[Relevant cutaneous manifestations as indications for inborn errors of immunity]. / Relevante Hautmanifestationen als Hinweis für angeborene Immundefekte.

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 a detailed patient history, clinical examination, and immunological diagnostics. Collaboration between immunologists and dermatologists is vital for comprehensive care and improvement of life quality.

Diagnostic yield of next-generation sequencing in suspect primary immunodeficiencies diseases: a systematic review and meta-analysis.

To determine the diagnostic yield of Next-generation sequencing (NGS) in suspect Primary Immunodeficiencies Diseases (PIDs). This systematic review was conducted following PRISMA criteria. Searching Pubmed and Web of Science databases, the following keywords were used in the search: ("Next-generation sequencing") OR "whole exome sequencing" OR "whole genome sequencing") AND ("primary immunodeficiency disease" OR "PIDs"). We used STARD items to assess the risk of bias in the included studies. The meta-analysis included 29 studies with 5847 patients, revealing a pooled positive detection rate of 42% (95% CI 0.29-0.54, P < 0.001) for NGS in suspected PID cases. Subgroup analyses based on family history demonstrated a higher detection rate of 58% (95% CI 0.43-0.71) in patients with a family history compared to 33% (95% CI 0.21-0.46) in those without (P < 0.001). Stratification by disease types showed varied detection rates, with Severe Combined Immunodeficiency leading at 58% (P < 0.001). Among 253 PID-related genes, RAG1, ATM, BTK, and others constituted major contributors, with 34 genes not included in the 2022 IUIS gene list. The application of NGS in suspected PID patients can provide significant diagnostic results, especially in patients with a family history. Meanwhile, NGS performs excellently in accurately diagnosing disease types, and early identification of disease types can benefit patients in treatment.

Accessibility to plasma-derived medicinal products in Malaysia: The challenges faced by patients with inborn errors of immunity.

Inborn errors of immunity (IEI) (also known as primary immunodeficiencies) is an umbrella term for a growing group of over 450 different disorders that are characterized by defects in some of the components of the immune system. IEI are chronic diseases of genetic origin that render individuals suffering from them susceptible to infections. The mainstay of treatments for most patients with IEI, that is, predominantly antibody deficiencies is immunoglobulin replacement therapy (IRT), which is commonly delivered intravenously. Immunoglobulin (IG) therapy contains antibodies to compensate for the defective immune system's inability to produce them. Individuals with IEI need IRT regularly throughout their lives to help combat infections and prevent organ damage. Without IRT, they are in danger of suffering from morbidity, poor quality of life, and reduced life expectancy. In the last 20 years, the use of IG preparation has tripled and this is partly attributed to the growing awareness and improved diagnoses of IEI cases. IG preparations are also used for the treatment of other medical conditions including secondary immunodeficiencies and autoimmune diseases. As IG is derived from human plasma, there are concerns about the availability of supply, particularly to treat life-threatening conditions that cannot be improved with other medications. It is estimated that 75% to 80% of IEI patients do not have access to adequate IG therapy throughout the world. This concern of supply and other challenges faced by patients with IEI in Malaysia are described from the patients' perspective.

Health-related quality of life in patients with inborn errors of immunity: a bibliometric analysis.

Background: Inborn Errors of Immunity (IEI) are characterized by a heightened susceptibility to infections, allergies, and various other health complications. Health-Related Quality of Life (HRQOL) in patients with IEI is a critical area of research that demands attention due to the impact of IEI on patients' lives. This study utilized bibliometric methods, aiming to comprehensively explore the research content and hotspots in the field of HRQOL in patients with IEI. Methods: This bibliometric analysis utilized data from the Science Citation Index Expanded (SCIE) and Social Sciences Citation Index (SSCI) within the Web of Science core datasets up to January 1, 2024. The study focused on literature that addressed HRQOL in IEI patients, involving a total of 1,807 authors and 309 articles published across 112 journals. The analysis included publication volume and growth trends, country and institutional contributions, authorship, and journal analysis. Results: The research found that despite the importance of HRQOL in IEI, the volume of publications in this field remains consistently low, with no significant increase in trend. The USA leads in publication and citation volumes, reflecting a geographical imbalance in research contributions. Key journals in this field include the Journal of Clinical Immunology, Frontiers in Immunology, and the Journal of Allergy and Clinical Immunology. The study highlights that while treatments like hematopoietic stem cell transplants and gene therapy have improved patient IEI survival rates, they still often come with significant side effects impacting HRQOL. The analysis underlines the need for comprehensive HRQOL assessments in IEI, considering the physical and psychological impacts of treatments. Conclusions: This study represents a bibliometric analysis focusing on HRQOL in patients with. It underscores the need for more extensive and systematic research in this area, emphasizing the importance of a multidisciplinary approach. Despite advancements in medical treatments for IEI, there is a crucial need to focus on HRQOL to enhance patient satisfaction and overall well-being. The findings advocate for more personalized treatment plans and a better understanding of the psychosocial needs of patients with IEI to improve their quality of life.

