Form Of Primary Immunodeficiency Research Articles

Experience with the use of Hizentra, an immunoglobulin preparation for subcutaneous administration, in patients with primary immunodeficiency diseases

Immunoglobulin replacement therapy is the gold standard of treatment for patients with antibody deficiencies. We aimed to investigate the efficacy and safety of replacement therapy with subcutaneous immunoglobulin (SCIG) Hizentra in patients with primary immunodeficiencies. This study was approved by the Independent Ethics Committee and the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. All patients and / or their legal representatives gave informed consent for this treatment. In our study, 12 patients under 18 years of age with various forms of primary immunodeficiencies who had previously received intravenous immunoglobulin were switched to SCIG treatment to receive weekly infusions of Hizentra. Therapy SCIG was administered weekly at a dose of 0.1–0.15 g/kg by rapid push infusion. All patients received Hizentra for at least 3 months. None of the patients included in the study developed severe infections. Immunoglobulin G levels in blood after 3 months of SCIG therapy were significantly higher compared to those achieved on previous intravenous immunoglobulin therapy. There were no severe adverse events associated with Hizentra administration. Our study demonstrated Hizentra to be effective and safe for the treatment of children with various forms of primary immunodeficiencies.

Newborn screening for primary immunodeficiencies as a way to detect syndromal disorders in neonates: a clinical case of 22q11.2DS syndrome

One of the main goals of newborn screening is the early detection of a number of severe disorders for which effective treatment is available, and early diagnosis prevents serious consequences. Primary immunodeficiencies (PIDs) are a heterogeneous group of congenital immune disorders and are urgent immunological conditions requiring prompt diagnosis and treatment. Screening for primary immunodeficiencies using T-cell receptor excision circles (TREC) is used in many countries around the world. However, in addition to severe combined immunodeficiency, other forms of PIDs with T cell deficiency such as 22q11.2 deletion syndrome (22q11.2DS), CHARGE syndrome, trisomy 21, etc., can be detected during newborn screening. 22q11.2DS syndrome is one of the most common chromosomal microdeletion syndromes with an estimated prevalence of 1 in 3000–6000 births. The clinical manifestations of 22q11.2DS are quite variable. Neonatal diagnosis is traditionally based on the recognition of classic features and cytogenetic testing but many patients only come to medical attention after later symptoms have been identified. Still, the early diagnosis of 22q11.2DS ensures adequate treatment and the highest possible quality of life in such patients. Here, we report a clinical case of 22q11.2DS syndrome identified during a pilot project of newborn screening for primary immunodeficiencies in the Russian Federation in 2022. The patient’s parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Bayesian Modeling Immune Reconstitution Apply to CD34+ Selected Stem Cell Transplantation for Severe Combined Immunodeficiency.

Severe combined immunodeficiencies (SCIDs) correspond to the most severe form of primary immunodeficiency. Allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy are curative treatments, depending on the donor's availability and molecular diagnostics. A partially human leukocyte antigen (HLA)-compatible donor used has been developed for this specific HSCT indication in the absence of a matched donor. However, the CD34+ selected process induces prolonged post-transplant T-cell immunodeficiency. The aim here was to investigate a modeling approach to predict the time course and the extent of CD4+ T-cell immune reconstitution after CD34+ selected transplantation. We performed a Bayesian approach based on the age-related changes in thymic output and the cell proliferation/loss model. For that purpose, we defined specific individual covariates from the data collected from 10 years of clinical practice and then evaluated the model's predicted performances and accuracy. We have shown that this Bayesian modeling approach predicted the time course and extent of CD4+ T-cell immune reconstitution after SCID transplantation.

Assessment of COVID-19 Incidence and the Ability to Synthesise Anti-SARS-CoV-2 Antibodies of Paediatric Patients with Primary Immunodeficiency.

