The spectrum of known monogenic inborn errors of immunity is growing, with certain disorders underlying a specific and narrow range of infectious diseases. These disorders reveal the core mechanisms by which these infections occur in various settings, including inherited and acquired immunodeficiencies, thereby delineating the essential mechanisms of protective immunity to the corresponding pathogens. These findings also have medical implications, facilitating diagnosis and improving the management of individuals at risk of disease.

The fungal community of the skin microbiome is dominated by a single genus, Malassezia. Besides its symbiotic lifestyle at the host interface, this commensal yeast has also been associated with diverse inflammatory skin diseases in humans and pet animals. Stable colonization is maintained by antifungal type 17 immunity. The mechanisms driving Th17 responses to Malassezia remain, however, unclear. Here, we show that the C-type lectin receptors Mincle, Dectin-1, and Dectin-2 recognize conserved patterns in the cell wall of Malassezia and induce dendritic cell activation in vitro, while only Dectin-2 is required for Th17 activation during experimental skin colonization in vivo. In contrast, Toll-like receptor recognition was redundant in this context. Instead, inflammatory IL-1 family cytokines signaling via MyD88 were also implicated in Th17 activation in a T cell-intrinsic manner. Taken together, we characterized the pathways contributing to protective immunity against the most abundant member of the skin mycobiome. This knowledge contributes to the understanding of barrier immunity and its regulation by commensals and is relevant considering how aberrant immune responses are associated with severe skin pathologies.

Brodalumab, a humanized monoclonal antibody that targets the interleukin-17 receptor A, is primarily used to manage moderate-to-severe plaque psoriasis. Although it has demonstrated favorable efficacy and safety in clinical trials, the strict inclusion and exclusion criteria may not fully reflect its safety profile in real-world settings. As its use becomes more widespread in clinical practice, understanding its safety in real-world applications is crucial.This study employed disproportionality analysis to assess the safety of brodalumab by examining all adverse event reports that identified brodalumab as the primary suspected drug in the FDA Adverse Event Reporting System database since 2017. Techniques such as the Reporting Odds Ratio, Proportional Reporting Ratio, Multi-item Gamma Poisson Shrinker, and Bayesian Confidence Propagation Neural Network were utilized to analyze the adverse events associated with brodalumab. Additionally, the Weibull distribution was used to model the temporal risk of adverse events.The study identified several adverse reactions already listed on the drug's label that showed positive signals, including arthralgia, headache, myalgia, suicidal ideation, oropharyngeal pain, injection site mass, and infections. Additionally, we found potential adverse reactions not noted on the drug's label that exhibited positive signals, including depression, increased blood pressure, peripheral swelling, gait disturbance, inability to walk, stress, myocardial infarction, sepsis, uveitis, nephrolithiasis, and interstitial lung disease. Moreover, this analysis highlighted the critical need for vigilant monitoring of adverse events, especially during the first month following the initiation of treatment.This study provides initial insights into the real-world safety of brodalumab, confirming known adverse reactions and uncovering additional potential risks. The results deliver vital information that can assist clinicians in making informed decisions when prescribing brodalumab for psoriasis treatment.

The gut microbiome plays a key role in the pathogenesis and disease activity of inflammatory bowel disease (IBD). While research has focused on the bacterial microbiome, recent studies have shifted towards host genetics and host-fungal interactions. The mycobiota is a vital component of the gastrointestinal microbial community and plays a significant role in immune regulation. Among fungi, Candida species, particularly Candida albicans (C. albicans), have been extensively studied due to their dual role as gut commensals and invasive pathogens. Recent findings indicate that various strains of C. albicans exhibit considerable differences in virulence factors, impacting IBD's pathophysiology. Intestinal fungal dysbiosis and antifungal mucosal immunity may be associated to IBD, especially Crohn's disease (CD). This article discusses intestinal fungal dysbiosis and antifungal immunity in healthy individuals and CD patients. It discusses factors influencing the mycobiome's role in IBD pathogenesis and highlights significant contributions from the scientific community aimed at enhancing understanding of the mycobiome and encouraging further research and targeted intervention studies on specific fungal populations. Our article also provided insights into a recent study by Wu et al in the World Journal of Gastroenterology regarding the role of the gut microbiota in the pathogenesis of CD.

Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency condition caused by a genetic abnormality that increases the risk of recurrent and persistent skin, nail, and mucous membrane infections with Candida species, typically Candida albicans. Signal transducer and activator of transcription 1 (STAT1) gene mutation is a genetic trigger that causes CMC, which increases the risk of infections, multisystem disorders, and cancer susceptibility. We describe the first case of a Saudi female patient with clinical features of CMC with an underlying (STAT1) gene mutation.

Mucosal barrier integrity is vital for homeostasis with commensal organisms while preventing pathogen invasion. We unexpectedly found that fungal-induced immunosurveillance enhances resistance to fungal outgrowth and tissue invasion by remodeling the oral mucosal epithelial barrier in mouse models of adult and neonatal Candida albicans colonization. Epithelial subset expansion and tissue remodeling were dependent on interleukin-22 (IL-22) and signal transducer and activator of transcription 3 (STAT3) signaling, through a non-canonical receptor complex composed of glycoprotein 130 (gp130) coupled with IL-22RA1 and IL-10RB. Immunosurveillance-induced epithelial remodeling was restricted to the oral mucosa, whereas barrier architecture was reset once fungal-specific immunity developed. Collectively, these findings identify fungal-induced transient mucosal remodeling as a critical determinant of resistance to mucosal fungal infection during early stages of microbial colonization.

Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.

The fungal community of the skin microbiome is dominated by a single genus, Malassezia. Besides its symbiotic lifestyle at the host interface, this commensal yeast has also been associated with diverse inflammatory skin diseases in humans and pet animals. Stable colonization is maintained by antifungal type 17 immunity. The mechanisms driving Th17 responses to Malassezia remain, however, unclear. Here, we show that the C-type lectin receptors Mincle, Dectin-1, and Dectin-2 recognize conserved patterns in the cell wall of Malassezia and induce dendritic cell activation in vitro, while only Dectin-2 is required for Th17 activation during experimental skin colonization in vivo. In contrast, Toll-like receptor recognition was redundant in this context. Instead, inflammatory IL-1 family cytokines signaling via MyD88 were also implicated in Th17 activation in a T cell-intrinsic manner. Taken together, we characterized the pathways contributing to protective immunity against the most abundant member of the skin mycobiome. This knowledge contributes to the understanding of barrier immunity and its regulation by commensals and is relevant considering how aberrant immune responses are associated with severe skin pathologies.

Recent case reports and epidemiological data suggest that fungal infections represent an underappreciated complication among people with severe COVID-19. However, the frequency of fungal colonization in patients with COVID-19 and associations with specific immune responses in the airways remain incompletely defined. We previously generated a single-cell RNA-sequencing data set characterizing the upper respiratory microenvironment during COVID-19 and mapped the relationship between disease severity and the local behavior of nasal epithelial cells and infiltrating immune cells. Our previous study, in agreement with findings from related human cohorts, demonstrated that a profound deficiency in host immunity, particularly in type I and type III interferon signaling in the upper respiratory tract, is associated with rapid progression to severe disease and worse clinical outcomes. We have now performed further analysis of this cohort and identified a subset of participants with severe COVID-19 and concurrent detection of Candida species-derived transcripts within samples collected from the nasopharynx and trachea. Here, we present the clinical characteristics of these individuals. Using matched single-cell transcriptomic profiles of these individuals' respiratory mucosa, we identify epithelial immune signatures suggestive of IL17 stimulation and anti-fungal immunity. Further, we observe a significant expression of anti-fungal inflammatory cascades in the nasal and tracheal epithelium of all participants who went on to develop severe COVID-19, even among participants without detectable genetic material from fungal pathogens. Together, our data suggest that IL17 stimulation-in part driven by Candida colonization-and blunted interferon signaling represent a common feature of severe COVID-19 infection.

