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Keywords:

  • cytokines;
  • pattern recognition receptors;
  • primary immunodeficiencies;
  • Toll-like receptors

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. PRRs: recognizing the pathogen and activating innate host defence
  5. Recognition of pathogenic microorganisms by PRRs
  6. PIDs because of defects in PRRs
  7. Conclusions and perspectives
  8. Conflict of interest
  9. Acknowledgements
  10. References

Primary immunodeficiencies (PIDs) are severe defects in the capacity of the host to mount a proper immune response, and are characterized by an increased susceptibility to infections. Although classical immunodeficiencies have been characterized based on broad defects in cell populations (e.g. T/B cells or polymorphonuclear leukocytes) or humoral factors (e.g. antibodies or complement), specific immune defects based on well-defined molecular targets have been described more recently. Among these, genetic defects in pattern recognition receptors (PRRs), leading to impaired recognition of invading pathogens by the innate immune system, play an important role in specific defects against human pathogens. Defects have been described in three of the major families of PRRs: the Toll-like receptors, the C-type lectin receptors and the nucleotide-binding domain leucine-rich repeat-containing receptors. By contrast, no defects in the intracellular viral receptors of the RigI helicase family have been described to date. Defects in the PRRs show a broad variation in severity, have a narrow specificity for certain classes of pathogens, and often decrease in severity with age; these characteristics distinguish them from other forms of PIDs. Their discovery has led to important insights into the pathophysiology of infections, and may offer potential novel therapeutic targets for immunotherapy.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. PRRs: recognizing the pathogen and activating innate host defence
  5. Recognition of pathogenic microorganisms by PRRs
  6. PIDs because of defects in PRRs
  7. Conclusions and perspectives
  8. Conflict of interest
  9. Acknowledgements
  10. References

Infections are diseases that are strongly influenced by the genetic make-up of each individual, as demonstrated by studies to determine the correlation between the cause of death in adopted children and their biological parents [1]. In the population as a whole, genetic susceptibility is most often multifactorial, with incremental increases in risk with each genetic variant. However, in a minority of patients who suffer from unusually severe infections because of common pathogens, or to infections from microorganisms that are usually non-pathogenic, primary immunodeficiencies (PIDs) because of severe defects in a particular gene have been described.

In the last two decades, improvement in genetic methodology has enabled the discovery of a multitude of novel PIDs. Some of the mutations identified are in genes that control the development of cell lineages as a whole, explaining the classical forms of immunodeficiencies [2-7], whereas others have identified specific defects in well-defined pathways of immune activation. Among these specific PIDs, defects in interleukin (IL)-12 or interferon (IFN)-γ receptor have been shown to result in defective cellular immunity and an increased susceptibility to infections by intracellular pathogens such as mycobacteria and Salmonella [8, 9], and defects in the IFN signalling pathway lead to increased susceptibility to viruses [10]. In addition, recent studies have identified genetic defects that impair pathogen recognition by the innate immune system, leading to an increased susceptibility to specific classes of microorganisms [11]. In this review, we will focus on the defects in the pattern recognition receptors (PRRs), which are considered to represent a novel group of PIDs.

PRRs: recognizing the pathogen and activating innate host defence

  1. Top of page
  2. Abstract
  3. Introduction
  4. PRRs: recognizing the pathogen and activating innate host defence
  5. Recognition of pathogenic microorganisms by PRRs
  6. PIDs because of defects in PRRs
  7. Conclusions and perspectives
  8. Conflict of interest
  9. Acknowledgements
  10. References

The first step in initiating a defence response is represented by the recognition of microbial ligands, termed pathogen-associated molecular patterns (PAMPs), by germ line-encoded PRRs. These receptors allow selective recognition within the innate immune system [12-14], and four major classes have been described to date: the Toll-like receptors (TLRs), the C-type lectin receptors (CLRs), the nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs) and the RigI helicases [12]. Although very often PAMPs are components of the cell wall of microorganisms, other components such as bacterial or fungal DNA, metabolic products or viral nucleic acids are also recognized as PAMPs by the innate PRRs. A distinction must be made between PRRs as activating receptors that induce intracellular signals which activate host defence, but not as molecules used by microorganisms to attach to and invade the host cell (e.g. TLRs can be considered as PRRs, but not CEACAM which is involved in the attachment of meningococci). In this review, we present a summary of the recent developments in the field of PIDs caused by defects in PRRs.

