Candida
species, including
C. albicans
in particular, can cause superficial or invasive disease, often in patients with known acquired immunodeficiencies or iatrogenic conditions. The molecular and ...cellular basis of these infections in patients with such risk factors remained largely elusive, until the study of inborn errors of immunity clarified the basis of the corresponding inherited and “idiopathic” infections. Superficial candidiasis, also known as chronic mucocutaneous candidiasis (CMC), can be caused by inborn errors of IL-17 immunity. Invasive candidiasis can be caused by inborn errors of CARD9 immunity. In this chapter, we review both groups of inborn errors of immunity, and discuss the contribution of these studies to the deciphering of the critical mechanisms of anti-
Candida
immunity in patients with other conditions.
Autosomal recessive CARD9 deficiency underlies life-threatening, invasive fungal infections in otherwise healthy individuals normally resistant to other infectious agents. In less than 10 years, 58 ...patients from 39 kindreds have been reported in 14 countries from four continents. The patients are homozygous (
n
= 49; 31 kindreds) or compound heterozygous (
n
= 9; 8 kindreds) for 22 different
CARD9
mutations. Six mutations are recurrent, probably due to founder effects. Paradoxically, none of the mutant alleles has been experimentally demonstrated to be loss-of-function. CARD9 is expressed principally in myeloid cells, downstream from C-type lectin receptors that can recognize fungal components. Patients with CARD9 deficiency present impaired cytokine and chemokine production by macrophages, dendritic cells, and peripheral blood mononuclear cells and defective killing of some fungi by neutrophils in vitro. Neutrophil recruitment to sites of infection is impaired in vivo. The proportion of Th17 cells is low in most, but not all, patients tested. Up to 52 patients suffering from invasive fungal diseases (IFD) have been reported, with ages at onset of 3.5 to 52 years. Twenty of these patients also displayed superficial fungal infections. Six patients had only mucocutaneous candidiasis or superficial dermatophytosis at their last follow-up visit, at the age of 19 to 50 years. Remarkably, for 50 of the 52 patients with IFD, a single fungus was involved; only two patients had IFDs due to two different fungi. IFD recurred in 44 of 45 patients who responded to treatment, and a different fungal infection occurred in the remaining patient. Ten patients died from IFD, between the ages of 12 and 39 years, whereas another patient died at the age of 91 years, from an unrelated cause. At the most recent scheduled follow-up visit, 81% of the patients were still alive and aged from 6.5 to 75 years. Strikingly, all the causal fungi belonged to the phylum Ascomycota: commensal
Candida
and saprophytic
Trychophyton
,
Aspergillus
,
Phialophora
,
Exophiala
,
Corynesprora
,
Aureobasidium
, and
Ochroconis
. Human CARD9 is essential for protective systemic immunity to a subset of fungi from this phylum but seems to be otherwise redundant. Previously healthy patients with unexplained invasive fungal infection, at any age, should be tested for inherited CARD9 deficiency.
Key Points
• Inherited CARD9 deficiency (OMIM #212050) is an AR PID due to mutations that may be present in a homozygous or compound heterozygous state.
• CARD9 is expressed principally in myeloid cells and transduces signals downstream from CLR activation by fungal ligands.
• Endogenous mutant CARD9 levels differ between alleles (from full-length normal protein to an absence of normal protein).
• The functional impacts of
CARD9
mutations involve impaired cytokine production in response to fungal ligands, impaired neutrophil killing and/or recruitment to infection sites, and defects of Th17 immunity.
• The key clinical manifestations in patients are fungal infections, including CMC, invasive (in the CNS in particular)
Candida
infections, extensive/deep dermatophytosis, subcutaneous and invasive phaeohyphomycosis, and extrapulmonary aspergillosis.
• The clinical penetrance of CARD9 deficiency is complete, but penetrance is incomplete for each of the fungi concerned.
• Age at onset is highly heterogeneous, ranging from childhood to adulthood for the same fungal disease.
• All patients with unexplained IFD should be tested for
CARD9
mutations. Familial screening and genetic counseling should be proposed.
• The treatment of patients with
CARD9
mutations is empirical and based on antifungal therapies and the surgical removal of fungal masses. Patients with persistent/relapsing
Candida
infections of the CNS could be considered for adjuvant GM-CSF/G-CSF therapy. The potential value of HSCT for CARD9-deficient patients remains unclear.
We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and ...laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.
It has been estimated that there are at least 1.5 million fungal species, mostly present in the environment, but only a few of these fungi cause human disease. Most fungal diseases are self-healing ...and benign, but some are chronic or life-threatening. Acquired and inherited defects of immunity, including breaches of mucocutaneous barriers and circulating leukocyte deficiencies, account for most severe modern-day mycoses. Other types of infection typically accompany these fungal infections. More rarely, severe fungal diseases can strike otherwise healthy individuals. Historical reports of fungi causing chronic peripheral infections (e.g. affecting the nails, skin, hair), and invasive diseases (e.g. brain, lungs, liver), in otherwise healthy patients, can be traced back to the mid-20th century. These fungi typically cause endemic, but not epidemic diseases, are more likely to underlie sporadic than familial cases, and only threaten a small proportion of infected individuals. The basis of this ‘idiosyncratic’ susceptibility has long remained unexplained, but it has recently become apparent that ‘idiopathic’ fungal diseases, in children, teenagers, and even adults, may be caused by single-gene inborn errors of immunity. The study of these unusual primary immunodeficiencies (PIDs) has led to the identification of molecules and cells playing a crucial role in human host defenses against certain fungi at particular anatomic sites. A picture is emerging of inborn errors of IL-17 immunity selectively underlying chronic mucocutaneous candidiasis, with little inter-individual variability, and of inborn errors of CARD9 immunity underlying various life-threatening invasive fungal diseases, differing between patients.
The nature of human IL-6 Puel, Anne; Casanova, Jean-Laurent
The Journal of experimental medicine,
09/2019, Volume:
216, Issue:
9
Journal Article
Peer reviewed
Open access
Countless functions have been attributed experimentally to IL-6. In this issue of
, Spencer et al. (https://doi.org/10.1084/jem.20190344) reveal essential, nonredundant functions of human IL-6. ...Patients with genetic deficiencies of the IL-6 receptor suffer from "hyper IgE syndrome."
Most Toll‐like‐receptors (TLRs) and interleukin‐1 receptors (IL‐1Rs) signal via myeloid differentiation primary response 88 (MyD88) and interleukin‐1 receptor‐associated kinase 4 (IRAK‐4). The ...combined roles of these two receptor families in the course of experimental infections have been assessed in MyD88‐ and IRAK‐4‐deficient mice for almost fifteen years. These animals have been shown to be susceptible to 46 pathogens: 27 bacteria, eight viruses, seven parasites, and four fungi. Humans with inborn MyD88 or IRAK‐4 deficiency were first identified in 2003. They suffer from naturally occurring life‐threatening infections caused by a small number of bacterial species, although the incidence and severity of these infections decrease with age. Mouse TLR‐ and IL‐1R‐dependent immunity mediated by MyD88 and IRAK‐4 seems to be vital to combat a wide array of experimentally administered pathogens at most ages. By contrast, human TLR‐ and IL‐1R‐dependent immunity mediated by MyD88 and IRAK‐4 seems to be effective in the natural setting against only a few bacteria and is most important in infancy and early childhood. The roles of TLRs and IL‐1Rs in protective immunity deduced from studies in mutant mice subjected to experimental infections should therefore be reconsidered in the light of findings for natural infections in humans carrying mutations as discussed in this review.
Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary ...SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.
The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in ...January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.
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