Pharmacokinetics, safety, and efficacy of 20% subcutaneous immunoglobulin (Ig20Gly) administered weekly or every 2 weeks in Japanese patients with primary immunodeficiency diseases: a phase 3, open-label study.

This phase 3, open-label, multidose study (NCT04346108) evaluated the pharmacokinetics, safety, tolerability, and efficacy of immunoglobulin subcutaneous (human) 20% solution (Ig20Gly) administered weekly and every 2 weeks in Japanese patients with primary immunodeficiency diseases (PIDs). The study was conducted at eight study sites in Japan and enrolled patients aged ≥2 years with PIDs treated using a stable intravenous immunoglobulin dose for ≥3 months prior to the study. Patients received intravenous immunoglobulin every 3 or 4 weeks at pre-study dose (200-600 mg/kg) for 13 weeks (Epoch 1), subcutaneous Ig20Gly (50-200 mg/kg) once weekly for 24 weeks (Epoch 2), and Ig20Gly (100-400 mg/kg) every 2 weeks for 12 weeks (Epoch 3). The primary endpoint was serum total immunoglobulin G (IgG) trough levels during Epochs 2 and 3. Overall, 17 patients were enrolled (median [range] age: 24 [5-69] years; 59% male) and participated in Epochs 1 and 2; seven patients entered Epoch 3. Serum total IgG trough levels were maintained at >8 g/l: geometric means (95% confidence intervals) at the end of Epochs 2 and 3 were 8.56 (8.03-9.12) g/l and 8.39 (7.89-8.91) g/l, respectively. Related treatment-emergent adverse events were all mild in severity; the most common treatment-emergent adverse events (excluding infections) in Epochs 2 and 3 were injection site swelling (24%) and injection site erythema (18%). This is the first trial to demonstrate the efficacy and favourable safety profile of 20% subcutaneous immunoglobulin administered every 2 weeks in adult and paediatric Japanese patients with PIDs.

HIV-1 Mediated Cortical Actin Disruption Mirrors ARP2/3 Defects Found in Primary T Cell Immunodeficiencies.

During cell movement, cortical actin balances mechanical and osmotic forces to maintain cell function while providing the scaffold for cell shape. Migrating CD4+ T cells have a polarized structure with a leading edge containing dynamic branched and linear F-actin structures that bridge intracellular components to surface adhesion molecules. These actin structures are complemented with a microtubular network beaded with membrane bound organelles in the trailing uropod. Disruption of actin structures leads to dysregulated migration and changes in morphology of affected cells. In HIV-1 infection, CD4+ T cells have dysregulated movement. However, the precise mechanisms by which HIV-1 affects CD4+ T cell movement are unknown. Here, we show that HIV-1 infection of primary CD4+ T cells causes at least four progressive morphological differences as a result of virally induced cortical cytoskeleton disruption, shown by ultrastructural and time lapse imaging. Infection with a ΔNef virus partially abrogated the dysfunctional phenotype in infected cells and partially restored a wild-type shape. The pathological morphologies after HIV-1 infection phenocopy leukocytes which contain genetic determinants of specific T cell Inborn Errors of Immunity (IEI) or Primary Immunodeficiencies (PID) that affect the actin cytoskeleton. To identify potential actin regulatory pathways that may be linked to the morphological deformities, uninfected CD4+ T cell morphology was characterized following addition of small molecule chemical inhibitors. The ARP2/3 inhibitor CK-666 recapitulated three of the four abnormal morphologies we observed in HIV-1 infected cells. Restoring ARP2/3 function and cortical actin integrity in people living with HIV-1 infection is a new avenue of investigation to eradicate HIV-1 infected cells from the body.

