Immune Defects Research Articles

Genomic profiling at a single center cracks the code in inborn errors of immunity.

Inborn errors of immunity (IEI) entail a diverse group of disorders resulting from hereditary or de novo mutations in single genes, leading to immune dysregulation. This study explores the clinical utility of next-generation sequencing (NGS) techniques in diagnosing monogenic immune defects. Eight patients attending the immunodeficiency clinic and with unclassified antibody deficiency were included in the analysis. Clinical records, immune characteristics, and family histories were reviewed, and a target gene panel (TGP) sequencing was performed to identify pathogenic variants. TGPs identified seven variants in TNFRSF13B (TACI), CARMIL2, STAT1, STAT3, and ORAI1 genes. These findings provided definitive diagnoses and proper prognostic assessment. Patients exhibited a wide range of clinical manifestations, including recurrent infections, autoimmune cytopenias, and organ-specific complications. The genetic diversity observed highlights the importance of genetic testing in diagnosing IEIs and tailoring treatments. This study underscores the role of TGPs in diagnosing IEIs, revealing significant genetic heterogeneity and phenotypic variability. They offer a precise tool for identifying underlying genetic defects, facilitating personalized medicine approaches, and eventually improving patient outcomes. The findings emphasize the need for comprehensive genetic testing to uncover novel pathogenic variants, enhancing our understanding of immune system dysfunction. NGS is a critical tool for the management of IEI, enabling precise diagnosis and personalized treatment strategies. Despite resource limitations, the progressive affordability is likely to expand its clinical utility, ultimately improving patient care and advancing the field of immunology. In the meantime, accurate phenotypic assessment is essential for resource optimization and case prioritization.

P0984 Treatment with allopurinol and low-dose azathioprine during pregnancy in patients with Inflammatory Bowel Disease. A Danish single center experience

Abstract Background Low-dose azathioprine in combination with allopurinol (LD-AZA/ALLO) is a widely used treatment option in inflammatory bowel disease (IBD). Data on pregnancy and birth outcomes from exposure to combination therapy are sparse. The aim of this study was to provide data on safety and risk for adverse pregnancy and birth outcomes in women with IBD treated with LD-AZA/ALLO at the Gastrounit, Hvidovre Hospital, Copenhagen. Methods The study was a retrospective single center study. Inclusion criteria were established IBD diagnosis and treatment with LD-AZA/ALLO (AZA 50-75 mg/ ALLO 100 mg) during conception and pregnancy between 2013-2023. Data was collected from electronic medical charts and by questionnaire to all included women. Data registered was; demographics, diagnosis, disease characteristics, disease activity, IBD medications and number of pregnancies. Pregnancy outcomes were neonatal characteristics, obstetric complications, lactation and congenital malformations, disease, infections and admission to the hospital during the first year of life. Results In all, 44 women with 62 pregnancies (one twin pregnancy) and 59 live births were included. There were 1 spontaneous and 3 provoked abortions due to genetic disorders (1 trisomy 21 and 2 spinocerebellar ataxia). Obstetric complications were present in 8 (13%) pregnancies, (1 pre-eclampsia, 1 HELLP syndrome, 6 hypertension and/or gestational diabetes mellitus). 7 (11%) women had an IBD flare during pregnancy, none resulting in obstetrical complications. 5 (9 %) children were born prematurely, 4 (7 %) had low birth weight. No congenital malformations were reported. One child was born with facial nerve paralysis and later diagnosed with hyper-IgD syndrome. 8 (14 %) were admitted to neonatal ward (hours to days), mainly due to immature lungs. During the first year of life, one child was admitted to the hospital due to COVID. One child was suspected to have an immune defect, but all symptoms and biochemical abnormalities resolved and interpreted as side effect to LD-AZA/ALLO. 5 children (9%) were treated with antibiotics due to minor infections. In total 84 % of the children were breastfed during LD-AZA/ALLO treatment. Conclusion In this large single center experience with 62 pregnancies in women treated with LD- AZA/ALLO, no malformations or indications of increased risk of complications of pregnancy and birth were observed. The majority of children were breastfed and no serious signals or complications were reported first year of life. Treatment with LD-AZA/ALLO during pregnancy and breastfeeding seems safe.

