Proteasome disorders and inborn errors of immunity.

Background: Due to the absence of curative treatments for inborn errors of immunity (IEI), children born with IEI require long-term follow-up for disease manifestations and related complications that occur over the lifespan. Effective transition from pediatric to adult services is known to significantly improve adherence to treatment and long-term outcomes. It is currently not known what transition services are available for young people with IEI in Europe. Objective: To understand the prevalence and practice of transition services in Europe for young people with IEI, encompassing both primary immunodeficiencies (PID) and systemic autoinflammatory disorders (AID). Methods: A survey was generated by the European Reference Network on immunodeficiency, autoinflammatory, and autoimmune diseases Transition Working Group and electronically circulated, through professional networks, to pediatric centers across Europe looking after children with IEI. Results: Seventy-six responses were received from 52 centers, in 45 cities across 17 different countries. All services transitioned patients to adult services, mainly to specialist PID or AID centers, typically transferring up to ten patients to adult care each year. The transition process started at a median age of 16–18 years with transfer to the adult center occurring at a median age of 18–20 years. 75% of PID and 68% of AID centers held at least one joint appointment with pediatric and adult services prior to the transfer of care. Approximately 75% of PID and AID services reported having a defined transition process, but few centers reported national disease-specific transition guidelines to refer to. Conclusions: Transition services for children with IEI in Europe are available in many countries but lack standardized guidelines to promote best practice.

Inborn errors of immunity (IEIs) can exhibit variant clinical manifestations beyond the classic presentation of recurrent infections. Allergic diseases represent an important subset that can arise as the primary feature or coexist with IEIs. In this study, we aimed to investigate the burden of the most frequent allergic diseases among individuals with primary immune deficiency. Over 70 registered patients with a definite diagnosis of IEI were enrolled in our study. Patients and their records were evaluated, and data were collected via a questionnaire. Additionally, laboratory investigations, including spirometry, skin prick tests, and specific IgE, were used to confirm the diagnosis of allergic diseases. Statistical analysis was performed via SPSS software. The most frequent IEIs in our study comprise agammaglobulinemia, hyper-IgE syndrome, and common variable immune deficiency. The overall prevalence of allergic diseases among IEI patients was 77.8%. Allergic rhinitis, with a prevalence of 47.2%, atopic dermatitis 40.3% and asthma 37.5% were the most frequent allergic diseases among these patients. The highest prevalence of allergic rhinitis and asthma was detected among patients with agammaglobulinemia (23.5% and 33.5%). Also, Atopic dermatitis and food allergy had the highest prevalence in hyper IgE syndrome (27.6% and 75%). Agammaglobulinemia was accounted for as the most frequent IEI accompanying allergic disorders in our study. The interplay between atopy and IEIs is complex, highlighting the role of immune dysregulation in allergic diseases. Our study investigated the prevalence of allergic diseases among individuals with inborn errors of immunity. According to the coexistence of allergic diseases and IEIs, in patients with unusual, early onset, and severe allergic manifestations, underlying IEI may be suspected.