Epigenetic immune cell quantification for diagnostic evaluation and monitoring of patients with inborn errors of immunity and secondary immune deficiencies.

BACKGROUND: Early detection and monitoring of primary immunodeficiencies (PID) in humans require quantitative determination of immune cells from fresh blood analyzed by flow cytometry. However, epigenetic immune cell quantification allows analysis from fresh, frozen, or dried blood samples. We demonstrate the utility of epigenetic immune cell quantification for patients with PID. METHODS: Epigenetic quantification of basic lymphocyte subpopulations of 259 samples from PID patients were compared to flow cytometric data. Epigenetic analysis was extended to T-cell subsets (Treg, Th17, Tfh, PD-1+, CCR6+) and memory B-cells and compared between venous EDTA and dried blood. RESULTS: A high correlation of >0.9 was observed for basic T- and B-cell subsets. Extended epigenetic analysis showed quantitative trends within PID subgroups, but individually these varied substantially within these groups. Epigenetic analysis of dried blood samples was equivalent to EDTA blood. CONCLUSION: Epigenetic immune cell quantification is suitable for immune cell profiling in PID patients.

Genetic characteristics of common variable immunodeficiency patients with autoimmunity.

Background: The pathogenesis of common variable immunodeficiency disorder (CVID) is complex, especially when combined with autoimmunity. Genetic factors may be potential explanations for this complex situation, and whole genome sequencing (WGS) provide the basis for this potential. Methods: Genetic information of patients with CVID with autoimmunity, together with their first-degree relatives, was collected through WGS. The association between genetic factors and clinical phenotypes was studied using genetic analysis strategies such as sporadic and pedigree. Results: We collected 42 blood samples for WGS (16 CVID patients and 26 first-degree relatives of healthy controls). Through pedigree, sporadic screening strategies and low-frequency deleterious screening of rare diseases, we obtained 9,148 mutation sites, including 8,171 single-nucleotide variants (SNVs) and 977 Insertion-deletions (InDels). Finally, we obtained a total of 28 candidate genes (32 loci), of which the most common mutant was LRBA. The most common autoimmunity in the 16 patients was systematic lupus erythematosis. Through KEGG pathway enrichment, we identified the top ten signaling pathways, including "primary immunodeficiency", "JAK-STAT signaling pathway", and "T-cell receptor signaling pathway". We used PyMOL to predict and analyse the three-dimensional protein structures of the NFKB1, RAG1, TIRAP, NCF2, and MYB genes. In addition, we constructed a PPI network by combining candidate mutants with genes associated with CVID in the OMIM database via the STRING database. Conclusion: The genetic background of CVID includes not only monogenic origins but also oligogenic effects. Our study showed that immunodeficiency and autoimmunity may overlap in genetic backgrounds. Clinical Trial Registration: identifier ChiCTR2100044035.

[Autoimmunity and Freiburg classification in common variable immunodeficiency]. / Autoinmunidad y clasificación de Freiburg en pacientes con inmunodeficiencia común variable.

Introduction: Up to 25% of patients with common variable immunodeficiency (CVID) debut with autoimmunity, which is related to the Freiburg classification, which is based on flow cytometry. Objective: to determine the frequency and type of autoimmune diseases and their association with the Freiburg classification in adults with CVID. Methods: A cross-sectional, analytical and observational study was carried out with 33 patients belonging to the Primary Immunodeficiency Clinic of a third level hospital, with a diagnosis of CVID. They were divided into 3 phenotypes according to the Freiburg classification. Results: Of the 33 patients studied, 66.6% presented autoimmune diseases, 19 of them (86.3%) had cytopenia; 42.1% belonged to Freiburg group Ia, 36.8% to Ib and 21% to phenotype II. In 36.6% of the patients, autoimmune cytopenia were the first manifestation of CVID; and up to 70% of them belong to the Freiburg phenotype Ia (p = 0.086). Patients with autoimmune cytopenia had a lower percentage of isotype-switched memory B cells (p = 0.018), no higher percentage of CD21low B cells (p = 0.226). Conclusions: Classification by CVID phenotypes allows the identification of the patient's profile according to the percentage of memory B cells with isotype change, which is useful to intentionally search for non-infectious complications of the disease.

