Shen-Ying Zhang

TLR3 Deficiency in Patients with Herpes Simplex Encephalitis

Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of TLR3.

Inborn errors of interferon (IFN)‐mediated immunity in humans: insights into the respective roles of IFN‐α/β, IFN‐γ, and IFN‐λ in host defense

Summary: Interferon (IFN) was originally identified as a substance ‘interfering’ with viral replication in vitro. The first IFNs to be identified were classified as type I IFNs (IFN‐α/β and related molecules), two other types have since been identified: type II IFN (IFN‐γ) and type III IFNs (IFN‐λ). Each IFN binds to one of three type‐specific receptors. In the mouse model of experimental infections in vivo, IFN‐α/β are essential for immunity to most viruses tested, whereas IFN‐γ is important for immunity to a smaller number of viruses, together with bacteria, fungi, and parasites, consistent with IFN‐γ acting as the ‘macrophage activating factor.’ The precise role of IFN‐λ remains unclear. In recent years, inborn errors affecting the production of, or the response to, IFNs have been reported in human patients, shedding light onto the function of IFNs in natura. Disorders of IFN‐γ production, caused by IL12B, IL12RB1, and specific NEMO mutations, or of IFN‐γ responses, caused by IFNGR1, IFNGR2, and dominant STAT1 mutations, confer predisposition to mycobacterial disease in patients resistant to most viruses. By contrast, disorders of IFN‐α/β and IFN‐λ production, caused by UNC93B1 and TLR3 mutations, confer predisposition to herpes simplex encephalitis (HSE) in otherwise healthy patients. Consistently, patients with impaired responses to IFN‐α/β, IFN‐γ, and presumably IFN‐λ (carrying recessive mutations in STAT1), or with impaired responses to IFN‐α/β and impaired IFN‐γ production (carrying mutations in TYK2), or with impaired production of IFN‐α/β, IFN‐γ, and IFN‐λ (carrying specific mutations in NEMO), are vulnerable to mycobacterial and viral infections, including HSE. These experiments of nature suggest that the three types of IFNs play at least two different roles in host defense. IFN‐γ is essential for anti‐mycobacterial immunity, whereas IFN‐α/β and IFN‐λ are essential for anti‐viral immunity. Future studies in humans aim to define the specific roles of IFN‐α/β and IFN‐λ types and individual molecules in host defense in natura.

Human Complete Stat-1 Deficiency Is Associated with Defective Type I and II IFN Responses In Vitro but Immunity to Some Low Virulence Viruses In Vivo

The autosomal recessive form of human complete Stat-1 deficiency is a rare disorder, thus far reported in two unrelated patients, both of whom developed disseminated bacillus Calmette-Guérin (BCG) and subsequently died of viral illnesses before detailed studies of the condition could be performed. It is associated with impaired cellular responses to both IFN-γ and IFN-αβ via Stat-1-containing complexes. We describe a third patient with complete Stat-1 deficiency and disseminated BCG infection, who died 3 mo after bone marrow transplantation. The patient’s EBV-transformed B cells did not express Stat-1 protein and did not activate Stat-1-containing transcription factors. We also report the ex vivo responses of a Stat-1-deficient patient’s fresh blood cells to IFN-γ and the in vitro responses of a SV40-transformed fibroblastic cell line to IFN-γ and IFN-αβ. There was no response to IFN-γ in terms of IL-12 production and HLA class II induction, accounting for vulnerability to BCG. Moreover, IFN-αβ did not suppress HSV and vesicular stomatitis virus replication in fibroblasts, although in vivo the patient was able to successfully clear at least some viruses. This study broadens our understanding of complete Stat-1 deficiency, a severe form of innate immunodeficiency. Stat-1 deficiency should be suspected in children with severe infections, notably but not exclusively patients with mycobacterial or viral diseases.

Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses.

Summary: Five of the 10 human Toll‐like receptors (TLRs) (TLR3, TLR4, TLR7, TLR8, and TLR9), and four of the 12 mouse TLRs (TLR3, TLR4, TLR7, TLR9) can trigger interferon (IFN)‐α, IFN‐β, and IFN‐λ, which are critical for antiviral immunity. Moreover, TLR3, TLR7, TLR8, and TLR9 differ from TLR4 in two particularly important ways for antiviral immunity: they can be activated by nucleic acid agonists mimicking compounds produced during the viral cycle, and they are typically present within the cell, along the endocytic pathway, where they sense viral products in the intraluminal space. Investigations in mice have demonstrated that the TLR7/9–IFN and TLR3–IFN pathways are different and critical for protective immunity to various experimental viral infections. Investigations in humans with interleukin‐1 receptor‐associated kinase‐4 (IRAK‐4) deficiency (unresponsive to TLR7, TLR8, and TLR9), UNC‐93B deficiency (unresponsive to TLR3, TLR7, TLR8, and TLR9), and TLR3 deficiency have recently shed light on the role of these two pathways in antiviral immunity in natural conditions. UNC‐93B‐ and TLR3‐deficient patients appear to be specifically prone to herpes simplex virus 1 (HSV‐1) encephalitis, although clinical penetrance is incomplete, whereas IRAK‐4‐deficient patients appear to be normally resistant to most viruses, including HSV‐1. These experiments of nature suggest that the TLR7‐, TLR8‐, and TLR9‐dependent induction of IFN‐α, IFN‐β, and IFN‐λ is largely redundant in human antiviral immunity, whereas the TLR3‐dependent induction of IFN‐α, IFN‐β, and IFN‐λ is critical for primary immunity to HSV‐1 in the central nervous system in children but redundant for immunity to most other viral infections.