Functional validation of a novel STAT3 'variant of unknown significance' identifies a new case of STAT3 GOF syndrome and reveals broad immune cell defects.

Signal transducer and activator of transcription 3 (STAT3) orchestrates crucial immune responses through its pleiotropic functions as a transcription factor. Patients with germline monoallelic dominant negative or hypermorphic STAT3 variants, who present with immunodeficiency and/or immune dysregulation, have revealed the importance of balanced STAT3 signaling in lymphocyte differentiation and function, and immune homeostasis. Here, we report a novel missense variant of unknown significance in the DNA-binding domain of STAT3 in a patient who experienced hypogammaglobulinemia, lymphadenopathy, hepatosplenomegaly, immune thrombocytopenia, eczema, and enteropathy over a 35-year period. In vitro demonstration of prolonged STAT3 activation due to delayed dephosphorylation, and enhanced transcriptional activity, confirmed this to be a novel pathogenic STAT3 gain-of-function variant. Peripheral blood lymphocytes from this patient, and patients with confirmed STAT3 Gain-of-function Syndrome, were collected to investigate mechanisms of disease pathogenesis. B cell dysregulation was evidenced by a loss of class-switched memory B cells and a significantly expanded CD19hiCD21lo B cell population, likely influenced by a skewed CXCR3+ TFH population. Interestingly, unlike STAT3 dominant negative variants, cytokine secretion by activated peripheral blood STAT3 GOF CD4+ T cells and frequencies of Treg cells were intact, suggesting CD4+ T cell dysregulation likely occurs at sites of disease rather than the periphery. This study provides an in-depth case study in confirming a STAT3 gain-of-function variant and identifies lymphocyte dysregulation in the peripheral blood of patients with STAT3 gain-of-function syndrome. Identifying cellular biomarkers of disease provides a flow cytometric-based screen to guide validation of additional novel STAT3 gain-of-function variants as well as provide insights into putative mechanisms of disease pathogenesis.

Effects of quantum dot zinc oxide, nano zinc oxide and zinc oxide on genes expression and aflatoxine production due to Aspergillus flavus ATCC50041

Aflatoxin, which is mainly produced by Aspergillus flavus and Aspergillus parasiticus, is a severe problem and threat in the fields of medicine and agriculture and is classified as the first class human carcinogen due to its carcinogenic, mutagenic, teratogenic, hepatotoxicity, and immune system defects. This toxin contaminates many agricultural products around the world. Considering the high toxicity of aflatoxin and the destructive effects of this metabolite, achieving low-risk and cost-effective methods to control toxin production is of great importance. In this study, the effects of different concentrations of quantum dot zinc oxide, nano zinc oxide, and zinc oxide on the expression of important key genes (aflR, aflP, aflM, aflD) in the gene cluster of aflatoxin production and also the amount of aflatoxin production (B1, B2) in Aspergillus flavus was studied. The fungus was cultured in different concentrations of quantum dot zinc oxide, nano zinc oxide, and zinc oxide (2000, 4000, 6000 ppm) for 3 days at 30 ◦C. The results showed that quantum dot zinc oxide significantly reduced toxin production and gene expression compared to other groups, in which the concentration of aflatoxin was decreased by increasing quantum dot zinc oxide. Regarding the obtained results, nano zinc oxide was effective just at 6000 ppm, and zinc oxide is suggested because nano zinc oxide and zinc oxide cannot completely dissolve in water. Hence, nano zinc oxide and zinc oxide showed weak activity in reducing aflatoxin concentration. All three agents under study significantly caused low gene expression, but quantum-dot zinc oxide showed more activity than the others. The formulation of highly active quantum dot zinc oxide to reduce aflatoxin may be a potential feed additive for the future management of mycotoxins.

