Inborn Errors Of Immunity Research Articles

Clinical, Immunological, and Genetic Features in Patients with NFKB1 and NFKB2 Mutations: a Systematic Review.

Inborn errors of immunity (IEIs) encompass various diseases with diverse clinical and immunological symptoms. Determining the genotype-phenotype of different variants in IEI entity precisely is challenging, as manifestations can be heterogeneous even in patients with the same mutated gene. In the present study, we conducted a systematic review of patients recorded with NFKB1 and NFKB2 mutations, two of the most frequent monogenic IEIs. The search for relevant literature was conducted in databases including Web of Science, PubMed, and Scopus. Information encompassing demographic, clinical, immunological, and genetic data was extracted from cases reported with mutations in NFKB1 and NFKB2. The comprehensive features of manifestations in patients were described, and a comparative analysis of primary characteristics was conducted between individuals with NFKB1 loss of function (LOF) and NFKB2 (p52-LOF/IκBδ-gain of function (GOF)) variants. A total of 397 patients were included in this study, 257 had NFKB1 mutations and 140 had NFKB2 mutations.There were 175 LOF cases in NFKB1 and 122 p52LOF/IκBδGOF cases in NFKB2 pivotal groups with confirmed functional implications. NFKB1LOF and p52LOF/IκBδGOF predominant cases (81.8% and 62.5% respectively) initially presented with a CVID-like phenotype. Patients with NFKB1LOF variants often experienced hematologic autoimmune disorders, whereas p52LOF/IκBδGOF patients were more susceptible to other autoimmune diseases. Viral infections were markedly higher in p52LOF/IκBδGOF cases compared to NFKB1LOF (P-value < 0.001). NFKB2 (p52LOF/IκBδGOF) patients exhibited a greater prevalence of ectodermal dysplasia and pituitary gland involvement than NFKB1LOF patients. Most NFKB1LOF and p52LOF/IκBδGOF cases showed low CD19 + B cells, with p52LOF/IκBδGOF having more cases of this type. Low memory B cells were more common in p52LOF/IκBδGOF patients. Patients with NFKB2 mutations, particularly p52LOF/IκBδGOF, are at higher risk of viral infections, pituitary gland involvement, and ectodermal dysplasia compared to patients with NFKB1LOF mutations. Genetic testing is essential to resolve the initial complexity and confusion surrounding clinical and immunological features. Emphasizing the significance of functional assays in determining the probability of correlations between mutations and immunological and clinical characteristics of patients is crucial.

Immunodeficiency-Related Vaccine-Derived Poliovirus (iVDPV) Excretion in an Infant with Severe Combined Immune Deficiency with Spillover to a Parent.

In order to maintain the polio eradication status, it has become evident that the surveillance of cases with acute flaccid paralysis and of environmental samples must be urgently supplemented with the surveillance of poliovirus excretions among individuals with inborn errors of immunity (IEI). All children with IEI were screened for the excretion of poliovirus during a collaborative study conducted by the ICMR-National Institute of Virology, Mumbai Unit, ICMR-National Institute of Immunohaematology, and World Health Organization, India. A seven-month -old male baby who presented with persistent pneumonia and lymphopenia was found to have severe combined immune deficiency (SCID) due to a missense variant in the RAG1 gene. He had received OPV at birth and at 20 weeks. Four stool samples collected at 4 weekly intervals yielded iVDPV type 1. The child's father, an asymptomatic 32-year-old male, was also found to be excreting iVDPV. A haploidentical hematopoietic stem cell transplant was performed, but the child succumbed due to severe myocarditis and pneumonia three weeks later. We report a rare case of transmission of iVDPV from an individual with IEI to a healthy household contact, demonstrating the threat of the spread of iVDPV from persons with IEI and the necessity to develop effective antivirals.

IL-12 drives the differentiation of human T follicular regulatory cells.

T follicular regulatory (Tfr) cells can counteract the B cell helper activity of T follicular helper (Tfh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (Treg) cells into Tfr cells is still missing. Herein, we report that low doses of the pro-Tfh cytokine interleukin-12 (IL-12) drive the induction of a Tfr cell program on activated human Treg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12-driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating Tfr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of Tfr cell differentiation in vivo and provides an approach for the in vitro generation of human Tfr-like cells.