Background: Data regarding the course of SARS-CoV-2 infection in children with primary immunodeficiency (PID) is insufficient. The purpose of the study was to evaluate the morbidity and clinical course of COVID-19 and the ability to produce anti-SARS-CoV-2 IgG antibodies in children with PID. Methods: In this retrospective study, medical records of 99 patients aged 0–18 were evaluated. The patients were divided into three groups: PID group (68.69%), control group (19.19%) and patients with ongoing or previous paediatric inflammatory multisystem syndrome (12.12%). Data such as morbidity, clinical outcome, and IgG anti-SARS-CoV-2 antibody titres were assessed. Results: A confirmed diagnosis of SARS-CoV-2 infection has been established in 26.47% of patients with PID. Among patients with PID infected with SARS-CoV-2, only three cases were hospitalised. Mortality in the PID group was 0%. Throughout an observation period of 1 year, 47.06% of patients with PID were tested positive for the anti-SARS-CoV-2 antibody. Conclusions: In the study group, in most cases the disease had a mild and self-limiting course. Remarkably, even though IgG deficiency was the most prevalent form of PID in the study group, the patients were able to respond satisfactorily to the infection in terms of anti-SARS-CoV-2 IgG.

T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIOLOS defect in patients.

AIOLOS/IKZF3 is a member of the IKAROS family of transcription factors. IKAROS/IKZF1 mutations have been previously associated with different forms of primary immunodeficiency. Here we describe a novel combined immunodeficiency due to an IKZF3 mutation in a family presenting with T and B cell involvement, Pneumocystis jirovecii pneumonia, and/or chronic lymphocytic leukemia. Patients carrying the AIOLOS p.N160S heterozygous variant displayed impaired humoral responses, abnormal B cell development (high percentage of CD21low B cells and negative CD23 expression), and abrogated CD40 responses. Naive T cells were increased, T cell differentiation was abnormal, and CD40L expression was dysregulated. In vitro studies demonstrated that the mutant protein failed DNA binding and pericentromeric targeting. The mutant was fully penetrant and had a dominant-negative effect over WT AIOLOS but not WT IKAROS. The human immunophenotype was recapitulated in a murine model carrying the corresponding human mutation. As demonstrated here, AIOLOS plays a key role in T and B cell development in humans, and the particular gene variant described is strongly associated with immunodeficiency and likely malignancy.

ДЕФИЦИТ LRBA: ОБЗОР ЛИТЕРАТУРЫ И ОПИСАНИЕ КЛИНИЧЕСКИХ НАБЛЮДЕНИЙ

Since the description of the first primary immunodeficiencies (PIDs) in the 50–60s of the last century, they have been the subject of intensive research aimed at elucidating their etiology and finding effective treatments. The development of next-generation sequencing (NGS) methods made it possible to reveal the genetic basis of many new forms of PID, which were previously attributed to various syndromes due to their clinical and immunological characteristics. An example of such a PID is the LRBA (the lipopolysaccharide-responsive and beige-like anchor protein) deficiency, sometimes called LATAIE [LRBA deficiency with autoantibodies, regulatory T (Treg) cell defects, autoimmune infiltration, and enteropathy]. The article provides information on the main role of the LRBA molecule in the functions of immunocompetent cells, describes immunological disorders and clinical manifestations of LRBA deficiency and the principles of treatment of diseases. Two own observations of LRBA deficiency are presented.

Non-infectious complications in the group of pediatric patients with chronic granulomatous disease

Chronic granulomatous disease (CGD) is a primary immunodeficiency (PID), characterized by a defective production of reactive oxygen species by phagocytes. Infectious diseases are a classic manifestation of this form of PID; however, many patients present with a variety of inflammatory and immune non-infectious complications. We analyzed non-infectious complications in a group of 60 patients with CGD, who were treated in Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) since 2012 to February 2020. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Non-infectious manifestations were recorded in 53/60 patients, the most frequent of which were granulomatous complications (81.7% (49/60) of cases) in the following organs - the gastrointestinal tract, lungs, liver and lymph nodes. The median age of granulomas presentation was 3 years, and 45.8% of patients had a combined granulomatous lesion of several organs. Hepatomegaly (40%), splenomegaly (31.7%), dermatitis (21.7%) and chorioretinal lesions (11.3%) were other non-infectious complications. Hematological features outside acute infectious episodes included monocytosis (26.7%), eosinophilia (20%), neutrophilia (13.3%). 96.7% of patients had anemia with a decrease level of serum iron (65%), 31.7% - with signs of hemolysis. Autoimmune manifestations included arthritis, thyroiditis, immune thrombocytopenia or immune neutropenia. Non-infectious complications comprise a significant part of the CGD manifestations and often are the first symptoms of the disease. Awareness of this fact is very important for multidisciplinary approach in treatment of CGD. Delayed diagnosis and immunosuppressive therapy of non-infectious complications without prophylactic antimicrobial therapy can be life-threatening for patients with CGD.

