Primary immunodeficiencies of protective immunity to primary infections

REVIEW

Primary immunodeficiencies of protective immunity to primary infections

Aziz Bousfiha

, Capucine Picard

, Stéphanie Boisson-Dupuis

, Shen-Ying Zhang

, Jacinta Bustamante

, Anne Puel

,

Emmanuelle Jouanguy

, Fatima Ailal

, Jamila El-Baghdadi

, Laurent Abel

, Jean-Laurent Casanova

aClinical Immunology Unit, Department of Pediatrics, CHU Ibn Rochd, Casablanca, Morocco

bStudy Center for Primary Immunodeficiencies, Necker Hospital, AP-HP, Paris, France

cLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale and University Paris Descartes, Necker Medical School, Paris, France

dLaboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA

eMilitary Hospital, Rabat, Morocco

Received 10 December 2009; accepted with revision 1 February 2010 Available online 16 March 2010

KEYWORDS Primary infection;

Secondary infection;

Latent infection;

Immunity;

Primary

immunodeficiencies (PIDs);

Infectious diseases;

Childhood

Abstract The vast majority of primary immunodeficiencies (PIDs) predispose affected individuals to recurrent or chronic infectious diseases, because they affect protective immunity to both primary and secondary or latent infections. We discuss here three recently described groups of PIDs that seem to impair immunity to primary infections without compromising immunity to secondary and latent infections. Patients with mutations inIL12BorIL12RB1typically present mycobacterial disease in childhood with a favorable progression thereafter. Cross-protection between mycobacterial infections has even been observed. Patients with mutations inIRAK4orMYD88suffer from pyogenic bacterial diseases, including invasive pneumococcal diseases in particular. These diseases often recur, although not always with the same serotype, but the frequency of these recurrences tails off, with no further infections observed from adolescence onwards. Finally, mutations inUNC93B1andTLR3are associated with childhood herpes simplex encephalitis, which strikes only once in most patients, with almost no recorded cases of more than two bouts of this disease. Unlike infections in patients with other PIDs, the clinical course of which typically deteriorates with age even if appropriate treatment is given, the prognosis of patients with these three newly described PIDs tends to improve spontaneously with age, provided, of course, that the initial infection is properly managed. In other words, although life-threatening in early childhood, these new PIDs are associated with a favorable outcome in adulthood. They provide proof-of-principle that infectious diseases of childhood striking only once may result from single-gene inborn errors of immunity.

© 2010 Published by Elsevier Inc.

⁎ Corresponding author. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale and University Paris Descartes, Necker Medical School, Paris, France.

E-mail address:casanova@rockefeller.edu(J.-L. Casanova).

1521-6616/$–see front matter © 2010 Published by Elsevier Inc.

doi:10.1016/j.clim.2010.02.001

a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m

C l i n i c a l I m m u n o l o g y

w w w . e l s e v i e r . c o m / l o c a t e / y c l i m

Contents

References . . . 207

When sulfonamides and antibiotics became widely available after World War II, the attention of a small group of physicians and scientists was drawn to rare children who displayed recurrent infectious diseases, particularly those displaying recurrent pyogenic bacterial diseases [1–12].

These children often also had multiple infectious diseases, caused by various bacterial species. Before the introduction of antibiotics, these children would have died during the first infectious episode, preventing the expression of this pheno- type. In their efforts to understand this unusual clinical presentation, distinguished pioneers discovered that these children also had striking immunological phenotypes, such as agammaglobulinemia or neutropenia. It was concomitantly or subsequently found that the syndromes were inherited as Mendelian traits, some of which were autosomal recessive (AR, neutropenia), whereas others were X-linked recessive traits (XR, agammaglobulinemia). Only later were XR forms of neutropenia and AR forms of agammaglobulinemia discovered[13,14]. This was the birth of the field of primary immunodeficiencies (PIDs), and these diseases have since been described as rare, fully penetrant, Mendelian recessive traits predisposing the individual to multiple and recurrent infections, occurring as the consequence of a detectable immunological phenotype [15–18]. Other rare infections thought to attest specifically to the presence of an immunodeficiency were later designated ‘opportunistic,’

an unfortunate expression neglecting the long-established fact that most infections in most individuals were asymp- tomatic[19,20].