In this paper, we present an analysis suggesting that symptomatic and asymptomatic fungal coinfections can impact patient disease progression during COVID-19 hospitalization. By looking into the presence of other pathogens and their effect on the host immune response during COVID-19 hospitalizations, we aim to offer insight into an underestimated scenario, furthering our current knowledge of determinants of severity that could be considered for future diagnostic and intervention strategies.

Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαβ+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αβ T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.

Staphylococcus aureus (S. aureus) is a significant human pathogen, in particular in patients with an underlying medical condition. It is equipped with a large variety of virulence factors enabling both colonization and invasive disease. The spectrum of manifestation is broad, ranging from superficial skin infections to life-threatening conditions like pneumonia and sepsis. As a major cause of healthcare-associated infections, there is a great need in understanding staphylococcal immunity and defense mechanisms. Patients with inborn errors of immunity (IEI) frequently present with pathological infection susceptibility, however, not all of them are prone to S. aureus infection. Thus, enhanced frequency or severity of S. aureus infections can serve as a clinical indicator of a specific underlying immunological impairment. In addition, the analysis of immunological functions in patients with susceptibility to S. aureus provides a unique opportunity of understanding the complex interplay between staphylococcal virulence and host immune predisposition. While the importance of quantitatively and qualitatively normal neutrophils is widely known, less awareness exists about the role of specific cytokines such as functional interleukin (IL)-6 signaling. This review categorizes well-known IEI in light of their susceptibility to S. aureus and discusses the relevant associated pathomechanisms. Understanding host-pathogen-interactions in S. aureus infections in susceptible individuals can pave the way for more effective management and preventive treatment options. Moreover, these insights might help to identify patients who should be screened for an underlying IEI. Ultimately, enhanced understanding of pathogenesis and immune responses in S. aureus infections may also be of relevance for the general population.

In the last 5 years, several new inborn errors of immunity (IEI) have been described, especially in the areas of immune dysregulation and autoinflammation. As a result, the clinical presentation of IEIs has broadened. We review the heterogeneous presentation of IEIs and detail several of the recently described IEIs with a focus on the noninfectious manifestations commonly seen.

IEIs may present with early onset and/or multiple autoimmune manifestations, increased risk for malignancy, lymphoproliferation, severe atopy, autoinflammation and/or hyperinflammation. Because of this, patients can present to a wide array of providers ranging from primary care to various pediatric subspecialists. The International Union of Immunological Societies (IUIS) expert committee has created a phenotypic classification of IEIs in order to help clinicians narrow their evaluation based on the laboratory and clinical findings.

Both primary care pediatricians and pediatric subspecialists need to be aware of the common clinical features associated with IEI and recognize when to refer to allergy-immunology for further evaluation. Early diagnosis can lead to earlier treatment initiation and improve clinical outcomes for our patients.

Streptococcus pyogenes is a Gram-positive pathogen that causes a significant global burden of skin pyoderma and pharyngitis. In some cases, infection can lead to severe invasive streptococcal diseases. Previous studies have shown that IL-17 deficiency in mice (IL-17-/-) can reduce S. pyogenes clearance from the mucosal surfaces. However, the effect of IL-17 on the development of severe invasive streptococcal disease has not yet been assessed.

Here, we modeled single or repeated non-lethal intranasal (IN) S. pyogenes M1 strain infections in immunocompetent and IL-17-/- mice to assess bacterial colonization following a final IN or skin challenge.

Immunocompetent mice that received a single S. pyogenes infection showed long-lasting immunity to subsequent IN infection, and no bacteria were detected in the lymph nodes or spleens. However, in the absence of IL-17, a single IN infection resulted in dissemination of S. pyogenes to the lymphoid organs, which was accentuated by repeated IN infections. In contrast to what was observed in the respiratory mucosa, skin immunity did not correlate with the systemic levels of IL-17. Instead, it was found to be associated with the activation of germinal center responses and accumulation of neutrophils in the spleen.

Our results demonstrated that IL-17 plays a critical role in preventing invasive disease following S. pyogenes infection of the respiratory tract.