Indolent B-cell non-Hodgkin lymphomas in children: high association with inborn errors of immunity

Indolent lymphomas are rare in children and mostly consist of pediatric type follicular (PTFL) and pediatric marginal zone lymphomas (PMZL) and extranodal marginal zone lymphoma (ENMZL). Twenty children with indolent lymphoma (10 PTFL, 6 PMZL, 3 ENMZL, 1 mixed type) among 307 Non-Hodgkin Lymphoma (NHL) were retrospectively evaluated. The mean age of the entire group was 10.4 ± 4.4 and was significantly lower in PTFL than in PMZL. Seven patients (35%) had an associated inborn error of immunity (IEI) which was higher than that seen in aggressive lymphomas (5.9%) (p < 0.0001). Seventeen patients (85%) had stage I/II disease. Two patients received no treatment after surgery. Eleven patients were treated only with 3-6 courses of rituximab. Four patients received 3-6 courses of R-CHOP protocol. The prognosis was excellent Five years overall and event-free survivals were 100% and 85%, respectively.

PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells.

The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses. Using mouse immunization models, we found that PI3Kγ functions cell intrinsically within activated B cells in a kinase activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of ASCs. Furthermore, ASC fate choice coincides with upregulation of PIK3CG expression and is impaired in the context of PI3Kγ disruption in naive B cells on in vitro CD40-/cytokine-driven activation, in memory B cells on toll-like receptor activation, or in human tonsillar organoids. Taken together, our study uncovers a fundamental role for PI3Kγ in supporting humoral immunity by integrating signals instructing commitment to the ASC fate.

Genetic Evaluation of the Patients with Clinically Diagnosed Inborn Errors of Immunity by Whole Exome Sequencing: Results from a Specialized Research Center for Immunodeficiency in Türkiye

Molecular diagnosis of inborn errors of immunity (IEI) plays a critical role in determining patients’ long-term prognosis, treatment options, and genetic counseling. Over the past decade, the broader utilization of next-generation sequencing (NGS) techniques in both research and clinical settings has facilitated the evaluation of a significant proportion of patients for gene variants associated with IEI. In addition to its role in diagnosing known gene defects, the application of high-throughput techniques such as targeted, exome, and genome sequencing has led to the identification of novel disease-causing genes. However, the results obtained from these different methods can vary depending on disease phenotypes or patient characteristics. In this study, we conducted whole-exome sequencing (WES) in a sizable cohort of IEI patients, consisting of 303 individuals from 21 different clinical immunology centers in Türkiye. Our analysis resulted in likely genetic diagnoses for 41.1% of the patients (122 out of 297), revealing 52 novel variants and uncovering potential new IEI genes in six patients. The significance of understanding outcomes across various IEI cohorts cannot be overstated, and we believe that our findings will make a valuable contribution to the existing literature and foster collaborative research between clinicians and basic science researchers.

Inborn Errors of Immunity in Adults with Autoimmune Liver Diseases.

Inborn errors of immunity (IEI) may associate with autoimmune diseases, including autoimmune liver diseases (AILD). However, both the IEI frequency and secondary effects of immunosuppressives are unknown in patients with AILD due to the lack of data. We aimed to evaluate the ratio of IEI in AILD. A total of 82 patients with AILD (39 autoimmune hepatitis, 32 primary biliary cholangitis, 7 variant syndromes (VS), and 4 primary sclerosing cholangitis patients) were included in this single-center, cross-sectional, and descriptive study. The patients were evaluated and classified according to diagnostic criteria for IEI. Out of 82 patients with AILD, female/male ratio was 3.6. Median age of diagnosis of AILD was 45 years. We diagnosed 15 (18%) patients with immunodeficiency (ID). Inborn errors of immunity ratio was highest in VS patient group (29%). Out of 15 patients with ID, 4 (4.8%) patients had common variable immunodeficiency, 4 (4.8%) had partial immunoglobulin A deficiency, 4 (4.8%) had selective immunoglobulin M deficiency, and 3 (3.6%) had combined immunodeficiency. We detect ID in about one-fifth of the patients with AILD. The present study showed a significant risk of IEI that is blurred by the shadow of immune suppressive treatments. We suggest that the AILD patients with ID will benefit from the individualized and targeted therapeutic options used in IEI. Further research with larger patient groups and long-term follow-up are desperately needed to elucidate the diagnostic, therapeutic, and prognostic impacts of IEI-related individualized therapy on AILD patients.

