Early recognition of the APECED rash can accelerate the diagnosis of APECED.

Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) is a monogenic autoimmune disease most often resulting from biallelic loss-of-function variants in the autoimmune regulator (AIRE) gene. Although typically characterized by the classic triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency, we have recently reported that the clinical spectrum of the syndrome is far broader that previously described and that incorporation of an adjunct triad of APECED rash, autoimmune enteritis-associated intestinal dysfunction, and enamel hypoplasia in the classic triad manifestations could lead to earlier diagnosis. Among the adjunct triad manifestations, APECED rash occurs in 66% of American APECED patients by age 3, most often developing in the first year of life. Here, we describe the clinical and histological features of protracted APECED rash manifesting together with recurrent mucocutaneous candidiasis as the first two disease components of APECED in a 10-month-old girl.

Anti-Interleukin-23 Autoantibodies in Adult-Onset Immunodeficiency.

BACKGROUND: Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation. METHODS: Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections. RESULTS: Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex. CONCLUSIONS: Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

GM-CSF-mediated epithelial-immune cell crosstalk orchestrates pulmonary immunity to Aspergillus fumigatus.

Aspergillus fumigatus causes life-threatening mold pneumonia in immune compromised patients, particularly in those with quantitative or qualitative defects in neutrophils. While innate immune cell crosstalk licenses neutrophil antifungal activity in the lung, the role of epithelial cells in this process is unknown. Here, we find that that surfactant protein C (SPC)-expressing lung epithelial cells integrate infection-induced IL-1 and type III interferon signaling to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) preferentially at local sites of fungal infection and neutrophil influx. Using in vivo models that distinguish the role of GM-CSF during acute infection from its homeostatic function in alveolar macrophage survival and surfactant catabolism, we demonstrate that epithelial-derived GM-CSF increases the accumulation and fungicidal activity of GM-CSF-responsive neutrophils, with the latter being essential for host survival. Our findings establish SPC + epithelial cells as a central player in regulating the quality and strength of neutrophil-dependent immunity against inhaled mold pathogens. HIGHLIGHTS: GM-CSF is essential for host defense against A. fumigatus in the lung IL-1 and IFN-λ promote GM-CSF production by lung epithelial cells in parallelEpithelial cell-derived GM-CSF increases neutrophil accumulation and fungal killing capacityEpithelial cells preferentially upregulate GM-CSF in local sites of inflammation.

Evaluation of murine renal phagocyte-fungal interactions using intravital confocal microscopy and flow cytometry.

Myeloid phagocytes are essential for antifungal host defense during systemic candidiasis. Here, we present a protocol for assessing phagocyte-fungal interactions in vivo in the kidney, the primary target organ of the murine systemic candidiasis model. We describe steps for intravital confocal microscopy and flow cytometry. We also detail a kidney tissue dissociation procedure to obtain highly pure functional phagocytes for utilization in downstream ex vivo fungal uptake and killing assays.

Tregs tame skin bacteria and IFN-γ-associated pathology.

Mibrobial dysbiosis worsens cutaneous leishmaniasis. In this issue of JEM, Singh et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20230558) show that Rorγt+ regulatory T cells suppress pathogenic IFN-γ responses to control Staphylococcus aureus growth and limit S. aureus- and Leishmamia braziliensis-associated immunopathology at the skin barrier.

Characterization of the antispike IgG immune response to COVID-19 vaccines in people with a wide variety of immunodeficiencies.

Research on coronavirus disease 2019 vaccination in immune-deficient/disordered people (IDP) has focused on cancer and organ transplantation populations. In a prospective cohort of 195 IDP and 35 healthy volunteers (HV), antispike immunoglobulin G (IgG) was detected in 88% of IDP after dose 2, increasing to 93% by 6 months after dose 3. Despite high seroconversion, median IgG levels for IDP never surpassed one-third that of HV. IgG binding to Omicron BA.1 was lowest among variants. Angiotensin-converting enzyme 2 pseudo-neutralization only modestly correlated with antispike IgG concentration. IgG levels were not significantly altered by receipt of different messenger RNA-based vaccines, immunomodulating treatments, and prior severe acute respiratory syndrome coronavirus 2 infections. While our data show that three doses of coronavirus disease 2019 vaccinations induce antispike IgG in most IDP, additional doses are needed to increase protection. Because of the notably reduced IgG response to Omicron BA.1, the efficacy of additional vaccinations, including bivalent vaccines, should be studied in this population.