Recognition of pathogenic microorganisms by PRRs

  1. Top of page
  2. Abstract
  3. Introduction
  4. PRRs: recognizing the pathogen and activating innate host defence
  5. Recognition of pathogenic microorganisms by PRRs
  6. PIDs because of defects in PRRs
  7. Conclusions and perspectives
  8. Conflict of interest
  9. Acknowledgements
  10. References

The concept of PRRs was proposed by the late Charles Janeway in 1992, and the first experimental proof was provided by Lemaitre and colleagues in a seminal study showing that Drosophila fruit flies lacking the haematocyte receptor Toll were highly susceptible to fungal and Gram-positive bacterial infections [15]. Since then, 10 human homologues termed TLRs have been identified, all of which contain an extracellular domain consisting of leucine-rich repeats (LRR) that recognizes microbial or fungal structures, and a cytoplasmic Toll/IL-1 receptor (TIR) domain for intracellular signalling [16]. Studies performed in the last 15 years have shown that TLRs are crucial for recognition of bacteria, viruses, fungi and parasites [17, 18], and play a central role in activation of innate immune responses (Fig. 1). Essential roles for TLRs in the recognition of bacteria have been reported. TLR4, one of the most important members of the family, is the cellular receptor for the lipopolysaccharide component of Gram-negative bacteria [19] and activates innate immunity for example in urinary tract infections with Escherichia coli [20]. Polymorphisms in TLR4 influence susceptibility to Gram-negative sepsis [21]. By contrast, TLR2 is the main receptor for lipopetides and peptidoglycans of Gram-positive bacteria [22], and modulates host defence against streptococcal and staphylococcal infections [23, 24]. As well as having effects on innate immune responses, TLRs have been shown to activate antigen-presenting cells and bridge innate and adaptive immunity [25, 26].

image

Figure 1. The four major classes of pattern recognition receptors (PRRs) and their ligands: Toll-like receptors (TLRs), C-type receptors (CLRs), nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs) and RigI helicases.

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In addition to TLRs, other important classes of PRRs, including CLRs, NLRs and RigI helicases, have also been identified. CLRs, termed because of their dependence on Ca2+ for activation (at least for some family members), are a large group of PRRs that recognize polysaccharide structures. It has recently been shown that these receptors have a central role in the recognition of fungi and bacteria [27]. Well-known members of the CLR family include dectin-1, the macrophage mannose receptor, the dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN), dectin-2 and the circulating mannose-binding lectin (MBL). These receptors share one or more carbohydrate-recognition domains originally found in MBL [28].

In addition to cell membrane-associated PRRs, such as the TLRs and CLRs, a second line of defence is represented by intracellular PRRs that recognize bacterial structures released after intracellular lysis of the microorganism; for example, the RigI helicases recognize nucleic acids and the NLRs recognize bacterial peptidoglycans [29, 30] (Fig. 1). Furthermore, NLRs are central for the activation of inflammasomes [31, 32]. Inflammasomes are protein platforms responsible for the conversion of pro-caspase-1 into active caspase-1, and the subsequent processing of the proinflammatory cytokines IL-1β and IL-18. Several inflammasome variants have been described [33] (Fig. 2).

image

Figure 2. Inflammasomes are complex protein platforms that cause the activation of caspase-1. In turn, caspase-1 processes and activates proinflammatory cytokines of the IL-1 family such as IL-1β and IL-18. The most well-studied of these protein platforms are the NLRP3 inflammasome activated by bacterial and fungal pathogen-associated molecular patterns, the NLRC4 inflammasome activated during intracellular bacterial infections by flagellin, and the AIM2 inflammasome activated by dsDNA.

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The knowledge that PRRs have a role in host defence against pathogens led to interest in their potential involvement in susceptibility to infections. Polymorphisms in the genes coding for PRRs have been described, some of which have an impact on susceptibility to infections [34, 35]. Even more significantly, however, recent studies have identified novel PIDs caused by genetic defects in PRR recognition pathways, that present with a very specific immunological and clinical phenotype.

PIDs because of defects in PRRs

  1. Top of page
  2. Abstract
  3. Introduction
  4. PRRs: recognizing the pathogen and activating innate host defence
  5. Recognition of pathogenic microorganisms by PRRs
  6. PIDs because of defects in PRRs
  7. Conclusions and perspectives
  8. Conflict of interest
  9. Acknowledgements
  10. References

Immune defects in three of the four major classes of PRRs (TLRs, CLRs and NLRs) have been described (Table 1). By contrast, defects in the RigI helicase family of PRRs have not yet been found, although future studies, especially in patients with severe and recurrent viral infections, may soon change this situation.

