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Front Immunol. 2024 Oct 23;15:1495564. doi: 10.3389/fimmu.2024.1495564. eCollection 2024.

ABSTRACT

PURPOSE: Calculated globulin (CG, total protein minus albumin levels) correlate well with IgG levels and has been proposed as a suitable screening method for individuals with primary antibody deficiencies (PADs). We aimed to show the correlation of CG with IgG levels in children and adolescents, utilizing a common method for albumin measurement, bromocresol green.

METHODS: Individuals from two Allergy and Immunology clinics were invited to participate. Inclusion criteria were age < 18, stable conditions, and signed informed consent. We included 1084 individuals. Immunoglobulin G values were determined by immunoturbidimetry; the colorimetric bromocresol green method and the Architect Biuret method were utilized for the albumin and total protein (TP) measurements, respectively.

RESULTS: A total of 1084 individuals were included in the analysis and divided into 4 age groups (0 to <1 year, 1 to <4 years, 4 to <10 years, and 10 to <18 years). For all patients, the mean age was 6.1 (± 5) years old, the mean IgG was 9.4 (± 4.7) g/L, and CG was 23.7 (± 5.9) g/L. The most frequent diagnosis were respiratory allergies, followed by inborn errors of immunity. IgG and CG varied according to age group. Cutoff values for hypogammaglobulinemia varied from 13.8 g/L in children < 1 year to 23.1 g/L in children and adolescents aged 10 to <18 years. CG sensitivity varied from 70.9% in children aged 1 to <4 years old to 95.8% in children 4 to <10. Specificity ranged from 87.5% in children 4 to <10 years old to 100% in children and adolescents aged 10 to <18 years.

CONCLUSION: CG is a suitable screening test for hypogammaglobulinemia in children less than 18 years of age.

PMID:39507534 | PMC:PMC11537921 | DOI:10.3389/fimmu.2024.1495564

J Clin Immunol. 2024 Nov 5;45(1):38. doi: 10.1007/s10875-024-01816-4.

ABSTRACT

Chronic neutropenia causes involve nutritional deficiencies and inborn errors of immunity(IEI), such as severe congenital neutropenia. To classify common chronic neutropenia causes in a pediatric immunology unit. We enrolled 109 chronic neutropenia patients admitted to a pediatric immunology department between 2002-2022. We recorded clinical/laboratory features and genetic characteristics. The male/female ratio was 63/46. Fifty-eight patients had parental consanguinity(57.4%). 26.6% (n = 29) patients had at least one individual in their family with neutropenia. Common symtpoms at presentation were upper respiratory tract infections(URTI)(31.1%), oral aphthae(23.6%), skin infections(23.6%), pneumonia(20.8%), and recurrent abscesses(12.3%). Common infections during follow-up were URTI(56.8%), pneumonia(33%), skin infections(25.6%), gastroenteritis(18.3%), and recurrent abscesses(14,6%). Common long-term complications were dental problems(n = 51), osteoporosis(n = 22), growth retardation(n = 14), malignancy(n = 16)[myelodysplastic syndrome(n = 10), large granulocytic leukemia(n = 1), acute lymphoblastic leukemia(n = 1), Hodgkin lymphoma(n = 1), EBV-related lymphoma(n = 1), leiomyosarcoma(n = 1), and thyroid neoplasm(n = 1)]. We performed a genetic study in 86 patients, and 69(71%) got a genetic diagnosis. Common gene defects were HAX-1(n = 26), ELA-2 (ELANE)(n = 10), AP3B1(n = 4), and ADA-2(n = 4) gene defects. The IEI ratio(70.6%) was high. GCSF treatment(93.4%), immunoglobulin replacement therapy(18.7%), and HSCT(15.9%) were the treatment options. The mortality rate was 12.9%(n = 14). The most common long term complications were dental problems that is three times more common in patients with known genetic mutations. We prepared an algorithm for chronic neutropenia depending on the present cohort. An important rate of inborn errors of immunity, especially combined immunodeficiency(11.9%) was presented in addition to congenital phagocytic cell defects. Early diagnosis will allow us tailor the disease-specific treatment options sooner, preventing irreversible consequences.

PMID:39499404 | DOI:10.1007/s10875-024-01816-4

Front Immunol. 2024 Oct 18;15:1461407. doi: 10.3389/fimmu.2024.1461407. eCollection 2024.

ABSTRACT

INTRODUCTION: In patients with Hereditary Angioedema (HAE) related to primary C1 inhibitor deficiency (C1INH), the defective clearance of immune complexes and apoptotic materials along with impairment of normal humoral response potentially leads to autoimmunity. Few studies report evidence on autoimmune diseases in C1INH-HAE, but no large population studies focus on rare connective tissue diseases (RCTDs). We aim at evaluating for the first time prevalence and distribution of RCTDs – Systemic Lupus Erytematosus (SLE), primary Sjogren Syndrome (SjS), primary antiphospholipid syndrome (APS), Systemic Sclerosis (SSc), and mixed connective tissue diseases (MCTD) in a large Italian cohort of C1INH-HAE patients.