Introducción: hasta el 25% de los pacientes con inmunodeficiencia común variable (IDCV) debutan con autoinmunidad, la cual guarda relación con la clasificación de Freiburg, que se basa en la citometría de flujo. Objetivo: determinar la frecuencia y tipo de enfermedades autoinmunes y su asociación con la clasificación de Freiburg en adultos con IDCV. Métodos: se realizó un estudio transversal, analítico y observacional con 33 pacientes pertenecientes a la Clínica de Inmunodeficiencias Primarias de un hospital de tercer nivel con diagnóstico de IDCV. Se dividieron en tres fenotipos según la clasificación de Freiburg. Resultados: de los 33 pacientes estudiados, el 66.6% presentó enfermedades autoinmunes, de ellos 19 (86.3%) tuvieron citopenias. El 42.1% se clasificó en el grupo Ia de Freiburg, el 36.8% en el grupo Ib y el 21% en el fenotipo II. En el 36.6% de los pacientes las citopenias autoinmunes fueron la primera manifestación de IDCV, y hasta el 70% de ellos pertenecen al fenotipo Ia de Freiburg (p = 0.086). Los pacientes con citopenias autoinmunes tuvieron un menor porcentaje de células B de memoria con cambio de isotipo (p = 0.018), sin mayor porcentaje de células B CD21low (p = 0.226). Conclusiones: la clasificación por fenotipos en IDCV permite identificar el perfil del paciente y el tipo de manifestaciones asociadas, lo que es útil para buscar de manera intencionada complicaciones no infecciosas propias de la enfermedad.

Molecular Linkage between Immune System Disorders and Atherosclerosis.

A strong relationship exists between immune dysfunction and cardiovascular disease. Immune dysregulation can promote the development of cardiovascular diseases as well as exacerbate their course. The disorders may occur due to the presence of primary immune defects (currently known as inborn errors of immunity) and the more common secondary immune deficiencies. Secondary immune deficiencies can be caused by certain chronic conditions (such as diabetes, chronic kidney disease, obesity, autoimmune diseases, or cancer), nutritional deficiencies (including both lack of nutrients and bioactive non-nutrient compounds), and medical treatments and addictive substances. This article unravels the molecular linkage between the aforementioned immune system disorders and atherosclerosis.

COVID-19 Vaccination Coverage and Factors Influencing Vaccine Hesitancy among Patients with Inborn Errors of Immunity in Latvia: A Mixed-Methods Study.

BACKGROUND: The European Society for Immunodeficiencies recommends that all patients with inborn errors of immunity (IEI) without contraindications should receive SARS-CoV-2 vaccination. The aim of this study was to investigate the reasons that discourage IEI patients from receiving the recommended vaccination and to assess vaccination coverage among IEI patients in Latvia. METHODS: In this multicenter mixed-methods study, the vaccination status of all patients with IEI within two tertiary centers in Latvia was reviewed using electronic health records. Semi-structured interviews were conducted with 16 IEI patients who did not undergo vaccination, and a thematic analysis was performed. RESULTS: A total of 341 patients (49.3% female; median age 19.7 years (IQR:17)) were included in the quantitative part. The proportion of fully vaccinated individuals aged ≥ 12 years was 66.8%-70.9% with patients with selective IgA deficiency and 58.8% with other IEI (χ² = 14.12, p < 0.001). The proportion of fully vaccinated individuals aged 5-11 years was 11.1%. Age was associated with vaccination status: younger patients were found to have a significantly lower likelihood of receiving vaccination (U = 8585, p < 0.001). The five main themes identified were as follows: (1) fear and uncertainty; (2) risk and benefit assessment: COVID-19 vaccine-is it worth it? (3) external influences: the dark horse of the decision-making-people around us; (4) individuals against the system; and (5) beliefs about vaccination and COVID-19. Under-representation of certain IEI groups and recall bias are possible limitations of this study. CONCLUSIONS: While most reasons for hesitancy were similar to those previously described in the general population, disease-specific concerns were also identified.