Interestingly, some disorders that we now consider to be PIDs were often described before Bruton's report of a child with recurrent invasive pneumococcal disease (IPD) and agammaglobulinemia but, for various reasons, these dis- orders made no major contribution to the development of the concept of PIDs. They include chronic mucocutaneous candidiasis (CMC), first described in 1929 [21]; epidermo- dysplasia verruciformis (EV), described as an autosomal recessive predisposition to oncogenic human papilloma- viruses in 1946[22,23]and X-linked recessive Wiskott-Aldrich syndrome (WAS), first described in 1937 [24,25]. The first case of Mendelian susceptibility to mycobacterial disease (MSMD) was also described before Bruton's work, probably in 1951[26]. However, these conditions were not recognized and described as PIDs at the time and did not directly contribute to the emergence of this field. They were eventually connected with more conventional PIDs, early in the 1950s for Wiskott-Aldrich syndrome, but much later for other conditions, such as EV, for which this link was established some 50 years later, in the early 2000s. Had these disorders been historically associated with the birth of PIDs, our current view of the field and its evolution might have been very different.

Various constitutive features of PIDs were identified as important from the 1950s onwards, but the idea that infections in patients with PIDs could be “recurrent” was

arguably the most important seminal feature leading to the description and definition of PIDs. Recurrent infections first triggered the curiosity of physicians and scientists in the late 1940s and early 1950s. The best example of recurrent disease is perhaps that provided by Bruton's first patient with agammaglobulinema, who had up to 14 episodes of IPD, each cured by antibiotics, until he received gamma globulins, which prevented subsequent recurrences[1]. As discussed elsewhere, the notion of multiple infections was almost as important, but exceptions to this rule began to accumulate from the 1970s onwards, with the descriptions of CMC, EV and MSMD being followed by description of other PIDs predisposing patients to a single type of infection, such as deficiencies of properdin and terminal components of complement (Neisseriainfections), and X-linked lymphopro- liferative syndrome (XLP, EBV infection)[15,27,28]. Excep- tions to all the other ‘cardinal features’ of PIDs were progressively found, ranging from PIDs obeying non-Mende- lian rules of inheritance (e.g. mitochondrial, polygenic, and even somatic) and common PIDs (e.g. autosomal dominant susceptibility to human immunodeficiency virus, norovirus, parvovirus, andPlasmodium vivax) to PIDs with various non- infectious phenotypes (e.g. autoimmunity, granulomas, hemophagocytosis, hemolytic uremic syndrome)[15].

We will consider this specific hallmark of PIDs by focusing on recently described PIDs, the infectious phenotypes of which generally include a single infectious episode, without recurrence, contrasting with that of most, if not all previously reported PIDs, including most of those conferring specific susceptibility to a single organism. We define

‘recurrence’as clinical disease caused by the same patho- gen, based on current microbiological criteria (bearing in mind that, strictly speaking, there is no such thing as recurrent disease as microbes are continually evolving), whether due to the reactivation of a latent infection or the establishment of a new infection. The tremendous diversity of clinical phenotypes, infectious and otherwise, and of immunological phenotypes, hematopoietic or otherwise, found to be associated with PIDs since the early 1950s has been reviewed elsewhere [15,16,29–34]. We have also discussed the notion that PIDs are not always rare, even when they are Mendelian, as highlighted by common, autosomal dominant predisposition to Plasmodium vivax, human immunodeficiency virus, norovirus, and parvovirus [28,35]. Infectious diseases in patients with PIDs were classically thought to be recurrent, multiple, disseminated, and/or opportunistic. However, it has been known since the 1950s that infections are not always disseminated in PIDs. We have discussed elsewhere how recently described PIDs have been shown to confer predisposition to a single infectious agent, with some PIDs predisposing patients to a narrow range of infections or even a single infection[28]. We have also discussed how these disorders may result in a predispo- sition to common infectious agents, not considered‘oppor- tunistic,’with all due semantic reservations concerning this

term and the equally ambiguous term‘immunodeficiency’ [27]. We focus here on the notion of‘recurrent’infections, considered central to the concept of PIDs.