Table 1. Immune deficiencies because of defective recognition by pattern recognition receptors (PRRs)
PRR defectDefective pathwayInfection/disorderInheritancePrevalence
  1. AD, autosomal dominant; AR, autosomal recessive; dsRNA, double stranded RNA; MBL, mannose-binding lectin.

Toll-like receptors (TLR) defects
MyD88 deficiencyTLR pathway Pneumococcus ARVery rare
IRAK4 deficiency  Staphylococcus Pseudomonas AR 
Unc93B deficiencydsRNA recognitionHerpes simplex virus (encephalitis)ARVery rare
TRIF deficiency
TLR3 deficiencydsRNA recognitionHerpes simplex virus (encephalitis)AD or ARVery rare
TRAF3dsRNA recognitionHerpes simplex virus (encephalitis)ADVery rare
TLR5 deficiencyFlagellin recognition Legionella ARCommon
C-type lectin defects
Dectin-1 deficiencyβ-glucan recognition Candida Tricophyton ARCommon
CARD9 deficiencyβ-glucan recognition Candida ARVery rare
MBL deficiencyComplement activationBacterial and fungalARCommon
Repeat-containing receptors defects
NOD2 deficiencyPeptidoglycan recognitionDefects in intestinal mucosal defenceARRare
NLRP3 mutationsIL-1β productionAutoinflammatory syndromesADVery rare

PIDs due to defects in TLRs

Inborn errors of the TLR/IL-1R pathway: MyD88 and IRAK-4 immunodeficiency

The intracellular signals induced by TLRs depend on a limited number of adaptor molecules, among which MyD88 is one of the most important. With the exception of TLR3, all other TLRs depend on MyD88 to induce intracellular signals [36, 37]. Moreover, signalling through the receptors IL-1R and IL-18R, which contain a TIR domain, also depends on MyD88. The further transmission of these signals towards translocation of transcription factors depends on a cascade of protein kinases, among which the serine–threonine kinase IRAK-4 plays an important role [17]. Recent studies have identified mutations in IRAK-4 [38-45] and MYD88 [46] that cause predisposition to pyogenic Gram-positive bacteria and Pseudomonas species in a Mendelian fashion, and MyD88/IRAK4 has been identified as an important novel PID [47].

Even before the existence of TLRs the MyD88 pathway had been reported, a patient with recurrent bacterial infections and endotoxin and IL-1 hyporesponsiveness had been described [48]. In subsequent studies, mutations in either IRAK-4 or MyD88 have been described as a cause for increased susceptibility to recurrent pyogenic infections [38-46]. Deficiencies in the MyD88/IRAK-4 pathway result in impairment of cell stimulation by both TLR and IL-1 ligands. Patients with these defects suffer from both invasive and localized bacterial diseases. The invasive infections are manifested most often by meningitis and septicaemia, and caused mainly by Streptococcus pneumoniae, and less frequently by Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella species. Diagnosis is often complicated and therefore delayed by the slow development of an inflammatory reaction, which can impair the outcome [47]. In contrast to the case of invasive disease, localized bacterial disease is caused mainly by S. aureus, and less commonly by P. aeruginosa or S. pneumoniae [46, 49].

A feature that distinguishes MyD88/IRAK-4 immunodeficiency from other PIDs is that although these life-threatening infections start in infancy, they become less frequent and less severe towards early adolescence, and have not been documented thereafter. A recent survey showed that although invasive infections in early childhood account for a cumulative mortality of 30–40% [44], most adult patients currently under observation show a favourable clinical course without major infections and mortality [49]. It has been hypothesized that development of proficient adaptive immune responses (either T or B cell mediated) later in life may compensate for the defects in the inflammatory reaction [44]. It is noteworthy that although 30–40% mortality is seen in the antibiotic era, it is likely that the natural history of the disease would have led to a much higher mortality if antibiotics were not available.