Prevalencia de manifestaciones dermatológicas en pacientes con inmunodeficiencia común variable

Objective: Estimate the prevalence of dermatological manifestations in Mexican patients with common variable immunodeficiency. Methods: Cross-sectional and retrospective study, based on the analysis of records of patients with a diagnosis of common variable immunodeficiency, treated at the Siglo XXI National Medical Center (Mexican Social Security Institute), according to the criteria of the European Society of Immunodeficiencies (ESID). and of which only 3 had a genetic diagnosis with the following mutations: IRF2, CTLA4 and PIK-3, belonging to the Immunodeficiency Clinic of the National Medical Center Siglo XXI (IMSS), to evaluate dermatological manifestations, review of laboratory tests: IgA, IgM, IgG and type of replacement therapy with Immunoglobulin. The statistical analysis was carried out with the SPSS program; Descriptive statistics were used to analyze the data, according to the type of variable to be analyzed. Results: 36 patients were included, of which 55.5% were women; with median age 34 years (18-94). The prevalence of dermatological manifestations was 70% (n = 25). 30.5% had a history of infectious dermatosis and 39.5% had a history of non-infectious dermatosis. The most common dermatosis was irritant contact dermatitis in 13.8% of patients. All received replacement therapy with human immunoglobulin, 33.3% intravenously and the rest subcutaneously. Conclusions: Common variable immunodeficiency is an inborn error of immunity, with different clinical manifestations in various organs and systems (the skin is one of these). Dermatological manifestations are not usually described in patients with common variable immunodeficiency; However, it is important to identify them due to their relationship with certain complications (increased risk of superinfection), due to skin disruption and biological therapies. Keywords: Antibody immunodeficiency; Common variable immunodeficiency; skin diseases.

Prevalencia de manifestaciones dermatológicas en pacientes con inmunodeficiencia común variable

Objective: Estimate the prevalence of dermatological manifestations in Mexican patients with common variable immunodeficiency. Methods: Cross-sectional and retrospective study, based on the analysis of records of patients with a diagnosis of common variable immunodeficiency, treated at the Siglo XXI National Medical Center (Mexican Social Security Institute), according to the criteria of the European Society of Immunodeficiencies (ESID). and of which only 3 had a genetic diagnosis with the following mutations: IRF2, CTLA4 and PIK-3, belonging to the Immunodeficiency Clinic of the National Medical Center Siglo XXI (IMSS), to evaluate dermatological manifestations, review of laboratory tests: IgA, IgM, IgG and type of replacement therapy with Immunoglobulin. The statistical analysis was carried out with the SPSS program; Descriptive statistics were used to analyze the data, according to the type of variable to be analyzed. Results: 36 patients were included, of which 55.5% were women; with median age 34 years (18-94). The prevalence of dermatological manifestations was 70% (n = 25). 30.5% had a history of infectious dermatosis and 39.5% had a history of non-infectious dermatosis. The most common dermatosis was irritant contact dermatitis in 13.8% of patients. All received replacement therapy with human immunoglobulin, 33.3% intravenously and the rest subcutaneously. Conclusions: Common variable immunodeficiency is an inborn error of immunity, with different clinical manifestations in various organs and systems (the skin is one of these). Dermatological manifestations are not usually described in patients with common variable immunodeficiency; However, it is important to identify them due to their relationship with certain complications (increased risk of superinfection), due to skin disruption and biological therapies. Keywords: Antibody immunodeficiency; Common variable immunodeficiency; skin diseases.

First report of Mycobacterium chimaera infection in a patient with chronic granulomatous disease

Chronic granulomatous disease (CGD) is an inborn error of immunity. NADPH oxidase is an enzyme complex that produces various reactive oxygen species, such as superoxide anions and hydrogen peroxide. Mycobacterial infections in CGD are commonly observed in countries with a high prevalence of these microorganisms, such as those receiving the BCG vaccination at birth or having a high prevalence of tuberculosis. Non-tuberculous mycobacteria (NTM) infections are rare in CGD. The patient also presented with hemophagocytic lymphohistiocytosis, which resolved with gammaglobulin and cyclosporine. Herein, we describe the first case of M. chimaera infection in a female patient with autosomal recessive CGD caused by a pathogenic variant in CYBA.

An Overview of the Strategies to Boost SARS-CoV-2-Specific Immunity in People with Inborn Errors of Immunity.