METHODS: A multicenter observational study includes C1INH-HAE patients from ITACA Centers throughout Italy (time frame Sept 2023-March 2024). Inclusion criteria are i. a defined diagnosis of type I or type II C1INH-HAE; ii. age ≥15 years (puberty already occurred); iii. enrollment in the ITACA Registry. The diagnosis of SLE, primary SjS, primary APS, SSc, and MCTD are made in accordance with international classification criteria.

RESULTS: Data are collected from a total of 855 C1INH-HAE patients referring to 15 ITACA Centers. Patients with concomitant RCTDs were 18/855 (2.1%) with F:M ratio 3.5 and a prevalent type I C1INH-HAE diagnosis (87.2%). A diagnosis of SLE results in 44.5% of cases (n=8) while the remaining diagnoses are primary SjS (22.2%, n=4), primary APS (16.6%, n=3), SSc (11.2%, n=2), and a single case of MCTD (5.5%). The female gender is prevalent in all the RCTDs. Patients on long term prophylaxis (LTP) are significantly prevalent in RCTDs group than in the whole C1INH-HAE population (p<0.01).

CONCLUSIONS: A relevant prevalence of RCTDs is documented in C1INH-HAE patients, mainly SLE. Patients with RCTDs are on LTP in a significant proportion supporting the idea of a bidirectional link between C1INH-HAE and autoimmunity.

PMID:39493762 | PMC:PMC11527674 | DOI:10.3389/fimmu.2024.1461407

J Allergy Clin Immunol Pract. 2023 Oct 28:S2213-2198(23)01196-0. doi: 10.1016/j.jaip.2023.10.041. Online ahead of print.

ABSTRACT

Inborn errors of immunity represent a rapidly expanding group of genetic disorders of the immune system. Significant advances have been made in recent years in diagnosis, including using genetic testing and newborn screening; treatment, including precision therapies, gene therapy and hematopoietic stem cell transplant; and development of patient registries to inform prevalence, understand morbidity of these disorders and guide the development of clinical trials. However, significant disparities due to age, race, ethnicity, socioeconomic status, or geographic location exist in all aspects of care of patients with inborn errors of immunity, beginning with delays in diagnosis and further compounded by impaired access to specialist care and treatment, leading to a notable impact on outcomes including morbidity and mortality. Addressing and correcting these disparities will require coordinated, deliberate and prolonged effort. Proposed strategies to improve equity at different levels include public health measures such as implementing universal newborn screening, supporting expanded health insurance coverage for diagnostic testing and treatment, improving access to novel therapeutics in low and middle income countries and developing artificial intelligence / machine learning tools to reduce delays in diagnosis, particularly in rural or less developed areas where access to specialist care is limited.

PMID:39492552 | DOI:10.1016/j.jaip.2023.10.041

Immunol Med. 2024 Nov 1:1-8. doi: 10.1080/25785826.2024.2422639. Online ahead of print.

ABSTRACT

X-linked NF-κB essential modulator (NEMO) deficiency is a primary immunodeficiency characterized by combined immunodeficiency and ectodermal dysplasia. Monocytes from the patients demonstrate a severely impaired response to tissue necrosis factor or lipopolysaccharide, whereas hyper-inflammation is found in some patients. Juvenile myelomonocytic leukemia (JMML) is a pediatric malignancy caused by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and aberrant RAS signaling activation. Patients with JMML demonstrate characteristic manifestations such as splenomegaly, monocytosis and the presence of myeloid or erythroid precursors in the peripheral blood. Here, we present the case of a male infant with ectodermal dysplasia, bacterial septicemia, Pneumocystis pneumonia, severe inflammation and transient manifestations mimicking JMML. Genetic analysis revealed a deep intronic germline variant of IKBKG. Full-length IKBKG cDNA and NEMO protein expression were almost inexistent. Peripheral mononuclear cells (PBMCs) from the patient showed increased RAS signaling activation with GM-CSF or Phorbol 12-myristate 13-acetate without the RAS-associated gene variant, although the increased RAS signaling activation in induced-pluripotent stem cell-derived myeloid lineage and bone marrow-derived mesenchymal cells was not evident. The patient with NEMO deficiency demonstrated JMML-like manifestation and severe inflammation. PBMCs of the patient demonstrated increased RAS signaling activation with unknown pathophysiology.

