Editorial: Autoimmune diseases in childhood.

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.

A report on the clinical efficacy of rituximab administration in patients with inborn errors of immunity and autoimmune manifestations

Efficacy and Safety of Anti-CD19 and Anti-BCMA Chimeric Antigen Receptor (CAR) T-Cell Therapies in Patients with Autoimmune Disease and Lymphoma or Myeloma

Systemic lupus erythematosus in a 15-year-old with graft-versus-host disease following liver transplant and unexpected full hematopoietic engraftment

Critical role of Th17 cells in development of autoimmune hemolytic anemia

ObjectiveIn this study, we analyzed a large cohort of Algerian patients with inborn errors of immunity (IEI) to delineate the burden, spectrum, and distribution of autoimmune and autoinflammatory manifestations.MethodsThis retrospective cohort study was based on recorded data from 825 Algerian patients with IEI. For each patient, autoimmune and autoinflammatory complications occurring before and/or after IEI diagnosis were systematically assessed and documented.ResultsAutoimmune and/or autoinflammatory manifestations were observed in 217 patients (26.3%) and, notably, represented the initial clinical presentation in nearly half. Autoimmune features were documented in 163 patients (19.8%), including 26 (3.2%) with concurrent autoinflammatory findings, whereas isolated autoinflammatory conditions were observed in 54 patients (6.5%). A broad spectrum was observed, with autoimmune cytopenias predominating (11.4%), followed by gastrointestinal (7.8%), rheumatologic (5.3%), and endocrine (3.4%) disorders. Immune dysregulation was a recurrent theme across all IEI categories, with a distinct, disease-specific, clustering of autoimmunity and autoinflammation. Autoimmune cytopenias predominated in T-cell defects, including hypomorphic RAG and CD3γ deficiencies; Inflammatory bowel disease (IBD) was enriched in ARPC1B, DOCK8, and CD55 deficiencies, as well as in chronic granulomatous disease (CGD); endocrine autoimmunity, while a cardinal feature of APECED and IPEX, also characterized STAT1 gain-of-function; inflammatory granulomatous lung disease was a consistent feature in LRBA deficiency; and granulomatous inflammation, whether confined to the lungs or extending to other organs, was prominent in common variable immunodeficiency.ConclusionRecognition of clustering patterns, particularly autoimmune cytopenias, IBD, and endocrine autoimmunity, has direct clinical implications. These manifestations should be regarded as red flags, guiding targeted evaluation and genetic testing. Mapping such associations not only refines our understanding of pathogenesis but also provides a practical framework for earlier diagnosis and tailored management.

ABSTRACTHuman inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially result in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as the single influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with radiosensitivity.

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.

Chapter 12 - Clinical efficacy of anti-CD20 antibodies in autoimmune diseases

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.

Background: During the last years new targeted regimen for several autoimmune diseases has been developed leading to an ameliorated quality of life for these patients. Nevertheless, their fertility potential seems to be impaired either by the activity of the autoimmune diseases or by the medical treatment used to suppress these conditions. This systematic review intends to reveal how autoimmune diseases and their regimen affect male fertility. Methods: A search of English-language articles from electronic databases was conducted. The results that were used referred to impaired fertility in male patients with Systemic Lupus Erythematosus, Behcet’s disease, gout, dermatomyositis, celiac disease, rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis and sarcoidosis. Conclusion: Thirty-nine articles were finally included regarding the following diseases: Dermatomyositis, Systemic Lupus Erythematosus, Behcet’s disease, Gout, Celiac disease, Rheumatoid arthritis, Ankylosing spondylitis, Inflammatory bowel disease, Psoriasis, Sarcoidosis as well as two systematic reviews. Cyclophosphamide therapy seems to impair fertility in male patients with Systemic Lupus Erythematosus and Behcet’s disease. Colchicine use may lead to sperm abnormalities in patients with gout whereas anti-TNF treatment in ankylosing spondylitis does not affect the fertility potential. Antisperm antibodies and sulphasalazine treatment in rheumatoid arthritis, as well as mesalazine, infliximab and methotrexate use in inflammatory bowel disease, result in gonadal dysfunction, respectively. More data addressing male fertility are needed for patients with Dermatomyositis, Sarcoidosis, Psoriasis and Celiac disease. Fertility impairment is common in autoimmune diseases. Henceforth, more studies are needed to identify the relationship between fertility and immunity.