The SARS-CoV-2 pandemic has heightened concerns about immunological protection, especially for individuals with inborn errors of immunity (IEI). While COVID-19 vaccines elicit strong immune responses in healthy individuals, their effectiveness in IEI patients remains unclear, particularly against new viral variants and vaccine formulations. This uncertainty has led to anxiety, prolonged self-isolation, and repeated vaccinations with uncertain benefits among IEI patients. Despite some level of immune response from vaccination, the definition of protective immunity in IEI individuals is still unknown. Given their susceptibility to severe COVID-19, strategies such as immunoglobulin replacement therapy (IgRT) and monoclonal antibodies have been employed to provide passive immunity, and protection against both current and emerging variants. This review examines the efficacy of COVID-19 vaccines and antibody-based therapies in IEI patients, their capacity to recognize viral variants, and the necessary advances required for the ongoing protection of people with IEIs.

Adaptive Cellular Responses following SARS-CoV-2 Vaccination in Primary Antibody Deficiency Patients.

Since the start of the COVID-19 pandemic, in a short span of 3 years, vaccination against SARS-CoV-2 has resulted in the end of the pandemic. Patients with inborn errors of immunity (IEI) are at an increased risk for SARS-CoV-2 infection; however, serious illnesses and mortality, especially in primary antibody deficiencies (PADs), have been lower than expected and lower than other high-risk groups. This suggests that PAD patients may mount a reasonable effective response to the SARS-CoV-2 vaccine. Several studies have been published regarding antibody responses, with contradictory reports. The current study is, perhaps, the most comprehensive study of phenotypically defined various lymphocyte populations in PAD patients following the SARS-CoV-2 vaccine. In this study, we examined, following two vaccinations and, in a few cases, prior to and following the 1st and 2nd vaccinations, subsets of CD4 and CD8 T cells (Naïve, TCM, TEM, TEMRA), T follicular helper cells (TFH1, TFH2, TFH17, TFH1/17), B cells (naïve, transitional, marginal zone, germinal center, IgM memory, switched memory, plasmablasts, CD21low), regulatory lymphocytes (CD4Treg, CD8Treg, TFR, Breg), and SARS-CoV-2-specific activation of CD4 T cells and CD8 T cells (CD69, CD137), SARS-CoV-2 tetramer-positive CD8 T cells, and CD8 CTL. Our data show significant alterations in various B cell subsets including Breg, whereas only a few subsets of various T cells revealed alterations. These data suggest that large proportions of PAD patients may mount significant responses to the vaccine.

Initiating immunoglobulin replacement therapy helps reduce severe infections and shifts healthcare resource utilization to outpatient services among US patients with inborn errors of immunity

Aims Patients with inborn errors of immunity (IEI) are predisposed to severe recurrent/chronic infections, and often require hospitalization, resulting in substantial burden to patients/healthcare systems. While immunoglobulin replacement therapies (IgRTs) are the standard first-line treatment for most forms of IEI, limited real-world data exist regarding clinical characteristics and treatment costs for patients with IEI initiating such treatment. This retrospective analysis examined infection and treatment characteristics in US patients with IEI initiating IgRT with immune globulin infusion (human), 10% (IG10%). Healthcare resource utilization (HCRU) and associated costs before and after treatment initiation were compared. Additionally, the impact of COVID-19 on infection diagnoses was evaluated. Methods Patients with IEI initiating IG10% between July 2012 and August 2019 were selected from Merative MarketScan Databases using diagnosis/prescription codes. Patients were followed 6 months before and after first IG10% claim date. Demographic and clinical characteristics were described. Treatment characteristics and HCRU before and after IG10% initiation were compared. Infection diagnoses during 2020 and 2019 (March–December) were compared. Results The study included 1,497 patients with IEI diagnoses (mean age = 43.4 years) initiating IG10%, with frequently reported comorbidities like asthma (32.1%). Following IG10% initiation, fewer severe infection diagnoses (11.6% vs 19.9%), fewer infection-related inpatient (10.8% vs 19.5%) and outpatient services (71.6% vs 79.9%), and lower infection-related total healthcare costs ($7,849 vs $13,995; p < 0.001)—driven by lower inpatient costs ($2,746 vs $9,900)—were observed than before. Fewer patients had infection diagnoses during COVID-19 (22.8%) than the prior year (31.2%). Conclusion Patients with IEI are susceptible to severe infections leading to high disease burden and treatment costs. Following IG10% initiation, we observed fewer infections, lower infection-related treatment costs, and shift in care (inpatient to outpatient) leading to significant cost savings. Among patients with IEI, 27% fewer infection diagnoses were observed during the early COVID-19 lockdown period than the prior year.