Dissolving microneedle patch loaded with adipokines-enriched adipose extract relieves atopic dermatitis in mouse via modulating immune disorders, microbiota imbalance, and skin barrier defects

Atopic dermatitis (AD) is a chronic relapsing dermatosis that demands new therapies. This research group previously developed a physically extracted adipose-derived extracellular matrix named adipose collagen fragments (ACF), which was determined containing massive adipose matrix-bound adipokines and medicable on AD through intradermal injection. However, problems concerning the control of drug release and inevitable pain caused by injection hinder the application of ACF in clinics. Microneedle (MN) is a rapid developing technique for precise and painless transdermal drug delivery. Therefore, a dissolving methacrylated gelatin/hyaluronic acid MN patch loaded with ACF was developed in this study. The morphological characteristics, mechanical properties, penetration ability, as well as biocompatibility and degradation efficiency of ACF-MN were evaluated, and its efficacy on ovalbumin-induced AD mice was also investigated. ACF-MN exhibited excellent penetration ability, biocompatibility, degradation efficiency, and satisfying efficacy on murine AD similar with fresh-made ACF. Furthermore, RNA-Seq combining bioinformatics were performed for mechanism exploration. ACF treatment showed a comprehensive efficacy on AD via restoring inflammatory dysregulation, microbiota imbalance, and skin barrier defects. This study offered a novel MN-based ACF-bound adipokines transdermal delivery system that may serve as a promising strategy for relieving AD.

A Rare Cause of Acute Kidney Injury in Previously Healthy Person: Mucormycosis

Abstract Opportunistic infections due to fungi are common in immunocompromised patients due to cell mediated immune dysfunction, humoral immunity defects, phagocytic defects and complement disorders.However,rarly these infections can affect previously healthy individuals as well.High index of suspicion is necessary for eary diagnosis and successful outcomes.We describe a case of previously healthy young male, who presented with acute kidney injury and was diagnosed to have disseminated abdominal mucormycosis involving kidneys.

Primary Antibody Deficiencies: Curation Of Gene-Disease Relationships Using A ClinGen Validation Framework.

The Clinical Genome Resource (ClinGen) is an international collaborative effort between scientists and clinicians, diagnostic and research laboratories as well as the patient community. Using a standardized framework, ClinGen has established guidelines to classify gene-disease relationships as Definitive, Strong, Moderate, and Limited based on available scientific and clinical evidence. When the genetic and functional evidence for a gene-disease relationship has conflicting interpretations or contradictory evidence, they can be Disputed or Refuted. The ClinGen Antibody Deficiencies Gene Curation Expert Panel (AD-GCEP), using the ClinGen framework, has classified genes related to Primary Antibody Deficiencies (PAD) that primarily affect B cell development and/or function and accounts for the largest proportion of Inborn Errors of Immunity (IEI) or Primary Immunodeficiencies (PIDs). The AD-GCEP curated a total of 65 genes associated with humoral immune defects to validate 74 gene-disease relationships. Of these, 40 gene-disease relationships were classified as Definitive, 1 as Strong, 16 as Moderate, 15 as Limited, and two as Disputed. The curation process involved the review of 490 patient records and 3,546 associated Human Phenotype Ontology (HPO) entries. The most frequently observed HPO terms related to PAD was decreased circulating antibody (Ab) level, pneumonia and lymphadenopathy. These curations represent the first effort by the Immunology Clinical Domain Working Group (CDWG) of ClinGen to provide a comprehensive genetic and phenotypic revision of genetic disorders affecting humoral immunity, and these were reviewed and approved by experts in the field. The curations are publicly available at www.clinicalgenome.org.

GATA2 deficiency: a long way to diagnosis (case report)

GATA2 deficiency is a form of inborn errors of immunity (or primary immunodeficiencies) with a wide range of symptoms. According to the international classification of primary immunodeficiency diseases it is classified as congenital defects of phagocyte number, function, or both. Heterozygous mutations in the GATA2 gene cause syndromes reported in the literature as dendritic cell, monocyte, B and NK lymphoid deficiency, MonoMAC syndrome (monocytopenia and mycobacterial infection), familial myelodysplastic syndrome, and Emberger syndrome (the combination of myelodysplasia and congenital lymphedema). Here we present a literature review on GATA2 deficiency and report a clinical case of an adult woman with the abovementioned immune defect, the results of laboratory and instrumental examinations, therapy, and outcome. The patient’s condition was complicated by lymphedema, myelodysplastic syndrome, endometrial carcinoma in situ, nonspecific pulmonary lesion, recurrent miscarriage, and rheumatic conditions (erythema nodosum). The mentioned diversity of clinical manifestations is a reason for long diagnostic search, as well as difficulties in diagnosis and selection of optimal treatment tactics.