Conflicts of Interests: EYW receives consulting and speaker fees from Pharming Healthcare, Inc. regarding their work on the medication leniolisib approved for activated PI3 kinase delta syndrome (APDS). The remaining authors AHS and MK declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The number of inborn errors of immunity (IEI) is growing rapidly (1). They can be challenging to diagnose given the expanding and variable clinical phenotypes (2,3). Specifically, there is an increasing recognition that immune dysregulation can be an initial or predominant manifestation of a substantive portion of IEIs (4,5). Immune dysregulation can also have a large impact on disease treatment, monitoring, and outcomes. Significant progress has been made in the elucidation of molecular and cellular mechanisms underlying the immune dysregulation of IEIs. Tremendous improvement has also been made in the management of IEIs with availability of therapies expanding to include biologics and small molecular inhibitors. Despite progress, more understanding is needed to tailor the use of immunomodulatory therapy in IEIs. This Research Topic "Immune Dysregulation in Inborn Errors of Immunity" highlights recent advances in the understanding of the prevalence, mechanisms, spectrum of manifestations, and management of immune dysregulation in IEIs. Gagne et al. provide a concise review of how Mendelian type I interferonopathies can masquerade as non-Mendelian autoimmune disorders like systemic lupus erythematosus (SLE) and dermatomyositis, which are also associated with increased type I interferon (IFN) expression. Similarly, Hetrick et al. described how autoinflammatory bone disorders characterized by sterile osteomyelitis can be seen with both monogenic forms including Majeed syndrome and deficiency of the interleukin-1 antagonist (DIRA) and the more common sporadic form chronic nonbacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO). Other autoimmune manifestations of IEIs include, but are not limited to, autoimmune cytopenia, endocrinopathies, inflammatory bowel disease, neutrophilic dermatoses, arthritis, and vasculitis as illustrated by the case of activated phosphoinositide 3-kinase delta (PI3Kd) syndrome (APDS) from Sood et al.The highly variable clinical manifestations of IEIs can contribute to diagnostic delays, which in turn, can lead to poorer outcomes. Autoimmunity and autoinflammation can negatively impact morbidity and mortality and are an independent prognostic factor for death among individuals with IEIs (5). Immune dysregulation may also contribute to the increased risk of malignancy observed in IEIs as with the APDS case presented by Sood et al.Improving awareness and early recognition of IEIs is also critical because making a diagnosis can impact treatment and surveillance. There may be disease-specific treatments available like leniolisib, an oral selective PI3Kd inhibitor, for APDS as discussed by Sood et al. Because type 1 IFN work through the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, Gagne et al. also consider the increasing use of JAK inhibition in autoinflammatory IFN-mediated monogenic diseases. The study by Berrueco et al. showed mycophenolate mofetil may be an effective and safe treatment for pediatric patients with autoimmune cytopenia and IEI, even cases of autoimmune cytopenia refractory to first-line therapies like corticosteroids and intravenous immunoglobulin (IVIG).These articles also nicely illustrate the need for a multidisciplinary approach to the immune dysregulatory manifestations in IEIs as there are contributions from Rheumatology (inteferonopathies and pediatric autoinflammatory bone disorders), Hematology (autoimmune cytopenias), and Allergy/Immunology (APDS). The conditions covered in this topic represent only a fraction of disordered immune conditions in IEIs and should be considered in more detail in the future.The recognition of immune dysregulation in IEIs continues to increase as the number of patients impacted expands. There is a clear need for ongoing investigation into the epidemiology and pathophysiology for clinical manifestations and the risk factors for developing immune dysregulation as well as a collaborative multidisciplinary approach to improve diagnosis and management of this population. Our hope is that this topic has piqued the interest of researchers and clinicians in this area to provide better understanding, care, and outcomes to these patients.Lastly, we would like to thank the reviewers for their time and valuable assessments. This important collection of articles would not be possible without their contributions.