Differential skin immune responses in mice intradermally infected with Candida auris and Candida albicans.

IMPORTANCE: Candida auris is a globally emerging fungal pathogen that transmits among individuals in hospitals and nursing home residents. Unlike other Candida species, C. auris predominantly colonizes and persists in skin tissue, resulting in outbreaks of nosocomial infections. Understanding the factors that regulate C. auris skin colonization is critical to develop novel preventive and therapeutic approaches against this emerging pathogen. We established a model of intradermal C. auris inoculation in mice and found that mice infected with C. auris elicit less potent innate and adaptive immune responses in the infected skin compared to C. albicans. These findings help explain the clinical observation of persistent C. auris colonization in skin tissue.

Isolation of Mouse Neutrophils.

Neutrophils represent the first line of defense against bacterial and fungal pathogens. Indeed, patients with inherited or acquired qualitative and quantitative neutrophil defects are at high risk for developing bacterial and fungal infections and suffering adverse outcomes from these infections. Therefore, research aiming at defining the molecular factors that modulate neutrophil effector function under homeostatic conditions and during infection is essential for devising strategies to augment neutrophil function and improve the outcomes of infected individuals. This article describes reproducible density-gradient-centrifugation-based as well as positive and negative immunomagnetic selection protocols that can be applied in any laboratory to harvest large numbers of highly enriched and highly viable neutrophils from the bone marrow of mice. In another protocol, we also present a method that combines gentle enzymatic tissue digestion with a positive immunomagnetic selection technique or fluorescence-activated cell sorting (FACS) to harvest highly pure and highly viable preparations of neutrophils directly from mouse tissues such as the kidney, the liver, or the spleen. Mouse neutrophils isolated by these protocols can be used to examine several aspects of cellular function ex vivo, including pathogen binding, phagocytosis, and killing, neutrophil chemotaxis, oxidative burst, degranulation, and cytokine production, and for performing neutrophil adoptive transfer experiments. © 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. Basic Protocol 1: Isolation of Neutrophils from Mouse Bone Marrow Using Positive Immunomagnetic Separation Alternate Protocol 1: Purification of Neutrophils from Bone Marrow Using Negative Immunomagnetic Separation Alternate Protocol 2: Purification of Neutrophils from Bone Marrow Using Histopaque-Based Density Gradient Centrifugation Basic Protocol 2: Isolation of Neutrophils from Mouse Tissues Using Positive Immunomagnetic Separation Alternate Protocol 3: Isolation of Neutrophils from Mouse Tissues Using FACS.

Host defense mechanisms against Candida auris.

INTRODUCTION: Candida auris is a pathogen of growing public health concern given its rapid spread across the globe, its propensity for long-term skin colonization and healthcare-related outbreaks, its resistance to a variety of antifungal medications, and the high morbidity and mortality associated with invasive disease. Despite that, the host immune response mechanisms that operate during C. auris skin colonization and invasive infection remains poorly understood. AREAS COVERED: In this manuscript, we review the available literature in the growing research field pertaining to C. auris host defenses and we discuss what is known about the ability of C. auris to thrive on mammalian skin, the role of lymphoid cell-mediated, IL-17-dependent defenses in controlling cutaneous colonization, and the contribution of myeloid phagocytes in curtailing systemic infection. EXPERT OPINION: Understanding the mechanisms by which the host immune system responds to and controls colonization and infection with C. auris and developing a deeper knowledge of tissue-specific host-C. auris interactions and of C. auris immune-evading mechanisms may help devise improved strategies for decolonization, prognostication, prevention, vaccination, and/or directed antifungal treatment in vulnerable patient populations.