Диагностика врожденных дефектов иммунитета в многопрофильном стационаре: обзор клинических наблюдений

Inborn errors of immunity (IEI) are rare heterogeneous diseases with a wide range of clinical manifestations that makes its diagnosis difficult for practitioners of different specialties. The purpose of this research was to describe a series of clinical case reports of primary immunodeficiencies (PIDs) diagnosis using the TREC/KREC assay in a multidisciplinary hospital. In order to verify the diagnosis, TREC/KREC determination, immunophenotyping and molecular genetic studies were performed. Thirty-nine patients with alarming signs of PIDs were examined within a period of 18 months. Primary immunodeficiencies were identified in 6 (31.6%) children with congenital malformations, in 5 (50%) with resistant cytopenias and in 3 (30%) with severe infections. Syndromal IDs were diagnosed in 8 (57.1%), combined immunodeficiency in a single patient (7.1%), immune regulation defects in 2 (14.3%) and antibody formation disorders in 3 (21.5%). Abnormal TREC/KREC values were established in 9 (64.3%) patients with IEI at the early stages of diagnostic search. Thus, TREC/KREC assay is an effective method for IEI diagnosis within a multidisciplinary hospital.

Методические рекомендации по маршрутизации, мониторингу и тактике ведения иммунокомпрометированных детей групп риска и пациентов с врожденными ошибками иммунитета [Рецензенты: О.В. Зайцева, Н.И. Захарова, О.В. Калюжин. Утверждены в качестве методических рекомендаций Учебно-методической комиссией ФГБУЗ МО НИКИ Детства МЗ МО. Протокол № 8 от 20.11.2024 г.

A.P. Prodeus, N.D. Odinayeva, S.V. Voronin, I.N. Zakharova, I.A. Tuzankina, N.N. Volodin, K.V. Zhdanov, A.N. Pampura, D.I. Sadykova, E.I. Kondratyeva, A.A. Korsunskiy, E.A. Degtyareva, K.V. Savostyanov, S.A. Trusova, A.Yu. Lobenskaya, Ye.S. Nikonova, A.S. Lebedeva, E.V. Loshkova, V.D. Denisova, A.G. Rumyantsev. Guidelines for routing, monitoring and management tactics of immunocompromised children at risk and patients with congenital immune defects. Pediatria n.a. G.N. Speransky. 2024; 103 (6): 218-245. DOI: 10.24110/0031-403X-2024-103-6-218-245. [Reviewed by Drs. O.V. Zaytseva, N.I. Zakharova and O.V. Kalyuzhin. Approved as official Guidelines for Practitioners by the Educational and Methodological Commission of the Research and Clinical Institute of Childhood with the Moscow Oblast Healthcare Ministry (Mytishchi, Moscow Oblast, Russia), Record No. 8 dated Nov. 11, 2024]

A case of severe folliculitis decalvans

Folliculitis decalvans is a difficult to treat rare neutrophilic dermatosis that affects the scalp and leads to permanent scarring. The pathogenesis is currently not well understood; the influence of Staphylococcus aureus antigens, a disorder of the skin microbiome, a defect in cell-mediated immunity, and an imbalance of pro-inflammatory cytokines are assumed. This disease is often associated with a marked decrease in quality of life, because in addition to significant external manifestations, the patient may experience pain, itching and burning in the areas of the rash. The main problem is that there is currently no effective therapy for this disease. Treatment options include systemic antibiotics, topical and intralesional corticosteroids, dapsone, isotretinoin, biologics, and photodynamic therapy. Administration of radiation therapy, adipose tissue transplantation, use of excimer laser, and intravenous injections of human immunoglobulin have also been reported. Decalving folliculitis is a disease that requires the earliest possible diagnosis, as its outcome is persistent scarring atrophy of the hair follicle, marked discomfort of the patient, constant sensation of soreness and burning. It is necessary to use the most effective therapy, change the treatment strategy if the disease continues to progress. We present a brief overview of the main methods of therapy and a clinical case of a long course of severe folliculitis decalvans, refractory to the main methods of treatment.