Inborn errors of the TLR3/TRIF/TRAF3/Unc3b pathway

Pattern recognition of viruses is mediated through recognition of the viral nucleic acids by both intracellular TLRs and members of the RigI helicase family. Several TLRs recognize nucleic acids: TLR9 for unmethylated bacterial or fungal DNA, TLR7 and TLR8 for single-stranded RNA and TLR3 for double-stranded RNA [50]. Although no defects in RigI helicase receptors have been reported to date, an increased susceptibility to herpes simplex virus (HSV) encephalitis has been described in patients with mutations in genes involved in the TLR3 pathway. Among these genes, autosomal dominant or recessive TLR3 or TRIF mutations, and autosomal dominant TRAF3 or UNC93B1 mutations [51-55] have been shown to result in recurrent HSV encephalitis. The disease occurs mainly in early childhood at the age of 3 months to 6 years, during primary infection with HSV-1 [49, 56]. Fewer infections occur later, although recurrences have been documented in two patients, providing unexpected insight into the role of TLR3 in virus latency [49].

A number of important characteristics should be highlighted regarding the deficiency in the TLR3 pathway. First, the deficiency seems to be confined to increased susceptibility to a very limited spectrum of viral infection, namely HSV encephalitis; children are otherwise healthy with normal resistance to other pathogens. Secondly, some of these immunodeficiencies have been characterized by incomplete clinical penetrance, as shown for TRIF defects that have been diagnosed in some family members with mutation, but a lack of symptoms [55]. Finally, the pathophysiological mechanism is probably represented by a decreased capacity to release type I IFNs, although this conclusion is based solely on in vitro experiments. In skin-derived fibroblasts, abolition of TLR3-dependent induction of IFNs, enhanced viral replication and cell death. These effects were partially reversed by exposure of cells to recombinant IFNβ [51]. The role of the type I IFN pathway in increasing susceptibility to HSV encephalitis is supported by the report of a child with STAT-1 deficiency who developed the disease [57, 58]. Based on all these studies, it appears that the TLR3/TRIF/TRAF3/UNC93-B1 pathway is central for protective immunity against primary infection with HSV-1 in childhood, although it seems to be redundant for host defence against other infections.

TLR5 deficiency

TLR5 recognizes flagellin, an important PAMP of flagellated bacteria [59]. A genetic polymorphism (TLR5392-stop) that results in a total loss of the receptor has been reported to increase susceptibility to Legionella pneumonia [60]. It is interesting, however, that individuals with this polymorphism are not characterized by the severe phenotype displayed by other immunodeficiencies. Moreover, the allele frequency of this mutation in European populations can be as high as 10%, suggesting that this defect is a risk factor rather than a PID. Consequently, individuals carrying this allele are more susceptible to infections because of L. pneumophila [60] and to recurrent cystitis [61], but not to the flagellated Gram-negative bacteria S. typhi, the agent of typhoid fever [62]. It is also interesting that protective effects of the stop TLR5 polymorphism against systemic lupus erythematous and Crohn's disease have been reported [63, 64]. In this respect, our description of a patient suffering from chronic Yersinia enterocolitica infection, whose white cells did not respond with production of cytokines after exposure to Yersinia, is of interest. The patient appeared to have a TLR5 mutation in combination with a complete NOD2 defect, an NLR receptor involved in recognition of bacterial peptidoglycans (see below) [65]. This suggests that the impaired TLR5 may have exerted a protective effect against the development of Crohn's disease, which is highly prevalent in individuals with NOD2 defects.

Although population genetic studies have suggested that TLR5 is under selective pressure, the high and variable frequencies in the human population of these polymorphisms suggests that this gene is not essential for host defence [66]. TLR5 mutations alone cannot be seen as classical immunodeficiency, but rather as a disease risk factor.

Immunodeficiencies because of defects in CLRs

C-type lectin receptors, a large family of PRRs, recognize carbohydrate structures of microorganisms and also have direct immune functions by recognizing endogenous ligands [27]. Their role in the recognition of mycobacteria, especially fungal pathogens, has been emphasized recently, and deficiencies of some CLRs have been described.

Deficiencies in the Dectin-1/Card9 pathway

Dectin-1, the major PRR expressed on monocytes and macrophages, mediates recognition of β1,3-glucans of the fungal cell wall [67, 68]. It also recognizes Mycobacterium tuberculosis, although the exact mycobacterial components that constitute its ligands are unknown [69, 70]. Recently, we have described a family including several patients with mucocutaneous fungal infections [71]. Genetic analysis identified an early stop codon in the Y238X position of dectin-1, leading to the loss of the last 10 amino acids of the extracellular carbohydrate recognition domain. As a consequence, transcription and translation cause a misfolded dectin-1 molecule that is not expressed on the cell membrane, resulting in a complete failure of mononuclear phagocytes to bind β-glucans. This in turn leads to impaired IL-6, TNF, and especially IL-17 production, after challenge of cells isolated from patients with β-glucans or fungal pathogens. By contrast, dectin-1-deficient neutrophils exhibit normal phagocytosis and killing of Candida albicans, suggesting that dectin-1 is not essential for the function of neutrophils. This can explain the absence of invasive candidiasis in these patients.

