Detection of Anti-IFNγ Autoantibodies From Dried Blood Spots.

Background: High titer, neutralizing anti-cytokine autoantibodies (ACAA) to interferon gamma (IFNγ) are an emerging cause of adult-onset immunodeficiency, and detection can direct clinical management. Currently, the detection of ACAAs is performed on blood or plasma, which is time-sensitive, relatively expensive to obtain, and must be shipped from remote locations in specialized containers. We have adapted an easier method of collecting blood or plasma onto a paper card as dried blood spots (DBS), which is simple, inexpensive, and does not require a medical facility or special mailing.

Neutralizing GM-CSF autoantibodies impair neutrophil antifungal effector function in a patient with aspergillosis.

Objectives: To present a putatively immunocompetent patient with locally invasive aspergillosis and neutralizing autoantibodies (Aabs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) and to characterize GM-CSF Aab-mediated impairments in neutrophil anti-Aspergillus effector function.

Methods: Imaging studies and histological analyses of infected tissue were employed to diagnose sino-orbital aspergillosis and monitor antifungal treatment responses. Whole genome sequencing (WGS), dihydrorhodamine testing, and particle-based Aab detection were employed to assess for the underlying etiology of fungal disease.

Prevalence and functional characterization of anti-interferon autoantibodies in inflammatory myopathies.

Objectives: Functional autoantibodies targeting interferons (IFNs) can lead to immunodeficiency and have been implicated in various autoimmune diseases. Despite the critical role of interferons in myositis pathogenesis, the significance of anti-IFN autoantibodies in inflammatory myopathies remains poorly understood. This study aimed to investigate the prevalence and functional impact of anti-IFN autoantibodies in patients with myositis.

Macroevolution: Marine biomass and biodiversity through deep time.

It has long been suspected that biomass and global marine biodiversity should be closely linked over the last half billion years, but historic biomass data have been lacking. A new study, compiling an innovative first-ever biomass dataset through deep time, confirms that long-suspected link.

Further Personalizing Medicine in Immune Disorders: Genomic Findings and Hematopoietic Cell Transplantation Survival.

Background: Hematopoietic cell transplantation (HCT) provides effective long-term management for some inborn errors of immunity. Genetic findings can inform donor selection, considerations in conditioning intensity and agents, and graft-versus-host disease prophylaxis. Exome/genome sequencing is increasingly accessible but of uncertain clinical utility.

Restoration of the human skin microbiome following immune recovery after hematopoietic stem cell transplantation.

The human skin microbiome is intricately intertwined with host immunity. While studies have elucidated microbial influences on immunity, understanding how immune alterations modulate this equilibrium remains limited. We investigated the dual impact of immune deficiency and hematopoietic stem cell transplantation (HSCT) on the skin microbiome in 24 patients with dedicator of cytokinesis 8 (DOCK8) deficiency, a rare inborn error of immunity.

Factors associated with and kinetics of anti-IFN-α autoantibodies in deficiency.

Background: Autoantibodies against IFN-α (anti-IFN-α) have been reported in recombinase activating gene (RAG) deficiency, attributed to impaired central and peripheral T-cell/B-cell tolerance. However, the clinical features, especially viral infections, associated with these autoantibodies at baseline, their kinetics over time, and their response to hematopoietic cell transplantation are not well defined.

Objective: We described the clinical and immunologic findings linked to anti-IFN-α IgG in RAG deficiency and tracked its kinetics longitudinally, including in those who underwent hematopoietic cell transplantation.

Unusual Presentation of Thigh Mass: A Case Report.

is a rapidly growing non- (NTM) primarily associated with pulmonary infections, particularly in individuals with underlying lung conditions. While soft tissue infections are less common, their incidence has been increasing. These infections are challenging to treat due to inherent resistance to many antibiotics obtained through spontaneous mutation as well as physical characteristics of the microbes.

A novel frameshift mutation in Phosphoinositide 3-kinase regulatory subunit 1 () causes immunodeficiency and Amyotrophic Lateral Sclerosis (ALS).

Mutations in , a regulatory subunit of Class I PI3K, are implicated in immune disorders and neurological conditions. We identified a novel heterozygous pathogenic frameshift mutation (c.1710dup) in in a patient with common variable immunodeficiency who developed slowly progressive Amyotrophic Lateral Sclerosis.

Olorofim for the treatment of invasive fungal diseases in patients with few or no therapeutic options: a single-arm, open-label, phase 2b study.

Background: Only a small number of antifungal therapies for invasive fungal disease (IFD) are currently available, and many pathogens are resistant to one or more of these therapies. Olorofim, the first orotomide antifungal agent to be developed, is active against fungi that are resistant to registered therapies. It impairs fungal pyrimidine biosynthesis, leading to cell death.

Novel C5α-substituted carbapenems enhance killing via selective target binding and reduced hydrolysis by Bla.

() poses significant clinical challenges and underscores the urgent need for safer and more effective treatments, including β-lactams. Among currently available carbapenems, imipenem is widely used to treat infections by combining with other antibiotics. Commercial carbapenems share a common scaffold with C2 modifications, whereas this study focuses on novel carbapenem candidates with C5α modifications.