The aim of this study was to screen for inborn errors of immunity (IEIs) within a pediatric critical care population and further evaluate the mortality-related factors.This study included 1203 pediatric patients aged between 1 month and 18 years admitted to the pediatric intensive care unit (PICU) at Antalya Education and Research Hospital (in Turkey) between January 2020 and December 2022. Patients with chronic diseases, ongoing chronic medication regimens, other known comorbidities, traumas, postsurgical cases, poisonings, and preexisting IEI diagnoses were excluded.In this single-center prospective study, a total of 28 warning signs for IEI diagnosis were applied, including 10 per the Jeffery Modell Foundation (JMF) and 18 per literature review. Patients with severe illness requiring intensive care and at least 1 IEI warning sign were evaluated. These patients underwent standardized immunological screening, then those with abnormal findings had an extended immunologic assessment including functional analyses. Genetic analyses were conducted on those with abnormal findings concerning for IEI. Diagnoses of IEI were established using the European Society for Immunodeficiencies criteria and further categorized based on the International Union of Immunological Societies classification.Of the 1203 patients admitted to the PICU, 75 (6.2%) patients had at least 1 IEI warning sign and no exclusionary diagnoses. This study found a 4.3% confirmed IEI prevalence rate in the PICU during the 3-year study period. More than half (51.5%) of these patients presented with sepsis, 36.4% with acute respiratory failure, and 12.1% with neuroinflammatory disorders. The median age was 16 months, and there was a male predominance (60.6%). Consanguinity was present in 66.7% of the patients. History of severe viral infections was the most common IEI warning sign (61%), followed by life-threatening infections (51.7%), sibling/cousin death (25%), and a history of more than 2 episodes of pneumonia per year (22.5%). Only 31% of patients had 2 or more of the JMF warning signs. Regarding types of IEIs identified, nearly half (48.5%) were diagnosed with an immune dysregulation disorder, with the most prominent IEI diagnosis being hemophagocytic lymphohistiocytosis. Combined immunodeficiencies were also commonly identified (24.2%), followed by defects in innate immunity (15.2%) and predominant antibody deficiencies (6.1%). Genetic testing was performed on 78.8% (26/33) of patients with an IEI diagnosis. Among the 33 patients with confirmed IEI, the mortality rate was 58%.Patients with IEI can present critically ill without classic warning signs and have a high mortality rate. This highlights the need for systematic screening to reach early diagnosis and treatment, especially in critically ill children.This study highlights a significant yet underrecognized prevalence of IEI in PICUs. The identification of IEI in nearly 1 in 20 critically ill children and reported high mortality rate of 58% emphasizes the need for earlier screening and detection with targeted immunologic/genetic evaluation. The study also found that only 31% of patients exhibited 2 or more JMF warning signs, suggesting a need for wider criteria, especially in the PICU. Limitations of the study include a single-center study in a country with high consanguinity, thus limiting generalizability. There was a small sample size of only 33 patients with new IEI diagnosis, and data were limited to their hospitalization without long-term follow-up related to mortality. Despite these limitations, this study reinforces that IEIs are more common than traditionally thought and general pediatricians, as well as PICU specialists, have a critical role in early suspicion, diagnosis, and seeking immunology consultation to reduce mortality and long-term morbidity.

New technologies in genetic diagnostics have revolutionized the understanding and management of rare diseases. This review highlights the significant advances and latest developments in genetic diagnostics in inborn errors of immunity (IEI), which encompass a diverse group of disorders characterized by defects in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and malignancies. Various diagnostic approaches, including targeted gene sequencing panels, whole exome sequencing, whole genome sequencing, RNA sequencing, or proteomics, have enabled the identification of causative genetic variants of rare diseases. These technologies not only facilitated the accurate diagnosis of IEI but also provided valuable insights into the underlying molecular mechanisms. Emerging technologies, currently mainly used in research, such as optical genome mapping, single cell sequencing or the application of artificial intelligence will allow even more insights in the aetiology of hereditary immune defects in the near future. The integration of genetic diagnostics into clinical practice significantly impacts patient care. Genetic testing enables early diagnosis, facilitating timely interventions and personalized treatment strategies. Additionally, establishing a genetic diagnosis is necessary for genetic counselling and prognostic assessments. Identifying specific genetic variants associated with inborn errors of immunity also paved the way for the development of targeted therapies and novel therapeutic approaches. This review emphasizes the challenges related with genetic diagnosis of rare diseases and provides future directions, specifically focusing on IEI. Despite the tremendous progress achieved over the last years, several obstacles remain or have become even more important due to the increasing amount of genetic data produced for each patient. This includes, first and foremost, the interpretation of variants of unknown significance (VUS) in known IEI genes and of variants in genes of unknown significance (GUS). Although genetic diagnostics have significantly contributed to the understanding and management of IEI and other rare diseases, further research, exchange between experts from different clinical disciplines, data integration and the establishment of comprehensive guidelines are crucial to tackle the remaining challenges and maximize the potential of genetic diagnostics in the field of rare diseases, such as IEI.