This mutation is present in up to 8% of Europeans in heterozygous form, and the prevalence is higher in some sub-Saharan populations [71]. This implies that approximately 1 : 400–1 : 600 Europeans may have complete dectin-1 deficiency, which does not seem to cause a severe immunodeficiency syndrome. Indeed, the phenotype we observed is relatively mild, being much less severe than the classical chronic mucocutaneous candidiasis [72, 73]. On the other hand, the high prevalence of heterozygosity of this variant is likely to increase the impact of dectin-1 deficiency at a population level. Indeed, the dectin-1 Y238X polymorphism has been associated with an increased likelihood of colonization with Candida, resulting in an increase in antifungal prophylaxis in patients with heterologous stem cell transplantation [74]. Moreover, several studies have shown an increased susceptibility to invasive aspergillosis in individuals with the variant allele [75-77]. Thus, it appears that dectin-1 deficiency as a result of this polymorphism increases the risk of fungal infections, rather than causing a classical immunodeficiency syndrome.

The role of CLRs for antifungal host defence is further strengthened by the identification of a family carrying mutations in Card9, which encodes an adaptor molecule that mediates intracellular signalling induced by dectin-1, dectin-2, Mincle and possibly other CLRs. Several individuals in this family with a Card9 mutation demonstrated increased susceptibility to fungal infections [78]. Most of these infections were mucocutaneous, but two members of the family developed severe invasive fungal infections. Defective Th17 differentiation with deficiency of IL-17 production has also been reported as a functional defect in patients with Card9 mutations [78]. The more severe phenotype of Card9 mutations, compared to dectin-1 deficiency, is likely to be because of the role of CARD9 as an adaptor molecule for mediating signals for several other CLRs in addition to dectin-1.

MBL deficiency

Mannose-binding lectin is a soluble lectin that binds microorganisms and activates the complement system [79]. Deficiencies in MBL were initially reported in an infant with recurrent bacterial infections, but later studies showed a high prevalence of individuals with low circulating MBL levels; commonly inherited polymorphisms in the MBL gene can result in a decrease in MBL levels in up to 40% of Caucasians, and considerably reduced levels in up to 8%. MBL deficiency has been associated with an array of bacterial infections (most notably Neisseria meningitidis), as well as fungal and viral infections (for a systematic review of the role of MBL in clinical infections see [80-82]). Several studies have also demonstrated an association between MBL deficiency and recurrent vulvovaginal candidiasis [83-86]. However, the majority of individuals in the general population with low MBL levels do not suffer from this condition, and high levels of MBL do not seem to have any clinical consequences. Thus, MBL deficiency can be characterized merely as a risk factor for infections [87].

Defects of the NLRs

Genomic studies have been conducted to identify conserved gene families with structures similar to those of other PRRs and have led to the discovery of the NLRs. These receptors are located intracellularly, and have two major biological functions in the immune system: (i) NOD1 and NOD2, the first two NLRs to be described, are the major receptors for bacterial peptidoglycans [29, 30] and (ii) a second group of receptors, NLRPs, are essential for formation of the inflammasome, activation of caspase-1 protease and the subsequent processing of the IL-1 family cytokines such as IL-1β and IL-18 [31, 32]. Genetic defects in both NOD2 and NLRP genes have been described.

NOD2 deficiency: Crohn's disease as a PID

The first reports of defects in NOD2 described several mutations in the LRR domain in selected familial cases of Crohn's disease [88, 89]. Furthermore, a mutation in the nucleotide-binding domain of NOD2 was found to be associated with Blau syndrome, a form of juvenile sarcoidosis [90].