Revisiting human primary immunodeficiencies

Human primary immunodeficiencies (PIDs) are often thought to be confined to a few rare, familial, monogenic, recessive traits impairing the development or function of one or several leucocyte subsets and resulting in multiple, recurrent, opportunistic and fatal infections in infancy. We highlight here the rapidly growing number of exceptions to each of these conventional qualifications. Indeed, bona fide PIDs include common and sporadic illnesses and may present as dominant, or even polygenic traits; their pathogenesis may involve non haematopoietic cells, and they may result in single episode of illness, with a single or multiple morbid phenotypes, some of which may involve infection, in otherwise healthy adults. We need to increase awareness of the multitude of clinical presentations of human PIDs considerably and rapidly in the medical community. Human PIDs should be considered in a wide range of clinical situations.

From infectious diseases to primary immunodeficiencies.

The field of primary immunodeficiencies has expanded, thanks to the exploration of novel clinical phenotypes and their connection with morbid genotypes, and the subsequent exploration of new patients who have known primary immunodeficiency-defining clinical phenotypes and their connection with novel morbid genotypes. This two-way process is becoming increasingly active, particularly for patients who have infectious diseases in whom the underlying immunologic and genetic causes remain mostly unexplained. The authors review how the exploration of children who have clinical infectious diseases caused by mycobacteria, pneumococcus, and herpes simplex virus recently led to the description of three new groups of primary immunodeficiencies. These three examples justify the continuation of the genetic exploration of novel infectious phenotypes and novel patients who have infections. This challenging process will eventually reap its rewards, to the benefit of patients and their families.

Addressing diagnostic challenges in primary immunodeficiencies: laboratory evaluation of Toll-like receptor- and NF-κB-mediated immune responses.

Abstract Toll-like receptors (TLRs) play an important role in immunity and mediate their actions via multiple signaling pathways, in particular, the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) pathway. Rare inherited defects of TLR- and NF-κB-dependent responses have recently been recognized. These primary immunodeficiencies predispose children to life-threatening infections and often remain undiagnosed. Establishing a sensitive, specific, cost-effective and simple method for diagnosis is therefore important. In this article, we review the known defects of TLR- and NF-κB-mediated pathways and the assays that can be used to screen for such defects.

Immunodeficiencies at the Interface of Innate and Adaptive Immunity

Abstract In the last 20 years, new primary immunodeficiencies (PIDs) affecting the immunity mediated by interferon (IFN)-γ, IFN-α/β-λ, Toll and interleukin-1 receptor (TIR) domain nuclear factor (NF)-κB, Toll-like receptor (TLR)-3 pathway, and interleukin (IL)-17 have been identified. Some of these genetic defects are “conventional” PIDs, associated with a broad range of infections, but others provide a molecular explanation for severe pediatric infectious diseases previously thought to be idiopathic. These “nonconventional” PIDs may be associated with severe and/or recurrent infections caused by a single family of microorganisms, a situation strongly contrasting with that for “conventional” PIDs. Standard immunological explorations are generally normal in these patients, whether they are susceptible to one infection or to many infectious agents. Despite the lack of a clear immunological abnormality, infections in these patients are typically severe and often fatal. All these disorders were initially thought to be rare, but they have since been diagnosed in about 800 patients around the world.

Mendelian Susceptibility to Infections with Viruses, Mycobacteria, Bacteria, and Candida

Classical primary immunodeficiencies confer a predisposition to multiple microorganisms or recurrent infectious diseases. However, over the last 30xa0years, a molecular explanation has been proposed for the severe idiopathic infections caused by viruses, mycobacteria, pyogenic bacteria, or fungi, such as Candida, in particular. Defects of several biologically related genes may confer a selective predisposition to infections with one of these specific groups of pathogens in otherwise healthy individuals. Such individuals present a new type of primary immunodeficiency, with severe and/or recurrent infections caused by a single family of microorganisms, as opposed to the broader defects in patients with ‘classical’ primary immunodeficiencies.