Inborn errors of immunity (IEIs) are a heterogeneous group of disorders, genetically diverse but phenotypically overlapping. Over 500 IEI-related genes have been identified. Next generation sequencing (NGS) enables the simultaneous evaluation of a large number of genes in multiple patients in parallel. Since 2017, in our setting, custom IEI panels have been useful mainly for patients displaying clinical phenotypes of immune dysregulation and autoinflammatory disorders. Our aim is to evaluate the performance of targeted NGS panels based on International Union of Immunological Societies (IUIS) gene categories by examining how many patients achieved a conclusive diagnosis. A retrospective analysis was performed on 361 index cases submitted to four chronologically successive targeted NGS custom panels. The first panel included 124 IUIS genes, most of them related to autoimmune and immune dysregulation disease categories. The second panel contained 143 IUIS genes, including defects of innate immunity. The third and fourth, large panels covering 314 and 325 IUIS genes, respectively, included/comprised the majority of IUIS disease categories, with focus on autoinflammatory, immune dysregulation, and intrinsic immunity disease categories. From a total of 361 samples studied, 264 were referred due to clinical suspicion of immune dysregulation, autoinflammatory disease, or defects in innate immunity. Twenty-three percent of them (61/264) achieved a confirmed or highly probable genetic etiology. According to the main IEI IUIS disease categories included in targeted panels, immune dysregulation represented 26% (32/123) of these diagnoses, autoinflammatory disorders 21% (18/85), and defects in innate immunity 19% (11/56). In the remaining patients studied, 42% (41/97) of them achieved a conclusive diagnosis in others IEI IUIS disease categories. The NGS approach demonstrated the expected IEI diagnostic rate. The strategy of designing panels oriented toward IEI disease categories that present the greatest variability in clinical presentations with overlapping phenotypes proved to be effective regarding achievement of conclusive diagnoses in our cohort.

The immune system protects the body. When defenses are compromised, people with hereditary immunological disorders become vulnerable to many life-threatening infections. Inborn errors of immunity (primary immunodeficiencies), manifested in patients in increased susceptibility to infectious diseases, autoimmune diseases, allergies, and malignant neoplasms. Today, this group of diseases is still considered quite rare. However, the development of diagnostic technologies expands the list of nosologies associated with inborn errors of immunity. Neonatal screening for inborn errors of immunity could solve many of the problems of these patients, but the procedure is not carried out in the Russian Federation. Therefore, diagnostics based on an analysis of the clinical manifestations of diseases. In most cases, the disease is diagnosed in early childhood. Here, the role of both the parents of the child-patient and the medical staff is important. The health and life of the child depends on their awareness of the disease, methods of diagnosis, treatment. This group of diseases is chronic, under an hour, severe. In the absence of timely diagnosis and proper therapy, it can be fatal. The article describes the experience of applied quantitative research conducted by the method of questioning patients with primary immunodeficiencies (parents of underage patients), about their disease, methods of treatment, problems arising in the long-term struggle with this complex disease. The author notes that patients and primary care doctors or general practitioners are poorly informed about diseases associated with primary immunodeficiencies. It is concluded that it is necessary to increase the informational medical culture of the population, especially the young, as participants in the interaction "doctor-patient" and representatives of the interests of minor children-patients with inborn errors of immunity.

Background Inborn errors of immunity (IEIs), formerly primary immune deficiencies (PIDs), are a group of rare yet profoundly impactful conditions that compromise immune function, leading to recurrent infections, autoimmunity, and malignancies. While early diagnosis is critical to improving outcomes, awareness of the Jeffrey Modell Foundation’s “10 Warning Signs of PID” remains insufficient among healthcare professionals. This study explores the knowledge and preparedness of pediatric residents at SUNY Downstate Health Sciences University to identify and manage IEIs. Objective To evaluate the baseline knowledge of IEIs among pediatric residents, highlight areas of strength and gaps, and assess the impact of training exposure on diagnostic confidence and accuracy. Methods An anonymous questionnaire assessing recognition of IEI warning signs, diagnostic protocols, and management strategies was distributed among pediatric residents. Out of the total 81 residents in the program, 43 completed the survey. Responses were analyzed by postgraduate year (PGY) and prior rotations in Allergy and Immunology (AI). Results Progressive knowledge growth: The overall percentage of correct answers improved with training level: PGY-1 residents answered 67.5% of questions correctly, PGY-2 residents 71%, and PGY-3 residents 79%. Specialized training matters: Residents with prior AI rotations had an accuracy rate of 79.5% compared with 69% among those without, emphasizing the value of targeted exposure. Key strengths: Most participants were able to recognize patterns of severe IEI presentations, such as persistent oral thrush (93%) and recurrent sepsis (97%). Critical gaps: Participants rate of recognizing cases with subtle signs such as frequent ear infections (27%) and recurrent sinusitis (54%) was lower, potentially delaying diagnoses. Misconceptions in management Misunderstandings about vaccine safety (70%) and universal immunoglobulin therapy (18%) further highlight the need for comprehensive education. Conclusions While residents show proficiency in identifying severe IEI manifestations, gaps remain in recognizing subtle presentations and understanding management protocols. These findings emphasize the need for targeted educational interventions, including case-based learning and diagnostic frameworks, to improve early detection, appropriate management, and patient outcomes.