Evaluation of Vaccines and Therapeutics Against Ebolaviruses in the Domestic Ferret.

Filoviruses, including Ebola and Marburg viruses, have caused periodic outbreaks of severe hemorrhagic disease in humans and nonhuman primates (NHP), resulting in major public health emergencies primarily in endemic areas. Filovirus disease has also been exported to developed nations, where it has been equally disruptive. There are four ebolaviruses (Ebola virus, Sudan virus, Bundibugyo virus, and Taï Forest virus) and two marburgviruses [Marburg virus (MARV) and Ravn virus] known to cause disease in humans, yet vaccines and therapeutics have only been approved for Ebola virus. NHPs have long served as the "gold standard" for medical countermeasure (MCM) evaluation and will most likely be required for regulatory approval for use in humans. However, screening and refinement of MCM dosing regimens are more efficiently and ethically performed in lower-order species such as rodents. However, mouse, hamster, and guinea pig models of filovirus infection require virus adaptation to cause disease in these animal models. Nonadapted filovirus strains can be used in immune-compromised rodent systems (genetic knockouts or humanized mice), but the immune defect must be accounted for when interpreting MCM efficacy. Recently, several groups have described the use of the domestic ferret (Mustela putorius furo) as a model for several ebolaviruses using wild-type (nonadapted) virus, with disease largely reflecting what has been observed in humans and NHPs. Interestingly, no disease has been observed in ferrets challenged with MARV. Here, we describe the use of the domestic ferret for vaccine and therapeutic evaluation against ebolaviruses.

Nijmegen breakage Syndrome - how much do we know about this rare condition of Slavs? - disease overview

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive defect of immunity, characterised by chromosomal instability and radiation sensitivity with a high predisposition to malignancy. The clinical manifestations of this condition include microcephaly, combined immunodeficiency, growth retardation and a range of additional abnormalities, including facial, skeletal and skin anomalies (such as café au lait spots and vitiligo). It is estimated that 40% of patients will develop cancer before reaching the age of 21 years. [1-2] The aetiology of this syndrome can be attributed to a mutation in the NBS1 gene, which is localised on chromosome 8q21 and is responsible for the production of the protein nibrin. [3] The most common mutation responsible for NBS (c.657_661del5) is consistent with a founder effect, with the majority of registered patients originating from Central and Eastern Europe and the largest cohort diagnosed in Poland. [4] This article provides an overview of Nijmegen breakage syndrome (NBS), including epidemiology, symptoms, diagnostic pathway and patient management, as well as treatment options. The objective of this study is to enhance awareness of this condition in order facilitate an early diagnosis and screening for malignancy in patients.

Genetic defects of brain immunity in childhood herpes simplex encephalitis.

Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in humans. It is life-threatening and has a first peak of incidence in childhood, during primary infection. Children with HSE are not particularly prone to other infections, including HSV-1 infections of tissues other than the brain. About 8-10% of childhood cases are due to monogenic inborn errors of 19 genes, two-thirds of which are recessive, and most of which display incomplete clinical penetrance. Childhood HSE can therefore be sporadic but genetic, enabling new diagnostic and therapeutic approaches. In this Review, we examine essential cellular and molecular mechanisms of cell-intrinsic antiviral immunity in the brain that are disrupted in individuals with HSE. These mechanisms include both known (such as mutations in the TLR3 pathway) and previously unknown (such as the TMEFF1 restriction factor) antiviral pathways, which may be dependent (for example, IFNAR1) or independent (for example, through RIPK3) of type I interferons. They operate in cortical or brainstem neurons, and underlie forebrain and brainstem infections, respectively. Conversely, the most severe inborn errors of leukocytes, including a complete lack of myeloid and/or lymphoid blood cells, do not underlie HSE. Thus congenital defects in intrinsic immunity in brain-resident neurons that underlie HSE broaden natural host defences against HSV-1 from the leukocytes of the immune system to other cells in the organism.

Outcomes of X-Linked Agammaglobulinaemia Patients.