Successful Treatment of Paecilomyces variotii Pneumonia and Lupus Nephritis With Posaconazole-Cyclophosphamide Co-administration Without Drug Interaction-Induced Toxicity.

Paecilomyces variotii is an opportunistic mold that causes pulmonary infections in immunosuppressed humans that are often treated with triazole therapy. Lupus nephritis is a major cause of progressive kidney disease in patients with systemic lupus erythematosus, often requiring cyclophosphamide-based therapies. Triazole-cyclophosphamide co-administration is challenging as triazoles increase cyclophosphamide concentrations, which can worsen cyclophosphamide toxicity. We describe herein a patient with Paecilomyces variotii pneumonia and concomitant lupus nephritis who was successfully treated with posaconazole and echinocandin-bridged interruptions to allow for cyclophosphamide therapy. This regimen was well-tolerated without cyclophosphamide toxicity and achieved improvements in both fungal pneumonia and renal function.

Transcription factor EGR2 controls homing and pathogenicity of TH17 cells in the central nervous system.

CD4+ T helper 17 (TH17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic TH17 cells in the central nervous system (CNS) but not that of protective TH17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4+ T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the TH17 cell transcriptional regulatory network and showed high interconnectivity with core TH17 cell-specific transcription factors. Mechanistically, EGR2 enhanced TH17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host's ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic TH17 cells in the CNS.

Targeting endothelial permeability in the EPR effect.

The characteristics of the primary tumor blood vessels and the tumor microenvironment drive the enhanced permeability and retention (EPR) effect, which confers an advantage towards enhanced delivery of anti-cancer nanomedicine and has shown beneficial effects in preclinical models. Increased vascular permeability is a landmark feature of the tumor vessels and an important driver of the EPR. The main focus of this review is the endothelial regulation of vascular permeability. We discuss current challenges of targeting vascular permeability towards clinical translation and summarize the structural components and mechanisms of endothelial permeability, the principal mediators and signaling players, the targeted approaches that have been used and their outcomes to date. We also critically discuss the effects of the tumor-infiltrating immune cells, their interplay with the tumor vessels and the impact of immune responses on nanomedicine delivery, the impact of anti-angiogenic and tumor-stroma targeting approaches, and desirable nanoparticle design approaches for greater translational benefit.

Alopecia areata and occurrence of vitiligo and hypothyroidism in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inherited disorder of immunity which leads to increased risk for mucocutaneous candidiasis and multiorgan autoimmune disease. While alopecia areata (AA) has been described in some patients with APECED, the extent and timing of AA is not well established and extent and timing of concomitant vitiligo and hypothyroidism has not been described. We evaluated an APECED cohort followed at the National Institutes of Health for the timing of development of associated diseases. We found AA occurred earlier in those with APECED than in the general population, was rarely the first sign of APECED, and the timing of AA onset did correlate with the timing of onset of vitiligo or hypothyroidism which also occurred at high rates and early age.

Susceptibility to Cryptococcus neoformans Infection with Bruton's Tyrosine Kinase Inhibition.

Patients receiving the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib have an increased likelihood of fungal infections. The objectives of this study were to determine if Cryptococcus neoformans infection severity was isolate dependent with BTK inhibition and whether blocking BTK impacted infection severity in a mouse model. We compared four clinical isolates from patients on ibrutinib to virulent (H99) and avirulent (A1-35-8) reference strains. BTK knockout (KO) and wild-type (WT) C57 mice and WT CD1 mice were infected by intranasal (i.n.), oropharyngeal aspiration (OPA), and intravenous (i.v.) routes. Infection severity was assessed by survival and fungal burden (CFU per gram of tissue). Ibrutinib (25 mg/kg) or vehicle was administered daily through intraperitoneal injections. In the BTK KO model, no isolate-dependent effect on fungal burden was observed, and infection severity was not significantly different from that of the WT with i.n., OPA, and i.v. routes. Ibrutinib treatment did not impact infection severity. However, when the four clinical isolates were compared to H99, two of these isolates were less virulent, with significantly longer survival and reduced rates of brain infection. In conclusion, C. neoformans infection severity in the BTK KO model does not appear to be isolate dependent. BTK KO and ibrutinib treatment did not result in significantly different infection severities. However, based on repeated clinical observations of increased susceptibility to fungal infections with BTK inhibitor therapy, further work is needed to optimize a mouse model with BTK inhibition to better understand the role that this pathway plays in susceptibility to C. neoformans infection.