The clinical course of three newly described PIDs has been shown to differ profoundly from that of other PIDs. The natural history of inborn errors ofIL12BandIL12RB1(MSMD), IRAK4 and MYD88 (IPD and other pyogenic bacterial diseases), andUNC93B1andTLR3(herpes simplex enceph- alitis, HSE) is characterized by life-threatening infectious diseases in childhood, with a spontaneously favorable progression in adulthood. Whereas most, if not all previously reported PIDs were associated with a gradual deterioration of the patients' condition over time, often despite medical treatment, these three PIDs were shown to be associated with a surprising and striking spontaneous improvement in clinical course once the infections identified on presentation were successfully controlled by medical treatment. These PIDs are relatively rare and seem to be associated with a narrow range of infections. One of these infections is clearly not‘opportunistic’(HSE, caused by herpes simplex virus 1 (HSV-1), is not more common in any of the known immunodeficiencies of childhood, whether inherited or acquired, whereas interestingly disseminated and recurrent mucocutaneous herpes disease is more common in many T cell immunodeficiencies, in which immunity to latent HSV-1 is impaired). Another may be‘opportunistic’(Streptococcus pneumoniaeinfections are more common in children with various known immunodeficiencies), and the third is always

‘opportunistic’ (infections with BCG and environmental mycobacteria (EM) are unanimously viewed as occurring only in children with immunodeficiency). The remarkable feature of these three disorders, which we discuss here, is that the corresponding infections very rarely recur.

Patients with recessive mutations in IL12B [36–38] or IL12RB1[39–41]present with MSMD due to impairment of the IL-12-dependent production of IFN-γ. Some patients have small proportions of IL-17-producing T cells[42], presumably due to the impairment of IL-23-mediated immunity, and the clinical consequences of this feature remain unclear. In these patients, mycobacterial disease caused by weakly virulent mycobacteria, whether BCG or EM, strikes only once, and typically in childhood[41]. In two large interna- tional series of 38 and 141 patients with mutations inIL12B andIL12RB1, respectively, only about 15% of the patients had some kind of mycobacterial recurrence, probably due to reactivation of the initial mycobacterial agent upon prema- ture treatment cessation in most cases [38,41]. Clinical disease caused by EM or BCG and even inoculation with BCG protect against subsequent EM disease (but not tuberculosis) [38,41,43]. Obviously, no patient with a history of EM disease has ever been inoculated with BCG. It thus appears that IL-12 is essential for protective immunity to primary infection with BCG or EM, but entirely redundant for immunity to these organisms in latent or secondary infections. This is surpris- ing, given the signature role initially ascribed to IL-12 in development of the broad ‘Th1’ response [44,45]. The clinical course of MSMD, which is associated with impaired, but not abolished IFN-γ production, differs from that of patients with various mutations inIFNGR1[46],IFNGR2[47], orSTAT1[48]resulting in impaired IFN-γresponses, or that of patients with mutations inNEMOdisrupting the CD40-IL-12 and TNF-α response pathways [49]. Patients with NEMO

mutations who survive the first mycobacterial episode, even if they display only partial defects, often suffer from multiple and/or recurrent clinical disease caused by BCG and EM. However, it is often difficult to diagnose recurrent mycobacterial disease. Similarly, we recently described macrophage-tropic mutations inCYBB, encoding the gp91^phox subunit of the NADPH oxidase, which were found to be associated with recurrent disease caused by BCG (Busta- mante et al. unpublished data). It appears that IFN-γand the respiratory burst, two effector mechanisms operating on the macrophages in which mycobacteria reside, are essential for both primary immunity and immunity to latent and second- ary mycobacterial infections.