Federal clinical guidelines. Primary immunodeficiency: severe combined immunodeficiency

Severe combined immunodeficiency (SCID) is the most life-threatening form of primary immunodeficiency, fatal within the first years of life if hematopoietic stem cell transplantation (HSCT) is not performed. Early diagnosis is crucial for prevention of multiple life-threatening complications, which in turn allows for successful HSCT. Current publication contains clinical recommendations for diagnosis of SCID and its complications, complex treatment, including HSCT, prenatal diagnostics and genetic family counselling.

Хронічний шкірно-слизовий кандидоз — нозологічна форма первинного імунодефіциту у дітей. Випадок шкірно-слизового кандидозу в дитини раннього віку

Хронічний шкірно-слизовий кандидоз — нозологічна форма первинного імунодефіциту у дітей. Випадок шкірно-слизового кандидозу в дитини раннього віку

Evaluation of Radiation Sensitivity in Patients with Hyper IgM Syndrome

ABSTRACT Background HIGM syndrome is a rare form of primary immunodeficiencies characterized by normal/increased amounts of serum IgM and decreased serum levels of other switched immunoglobulin classes. Since the affected patients are continuously infected with various types of pathogens and are susceptible for cancers, diagnostic and therapeutic tests including imaging techniques are recommended for the diagnosis and treatment of these patients, which predispose them to higher accumulated doses of radiation. Given the evidence of class switching recombination machinery defect and its association with an increased rate of DNA repair, we aimed to evaluate radiation sensitivity among a group of patients diagnosed with HIGM syndrome. Methods 19 HIGM patients (14 CD40 L and 3 AID deficiencies and 2 unsolved cases without known genetic defects) and 17 control subjects (10 healthy subjects as negative control group, 7 ataxia-telangiectasia patients as positive control group) were enrolled. G2 assay was carried out for the determination of radiosensitivity. Results Based on radiation-induced chromosomal changes among the studied HIGM patients and their comparison with the controls, almost all (95%) the patients had degrees of radiosensitivity: 6 patients with low to moderate, 1 patient with moderate, 11 patients with severe and 1 patient without radiation sensitivity. Conclusion Today, X-ray radiation plays a very important role in diagnostic and therapeutic procedures; while increased exposure has devastating effects especially in radiosensitive patients. Considering higher sensitivity in HIGM patients, utilizing radiation-free techniques could partly avoid unnecessary and high-level exposure to radiation, thus preventing or reducing its harmful effects on the affected patients.

Autoimmune and inflammatory manifestations in pediatric patients with primary immunodeficiencies and their importance as a warning sign

Introduction and objectivesAs well as increased susceptibility to infections, autoimmune and inflammatory manifestations also eventuate due to dysregulation of immune system in a substantial proportion of patients with primary immunodeficiency (PID). Autoimmune and inflammatory manifestations can occur prior or after diagnosis of PID. This study aimed to evaluate autoimmune and inflammatory complications among all types of PID patients in childhood and to emphasize the importance of these findings as a warning sign to diagnose PIDs. MethodsMedical records of 1036 patients with PID, followed up between 2003 and 2019, were retrospectively screened for occurrence of autoimmunity and inflammation. During this time, demographic features, autoimmune/inflammatory findings and initial time, genetic mutations, laboratory and clinical follow up findings, treatment regimens and outcomes were recorded. ResultsAutoimmune and inflammatory manifestations were observed in 83 patients (10.1%). The median age of autoimmunity initial time was 61.3±53 months. Sixty-seven (80.7%) patients presented with autoimmune and inflammatory manifestations, and these findings had occurred during 16 patients’ (19.3%) follow-up. The most common autoimmune manifestations were autoimmune hematologic (51.8%) and endocrine diseases (26.5%). Fifty patients (60.2%) had a single autoimmune/inflammatory manifestation, however 23 patients (27.7%) had two, eight patients (9.6%) had three and two patients (2.4%) had four different types of autoimmune/inflammatory manifestations. The frequency of autoimmune and inflammatory manifestations in phagocyte defects (56%), combined immune deficiencies (53%) and immune dysregulation diseases (52%) were observed higher than other forms of PIDs. During follow-up 13 (15.7%) patients died. ConclusionAutoimmune/inflammatory manifestations are associated with high morbidity in patients with PIDs and may precede the diagnosis of PID in childhood. Therefore, physicians must be aware of underlying possible immune deficiency and patients with known PIDs should be evaluated for autoimmune and inflammatory complications.