Phenotypic Variability in PRKCD: a Review of the Literature.

PURPOSE: Protein kinase C δ (PKCδ) deficiency is a rare genetic disorder identified as a monogenic cause of systemic lupus erythematosus in 2013. Since the first cases were described, the phenotype has expanded to include children presenting with autoimmune lymphoproliferative syndrome-related syndromes and infection susceptibility similar to chronic granulomatous disease or combined immunodeficiency. We review the current published data regarding the pathophysiology, clinical presentation, investigation and management of PKCδ deficiency. METHODS: Literature review was performed using MEDLINE. RESULTS: Twenty cases have been described in the literature with significant heterogeneity. CONCLUSION: The variation in clinical presentation delineates the broad and critical role of PKCδ in immune tolerance and effector functions against pathogens.

Interplay between epigenetic and genetic alterations in inborn errors of immunity.

Inborn errors of immunity (IEIs) comprise a variety of immune conditions leading to infections, autoimmunity, allergy, and cancer. Some IEIs have no identified mutation(s), while others with identical mutations can display heterogeneous presentations. These observations suggest the involvement of epigenetic mechanisms. Epigenetic alterations can arise from downstream activation of cellular pathways through both extracellular stimulation and genetic-associated changes, impacting epigenetic enzymes or their interactors. Therefore, we posit that epigenetic alterations and genetic defects do not exclude each other as a disease-causing etiology. In this opinion, encompassing both basic and clinical viewpoints, we focus on selected IEIs with mutations in transcription factors that interact with epigenetic enzymes. The intricate interplay between these factors offers insights into genetic and epigenetic mechanisms in IEIs.

Navigating the transition of care in patients with inborn errors of immunity: a single-center's descriptive experience.

The transition from pediatric to adult care is a critical milestone in managing children, especially in those with complex chronic conditions. It involves ensuring the patient and family adapt correctly to the new phase, maintaining continuity of ongoing treatments, and establishing an appropriate follow-up plan with specialists. Patients with Inborn error of immunity (IEI), formerly known as Primary Immune Disorders (PID) are part of a group of disorders characterized by alterations in the proper functioning of the immune system; as the diagnostic and treatment tools for these entities progress, life expectancy increases, and new needs emerge. These children have special needs during the transition. Particularly important in the group of children with PID and syndromic features, who often present multiple chronic medical conditions. In these cases, transition planning is a significant challenge, involving not only the patients and their families but also a wide range of specialists. To achieve this, a multidisciplinary transition team should be established between the pediatric specialists and the adult consultants, designing a circuit in which communication is essential. As few transition care guidelines in the field of PID are available, and to our knowledge, there is no specific information available regarding patients with PID associated with syndromic features, we share our experience in this issue as a Primary Immunodeficiencies Unit that is a National Reference Center for PID, and propose a guide to achieve an adequate and successful transition to adulthood in these patients, especially in those with associated syndromic features.

A History and Atlas of the Human CD4+ T Helper Cell.

CD4+ T cells have orchestrated and regulated immunity since the introduction of jawed vertebrates, yet our understanding of CD4+ T cell evolution, development, and cellular physiology has only begun to be unearthed in the past few decades. Discoveries of genetic diseases that ablate this cellular population have provided insight into their critical functions while transcriptomics, proteomics, and high-resolution microscopy have recently revealed new insights into CD4+ T cell anatomy and physiology. This article compiles historical, microscopic, and multi-omics data that can be used as a reference atlas and index to dissect cellular physiology within these influential cells and further understand pathologies like HIV infection that inflict human CD4+ T cells.

The PID Odyssey 2030: outlooks, unmet needs, hurdles, and opportunities - proceedings from the IPOPI global multi-stakeholders' summit (June 2022).

