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Scand J Immunol. 2024 Oct 30:e13418. doi: 10.1111/sji.13418. Online ahead of print.

ABSTRACT

Infants with congenital heart disease (CHD) often undergo thymectomy during corrective cardiac surgery (CCS). The long-term immunological effects remain controversial, with concerns regarding increased susceptibility to infections, allergies, autoimmunity due to compromised immune tolerance mechanisms. This study aims to elucidate the long-term immunological effects of early thymectomy. We enrolled 22 patients who underwent thymectomy in infancy and were followed up in the Pediatric Allergy and Immunology Clinic at Marmara University. We performed demographic characteristics and detailed immunological evaluation, including immunoglobulins, vaccine responses, lymphocyte subset analyses, upregulation, proliferation of T cells and T-cell receptor excision circles (TRECs). Sixteen patients had a history of infection, including six serious infections, all in the first year. Lymphopenia was observed in 27% of patients, with a significant decrease in naive CD4⁺ and recent thymic emigrant T cells counts and an increase in the proportion of memory T-cells, indicating premature immune senescence. Low levels of IgG, IgA and IgM were found in 36%, 40% and 22% of patients respectively. Vaccine responses were positive in 90% of patients. TREC levels were low in all 10 patients analysed. Seven of nine patients had normal proliferation. Twenty-two percent of patients had allergic disease, and autoimmunity was not observed. Early thymectomy leads to permanent immunological changes that are indicative of early immunosenescence. It is recommended to preserve thymic tissue during surgery and requires long-term follow-up in terms of findings such as allergy and autoimmunity as well as infections due to impaired immune tolerance mechanisms.

PMID:39474990 | DOI:10.1111/sji.13418

Sci Signal. 2024 Oct 29;17(860):eadl5100. doi: 10.1126/scisignal.adl5100. Epub 2024 Oct 29.

ABSTRACT

Both cell-intrinsic and niche-derived, cell-extrinsic cues drive the specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow, which comprise multipotent MPP1 cells and lineage-restricted MPP2, MPP3, and MPP4 subsets. Patients with WHIM syndrome, a rare congenital immunodeficiency caused by mutations that prevent desensitization of the chemokine receptor CXCR4, have an excess of myeloid cells in the bone marrow. Here, we investigated the effects of increased CXCR4 signaling on the localization and fate of MPPs. Knock-in mice bearing a WHIM syndrome-associated CXCR4 mutation (CXCR4¹⁰¹³) phenocopied the myeloid skewing of bone marrow in patients. Whereas MPP4 cells in wild-type mice differentiated into lymphoid cells, MPP4s in CXCR4¹⁰¹³ knock-in mice differentiated into myeloid cells. This myeloid rewiring of MPP4s in CXCR4¹⁰¹³ knock-in mice was associated with enhanced signaling mediated by the kinase mTOR and increased oxidative phosphorylation (OXPHOS). MPP4s also localized further from arterioles in the bone marrow of knock-in mice compared with wild-type mice, suggesting that the loss of extrinsic cues from the perivascular niche may also contribute to their myeloid skewing. Chronic treatment with the CXCR4 antagonist AMD3100 or the mTOR inhibitor rapamycin restored the lymphoid potential of MPP4s in knock-in mice. Thus, CXCR4 desensitization drives the lymphoid potential of MPP4 cells by dampening the mTOR-dependent metabolic changes that promote myeloid differentiation.

PMID:39471249 | DOI:10.1126/scisignal.adl5100

J Clin Immunol. 2024 Oct 28;45(1):34. doi: 10.1007/s10875-024-01810-w.

ABSTRACT

BACKGROUND: Patients with inborn errors of immunity (IEI) are susceptible to developing cancer due to defects in the immune system. The prevalence of cancer is higher in IEI patients compared to the immunocompetent population and cancers are considered as an important and common cause of death in IEI patients.

OBJECTIVES: To systematically review demographic, genetic and cancer-related data of IEI patients with a history of malignancy. Moreover, we performed a meta-analysis aiming to determine the frequency of cancer in patients with different types of IEI.

METHODS: We conducted electronic searches on Embase, Web of Science, PubMed, and Scopus (until September 2023) introducing terms related to IEI and cancer. Studies with human subjects with confirmed IEI who had developed at least one malignancy during their lifetime were included.