Pharmacogenetic implementation for CYP2C19 and pharmacokinetics of voriconazole in children with malignancy or inborn errors of immunity

BackgroundVoriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity. MethodsCYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination. ResultsVoriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax, inh] = 100 %; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher. ConclusionCYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.

Elevated Immunoglobulin E Serum Levels: Possible Underlying Factors That Can Cause an Inborn Error of Immunity in the Pediatric Population with Recurrent Infections.

Elevated immunoglobulin E (IgE) levels are commonly associated with allergies. However, high IgE levels are also found in several other infectious and non-infectious disorders. Elevated IgE levels typically suggest allergies, eczema, or recurrent skin infections. Hyperimmunoglobulin E (hyper-IgE) levels typically reflect a monogenic atopic condition or inborn immune defects with an atopic phenotype. The aim of our research is to investigate and observe the clinical characteristics of children with increased IgE levels who have previously manifested infectious diseases. Furthermore, the retrospective study considers other factors, such as demographic characteristics (sex, area/environment, and age), and their effect on IgE serum levels. To answer this question, we conducted a one-year hospital-based retrospective study that included 200 hospitalized children who had at least two viral or bacterial infections in the six months preceding hospitalization. Measurements of IgE and allergen panels (respiratory and digestive) using blood samples revealed that individuals who tested positive for the body's synthesis of hyper-IgE were not observably allergic to any potential allergens despite having higher total serum IgE. According to the results, there was a strong correlation between elevated IgE serum levels and a history of infectious diseases among the patients.

New coronavirus infection SARS-CoV-2 in adult patients with inborn errors of immunity

BACKGROUND: Diagnosis and treatment of COVID-19 in patients with primary immunodeficiency, or inborn errors of immunity, are often challenging. AIM: Description of the COVID-19 course and therapy of adult patients with primary immunodeficiency treated in medical organizations of Moscow Healthcare Department. MATERIALS AND METHODS: We analyzed a cohort of 68 patients over 18 years (median ― 35 years) with primary immunodeficiency; 91% of patients have primary immunodeficiency with predominantly antibody deficiencies. Altogether 90 cases of the new СOVID-19 were analyzed: in 68 cases infection occurred for the first time, in 22 cases it recurred. The duration of the disease ranged from 3 to 80 days. Duration of PCR-positivity ranged from 0 to 59 days, median 8 days. RESULTS: Patients with Wuhan and Delta strains had more severe inflammatory signs according to C-reactive protein and lactate dehydrogenase, in patients with Wuhan lung involvement on CT-scam was larger. In demonstrated group of patients higher C-reactive protein correlated with larger lung involvement, longer duration of the disease and PCR-positivity, significant lymphopenia also correlated with higher C-reactive protein. To our data regularity of intravenous immunoglobulin therapy and IgG trough level didn’t correlate with infection severity and duration of the disease and virus-carriage. Indirectly, the change in the spectrum of medicine used in patients of the analyzed group coincided with the virus strain evolution. Anti-inflammatory therapy was mainly presented by dexamethasone and antagonists to interleukin 6 or its receptor (anti-IL-6): 55% and 73% for Wuhan, 63% and 50% for Delta, 17% and 39% for Omicron. Then, preference was gradually given to the target anti-cytokine medicine. Etiotropic antiviral therapy was more often used to treat infection caused by Wuhan and Delta strains ― 32% and 38%, respectively (in 17% for Omicron). With shifting toward immunotherapy by specific against COVID-19 immunoglobulins and monoclonal antibody to SARS-CoV-2: 5% and 9% for Wuhan, 0% and 75% for Delta, 48% and 83% for Omicron, respectively. Immune and etiotropic therapy was not carried out in Wuhan in 39%, in Delta in 43%, in Omicron in 41% of cases. The overall mortality rate from COVID-19 in the analyzed group was 3%. CONCLUSION: Patients with primary immunodeficiency represent a vulnerable group to the SARS-CoV-2 virus with a high risk of not only severe, but also a protracted and undulating course of infection, what must be taken into account for the correct interpretation of the patient's condition and the timely administration of the appropriate therapy.