There has been much discussion regarding the exact mechanisms through which the NOD2 defects result in the inflammation of Crohn's disease [91, 92], however most data point to a loss-of-function mutation leading to decreased production of defensins in the gut mucosa [93] and a dysregulated cytokine response [94, 95]. These events are followed by impaired elimination of invading microorganisms from the mucosa, with a granulomatous inflammatory reaction. Thus, it has been hypothesized that Crohn's disease in patients with NOD2 defects is because of impaired mucosal host defence. Of interest, the results of studies in autophagy genes (ATG16L1, IRGM) have supported this hypothesis of genetic defects in innate immunity as the cause of Crohn's disease [96, 97]. Moreover, considering the pathological immune reactions observed in patients with Crohn's disease such as defective neutrophil function and dysregulated cytokine responses [98, 99], it has been proposed that this condition is a PID of gut mucosal immunity [100, 101]. One could argue that this would be an atypical phenotype for a PID, but the scientific arguments for this position have been steadily accumulating in the past years.

NLRP3 defects and autoinflammatory syndromes

Inflammasomes are necessary for the activation of caspase-1 and cleavage of the proinflammatory cytokines IL-1β and IL-18. All inflammasomes need a backbone formed by an NLR (e.g. NLRP1, NLRP3 or NLRC4), with the adaptor molecule ASC connecting it with caspase-1. Mutations in NLRP3 have been described in the so-called cryopyrin-associated periodic syndromes (NLRP3 was previously known as cryopyrin), of which familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease [NOMID; or chronic infantile neurological cutaneous articular syndrome (CINCA)] are various phenotypic expressions [102]. These syndromes are characterized by increasing severity of the symptoms: cold-induced fever, urticaria-like rash and systemic symptoms for FCAS; fever, hives, sensorineural hearing loss and arthritis unrelated to cold exposure for MWS; and fever, urticaria, epiphyseal overgrowth of the long bones and chronic aseptic meningitis for NOMID/CINCA [103]. An autoinflammatory disorder also characterizes NLRP12 deficiency, although the precise pathway of autoinflammation mediated by NLRP12 is not known [104].

Together, these findings demonstrate that the currently known genetic defects in NLRPs result in autoinflammatory diseases, rather than an increased susceptibility to infections. This means that NLRP defects are not PIDs, but can be attributed to a new class of disorders, autoinflammatory diseases, based on the dysregulated production of the IL-1 family of cytokines.

Conclusions and perspectives

  1. Top of page
  2. Abstract
  3. Introduction
  4. PRRs: recognizing the pathogen and activating innate host defence
  5. Recognition of pathogenic microorganisms by PRRs
  6. PIDs because of defects in PRRs
  7. Conclusions and perspectives
  8. Conflict of interest
  9. Acknowledgements
  10. References

In recent years, immunodeficiencies because of isolated defects in specific arms of the immune response have been described with increasing frequency; this illustrates a shift from rare familial recessive traits leading to general defects in the immune response, towards common, but sporadic immunodeficiencies that are ultimately present in a large number of individuals [105]. PIDs with defects in PRRs are an example of this shift (Table 1).

There are important differences in the phenotypes of patients affected by PRR defects compared with those with classical immunodeficiencies, including: (i) variable clinical severity of patients lacking PRRs, from severe (MyD88, IRAK4 and CARD9 deficiencies) to mild (MBL, TLR5 and dectin-1 deficiencies), (ii) narrow infection susceptibility, depending on the particular microorganisms that are recognized by the PRR pathway involved (e.g. defects in TLR3/TRIF/TRAF3/Unc3b lead to increased susceptibility to HSV encephalitis, but not to other viruses) and (iii) clinical presentation may be severe in early infancy, but decrease thereafter. The latter implies that adaptive immune responses that develop with age may be able to compensate in time for the lack of effective innate immunity. This contrasts with the classical PIDs, in which a patient's clinical situation deteriorates throughout life.

The importance of understanding PRR immunodeficiencies is clear from several points of view. First, their description is important for the clinician treating patients with these disorders. Secondly, their discovery has increased insight into immunological pathways that until now have been studied exclusively in experimental models of infection. Thirdly, genetic defects in PRR pathways increase understanding of the role of these receptors in the pathophysiology of infections. Considering the advances in the fields of immunology and genetics, descriptions of more of these selective PRR immunodeficiency syndromes can be expected in the near future.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. PRRs: recognizing the pathogen and activating innate host defence
  5. Recognition of pathogenic microorganisms by PRRs
  6. PIDs because of defects in PRRs
  7. Conclusions and perspectives
  8. Conflict of interest
  9. Acknowledgements
  10. References