Novel primary immunodeficiencies revealed by the investigation of paediatric infectious diseases
Introduction
Primary immunodeficiencies (PIDs) cannot easily be divided into ‘innate’ and ‘adaptive’ conditions. Mutations in only a few genes would be predicted to have a direct and exclusive effect on T-cell or B-cell adaptive immunity, or both. These genes would include those specifically controlling the production or function of antigen receptors. Similarly, only a few known conditions are caused by genes expressed exclusively in innate cells. Indeed, most PID-causing mutations directly affect both innate and adaptive immunity. Moreover, the impairment of one type of immunity indirectly affects the other type of immunity. There is currently no ideal classification of PIDs, which may be classified on the basis of clinical phenotype, cellular phenotype or PID-causing genotype [1•, 2, 3, 4, 5]. We review here a small but expanding group of PIDs with the following features in common: (i) seemingly normal development of the principal myeloid and lymphoid leukocyte subsets (CD4 and CD8 T cells, B cells, granulocytes, monocytes, NK cells, and NK-T cells, the status of blood DCs and T regs being undefined in most patients), (ii) apparently normal T-cell and B-cell responses to antigens, at least in vitro, (iii) impaired myeloid and/or lymphoid leukocyte activation by receptors other than antigen receptors, whether because of a lack of ligand, a lack of receptor, or a lack of signalling component, and (iv) predisposition to infectious disease, with few, if any, other clinical phenotypes. The infections occurred either in the context of a well-defined complex primary immunodeficiency – occasionally associated with developmental features – or as unexplained, ‘idiopathic’ infectious disease. The various infectious phenotypes observed led to the description of PIDs affecting various leukocyte-signalling pathways (Figure 1).
Section snippets
Inborn errors of NF-κB-mediated immunity (NEMO and IKBA)
X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (XR-EDA-ID) was found in 2001 to result from hypomorphic mutations in IKBKG/NEMO, encoding the regulatory subunit of the IKK complex [6, 7, 8]. In 2003, an autosomal dominant form of EDA-ID (AD-EDA-ID) was identified, caused by a hypermorphic heterozygous mutation of IKBA, impairing the phosphorylation and degradation of NF-κB inhibitor α (IκBα) [9] (Figure 1, Figure 2). This disease does not strictly belong to the group
Inborn errors of the TLR and IL-1R pathways (IRAK4, MYD88)
IRAK-4 is a serine-threonine kinase acting downstream from TLRs and IL-1Rs. Autosomal recessive IRAK-4 deficiency was first discovered in 2003 [32]. Up to 28 patients [10, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45] have since been identified [46•]. Patients with autosomal recessive MyD88 deficiency have also recently been identified (von Bernuth H. et al., in preparation). MyD88 is a key adaptor molecule in the TLR and IL-1R (TIR) pathway, connecting surface TLRs and IL-1Rs with
Inborn errors of the TLR3-IFN-α-IFN-β and IFN-λ pathway (TLR3, UNC93B1)
The role in host defences of the TLRs dependent on MyD88 and IRAK-4 remains to be clarified, but that of TLR3, which is independent of MyD88 and IRAK-4, has recently been defined. HSE is the most common cause of acute, sporadic viral encephalitis in the Western world [47]. In 2006, autosomal recessive UNC-93B deficiency was identified as the first genetic aetiology of HSE [48•] (Figure 1, Figure 3). UNC-93B is a 12-transmembrane domain protein present in the endoplasmic reticulum. Physical
Inborn errors of the STAT-1-dependent, IFN-α, IFN-β, IFN-γ and IFN-λ pathways (STAT1)
The first disorder of human IFN-α/β-mediated immunity was described in 2003, with the discovery of two children with complete STAT-1 deficiency [56]. A few other patients have since been identified [57]. All these patients had homozygous STAT1 mutations, leading to a complete absence of the protein. The patients’ cells do not respond to type I IFNs (IFN-α and IFN-β) and to type II IFN (IFN-γ) in terms of ISGF-3 (STAT-1, STAT-2 and p48 complexes activated by IFN-α and IFN-β) and GAF (STAT-1
Inborn errors of the IFN-γ pathway (IFNGR1, IFNGR2, STAT1)
Mendelian susceptibility to mycobacterial disease (MSMD) is characterised by a selective predisposition to infection by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy patients (Figure 1, Figure 4). Since the discovery of the first genetic aetiology of this syndrome in 1996 – with mutations in IFNGR1, encoding the ligand-binding chain of the IFN-γ receptor [60, 61] – two related MSMD-causing genes have been identified: IFNGR2, encoding the
Inborn errors of the IL-12 and IL-23 pathways (IL12B, IL12RB1)
It was shown in 1998 that patients with MSMD might harbour mutations of the IL-12 and IL-23 pathways [72, 73, 74], indicating that these cytokines play a key role in controlling anti-mycobacterial IFN-γ levels. Mutations were found in IL12B, which encodes IL-12p40, common to both IL-12 and IL-23 [73], and in IL12RB1, which encodes the first chain of IL-12 receptor (IL-12Rβ1), common to the IL-12 and IL-23 receptors [72, 74]. IL-12Rβ1 deficiency is the most common genetic aetiology of MSMD [59],
Inborn errors of the IL-6 pathway (STAT3, TYK2)
Insight into the pathogenesis of staphylococcal infections was recently provided by investigations of patients with HIES [84, 85]. Autosomal dominant (AD) HIES is a distinct entity – a complex primary immunodeficiency associated with developmental traits and a poor inflammatory response [84] (Figure 1, Figure 2). By contrast, autosomal recessive (AR) HIES groups together patients with little in common, other than high serum IgE concentrations, and whose immunological phenotypes may range from
Concluding remarks
The past ten years have witnessed the emergence of a novel group of primary immunodeficiencies in patients with various infectious diseases, associated in some instances with a complex immunological and developmental syndrome involving predisposition to multiple infections, such as EDA-ID or HIES, but in most cases isolated and ‘idiopathic’, such as MSMD and HSE in otherwise healthy children. In patients with such primary immunodeficiencies, myeloid and/or lymphoid cells fail to activate one or
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
Acknowledgements
We warmly thank our patients, their families and physicians, our scientific collaborators, and past and present members of the laboratory. We apologise to colleagues whose publications could not be cited owing to space limitations. The laboratory is supported by grants from the INSERM, the ANR, the University Paris René Descartes, the BNP-Paribas Foundation, the Dana Foundation, and the March of Dimes. Jean-Laurent Casanova is an International Scholar of the Howard Hughes Medical Institute.
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All authors contributed equally to this work.