RESULTS: A total number of 4607 IEI patients with a cancer history were included in the present study. Common variable immunodeficiency (CVID) had the highest number of reported cases (1284 cases), mainly due to a higher relative proportion of patients with predominantly antibody deficiencies (PAD) and their increased life expectancy contributing to the higher detection and reporting of cancers among these patients. The most common malignancy was hematologic/blood cancers (3026 cases, mainly diffuse large B cell lymphoma). A total number of 1173 cases (55.6%) succumbed to cancer, with the highest rate of bone marrow failure (64.9%). Among the patients with monogenic defects in IEI-associated genes, the majority of cases had ATM deficiency (926 cases), but the highest cancer frequency rate belonged to NBS1 deficiency (50.5%). 1928 cases out of total 4607 eligible cases had detailed data to allow further statistical analysis that revealed BRCA2 deficiency had the earliest cancer development (~ 38 months), lowest cure frequency, and highest fatality rate (85%), while ATM deficiency had the lowest cure frequency and highest fatality rate (72%) among total cases reviewed with exclusion of Fanconi anemia.

CONCLUSION: The overall reported cancer frequency in the cases reviewed with and without exclusion of Fanconi anemia was 11.1% (95% confidence interval: 9.8-12.5%) and 12.0% (95% confidence interval: 10.6-13.5%), respectively. Our study revealed that the incidence of cancer is significantly dependent on the molecular and pathway defects in IEI patients, and individualized early screening and appropriate treatment, might improve the prognosis of these patients.

PMID:39466473 | DOI:10.1007/s10875-024-01810-w

Lung India. 2024 Nov 1;41(6):464-471. doi: 10.4103/lungindia.lungindia_332_24. Epub 2024 Oct 29.

ABSTRACT

Recurrent pulmonary infections starting from childhood often prompt evaluation for primary immunodeficiency disorders (PIDs). Hyper IgE syndrome (HIES) is a less common PID characterised by recurrent skin and pulmonary infections associated with elevated IgE levels. Staphylococcal infections are more commonly seen in these individuals, resulting in structural lung abnormalities such as pneumatoceles and bronchiectasis. The associated non-immunologic features (characteristic facies, retained primary dentition, scoliosis, osteopenia, and hyperextensible joints) should raise suspicion of this syndrome. We present four cases of HIES and review the pulmonary manifestations in this disease as reported in the Indian literature.

PMID:39465929 | DOI:10.4103/lungindia.lungindia_332_24

World J Clin Cases. 2024 Oct 26;12(30):6339-6345. doi: 10.12998/wjcc.v12.i30.6339.

ABSTRACT

In this editorial, we discuss the clinical implications of the article by Zhang et al. Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by excessive surfactant accumulation in the alveoli. It is classified into four categories: Primary, secondary, congenital, and unclassified forms. Primary PAP is caused by the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor signaling, which is necessary for the clearance of surfactant by alveolar macrophages. It is further divided into autoimmune PAP, caused by anti-GM-CSF antibodies blocking alveolar macrophage activation, and hereditary PAP, resulting from mutations in genes encoding GM-CSF receptors. Secondary PAP develops due to conditions affecting the number or function of alveolar macrophages, such as infections, immunodeficiency, hematological disorders, or exposure to inhaled toxins. Congenital PAP is linked to mutations in genes involved in surfactant protein production. Notably, the causes of PAP differ between children and adults. Diagnostic features include a characteristic “crazy-paving” pattern on high-resolution computed tomography, accompanied by diffuse ground-glass opacities and interlobular septal thickening. The presence of PAP can be identified by the milky appearance of bronchoalveolar lavage fluid and histological evaluation. However, these methods cannot definitively determine the cause of PAP. Whole lung lavage remains the standard treatment, often combined with specific therapies based on the underlying cause.

PMID:39464322 | PMC:PMC11438685 | DOI:10.12998/wjcc.v12.i30.6339

Swiss Med Wkly. 2024 Sep 9;154:3559. doi: 10.57187/s.3559.

ABSTRACT

Immunoglobulins for intravenous use (IVIgs) and subcutaneous use (SCIgs) can prevent recurrent and severe infections in patients with secondary antibody deficiencies that are frequently linked to haematological/oncological malignancies as well as other clinical conditions and their respective treatments. Even so, as IVIgs and SCIgs are costly and their supply is limited, their clinical use must be optimised. The aim of this position paper is to provide structured practical guidance on the optimal use of IVIgs and SCIgs in secondary antibody deficiencies, particularly in haematological and oncological practice. The authors agree that the occurrence of severe infections is a prerequisite for the use of IVIgs. Serum IgG levels in general as well as IgG subclass levels can be additional indicators of whether a patient could benefit from IVIgs. Responsiveness to vaccines can help to identify immunodeficiency. Patients with chronic lymphocytic leukaemia or multiple myeloma who are receiving respective treatment, especially B-cell depletion therapy, but also some patients with autoimmune diseases are prone to antibody deficiencies and need IVIgs. For the optimal use of IVIgs and to maximise their potential benefit, the indication must be individually assessed for each patient. As a primary treatment goal, the authors define a sufficient prophylaxis of severe infections, which can be supported by normalising IgG levels. If the initiated treatment is insufficient or linked to intolerable adverse reactions, switching the product within the class of IVIgs or changing to a different batch of the same product can be considered. Pausing treatment can also be considered if there are no infections, which happens more frequently in summer, but treatment needs to be resumed once infections return. These structured recommendations for IVIg treatment in patients with secondary antibody deficiency may provide guidance for clinical practice and therefore help to allocate IVIgs to those who will benefit the most, without overusing valuable resources.