Inborn errors of immunity in Canadian First Nations and Nunavut Inuit Children: the tip of the iceberg

Abstract Objectives Inborn errors of immunity (IEI) are a heterogeneous group of genetic diseases that impact normal immune development and function. Individual IEI are rare, but collectively, can represent an important health burden. Little is known about the types of IEI seen in Canadian First Nations (FN) and Inuit populations. We sought to understand the spectrum of serious IEI in FN and Nunavut Inuit children, as a starting point for improving the awareness of these conditions in the community and for health care workers. Methods A questionnaire was distributed to participating Canadian pediatric tertiary-care centers. Providers were asked to report cases of confirmed or suspected severe immunodeficiencies seen in FN and Nunavut Inuit children. Results From 2004 to 2022, IEI were reported in 63 FN and 21 Inuit children by 4 pediatric hospitals across 3 Canadian provinces. The majority of cases were immunodeficiencies affecting cellular and humoral immunity (62% of cases in FN and 57% in Inuit children). IKBKB deficiency, adenosine-deaminase severe combined immune deficiency (SCID), and chronic granulomatous disease were the most common IEI. A wide variety of other IEI was reported, many of which would not be detected by current newborn screening for SCID and for which live-attenuated vaccines would have been contraindicated. Conclusions IEI occur in FN and Inuit children and may be underrecognized. Better understanding the prevalence of these conditions in specific communities could help inform public health policies including newborn screening and immunization programs and ultimately improve the health of FN and Inuit children in Canada.

Monogenic Inborn Errors of Immunity with impaired IgG response to polysaccharide antigens but normal IgG levels and normal IgG response to protein antigens.

In patients with severe and recurrent infections, minimal diagnostic workup to test for Inborn Errors of Immunity (IEI) includes a full blood count, IgG, IgA and IgM. Vaccine antibodies against tetanus toxoid are also frequently measured, whereas testing for anti-polysaccharide IgG antibodies and IgG subclasses is not routinely performed by primary care physicians. This basic approach may cause a significant delay in diagnosing monogenic IEI that can present with an impaired IgG response to polysaccharide antigens with or without IgG subclass deficiency at an early stage. Our article reviews genetically defined IEI, that may initially present with an impaired IgG response to polysaccharide antigens, but normal or only slightly decreased IgG levels and normal responses to protein or conjugate vaccine antigens. We summarize clinical, genetic, and immunological findings characteristic for these IEI. This review may help clinicians to identify patients that require extended immunologic and genetic evaluations despite unremarkable basic immunologic findings. We recommend the inclusion of anti-polysaccharide IgG antibodies as part of the initial routine work-up for possible IEI.

Relevant cutaneous manifestations as indications for inborn errors of immunity

Inborn errors of immunity (IEI) can affect different parts of the immune system and manifest especially through pathological infection susceptibility and immune dysregulation. Cutaneous manifestations of IEI can hint at the underlying immunodeficiency and the tendency for infection and inflammation. These manifestations can present as recurring eczema, erythema, abscesses, and hair loss with poor response to therapy. Cutaneous manifestations can be specific for certain IEI, or rather unspecific. Together with clinical course and severity, they can indicate the diagnosis. Early and accurate recognition, diagnosis, and treatment are crucial for optimizing patient outcomes. The diagnosis can be determined through adetailed patient history, clinical examination, and immunological diagnostics. Collaboration between immunologists and dermatologists is vital for comprehensive care and improvement of life quality.

Phenotypic and pathomechanistic overlap between tapasin and TAP deficiencies

Human tapasin deficiency is reported to cause an autosomal-recessive inborn error of immunity characterized by substantially reduced cell surface expression of major histocompatibility complex class I (MHC-I). We evaluated the immunologic and clinical consequences of tapasin deficiency. A novel homozygous variant in TAPBP was identified by means of whole genome sequencing. The expression of tapasin and both subunits of the transporter associated with antigen presentation (TAP) were evaluated by Western blot analysis. Cell surface and intracellular expression of MHC-I were evaluated by flow cytometry. Small interfering RNAs were used for silencing TAPBP expression in HEK293T cells. We identified a deletion in TAPBP (c.312del, p.(K104Nfs∗6)) causing tapasin deficiency in a patient with bronchiectasis and recurrent respiratory tract infections as well as herpes zoster. Besides substantial reduction in TAP1 and TAP2 expression, peripheral blood mononuclear cells from this patient and TAPBP-knockdown HEK293T cells, displayed reduced cell surface expression of MHC-I, while reduction in intracellular expression of MHC-I was less prominent, suggesting a defect in MHC-I trafficking to the plasma membrane. IFN-α improved cell surface expression of MHC-I in tapasin deficient lymphocytes and TAPBP-knockdown HEK293T cells, representing a possible therapeutic approach for tapasin deficiency. Tapasin deficiency is a very rare inborn error of immunity, the pathomechanism and clinical spectrum of which overlaps with TAP deficiencies.