Interferon-γ therapy in patients with refractory disseminated coccidioidomycosis.

Refractory disseminated coccidioidomycosis (DCM) is a severe disease with limited treatment options. This report reviews our own and prior published experiences using adjunctive interferon-γ therapy in refractory DCM, showing overall favorable responses in patients without Signal Transducer and Activator of Transcription 1 gain-of-function mutations.

Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. Clemastine fumarate, the over-the-counter antihistamine and muscarinic receptor blocker, has remyelinating potential in MS. A clemastine arm was added to an ongoing platform clinical trial, targeting residual activity by precision, biomarker-guided combination therapies of multiple sclerosis (TRAP-MS) (ClinicalTrials.

Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency.

Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature.

Genotype-specific immune responses at the intestinal barrier predispose to colitis in mouse models of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inborn error of immunity that is caused by defects in any 1 of the 5 subunits (gp91phox, p47phox, p22phox, p67phox, p40phox) that form the NAD phosphate oxidase complex 2 (NOX2) or in the chaperone protein essential for reactive oxygen species (ROS) that supports its assembly. These defects lead to severely reduced phagocyte-derived ROS production. Almost 50% of patients with CGD have inflammatory bowel disease (IBD) associated with dysbiosis, and the age of IBD onset may vary according to the CGD genotype.

IRF2BP2 deficiency: An important form of common variable immunodeficiency with inflammation.

Background: IRF2BP2 is a transcription factor that plays an important role in regulating immune pathways, angiogenesis, apoptosis, and cell differentiation. Defects in this gene have been implicated in immunodeficiency.

Objectives: To deepen the understanding of the clinical implications of IRF2BP2 variants, we sought to clinically characterize and functionally test 34 individuals with IRF2BP2 variants.

Clinical significance and antifungal susceptibility profile of 103 clinical isolates of species complex and obtained from NIH patients.

Reduced susceptibility to antifungals is common among members of genera and , with optimal treatments still not fully defined. antifungal susceptibility results and clinical data do not comprehensively account for the advent of new species identified by molecular phylogenetics. Using Clinical and Laboratory Standards Institute (CLSI) methodology, we tested a total of 103 clinical isolates obtained from patients at the NIH Clinical Center.

The intestinal microbiome and metabolome discern disease severity in cytotoxic T-lymphocyte-associated protein 4 deficiency.

Background: Cytotoxic T-lymphocyte-associated protein 4 deficiency (CTLA4-D) is an inborn error of immunity (IEI) caused by heterozygous mutations, and characterized by immune cell infiltration into the gut and other organs, leading to intestinal disease, immune dysregulation and autoimmunity. While regulatory T-cell dysfunction remains central to CTLA4-D immunopathogenesis, mechanisms driving disease severity and intestinal pathology are unknown but likely involve intestinal dysbiosis. We determined whether the intestinal microbiome and metabolome could distinguish individuals with severe CTLA4-D and identify biomarkers of disease severity.

Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS). Clemastine fumarate, the over-the-counter antihistamine and muscarinic receptor blocker, has remyelinating potential in MS. A clemastine arm was added to an ongoing platform clinical trial TRAP-MS (NCT03109288) to identify a cerebrospinal fluid (CSF) remyelination signature and to collect safety data on clemastine in patients progressing independently of relapse activity (PIRA).

Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature.

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons.

Durlobactam in combination with β-lactams to combat .

() presents significant clinical challenges. This study evaluated the synergistic effects of a β-lactam and β-lactamase inhibitor combination against and explored the underlying mechanisms. Synergy was assessed through MIC tests and time-kill studies, and binding affinities of nine β-lactams and BLIs to eight target receptors (L,D-transpeptidases [LDT] 1-5, D,D-carboxypeptidase, penicillin-binding protein [PBP] B, and PBP-lipo) were assessed using mass spectrometry and kinetic studies.

Altered Purinergic Signaling and CD8+ T Cell Dysregulation in STAT3 GOF Syndrome.

Signal transduction downstream of activating stimuli controls CD8+ T cell biology, however these external inputs can become uncoupled from transcriptional regulation in Primary Immune Regulatory Disorders (PIRDs). Gain-of-function (GOF) variants in STAT3 amplify cytokine signaling and cause a severe PIRD characterized by early onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity.

Implementation of a Pilot Study in Adolescent Health Care Transition Program for Chronic Granulomatous Disease: A Single Institution Experience.

Background: The transition to adult health care is challenging for adolescents and young adults (AYA) with Chronic Granulomatous Disease (CGD). This pilot study aimed to facilitate the learning of AYA with CGD about their health care and to aid in the development of life skills to enhance self-care.

Methods: AYA and caregivers (for participants <18 years of age) completed an adapted Transition Readiness Assessment.

Coinfection of Leprosy and Chronic Mucocutaneous Candidiasis in a Family with STAT1 Gain-of-Function Mutation.

This report documents the first known cases of lepromatous leprosy in patients with chronic mucocutaneous candidiasis (CMC) linked to a gain-of-function mutation in the STAT1 gene. Two related patients, a mother and daughter, who both suffer from CMC and lepromatous leprosy, carry a heterozygous STAT1 mutation (c.821G>A; p.