PMID:39462479 | DOI:10.57187/s.3559

Life (Basel). 2024 Oct 18;14(10):1329. doi: 10.3390/life14101329.

ABSTRACT

Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders.

PMID:39459629 | DOI:10.3390/life14101329

Children (Basel). 2024 Oct 17;11(10):1251. doi: 10.3390/children11101251.

ABSTRACT

Background: The multisystemic features of Down syndrome (DS) in children are accompanied by immunodeficiency, making them susceptible to infections and immune dysregulation with autoimmune, allergic, inflammatory, and hematological complications. This study was aimed at a better understanding of the abnormalities within the B and T cell compartments and their correlations with clinical immunophenotypes. Methods: Medical records of 35 DS children were retrospectively reviewed, referring to clinical symptomatology including history of infections, immune dysregulation disorders, and humoral and cellular immune response. Results: While the etiology of respiratory tract infections included typical viral and bacterial pathogens, SARS-CoV2-induced inflammatory disease and syndromic immunodeficiency contributed significantly to the deterioration of the clinical course. Allergic diseases in the form of asthma, allergic rhinitis, and alimentary allergy were the most frequent manifestations of immune dysregulation and were followed by autoimmune disorders, such as Crohn’s disease, celiac disease, autoimmune thyroiditis, and alopecia, as well as inflammatory disorders, balanitis xerotica obliterans and lymphadenopathy, and a hematological disorder of myelopoiesis. Deficiency of serum immunoglobulin levels, reduced numbers of naïve B cells, and non-switched memory B cells along with low naïve T helper cells and significantly reduced regulatory T helper cells were the most prominent immune abnormalities. Conclusions: The loss of naïveté in B and T lymphocyte compartments with a deficiency of regulatory T cells may be underpinning pathomechanisms for the skewed immune response. The clinical immunophenotype in DS is complex and represents syndromic primary immunodeficiency with immune dysregulation.

PMID:39457216 | DOI:10.3390/children11101251

Biomolecules. 2024 Oct 14;14(10):1298. doi: 10.3390/biom14101298.

ABSTRACT

Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder, constituting approximately 2% of all clinical cases of angioedema, with a global prevalence estimated between 1 in 50,000 and 1 in 150,000 individuals. The condition affects individuals of all genders and ethnic backgrounds without significant variation. HAE is classified into three types. Type I HAE, which accounts for 85% of cases, is characterized by a deficiency of the C1 esterase inhibitor (C1-INH) gene. Type II HAE, making up 15% of cases, involves a dysfunctional C1-INH. Type III HAE, which represents about 5% to 10% of cases, is often estrogen-dependent and although several mutations have been identified, it typically involves normal C1-INH activity. Despite the differences in C1-INH functionality, all three types of HAE manifest with similar clinical symptoms. HAE leads to recurrent episodes of non-pruritic angioedema, which occurs in the absence of urticaria. Breakthroughs in understanding HAE pathophysiology have revolutionized treatment, leading to the development of highly targeted therapies for both acute management and long-term prevention. Meanwhile, cutting-edge advancements in omics technologies are unlocking new possibilities for biomarker discovery, paving the way for more precise diagnoses and personalized treatment strategies that could significantly enhance patient outcomes. This review will delve into the intricate pathophysiology, diverse clinical presentations, and diagnostic challenges of HAE while exploring emerging biomarkers and innovative approaches to therapeutic management and prevention strategies. Additionally, it will underscore the vital importance of screening family members of affected individuals, even when symptoms are not present.

PMID:39456231 | DOI:10.3390/biom14101298

Biomolecules. 2024 Oct 8;14(10):1264. doi: 10.3390/biom14101264.

ABSTRACT

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder characterized by immunodeficiency, progressive cerebellar ataxia, and an increased malignancy risk. Cells derived from individuals with AT show multiple defects, including high oxidant and ionizing radiation sensitivities, poor DNA repair, low iron-sulfur cluster levels, and low reduced glutathione. The clinical course of AT is progressive and unrelenting, with most individuals having a survival time of approximately twenty-five years. Presently, AT has no effective treatments, and most patients receive supportive care only. Recently, pioglitazone, a thiazolidinedione class used to treat type 2 diabetes, has been demonstrated to exert beneficial effects on AT cells and on diabetic individuals with AT. Here, I will discuss the possible molecular mechanisms of pioglitazone’s favorable effects on the AT phenotype and why it may have utility in treating some aspects of AT.

PMID:39456197 | DOI:10.3390/biom14101264