Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features.

Mendelian susceptibility to mycobacterial diseases confers predisposition to clinical disease caused by weakly virulent mycobacterial species in otherwise healthy individuals. Since 1996, disease-causing mutations have been found in five autosomal genes (IFNGR1, IFNGR2, STAT1, IL12B, IL12BR1) and one X-linked gene (NEMO). These genes display a high degree of allelic heterogeneity, defining at least 13 disorders.

IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease.

Background: About 2% of childhood episodes of invasive pneumococcal disease (IPD) are recurrent, and most remain unexplained.

Objective: To report two cases of otherwise healthy, unrelated children with recurrent IPD as the only clinical infectious manifestation of an inherited disorder in nuclear factor-kappaB(NF-kappaB)-dependent immunity.

Results: One child carried two germline mutations in IRAK4, and had impaired cellular responses to interleukin (IL)1 receptor and toll-like receptor (TLR) stimulation.

Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.

The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)-induced gamma-activating factor-mediated immunity and interferon alpha (IFNA)-induced interferon-stimulated genes factor 3-mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles.

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

Germline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-gamma-mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)-MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-kappaB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD.

TLR8-mediated NF-kappaB and JNK activation are TAK1-independent and MEKK3-dependent.

TLR8-mediated NF-kappaB and IRF7 activation are abolished in human IRAK-deficient 293 cells and IRAK4-deficient fibroblast cells. Both wild-type and kinase-inactive mutants of IRAK and IRAK4, respectively, restored TLR8-mediated NF-kappaB and IRF7 activation in the IRAK- and IRAK4-deficient cells, indicating that the kinase activity of IRAK and IRAK4 is probably redundant for TLR8-mediated signaling. We recently found that TLR8 mediates a unique NF-kappaB activation pathway in human 293 cells and mouse embryonic fibroblasts, accompanied only by IkappaBalpha phosphorylation and not IkappaBalpha degradation, whereas interleukin (IL)-1 stimulation causes both IkappaBalpha phosphorylation and degradation.

A novel primary immunodeficiency with specific natural-killer cell deficiency maps to the centromeric region of chromosome 8.

We describe four children with a novel primary immunodeficiency consisting of specific natural-killer (NK) cell deficiency and susceptibility to viral diseases. One child developed an Epstein-Barr virus-driven lymphoproliferative disorder; two others developed severe respiratory illnesses of probable viral etiology. The four patients are related and belong to a large inbred kindred of Irish nomadic descent, which suggests autosomal recessive inheritance of this defect.

Tuberculosis in children and adults: two distinct genetic diseases.

Disseminated disease in children and pulmonary disease in adults constitute two major epidemiological and clinical forms of tuberculosis. Paradoxically, only a small fraction of infected individuals develop clinical tuberculosis, typically one form of the disease or the other. Mendelian and complex genetic predispositions to tuberculosis were reported recently in children and adults, respectively.

Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses.

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells.

Septicemia without sepsis: inherited disorders of nuclear factor-kappa B-mediated inflammation.

Septicemia is a life-threatening condition that may lead to sepsis and even septic shock. This cascade is usually accompanied by a pronounced inflammatory response, leading to high body temperature and elevated levels of laboratory markers of inflammation. However, this response can be significantly diminished in children with inherited disorders of nuclear factor (NF)-kappa B-mediated immunity.

Inborn errors of immunity to infection: the rule rather than the exception.

The immune system's function is to protect against microorganisms, but infection is nonetheless the most frequent cause of death in human history. Until the last century, life expectancy was only approximately 25 years. Recent increases in human life span primarily reflect the development of hygiene, vaccines, and anti-infectious drugs, rather than the adjustment of our immune system to coevolving microbes by natural selection.

Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations.

Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of the new carbohydrate chains has never been formally established. We identified three children with mendelian susceptibility to mycobacterial disease who were homozygous with respect to a missense mutation in IFNGR2 creating a new N-glycosylation site in the IFNgammaR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNgamma.

NEMO mutations in 2 unrelated boys with severe infections and conical teeth.

X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency is a developmental and immunologic disorder caused by mutations in nuclear factor-kappaB essential modulator (NEMO), which is essential for nuclear factor-kappaB activation. Early in life, affected boys present a typical appearance, with hypotrichosis or atrichosis, hypohidrosis or anhidrosis, and hypodontia or anodontia with conical incisors. They are also susceptible to various microorganisms, mostly pyogenic bacteria and mycobacteria.

Inherited disorders of human Toll-like receptor signaling: immunological implications.

In vitro nine of 10 known human Toll-like receptors (TLRs) are engaged by well-defined chemical agonists that mimic microbial compounds, raising the possibility that human TLRs play a critical role in protective immunity in vivo. We thus review here the recently described human primary immunodeficiencies caused by germline mutations in genes encoding molecules involved in cell signaling downstream from TLRs. Subjects with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) carry either X-linked recessive hypomorphic mutations in NEMO or autosomal dominant hypermorphic mutations in IKBA.

Association of IL12RB1 polymorphisms with pulmonary tuberculosis in adults in Morocco.

Five disease-causing genes, including the IL12RB1 gene that encodes the beta 1 chain of the receptor for interleukin (IL)-12 (IL-12R beta 1), are known to be associated with the syndrome of Mendelian susceptibility to mycobacterial diseases. Some IL-12R beta 1-deficient patients present with tuberculosis as the only clinical phenotype. A comprehensive genetic study of IL12RB1 was conducted among 101 Moroccan families, including 157 offspring (age, >15 years) who had culture-positive pulmonary tuberculosis (PTB).

A novel form of complete IL-12/IL-23 receptor beta1 deficiency with cell surface-expressed nonfunctional receptors.

Complete interleukin-12/interleukin-23 receptor beta1 (IL-12Rbeta1) deficiency is the most frequent known genetic etiology of the syndrome of Mendelian susceptibility to mycobacterial disease. The patients described to date lack IL-12Rbeta1 at the surface of their natural killer (NK) and T cells due to IL12RB1 mutations, which either interrupt the open reading frame or disrupt protein folding. We describe a patient with a large in-frame deletion of 12165 nucleotides (nt) in IL12RB1, encompassing exons 8 to 13 and resulting in the surface expression of nonfunctional IL-12Rbeta1.

The human model: a genetic dissection of immunity to infection in natural conditions.

Tremendous progress has been achieved in developmental, cellular and molecular immunology in the past 20 years, largely due to studies using the mouse as a model system and the arrival of molecular genetics. Immunology is now faced with a difficult challenge. What are the functions of the individual cells and molecules in achieving immunity to infection? Renewed interest in animal models of disease has provided considerable insight in this area, but such models of infection suffer from the inherent limitation of being experimental.

Primary immunodeficiencies associated with pneumococcal disease.

Purpose Of Review: Streptococcus pneumoniae may cause disease in patients with a variety of primary immunodeficiencies. However, no previous review has dealt with the issue of which primary immunodeficiencies predispose affected individuals to pneumococcal disease. We thus reviewed the medical literature on cases of S.

The role of interleukin-12 in human infectious diseases: only a faint signature.

IL-12 is the signature IFN-gamma-inducing cytokine and, as such, is thought to be crucial for protective immunity against intracellular microorganisms. This concept is supported by results from experimental infections of knockout mice lacking IL-12 or the IL-12 receptor. The description of human patients with inherited IL-12 or IL-12-receptor deficiency challenges this view.