Disease-associated dominant negative CARD11 mutations interfere with the CARD11 Opening Step during antigen receptor signaling to NF-κB and JNK2

Abstract CARD11 mediates lymphocyte activation by functioning as a scaffold in antigen receptor signaling to NF-κB, JNK, and mTOR. Antigen-induced CARD11 signaling proceeds through an ordered series of steps, including Opening, Cofactor Recruitment, Enzyme Activation, and Complex Disassembly. Recently, several forms of Primary Immunodeficiency have been described that are due to germline CARD11 mutations. One of these syndromes, Combined Immunodeficiency (CID) with atopy, is inherited in an autosomal dominant manner and caused by loss-of-function (LOF) CARD11 alleles, which display dominant negative activity that poisons signaling from co-expressed wild-type CARD11. To investigate the mechanistic basis for disease-associated dominant negative activity we reconstituted CARD11-deficient T cells with a panel of LOF CARD11 variants in the absence and presence of co-expressed wild-type CARD11. In the absence of wild-type CARD11, the LOF variants were indistinguishable, such that each variant failed to promote the signal-induced 1) recruitment of the cofactors Bcl10, HOIP, and MALT1 to CARD11, 2) Bcl10 polyubiquitinylation, 3) MALT1 protease activation, 4) NF-κB activation, and 5) JNK2 activation. In the presence of co-expressed wild-type CARD11, the LOF variants surprisingly displayed a range of dominant negative activity from strong to intermediate to weak, indicating a specific potency of some mutations to disrupt signaling when heterozygous. Our results suggest that disease-associated dominant negative CARD11 mutations interfere with the Opening Step in the CARD11 signaling cycle and provide a mechanistic basis to explain why some LOF CARD11 mutations can cause disease when heterozygous while others do so when homozygous.

Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders

Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency (PID) in adulthood and is characterized by severe reduction of immunoglobulin serum levels and impaired antibody production in response to vaccines and pathogens. Beyond the susceptibility to infections, CVID encompasses a wide spectrum of clinical manifestations related to a complex immune dysregulation that also affects liver. Although about 50% CVID patients present persistently deranged liver function, burden, and nature of liver involvement have not been systematically investigated in most cohort studies published in the last decades. Therefore, the prevalence of liver disease in CVID widely varies depending on the study design and the sampling criteria. This review seeks to summarize the evidence about the most relevant causes of liver involvement in CVID, including nodular regenerative hyperplasia (NRH), infections and malignancies. We also describe the clinical features of liver disease in some monogenic forms of PID included in the clinical spectrum of CVID as ICOS, NFKB1, NFKB2, CTLA-4, PI3Kδ pathway, ADA2, and IL21-R genetic defects. Finally, we discuss the clinical applications of the various diagnostic tools and the possible therapeutic approaches for the management of liver involvement in the context of CVID.

P173 Very–Early-Onset inflammatory bowel disease: Russian single centre experience

Abstract Background The incidence of very early-onset inflammatory bowel disease (VEOIBD) is on the rise in Russia but the clinical data is lacking. We aim to study the disease phenotype, clinical course and the presence of primary immunodeficiency (PID) patients in this group. Methods Clinical records of VEOIBD patients treated in Russian State Pediatric Hospital between 2000 and 2018 were revised. In 60 patients admitted between 2016 and 2018 targeted sequencing (PID panel) was performed. 10 patients received genetic testing previously. Results 135 VEOIBD patients were identified: 95 (70%)with ulcerative colitis (UC), 31 (23%) with Crohn’s disease, 9 (7%) with PID. In 14 (11%) IBD patients the diagnosis was changed from UC to CD and vice versa. Median time of diagnosis was 7 months in UC, 24 months in CD and 44 months in PID. The most common clinical symptoms were loose stools (UC—98%, CD—84%), bloody stools (UC—93, CD—65%), stomach ache (UC—53%, CD—52%), fever (UC—35%, CD—42%). Common laboratory features included anemia (UC—56%, CD—39%), low serum ferrum level (UC—75%, CD—61%), thrombocytosis (UC—53%, CD—45%). From 103 patients tested for ANCA 26% had positive results (24—UC, 3—CD). Mean calprotectin level (76 patients) was 750 ± 54.4 μg/g. Pancolitis was seen in UC (84%), as well as in CD (61%). Epithelioid granulomas in CD were present in 7 patients, in 5 of them they were detected years after initial diagnosis. Sixty-nine% of UC and 90% of CD patients received steroids as induction therapy, steroid-dependency was common (42% in UC and 55% in CD). Forty-nine% of patients with UC and 23% od CD patients received azathioprine, anti-TNF agents were used in 26% UC patients and 77% CD patients. In 35% of patients receiving anti-TNF biologic therapy was started before the age of 6 years. 23,8% of VEOIBD patients failed to achieve clinical remission. Total colectomy was performed in 11 patients, in 3 of them the diagnosis was subsequently changed to CD. Segmental resection was performed in 9 CD patients, in 3 of them while on therapy. The most common form of PID was XIAP deficiency (3 patients), 2 of them achieved endoscopic remission after allogenic stem cell transplantation. Conclusion In the VEOIBD group CD resembles UC clinically and endoscopically. A substantial number of patients requires immunosuppressive and biologic therapy before the age of 6 years. Colectomy rates are still high regardless the use of biologics. Boys with refractory VEOIBD should be screened for XIAP deficiency.

