosis of disorders and their complications. Several evidences support the theory that the immune system plays a major role in the occurrence of many malignant diseases. Articles have been searched on Google Scholar، PubMed، Web of Science، and Scopus databases. In this review، the latest and most reliable articles related to the subject that had been published in English language were used.
 Conclusion: Since the patients with primary immunodeficiency are prone to multiple infections, various malignancies can be seen in these people. The recurrence of some malignancies in families, especially blood malignancies may be due to primary immunodeficiency and we should consider evaluation of immune system.

Inborn errors of immunity with kidney and urinary tract disorders: a review.

Human inborn errors of immunity (IEIs), previously referred to as primary immunodeficiency disorders (PIDs), are a heterogeneous spectrum of inherited abnormalities of the immune system with different organ involvement. The number of identified IEIs is rapidly increasing, highlighting the non-negligible role of an interdisciplinary approach in clinical diagnosis. Kidney disorders are one of the important comorbidities in some of the affected patients and play a significant role in the diagnosis and course of disease. According to recent studies, 22 types of human IEI with renal manifestations have been identified so far, including immunodeficiency with congenital thrombocytopenia, thymic defects with additional congenital anomalies, complement deficiencies, type 1 interferonopathies, immunity related to non-hematopoietic tissues, congenital neutropenia's, common variable immunodeficiency disorder (CVID) phenotype and immuno-osseous dysplasia. Based on this classification, we herein review IEIs with renal features and explain the genetic defect, inheritance, and type of renal manifestations.

Approach to primary immunodeficiency disorders

Abstract: Primary immunodeficiency disorder also known as Inborn errors of immunityare potentially life threatning disorders, frequently remain undiagnosed in both developing and underdeveloped nations. A systematic and thorugh evaluation is required to attain a definitive diagnosis. This review outline the standardised approach essential for unravelling the diagnosis of such clinical condition during childhood.

Expression of IL-17RA in Innate Cells of Patients with Common Variable Immunodeficiency (CVID) and its Clinical Implications.

Background. Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by B-cell dysfunction and immunoglobulin production deficiency. Dysregulation of interleukin-17 (IL-17) and its receptor IL-17RA have been reported in various immune disorders. This study aimed to investigate the expression of IL-17RA in innate immune cells of CVID patients and its correlation with clinical manifestations. Methods. A cross-sectional study included 22 CVID patients and 14 age- and sex-matched healthy controls. IL-17RA expression was assessed in various immune cell subsets using flow cytometry. Demographic and clinical data were collected, and statistical analysis was performed. Results. CVID patients had elevated IL-17RA expression in neutrophils, non-classical monocytes, and dendritic cells compared to healthy controls. Patients with a history of intestinal microbial colonization, particularly with Campylobacter jejuni and Giardia intestinalis, showed significantly higher IL-17RA expression in innate cells. Elevated IL-17RA expression in monocytes and dendritic cells also correlated with higher fecal calprotectin levels in CVID patients, regardless of microbial colonization. Conclusions. The study suggests that despite previous reports of reduced circulating Th17 cells and IL-17 levels in CVID patients, IL-17RA expression in innate cells may be elevated, potentially indicating altered IL-17 signaling. This heightened IL-17RA expression could contribute to a persistent pro-inflammatory state, possibly due to microbial translocation or other inflammatory factors. The association of IL-17RA expression with gastrointestinal microbial colonization and its correlation with fecal calprotectin underscores the complexity of IL-17RA's role in CVID pathophysiology. Further research in larger cohorts could elucidate the implications of IL-17RA expression in both infectious and non-infectious inflammatory aspects of CVID.

Novel gene therapy advances for treating primary immunodeficiency disorders – an update

Novel gene therapy advances for treating primary immunodeficiency disorders – an update