X-linked agammaglobulinaemia (XLA), caused by mutations in BTK, is characterised by low or absent peripheral CD19 + B lymphocytes and agammaglobulinaemia. The mainstay of treatment consists of immunoglobulin replacement therapy (IgRT). As this cannot fully compensate for the immune defects in XLA, patients may therefore continue to be at risk of complications. To describe the clinical outcomes of XLA patients in the United Kingdom and Hong Kong and evaluate current treatment strategies. Patients with a definitive diagnosis of XLA were included in this cross-sectional and retrospective analysis of clinical health outcomes. Data pertaining to diagnosis, infection incidence, IgG trough levels and lung function were collected and analysed. 99 patients with a median age of 29.02 years (IQR 12.83-37.41) and a total follow up of 1922 patient years, were included this study. The median age at diagnosis was 3.30 years (IQR 1.04-8.38) which decreased over time (p = 0.004). 40% of the cohort had radiological evidence of bronchiectasis. Risk of bronchiectasis was not significantly associated with clinical infection incidence (p = 0.880) or IgG trough levels (p = 0.407). Two patients demonstrated novel complications, namely persistent norovirus infection, leading to haemopoietic stem cell transplantation (HSCT). Despite modern therapy, most XLA patients continue to experience complications, most notably bronchiectasis, likely due to absence of IgA/M in current therapies, but lack of B lymphocytes may also lead to additional sequalae. These data strongly support the need for further research, particularly that of curative modalities including HSCT and gene therapy.

The danger theory of immunity revisited.

The danger theory of immunity, introduced by Polly Matzinger in 1994, posits that tissue stress, damage or infection has a decisive role in determining immune responses. Since then, a growing body of evidence has supported the idea that the capacity to elicit cognate immune responses (immunogenicity) relies on the combination of antigenicity (the ability to be recognized by T cell receptors or antibodies) and adjuvanticity (additional signals arising owing to tissue damage). Here, we discuss the molecular foundations of the danger theory while focusing on immunologically relevant damage-associated molecular patterns, microorganism-associated molecular patterns, andneuroendocrine stress-associated immunomodulatory molecules, as well as on their receptors. We critically evaluate patient-relevant evidence, examining how cancer cells and pathogenic viruses suppress damage-associated molecular patterns to evade immune recognition, how intestinal dysbiosis can reduce immunostimulatory microorganism-associated molecular patterns and compromise immune responses, and which hereditary immune defects support the validity of the danger theory. Furthermore, we incorporate the danger hypothesis into a close-to-fail-safe hierarchy of immunological tolerance mechanisms that also involve the clonal deletion and inactivation of immune cells.

Current Practice and Perspectives on Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Antibody Deficiency Among Specialized Nurses in Poland.

Inborn errors of immunity (IEI) encompass various congenital disorders, resulting in immunity defects and recurrent infections. Home-based subcutaneous immunoglobulin replacement therapy (scIgRT) is the best treatment option for those with primary antibody deficiency (PAD). However, the lack of standardized procedures in patient training remains a challenge. Our study investigates nurses' practice and perspectives, aiming to identify areas for improvement in at-home scIgRT practice. We prepared a structured survey regarding scIgRT, including needle choice experience and perception of adverse events, and distributed it among qualified nurses involved in patient training and scIgRT supervising. We included 56 nurses with a median age of 50 years. Among them, 67.9% represented adult care providers, while 32.1% supervised IgRT in children. Most respondents (83.9%) used the classic or assisted with hyaluronidase scIgRT preparations. Single-channel needles were administered most commonly (85.7%). The needle length was mostly chosen solely by a nurse (57.1%) or in cooperation with the patient (23.2%). Next, 9 mm and 12 mm needles were used most often (92.9% and 78.6%, respectively). As expected, the 6 mm needle was more frequently applied for children compared to adults (n = 16, 88.9% vs. n = 11, 28.9%, p < 0.001), while 12 mm was primarily used in adults (n = 35, 92.1% vs. n = 9, 50.0%, p < 0.001). Visual skin fold assessment was the basis for the needle selection (58.9%), followed by the injection site rule (26.8%) or a choice between two available needle types for thinner or thicker patients (25.0%). Results of this survey indicate that, according to nurses' opinions presented in this survey, the needle length could be associated with local scIgRT adverse events, such as side needle leakage or local burning. Yet, it was likely unrelated to general adverse signs, such as headaches or dizziness. Most respondents (66.1%) indicated that, even if local adverse events occur, patients are reluctant to change scIgRT preparation or needle length. Most participants (69.6%) reported that the optimal administration technique needs to be discussed with the patient before and during scIgRT. This study sheds light on scIgRT practice in Poland, emphasizing deficiency in needle selection technique. Future research should focus on standardized training and advanced needle selection procedures on patient outcomes, investigating the correlation between needle strategies and adverse events, as well as the effectiveness of scIgRT.