PMID:39485070 | DOI:10.1080/25785826.2024.2422639

Pediatr Allergy Immunol. 2024 Nov;35(11):e14264. doi: 10.1111/pai.14264.

ABSTRACT

BACKGROUND: Primary immunodeficiency diseases (inborn errors of immunity) with partial albinism are a group of autosomal recessive syndromes including Chediak Higashi Syndrome (CHS), Griscelli Syndrome type 2 (GS2), Hermansky-Pudlak Syndromes type 2 and 10 (HPS2, HPS10), Vici syndrome and P14/LAMTOR2 deficiency.

METHODS: Twenty-five patients including 10 CHS, 10 GS2, and 5 HPS2 were evaluated in this study within the last 10 years. Five cases with oculocutaneous albinism (OCA) and 5 healthy subjects without albinism were used as two control groups. Genetic analyses were performed by whole exome or panel sequencing or targeted Sanger sequencing. Subsequently, leukocyte granules in peripheral blood smear and hair shaft were examined as screening tests.

RESULTS: Giant granules were only presented in the leukocytes cytoplasm of 10/10 CHS patients. The uneven cluster of pigments and giant melanin granules in hair samples were observed in 10/10 GS2 and 10/10 CHS patients, respectively. In both 5/5 OCA and 5/5 HPS2 patients, there were regular pigments in the middle of hair shafts. Genetic analyses were performed for all patients, revealing 7 novel variants in LYST gene for CHS patients and 4 novel variants in AP3B1 for HPS2 patients.

CONCLUSION: Receiving hematopoietic stem cell transplantation (HSCT) in a timely manner is crucial in CHS and GS2 patients; therefore, screening tests may provide a vital clue for early diagnosis in these patients. However, the final confirmation of CHS, GS2, and HPS2 disorders is done by genetic assay.

PMID:39485047 | DOI:10.1111/pai.14264

Front Immunol. 2024 Oct 2;15:1384195. doi: 10.3389/fimmu.2024.1384195. eCollection 2024.

ABSTRACT

PURPOSE: The measurement of T-cell receptor excision circle (TREC) is used for newborn screening (NBS) in dried blood spot (DBS) samples from Guthrie card for severe combined immunodeficiency (SCID). Here, we report the results of first newborn screening pilot program for SCID conducted in Türkiye.

METHODS: The study was carried out together with Ankara University School of Medicine and The Ministry of Health, Public Health General Directorate, Pediatric and Adolescent Health Department. TREC measurements were performed in randomly selected Guthrie card samples obtained from 20253 babies born between October 2018 and October 2020. The TREC analyses were performed together with beta Actin (β-Actin) via RT-PCR (Real Time Polymerase Chain Reaction).

RESULTS: TRECs found to be normal (≥15 copies/µl) in 98,6% of the newborns (n: 19975) but low (<15 copies/µl) in 1.4% (n:278) at the initial analyses. TRECs were retested in 278 suspected infants and found to be normal in 160 (0.8%) while low in 118 (0.58%). New DBS were obtained from the babies with low TRECs (new sample test). TRECs were normal in 108 (0.53%) of the new sample tests and low in 10 (0.049%). Two among 10 babies who had abnormal (undetectable) TRECs were diagnosed as SCID; ADA (P1) and RAG1 (P2) defects were confirmed respectively. They both received curative treatments [gene therapy (P1) and HSCT (P2)]. The remaining 6 of 8 newborns with abnormal TRECs were found normal after clinical and laboratory immune work-up, while medical records of other two revealed early postnatal death due to extreme prematurity.

CONCLUSION: In the light of this study the incidence of SCID was detected at least 1/10000 live births in Türkiye. This study shows the feasibility and usefulness of initiating SCID screening in Türkiye.

PMID:39483481 | PMC:PMC11526446 | DOI:10.3389/fimmu.2024.1384195

Autoimmun Rev. 2024 Oct 29:103675. doi: 10.1016/j.autrev.2024.103675. Online ahead of print.

ABSTRACT

The concept of an “immunological continuum model,” introduced by McGonagle and McDermott in 2006, redefines the traditional dichotomy between autoimmunity and autoinflammation, proposing a spectrum where innate and adaptive immune dysregulation can co-occur, reflecting a more nuanced understanding of immune disorders. Systemic lupus erythematosus (SLE) exemplifies the complexity of this continuum, often displaying manifestations of autoimmunity, autoinflammation, and immunodeficiency. The interplay between genetic, epigenetic, hormonal, psychological, and environmental factors contributes to its distinctive immunopathological signatures. Historically recognized as a systemic disease with diverse clinical manifestations, SLE is primarily a polygenic autoimmune condition but can, however, present in monogenic forms. Examining SLE through the lens of the immunological continuum model allows for emphasis on the contributions of both innate and adaptive immunity. SLE and primary immunodeficiencies share genetic susceptibilities and clinical manifestations. Additionally, autoinflammatory mechanisms, such as inflammasome activation and interferonopathies, can play a role in SLE pathogenesis, illustrating the disease’s position at the crossroads of immune dysregulation. Recognizing the diverse clinical expressions of SLE and its mimickers is critical for accurate diagnosis and targeted therapy. In conclusion, the immunological continuum model provides a comprehensive framework for understanding SLE, acknowledging its multifaceted nature and guiding future research and clinical practice toward more effective and individualized treatments. After the Mosaic of Autoimmunity, it is now the time to focus and attempt to solve the intricate mosaic of SLE.