Germline human heterozygous STAT1 gain-of-function (GOF) variants were first discovered a common cause of chronic mucocutaneous candidiasis (CMC) in 2011. Since then, numerous STAT1 GOF variants have been identified. A variety of clinical phenotypes, including fungal, viral, and bacterial infections, endocrine disorders, autoimmunity, malignancy, and aneurysms, have recently been revealed for STAT1 GOF variants, which has led to the expansion of the clinical spectrum associated with STAT1 GOF. Among this broad range of complications, it has been determined that invasive infections, aneurysms, and malignancies are poor prognostic factors for STAT1 GOF. The effectiveness of JAK inhibitors as a therapeutic option has been established, although further investigation of their long-term utility and side effects is needed. In contrast to the advancements in treatment options, the precise molecular mechanism underlying STAT1 GOF remains undetermined. Two primary hypotheses for this mechanism involve impaired STAT1 dephosphorylation and increased STAT1 protein levels, both of which are still controversial. A precise understanding of the molecular mechanism is essential for not only advancing diagnostics but also developing therapeutic interventions. Here, we provide a comprehensive review of STAT1 GOF with the aim of establishing a stronger connection between bedside observations and laboratory research.

Oral thrush is a familiar presentation in both general practice and paediatrics, and is usually responsive to treatment in the community. Here, we present the diagnostic journey of a previously well boy aged 3 years who presented with treatment-resistant thrush and describe how 'unexpected' results led to eventual diagnosis and management. This intriguing case was managed jointly by district hospital general paediatric team and tertiary hospital specialist teams.

Interleukin-17 s (IL-17s) are well-known proinflammatory cytokines, and their antagonists perform excellently in the treatment of inflammatory skin diseases such as psoriasis. However, their physiological functions have not been given sufficient attention by clinicians. IL-17s can protect the host from extracellular pathogens, maintain epithelial integrity, regulate cognitive processes and modulate adipocyte activity through distinct mechanisms. Here, we present a systematic review concerning the physiological functions of IL-17s. Our goal is not to negate the therapeutic effect of IL-17 antagonists, but to ensure their safe use and reasonably explain the possible adverse events that may occur in their application.

Anticytokine autoantibodies (ACAAs) are a fascinating group of antibodies that have gained more and more attention in the field of autoimmunity and secondary immunodeficiencies over the years. Some of these antibodies are characterized by their ability to target and neutralize specific cytokines. ACAAs can play a role in the susceptibility to several infectious diseases, and their infectious manifestations depending on which specific immunological pathway is affected. In this review, we will give an outline per infection in which ACAAs might play a role and whether additional immunomodulatory treatment next to antimicrobial treatment can be considered. Finally, we describe the areas for future research on ACAAs.

Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Among inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a 7-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant.

Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation.

The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of 3 months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs*16 or p.D457Afs*17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient's SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype.

The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for the diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants.

The gut microbiome is a diverse microbial community composed of bacteria, viruses, and fungi that plays a major role in human health and disease. Dysregulation of these gut organisms in a genetically susceptible host is fundamental to the pathogenesis of inflammatory bowel disease (IBD). While bacterial dysbiosis has been a predominant focus of research for many years, there is growing recognition that fungal interactions with the host immune system are an important driver of gut inflammation. Candida albicans is likely the most studied fungus in the context of IBD, being a near universal gut commensal in humans and also a major barrier-invasive pathogen. There is emerging evidence that intra-strain variation in C. albicans virulence factors exerts a critical influence on IBD pathophysiology. In this review, we describe the immunological impacts of variations in C. lbicans colonisation, morphology, genetics, and proteomics in IBD, as well as the clinical and therapeutic implications.

Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Amongst inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a seven-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant.

Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation.

The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of three months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+ 131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs*16 or p.D457Afs*17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient's SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype.

The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants.

Chronic mucocutaneous candidiasis leads to persistent or recurrent fungal infections of the nail, skin, oral, and genital mucosa. Impaired interleukin 17-mediated immunity is a cause of chronic mucocutaneous candidiasis. We aimed to show the pathogenicity of a novel interleukin 17 receptor A mutation through functional studies.

After next-generation sequencing analysis showed the interleukin 17 receptor A variant, we confirmed the variant by Sanger sequencing and functional validation of the variant by flow cytometry.