More than 500 primary immunodeficiencies (PIDs) or inborn errors of immunity (IEIs) have been reported. In general, IEIs are caused by monogenic germinal variants resulting in immunodeficiency and immune dysregulation symptoms. These "in natura" experiments have highlighted selective factors and pathways required for the immune control of a given pathogen, including Epstein-Barr virus (EBV). Several IEIs predominantly predispose to develop severe EBV infections and associated diseases including infectious mononucleosis (IM), hemophagocytic lymphohistiocytosis (HLH) and nonmalignant or malignant B cell lymphoproliferative disorders (B-LPD). Identification of these IEIs revealed critical components/molecules of the immune response to EBV. Notably, these elements differ depending on the type of the EBV viral disease. On one hand, defects in factors involved in the cytotoxic responses of lymphocytes preferentially underlie HLH, whereas, on the other hand, factors implicated in the expansion of EBV-specific T cells are mostly responsible for B-LPD when impaired. IEIs also inform on mechanisms underlying rare EBV viral diseases such as EBV+ smooth muscle tumors(EBV+SMT) and the "atypical" T/NK cell lymphoproliferative disorders (NK/T-LPD) including chronic active EBV infections (CAEBV). Finally, IEIs not predisposing to EBV provide information on immune components not necessary or redundant for EBV immunity. All these aspects are discussed in this chapter.

PurposeSignificant improvements in the prognosis for young patients with Primary Immunodeficiency Diseases (PID) and Autoinflammatory Disorders (AID), which together make up the majority of Inborn Errors of Immunity (IEI), have resulted in the need for optimisation of transition and transfer of care to adult services. Effective transition is crucial to improve health outcomes and treatment compliance among patients. Evaluations of existing transition programmes in European health centres identified the absence of disease-specific transition guidelines for PID and AID, as a challenge to the transition process. This research aimed to establish expert consensus statements for the transition of young patients with PID and AID to adult services.MethodsThis project used the Delphi method to establish mutual agreement for the proposed recommendations. A draft set of statements was developed following a literature review of existing transition programmes. Then the ERN RITA Transition Working Group convened to review the drafted recommendations and develop them into a survey. This survey was circulated among healthcare professionals to determine consensus using a five-point Likert scale, with the level of agreement set to 80% or greater. Statements that did not reach consensus were revised by the Working Group and recirculated among respondents.ResultsThe initial survey received 93 responses from 68 centres across 23 countries, while the following survey outlining revised recommendations received 66 responses. The respondents agreed upon recommendations detailing the structure and administration of transition programmes, collaborative working with social systems, and contraindications to transfer of care.ConclusionThis paper sets out a comprehensive set of recommendations to optimise transitional care for PID and AID.