Management and outcome of COVID-19 in CTLA-4 insufficiency.

Despite the high incidence of COVID-19 worldwide, clinical experience with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in inborn errors of immunity remains limited. Recent studies have shown that patients with defects in type 1 interferon (IFN)-related pathways or those with autoantibodies against type 1 IFNs develop severe COVID-19. We reported the clinical course of 22 patients with CTLA-4 insufficiency and COVID-19 and retrospectively examined autoantibodies against type 1 IFNs at baseline. Data were obtained from the patient interviews and chart reviews. Screening for anti-IFN autoantibodies was performed using a multiplex particle-based assay. Student t test, Mann Whitney, analysis of variance, or χ2 tests were used where appropriate. Twenty-two patients aged from 8 months to 54 years, with genetically confirmed CLTA-4 insufficiency, developed COVID-19 from 2020 to 2022. The most common symptoms were fever, cough, and nasal congestion, and the median duration of illness was 7.5 days. Twenty patients (91%) developed mild COVID-19 and were treated as outpatients. Two patients were hospitalized because of COVID-19 pneumonia but did not require mechanical ventilation. Ten (45%) patients were vaccinated at the time of their first COVID-19 infection. Eleven patients received outpatient treatment with monoclonal antibodies against the SARS-CoV-2 spike protein. During the study period, 17 patients were vaccinated against SARS-CoV-2, with no severe vaccine-related adverse effects. Although median anti-S titers following vaccination or infection were lower in patients receiving immunoglobulin replacement therapy (IGRT) (349 IU/dL) than in those not receiving IGRT (2594 IU/dL; P = .15); 3 of 9 patients on IGRT developed titers >2000 IU/dL. All patients tested negative for autoantibodies against IFN-α, IFN-ß, and IFN-ω at baseline. Most patients with CTLA-4 insufficiency and COVID-19 had nonsevere disease, lacked autoantibodies against type 1 IFNs, and tolerated messenger RNA vaccines with few adverse effects. Whether our findings can be extrapolated to patients receiving CTLA-4-targeting checkpoint inhibitors requires further studies.

Assessing the threat of bat-associated fungal pathogens.

Fungal pathogens have become an increasingly important topic in recent decades. Yet whilst various cankers and blights have gained attention in temperate woodlands and crops, the scope for fungal pathogens of animals and their potential threat has received far less attention. With a shifting climate, the threat from fungal pathogens is predicted to increase in the future, thus understanding the spread of fungi over landscapes as well as taxa that may be at risk is of particular importance. Cave ecosystems provide potential refugia for various fungi, and roosts for bats. With their well vascularized wings and wide-ranging distributions, bats present potential fungal vectors. Furthermore, whilst bat immune systems are generally robust to bacterial and viral pathogens, they can be susceptible to fungal pathogens, particularly during periods of stress such as hibernation. Here we explore why bats are important and interesting vectors for fungi across landscapes and discuss knowledge gaps that require further research.

NF-kappa-B essential modulator (NEMO) gene polymorphism in an adult woman with systemic lupus erythematosus and recurrent non-tuberculous mycobacterial disseminated infections.

Infections are among the most serious complications in patients with systemic lupus erythematosus (SLE), with bacterial and viral infections being the most common. Non-tuberculous mycobacterial (NTM) infections are quite rare and are typically seen in older patients with SLE with longstanding disease duration treated with corticosteroids. Here, we describe a 39-year-old woman with SLE and an unusual pattern of recurrent NTM disseminated infections. After excluding the presence of autoantibodies against interferon-γ, whole exome sequencing revealed a homozygous polymorphism in the NF-kappa-B essential modulator (NEMO) gene. Primary immunodeficiencies should be included in the differential diagnosis of patients with recurrent opportunistic infections, even in those with iatrogenic immunosuppression.