PMID:39481623 | DOI:10.1016/j.autrev.2024.103675

Nanoscale Adv. 2024 Oct 18. doi: 10.1039/d4na00808a. Online ahead of print.

ABSTRACT

Statins, traditionally used for managing hyperlipidemia and cardiovascular diseases, have garnered significant interest for their potential anti-cancer properties. Research indicates that statins can inhibit critical processes in cancer development, such as apoptosis, angiogenesis, and metastasis. Despite their promising anti-cancer effects, the clinical application of statins in oncology has been hampered by their inherent low solubility and bioavailability. These pharmacokinetic challenges can be effectively addressed through the use of nano-based drug delivery systems. Nano-formulations enhance the delivery and therapeutic efficacy of statins by improving their solubility, stability, and targeting ability, thus maximizing their concentration within the tumor microenvironment and minimizing systemic side effects. This review delves into the potential of nanoparticles as carriers for statins in cancer therapy. It explores the mechanisms by which statins exert their anti-cancer effects, such as through the inhibition of the mevalonate pathway, modulation of immune responses, and induction of apoptosis. Furthermore, the review examines the development of various statin-loaded nano-formulations, highlighting their advantages over conventional formulations. The novelty of this review lies in its focus on recent advancements in nanoformulations that enhance statin delivery to the tumor microenvironment. By discussing the current advancements and prospects of statin nano-formulations, this review aims to provide a comprehensive understanding of how these innovative strategies can improve cancer treatment outcomes and enhance the quality of life for patients. The integration of nanotechnology with statin therapy offers a novel approach to overcoming existing therapeutic limitations and paving the way for more effective and safer cancer treatments.

PMID:39478996 | PMC:PMC11515941 | DOI:10.1039/d4na00808a

Iran J Child Neurol. 2024 Fall;18(4):33-45. doi: 10.22037/ijcn.v18i4.43749. Epub 2024 Sep 29.

ABSTRACT

OBJECTIVES: Acute Flaccid Paralysis (AFP) in children can stem from a diverse array of potential diagnoses.

MATERIALS & METHODS: This retrospective study sought to diagnose children referred to a referral pediatric emergency unit with AFP between 2011 and 2016. The study gathered clinical observations, conducted stool and cerebrospinal fluid analyses, and assessed electrophysiological and imaging data.

RESULTS: The present study enrolled 118 fully immunized children with a mean age of 6.09 ± 3.60 years. The most prevalent diagnoses included Guillain-Barré Syndrome (GBS-80 cases), acute viral myositis (20 cases), Transverse Myelitis Syndrome (TMS) (TMS-6 cases), and Vaccine-Associated Paralytic Poliomyelitis (VAPP) (VAPP-6 cases). All these six patients had primary immunodeficiency. Notably, all patients tested negative for poliovirus in stool analyses. This study encountered a unique case of a 2.5-month-old male patient who presented with acute limb motor weakness, along with fever, irritability, new-onset hypotonia, and generalized decreased deep tendon reflexes. Notably, no signs of upper motor neuron involvement were found. The Cerebrospinal Fluid (CSF) analysis was compatible with the diagnosis of viral meningitis. Moreover, among the 60 brain and spinal imaging series performed, five were indicative of GBS, six cases showed evidence of TMS, and one revealed a spinal mass. Besides, clinical investigations pointed toward acute viral myositis as a secondary etiology of AFP in 20 patients in this study.

CONCLUSION: In this hospital-based study, the most frequent diagnoses for children arriving at a third-level pediatric Emergency Room (ER) with acute flaccid paralysis AFP were GBS, acute viral myositis, TMS, and VAPP). These findings suggest a distinct pattern of AFP causes compared to those found in community-based epidemiological studies. Additionally, notably, unusual conditions, such as viral meningitis, can rarely present with AFP-like symptoms. Assessment for primary immune deficiency should be considered in cases of VAPP. Lastly, this research has implemented a pediatric AFP Management Protocol: A Local Practical Approach.

PMID:39478947 | PMC:PMC11520268 | DOI:10.22037/ijcn.v18i4.43749