IPOPI held its first Global Multi-Stakeholders' Summit on 23-24 June 2022 in Cascais, Portugal. This IPOPI initiative was designed to set the stage for a stimulating forward-thinking meeting and brainstorming discussion among stakeholders on the future priorities of the PID community. All participants were actively engaged in the entire Summit, bringing provocative questions to ensure a high level of discussion and engagement, and partnered in identifying the outlooks, unmet needs, hurdles and opportunities of PIDs for 2030. The topics that were covered include diagnosis (e.g., newborn screening [NBS], genomic sequencing- including ethical aspects on the application of genomics on NBS, the role of more accurate and timely diagnostics in impacting personalized management), treatment (e.g., the therapeutic evolution of immunoglobulins in a global environment, new therapies such as targeted therapies, new approaches in curative therapies), the interactions of Primary ID with Secondary ID, Autoinflammatory Diseases and other diseases as the field experiences an incessant evolution, and also the avenues for research in the field of humanities and human sciences such as Patient-Reported Outcome Measures (PROMs), Patient-Reported Experience Measures (PREMs), and Health-Related Quality Of Life (HRQoL). During this meeting, all participants contributed to the drafting of recommendations based on our common understanding of the future opportunities, challenges, and scenarios. As a collection of materials, perspectives and summaries, they are succinct and impactful and may help determine some of the next key steps for the PID community.

Points to Consider in Health Assessment of Adult Patients with Primary Antibody Deficiencies.

An improved recognition of inborn errors of immunity (IEI) is associated with an increase in life expectancy and a higher incidence of complications and related conditions. The aim of the study was to analyze factors enabling the primary prevention: BMI, smoking and selected laboratory tests (morphology with smear, creatinine, eGFR, total protein, albumin, ferritin, folic acid, vitamin B12, vitamin D3) included in the protocols of standard of care for adult patients with primary antibody deficiencies (PADs). The study included 94 participants ≥ 18 years old, diagnosed with PADs. Overweight was found in 17%, obesity in 14% and underweight in 15% of patients; 11.5% of patients smoked. Leukopenia was diagnosed in 16%, neutropenia in 8.5%, lymphopenia in 22.5% and thrombocytopenia in 14% of patients. A decreased concentration of hemoglobin was found in 32%, total protein in 19%, albumin in 17%, vitamin D3 in 52%, vitamin B12 in 6.5%, folic acid in 34% and ferritin in 26% of patients. Creatinine concentrations were elevated in 16% of patients, while in 20%, eGFR was reduced. Only a holistic assessment of comorbidities and complications of deficiency, as well as regular follow-up and lifestyle changes, can yield the best results in the long-term care of patients.

Chronic Diarrhea with Villous Blunting of the Small Intestine Under Capsule Endoscopy in Common Variable Immunodeficiency and X-Linked Agammaglobulinemia: A Case Series.

Introduction: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders, common variable immunodeficiency disorder (CVID) and X-linked agammaglobulinemia (XLA) are PIDs related to B-cell defect, characterized by reduced levels of immunoglobulins and immune dysregulation. Infections are the most common clinical manifestations, while underlying autoimmune and inflammatory conditions are present in some patients with CVID and XLA, leading to clinical misdiagnosis and diagnostic delay. Chronic diarrhea in patients with CVID and XLA, particularly complicated malabsorption and protein-energy malnutrition, is responsible for poor prognostic outcomes. Methods: In this study, we described three PID adult patients (two with CVID and one with XLA) who presented with varying degrees of chronic diarrhea, weight loss, and protein-energy malnutrition. We suggest that villous blunting of the small intestine under capsule endoscopy may be an endoscopic feature of PID-related enteropathy, thus highlighting the application of capsule endoscopy in patients with CVID and XLA presenting with chronic diarrhea. Conclusion: We also summarize regular Ig supplementation is the basic treatment for CVID and XLA patients, proper enteral nutrition and probiotic therapy can be explored to use to alter gut microbiota and modulate intestinal immune response. However, vedolizumab is not helpful to PID-related enteropathy therapy, as it exacerbates the inflammatory response in extra-intestinal organs and ultimately causes poor clinical outcomes.