We present the case of a 6-year-old male patient who presented with recurrent oral and genital Candida infections and eczema. He had staphylococcal skin lesions, fungal susceptibility, and eczema. The patient carried a novel homozygous nonsense [(c.787C> T) (p.Arg263Ter)] mutation in the interleukin 17 receptor A gene. Sanger sequencing confirmed the variant and revealed the segregation of the variant in the family. We used flow cytometry to detect interleukin 17 receptor A protein expression in peripheral blood mononuclear cells from patients and measured Th17 cell percentage. We observed low interleukin 17 receptor A protein expression in patient peripheral blood mononuclear cells, decreased CD4+ interleukin 17+ cell percentage, and decreased interleukin 17F expression in CD4+ cells compared to healthy controls.

Innate immune defects may lead to chronic recurrent fungal and bacterial infections of the skin, mucosa, and nails. Generally, genetic and functional analysis is needed in addition to basic immunological tests.

Pathogenic fungi have emerged as significant causes of infectious morbidity and death in patients with acquired immunodeficiency conditions such as HIV/AIDS and following receipt of chemotherapy, immunosuppressive agents or targeted biologics for neoplastic or autoimmune diseases, or transplants for end organ failure. Furthermore, in recent years, the spread of multidrug-resistant Candida auris has caused life-threatening outbreaks in health-care facilities worldwide and raised serious concerns for global public health. Rapid progress in the discovery and functional characterization of inborn errors of immunity that predispose to fungal disease and the development of clinically relevant animal models have enhanced our understanding of fungal recognition and effector pathways and adaptive immune responses. In this Review, we synthesize our current understanding of the cellular and molecular determinants of mammalian antifungal immunity, focusing on observations that show promise for informing risk stratification, prognosis, prophylaxis and therapies to combat life-threatening fungal infections in vulnerable patient populations.

Biologic immunomodulatory medications have rapidly expanded in the previous decades, providing new treatment options for individuals with a spectrum of oncologic, allergic, rheumatologic, and neurologic conditions. Biologic therapies alter immune function and can impair key host defense mechanisms, resulting in secondary immunodeficiency and increased infectious risks. Biologic medications can increase general risk for upper respiratory tract infections but can also be associated with unique infectious risks owing to distinct mechanisms of action. With the widespread use of these medications, providers in every area of medicine will likely care for individuals receiving biologic therapies and understanding their potential infectious complications can help mitigate these risks. This practical review discusses the infectious implications of biologics by class of medication and provides recommendations regarding the examination and screening both before therapy initiation and while the patient is receiving the medication. With this knowledge and background, providers can reduce risk whereas patients receive the treatment benefits of these biologic medications.

The continuous expansion of immunocompromised patient populations at-risk for developing life-threatening opportunistic fungal infections in recent decades has helped develop a deeper understanding of antifungal host defenses, which has provided the foundation for eventually devising immune-based targeted interventions in the clinic. This review outlines how genetic variation in certain immune pathway-related genes may contribute to the observed clinical variability in the risk of acquisition and/or severity of fungal infections and how immunogenetic-based patient stratification may enable the eventual development of personalized strategies for antifungal prophylaxis and/or vaccination. Moreover, this review synthesizes the emerging cytokine-based, cell-based, and other immunotherapeutic strategies that have shown promise as adjunctive therapies for boosting or modulating tissue-specific antifungal immune responses in the context of opportunistic fungal infections.

Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections.

BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed.

The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals.

EUPAS30280.

Candida albicans is a commensal yeast fungus of the human oral, gastrointestinal, and genital mucosal surfaces, and skin. Antibiotic-induced dysbiosis, iatrogenic immunosuppression, and/or medical interventions that impair the integrity of the mucocutaneous barrier and/or perturb protective host defense mechanisms enable C. albicans to become an opportunistic pathogen and cause debilitating mucocutaneous disease and/or life-threatening systemic infections. In this review, we synthesize our current knowledge of the tissue-specific determinants of C. albicans pathogenicity and host immune defense mechanisms.

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α- and IL-1β-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.