Optimization of Therapy of Patient with Genetic Defect Antibody Production

Development of molecular genetics and immunological diagnostics, disclosure of pathogenesis of various forms of primary immunodeficiency (PID), improvement of therapeutic techniques contributed to the formation of a generation patients with PID older than 18 years. Experience shows that isolated replacement therapy, leading to a reduction in the frequency and severity of reactivation chronic foci of infection, is not able in some cases to fully stabilize the condition of patients, and the use of antibiotics remains inevitable. Interesting is the development and implementation of the concept of combined therapy of PID humoral therapy, the ideology of which is based on the combination of substitution therapy with exposure on the functional potential of the cellular link of the immune system. One of the perspective variants of influence on functions of cellular components of immune is the use of innate immunity receptor agonists. From the position of the specific clinical application deserves the attention medication Likopid (glucosaminilmuramyl dipeptide) - semi-synthetic analogue of muramyldipeptide, minimally biologically active substance peptidoglycan fragment of the cell wall of all known bacteria. Presented clinical case of X-linked agammaglobulinemia. The patient, despite regular replacement therapy with intravenous immunoglobulins with maintaining a pretransfusion IgG level of at least 8 g/l, continued to register episodes of exacerbation of chronic conjunctivitis up to 10 times a year. Application of licopid in addition to IVIG therapy contributed to the improvement quality of life, reducing the frequency of exacerbations, conjunctivitis and duration of use antibiotics. This example illustrates the role of cellular components innate immune response in clinical manifestation of insufficiency humoral link adaptive immunity, and confirms the possibility of additional correction of these parameters to improve the efficiency of the standard substitution therapy.

Severe combined immunodeficiency: The time for newborn screening has come

Primary immunodeficiencies (PIDs) are a set of about 350 genetic disorders that affect the normal function of the immune system. Advances in genetic diagnosis have allowed the description of new defects in the immune system, broadening the clinical spectrum of PIDs' manifestations beyond susceptibility to infection. Although most PIDs present with recurrent or opportunistic infections, a subgroup of them may be recognized by the early development of auto-inflammatory events, tumors and, paradoxically, the coexistence of autoimmunity and immunodeficiency in the same patient. As their clinical manifestations, the severity of PIDs is highly variable. Severe combined immunodefi ciency (SCID), a PID that affects cellular and humoral immunity, is one of the most severe forms of PIDs and the only available curative treatment in Latin America is hematopoietic stem cells trans plantation. All patients affected by SCID die during the first two years of life if they are not diagnosed and treated opportunely. In contrast, early transplantation of patients with SCID can lead to excellent survival outcomes. Despite recent advances in the diagnosis of PIDs in Chile, diagnostic resources are not available throughout the country, making the early diagnosis of SCID and other forms of PID difficult in big areas of Chile. The objective of this article is to review general concepts on the patho physiology, diagnosis, and initial management of SCID and raise the need for the implementation of neonatal screening for SCID in Chile.

Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Diseases: Current Status and Future Perspectives.