Normalization of Cystic Fibrosis Immune System Reverses Intestinal Neutrophilic Inflammation and Significantly Improves the Survival of Cystic Fibrosis Mice

Cystic fibrosis (CF) is an autosomal recessive genetic disorder, affecting multiple organ systems. CF intestinal disease develops early, manifesting as intestinal bacterial overgrowth/dysbiosis, neutrophilic inflammation, and obstruction. As unresolvable infection and inflammation reflect host immune deficiency, we sought to determine if the CF-affected immune system plays any significant role in CF intestinal disease pathogenesis. CF and sibling wild-type (WT) mice underwent reciprocal bone marrow transplantation. After immune reconstitution, their mortality, intestinal transit, fecal inflammatory markers, and mucosal immune cell composition were assessed. Moreover, reciprocal neutrophil transfusion was conducted to determine if neutrophil function affects intestinal movement. Furthermore, expression of induced nitric oxide synthase (iNOS) and production of nitric oxide (NO) in CF and WT neutrophils were compared. Lastly, specific iNOS inhibitor 1400W was tested to prevent CF intestinal obstruction. Immune restoration in CF mice reversed the intestinal neutrophilic inflammation, improved the intestinal dysmotility, and rescued the mice from mortality. Transfusion of WT neutrophils into CF mice ameliorated the retarded bowel movement. CF neutrophils expressed significantly more iNOS and produced significantly more NO. Pharmaceutical blocking of iNOS significantly improved intestinal transit and survival of CF mice. CF immune defect plays a critical role in CF intestinal disease development. Activation of iNOS in inflammatory cells produces excessive NO, slows the bowel movement, and facilitates intestinal paralysis and obstruction in CF. Thus, normalization of the CF immune system may offer a novel therapy to treat CF intestinal disease.

Gastrointestinal germinal center B cell depletion and reduction in IgA+ plasma cells in HIV-1 infection.

Gastrointestinal (GI) B cells and plasma cells (PCs) are critical to mucosal homeostasis and the host response to HIV-1 infection. Here, high-resolution mapping of human B cells and PCs sampled from the colon and ileum during both viremic and suppressed HIV-1 infection identified a reduction in germinal center (GC) B cells and follicular dendritic cells (FDCs) during HIV-1 viremia. Immunoglobulin A-positive (IgA+) PCs are the major cellular output of intestinal GCs and were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling, persisted in antiretroviral therapy (ART)-treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations were associated with changes in the intestinal microbiome composition and systemic inflammation. These findings highlight a key immune defect in the GI mucosa due to HIV-1 viremia.

The role of lipids in regulating macrophage antifungal immunity.

Macrophages are critical components of the antifungal immune response. Disturbance in the number or function of these innate immune cells can significantly increase susceptibility to invasive fungal infections. Pathogenic fungi cause billions of infections every year and have an unmet clinical need, with many infections associated with unacceptably high mortality rates that primarily affect vulnerable patients with underlying immune defects. Lipid metabolism has been increasingly appreciated to significantly influence macrophage function, particularly of macrophages residing in lipid-rich organs, such as the brain, or macrophages specialized at clearing dead cells including alveolar macrophages in the lungs. In this review, we provide an overview of macrophage lipid metabolism, and discuss how lipid recycling and dysregulation affect key macrophage functions relevant for antifungal immunity including phagocytosis, functional polarization, and inflammasome activation. We focus on the fungal pathogen Cryptococcus neoformans, as this is the most common cause of death from fungal infection in humans and because several lines of evidence have already linked lipid metabolism in the regulation of C. neoformans and macrophage interactions.