Autoimmune Liver Disease in Three Children with Sickle Cell Disease

Introduction X-linked lymphoproliferative disease (XLP) is a rare inborn error of immunity (IEI) characterized by increased susceptibility to Epstein–Barr Virus (EBV) and other features of immune dysregulation. We present a case of XLP1, diagnosed in a 37-year-old male with EBV viremia treated with nivolumab. Case The proband was diagnosed with common variable immunodeficiency (CVID) and started on IVIG at age 8. Infections were recurrent pneumonias and an episode of septic hip arthritis. He remained infection free over the next 3 decades until presenting with Evans syndrome at age 37, which was initially treated with prednisone. Shortly after, his course was complicated with hepatic and brain abscesses and liver decompensation. Thus, he was referred to our service for workup. Genetic testing revealed the diagnosis of XLP1 (SH2D1A c.138-2A>G). He was found to have EBV viremia, and a liver biopsy suggested EBV hepatitis. He was not a liver transplant candidate due to concern of sepsis given his immunosuppression and IEI. Hematopoietic stem cell transplant (HSCT) was not offered due to high risk of mortality. Despite treatment with rituximab, his repeat EBV titers continued to rise. Virus-specific T cell therapy was pursued; however, the patient was clinically too unstable to be transferred for treatment to the United States from Canada. He was given one nivolumab dose, significantly reducing his viremia. He ultimately succumbed to sepsis and respiratory failure. EBV is the leading cause of mortality in patients with XLP who forego HSCT. Rituximab has been well-documented in the treatment of EBV. We present a patient with an EBV susceptibility syndrome and progressive viremia, who responded well to one dose of nivolumab which significantly reduced his EBV viral load. Despite limited literature, nivolumab may play a significant role in the treatment of certain EBV-associated conditions, particularly in patients with IEIs. In conclusion, nivolumab should be considered for any patient with an overwhelming EBV infection. Severe EBV-induced disease is an unexpected finding in an individual with CVID and warrants genetic testing to exclude other primary immunodeficiencies. Treatment options for EBV susceptibility syndromes need further exploration and accessibility.

Background: Inborn errors of immunity (IEIs) are a heterogeneous group of genetically determined disorders that lead to immune dysfunction, recurrent infections, and organ-specific complications. The lungs are among the most commonly affected organs, with both infectious and noninfectious manifestations that significantly contribute to morbidity and mortality. This study aimed to provide a comprehensive overview of pulmonary manifestations in IEI, with emphasis on pathophysiological mechanisms, diagnostic approaches, and therapeutic strategies. Methods: A narrative review and synthesis of current literature and clinical guidelines were conducted, focusing on pulmonary involvement in IEI as classified by the International Union of Immunological Societies (IUIS). The analysis included data on infectious and noninfectious complications, imaging findings, immunological assessments, and management strategies, supported by clinical evidence and expert consensus. Results: Pulmonary manifestations in IEI encompass a wide spectrum of conditions. Infectious complications include recurrent bacterial pneumonias, bronchitis, and opportunistic infections, frequently resulting in irreversible lung damage such as bronchiectasis. Noninfectious complications, including granulomatous–lymphocytic interstitial lung disease (GLILD) and interstitial lung disease (ILD), are common in disorders such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). Early diagnosis using high-resolution computed tomography (HRCT) and immunological testing, combined with the timely initiation of immunoglobulin replacement therapy and anti-biotic prophylaxis, significantly improves prognosis. Conclusions: Pulmonary complications are key clinical indicators of IEI and often precede systemic manifestations. Early, integrated, and interdisciplinary diagnostic and therapeutic management are crucial for preventing irreversible lung damage and improving patient outcomes. Regular monitoring and individualized therapy, including immunoglobulin replacement, targeted immunosuppression, and vaccination, are the cornerstones of effective long-term care in IEI.

Giant Cell Hepatitis and Autoimmune Hemolytic Anemia Successfully Treated With Rituximab