Primary immunodeficiencies (PID) are disorders that for the most part result from mutations in genes involved in immune host defense and immunoregulation. These conditions are characterized by various combinations of recurrent infections, autoimmunity, lymphoproliferation, inflammatory manifestations, atopy, and malignancy. Most PID are due to genetic defects that are intrinsic to hematopoietic cells. Therefore, replacement of mutant cells by healthy donor hematopoietic stem cells (HSC) represents a rational therapeutic approach. Full or partial ablation of the recipient's marrow with chemotherapy is often used to allow stable engraftment of donor-derived HSCs, and serotherapy may be added to the conditioning regimen to reduce the risks of graft rejection and graft versus host disease (GVHD). Initially, hematopoietic stem cell transplantation (HSCT) was attempted in patients with severe combined immunodeficiency (SCID) as the only available curative treatment. It was a challenging procedure, associated with elevated rates of morbidity and mortality. Overtime, outcome of HSCT for PID has significantly improved due to availability of high-resolution HLA typing, increased use of alternative donors and new stem cell sources, development of less toxic, reduced-intensity conditioning (RIC) regimens, and cellular engineering techniques for graft manipulation. Early identification of infants affected by SCID, prior to infectious complication, through newborn screening (NBS) programs and prompt genetic diagnosis with Next Generation Sequencing (NGS) techniques, have also ameliorated the outcome of HSCT. In addition, HSCT has been applied to treat a broader range of PID, including disorders of immune dysregulation. Yet, the broad spectrum of clinical and immunological phenotypes associated with PID makes it difficult to define a universal transplant regimen. As such, integration of knowledge between immunologists and transplant specialists is necessary for the development of innovative transplant protocols and to monitor their results during follow-up. Despite the improved outcome observed after HSCT, patients with severe forms of PID still face significant challenges of short and long-term transplant-related complications. To address this issue, novel HSCT strategies are being implemented aiming to improve both survival and long-term quality of life. This article will discuss the current status and latest developments in HSCT for PID, and present data regarding approach and outcome of HSCT in recently described PID, including disorders associated with immune dysregulation.

The role of genomics in common variable immunodeficiency disorders.

The advent of next-generation sequencing (NGS) and 'omic' technologies has revolutionized the field of genetics, and its implementation in health care has the potential to realize precision medicine. Primary immunodeficiencies (PID) are a group of rare diseases which have benefited from NGS, with a massive increase in causative genes identified in the past few years. Common variable immunodeficiency disorders (CVID) are a heterogeneous form of PID and the most common form of antibody failure in children and adults. While a monogenic cause of disease has been identified in a small subset of CVID patients, a genomewide association study and whole genome sequencing have found that, in the majority, a polygenic cause is likely. Other NGS technologies such as RNA sequencing and epigenetic studies have contributed further to our understanding of the contribution of altered gene expression in CVID pathogenesis. We believe that to unravel further the complexities of CVID, a multi-omic approach, combining DNA sequencing with gene expression, methylation, proteomic and metabolomics data, will be essential to identify novel disease-associated pathways and therapeutic targets.

RETRACTED: Generalized verrucosis and abnormal T cell activation due to homozygous TAOK2 mutation

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. The authors have notified the Editor of a serious error in their initial assumptions and, therefore, the overall conclusions presented in this article. The causative mutation is essential for the analysis and, therefore, it is difficult to correct part of the article. Had the Editor been aware of the issues flagged by the authors, the article would not have been accepted for publication. The authors have requested that the article is retracted because their data and conclusions are incorrect, and the Editor has agreed to retract the article.

Primary immunodeficiencies due to abnormalities of the actin cytoskeleton.

Primary immunodeficiencies (PIDs) are inherited conditions where components of the immune system are missing or dysfunctional. Over 300 genes have been causally linked to monogenic forms of PID, including a number that regulate the actin cytoskeleton. The majority of cytoskeletal defects disrupt assembly and disassembly of filamentous actin in multiple immune cell lineages impacting functions such as cell migration and adhesion, pathogen uptake, intercellular communication, intracellular signalling, and cell division. In the past 24 months, new actin defects have been identified through next generation sequencing technologies. Substantial progress has also been made in understanding the pathogenic mechanisms that contribute to immunological dysfunction, and also how the cytoskeleton participates in normal physiological immune processes. This review summarises recent advances in the field, raising awareness of these conditions and our current understanding of their presentation. Description of further cases and new conditions will extend the clinical phenotype of actin-related disorders, and will promote the development of more effective and targeted therapies.