Validating inborn error of immunity prevalence and risk with nationally representative electronic health record data

Inborn errors of immunity (IEIs) are genetic disorders that impair immune defense and regulation, increasing susceptibility to infections, including those in the oral cavity. The oral microbiota plays a vital role in maintaining oral health, and in pediatric patients with IEIs, disruptions in this balance can lead to dental caries and other oral diseases. This chapter provides a comprehensive analysis of the relationship between immune deficiencies and oral microbiota dysbiosis, focusing on dental caries in children with IEIs. Omics technologies, particularly metagenomics, have enhanced understanding of the microbial diversity and metabolic activities within the oral microbiota of the patients. Key findings reveal that compromised immune responses in children with IEIs disrupt the balance of oral bacteria, making them more prone to dental caries. The chapter highlights the importance of an interdisciplinary approach, integrating microbiology, immunology, dentistry, and bioinformatics, to uncover the complex interactions between the oral microbiome and the immune system. The insights gained from this research will contribute to the development of personalized therapeutic strategies, improving the dental and overall health of pediatric patients with IEIs.

Genetic defects in the development, maturation, and/or function of the immune cells can lead to Inborn errors of immunity (IEI) which may predispose patients to malignancies. The overall risk for cancer in children with IEI ranges from 4 to 25% and the type of malignancy is highly dependent on the specific mutant gene underlying IEI. We investigated 3056 IEI patients registered in the Iranian national registry between the years 1999 and 2020 in this retrospective cohort study. The frequency of malignancy and its association with the type of IEI in these patients were evaluated. A total of 82 IEI patients with malignancy were enrolled in this study. Among them, predominantly lymphoma was the most common type of malignancy (67.1%), followed by leukemia (11%), and cancers of the head and neck (7.3%). Among identified lymphoma cancers, non-Hodgkin’s lymphomas were the most frequent type (43.9%) followed by different subtypes of Hodgkin’s lymphoma (23.2%). Solid tumors (18.3%) appeared to be very heterogeneous by type and localization. The correlation between the type of malignancy and survival status and the association between the type of malignancy and IEI entities were unremarkable. The awareness of the association between the presence of IEI and cancer highlights the importance of a synergistic effort by oncologists and immunologists in the early diagnosis of malignancy and personalized therapeutic strategies in IEI patients.

More than 450 genetic defects result in inborn errors of immunity (IEI). Their individual prevalence in specific cohorts is influenced by national characteristics and other factors. We present results of genetic testing conducted in 1809 Russian children with IEI. Genetic defects confirming IEI were found in 1112 out of 1809 (61.5%) probands. These defects included variants in 118 single genes (87.9% of patients) and aberrations in 6 chromosomes (11.8%). Notably, three patients harbored pathogenic variants in more than one IEI gene. Large deletions constituted 5% of all defects. Out of the 799 original variants, 350 (44%) have not been described previously. Rare genetic defects (10 or fewer patients per gene) were identified in 20% of the patients. Among 967 probands with germline variants, defects were inherited in an autosomal dominant manner in 29%, X-linked in 34%, and autosomal recessive in 37%. Four females with non-random X-inactivation exhibited symptoms of X-linked diseases (BTK, WAS, CYBB, IKBKG gene defects). Despite a relatively low rate of consanguinity in Russia, about 50% of autosomal recessive gene defects were found in a homozygous state. Notably, 28% of these cases carried “Slavic" mutation of the NBN gene or known hot-spot mutations in other genes. The diversity of IEI genetic forms and the high frequency of newly described variants underscore the genetic heterogeneity within the Russian IEI group. The new variants identified in this extensive cohort will enriching genetic databases.

SummaryInborn errors of immunity (IEI), comprise a diverse spectrum of 485 disorders as recognized by the International Union of Immunological Societies Committee on Inborn Error of Immunity in 2022. While IEI are monogenic by definition, they illuminate various pathways involved in the pathogenesis of polygenic immune dysregulation as in autoimmune or autoinflammatory syndromes, or in more common infectious diseases that may not have a significant genetic basis. Rapid improvement in genomic technologies has been the main driver of the accelerated rate of discovery of IEI and has led to the development of innovative treatment strategies. In this review, we will explore various facets of IEI, delving into the distinctions between PIDD and PIRD. We will examine how Mendelian inheritance patterns contribute to these disorders and discuss advancements in functional genomics that aid in characterizing new IEI. Additionally, we will explore how emerging genomic tools help to characterize new IEI as well as how they are paving the way for innovative treatment approaches for managing and potentially curing these complex immune conditions.