Patients with mutations in IRAK4[50,51]or MYD88[52]

present a Mendelian predisposition to infections with pyogenic bacteria, including IPD in particular, due to the impairment of inflammation. Like Bruton's agammaglobulin- emia, this group of disorders was genetically deciphered following the investigation of selected patients with IPD [53,54]. One of the first reports of a patient with IPD and impaired inflammation was actually written by Robert Good, about 50 years after his seminal contributions to the field of inborn errors of antigen-specific immune responses[50,54].

A recent international clinical survey described the clinical features and outcome of 58 patients[55]. IRAK-4 and MyD88 deficiencies are immunological phenocopies, as both impair TLR (except TLR3) and IL-1R (at least IL-1, IL-18, and IL-33) signaling pathways (TIR). Invasive bacterial disease (typically meningitis and septicemia) is caused principally by S.

pneumoniae, followed by Staphylococcus aureus, Pseudo- monas aeruginosa, Salmonella enteritidis, and Shigella sonnei. Non-invasive bacterial disease is caused mostly by S. aureus, followed by P. aeruginosa andS. pneumoniae.

Invasive infections may occur begin in the neonatal period, subsequently becoming rarer with age, until the age of about 14 years, after which no invasive disease is documented. All five adult patients (N18 years old) identified are doing well with no prophylaxis (a total of 8.6 patient-years). The seven patients over the age of 14 years are also no longer on prophylaxis, giving a cumulative follow-up time of 49 years without invasive bacterial disease. The oldest patient is now 36 years old and is well. The establishment of T- and B-cell responses with age probably compensates for the inflamma- tion defect, which may mirror the maturation of B-cell responses in the first two years of life. Recurrences have been reported–including recurrent IPD in particular–but recurrence of the same pneumococcal serotype has been documented only three times. In any event, no further episodes of IPD have been recorded after adolescence. The mechanism involved is unclear, but does not involve any age- dependent leakiness of IRAK-4 and MyD88 deficiency. This experiment of nature is not consistent with the view that TLRs play an essential role in the development of antigen- specific immune responses [56]. Instead, it suggests that antibody responses to bacterial antigens progressively compensate for impaired TIR immunity. These disorders are therefore associated with impaired immunity to primary infection by a restricted set of pyogenic bacteria, including pneumococcus (S. pneumoniae) in particular. TIR immunity appears to be largely redundant for immunity to the corresponding secondary infections. This implies that not only TLRs, but also cytokines, such as IL-1, IL-18 and IL-33,

are redundant for protective immunity during latent and secondary infections. Caution is however needed, as the oldest patient being 36 years old, it is unknown whether these patients may display enhanced vulnerability to pyogenic bacteria (or other infectious agents) at a more advanced age.

Patients with mutations inUNC93B1[57]andTLR3 [58]

present with childhood HSE, typically occurring between the ages of 3 months and 6 years, during primary infection with HSV-1 [59,60]. HSE is the most common sporadic viral encephalitis in Western countries [61-63], and strikes otherwise healthy children, normally resistant to other infectious agents. Recurrences are rare, documented in less than 10% of cases[60,64,65]. Children with autosomal recessive UNC-93B or autosomal dominant TLR3 deficiency develop HSE due to impaired production of anti-viral interferons (IFNs) in the central nervous system (CNS). This conclusion is based on inference from studies of skin-derived fibroblasts showing the abolition of TLR3-dependent induc- tion of IFNs, enhanced viral replication and enhanced cell death, which could be rescued by treatment with recombi- nant IFN-α. Consistent with this hypothetical pathogenic mechanism, TLR3 is widely expressed in the CNS, and HSE has been reported in a STAT-1-deficient child, whose cells do not respond to IFN-α/βand IFN-λ[66,67]. These data not only provided the first demonstration that a TLR had a non- redundant rolein natura[68], but also indicated that TLR3 was redundant for secondary and latent responses, at odds with previous predictions[56]. Two of the four patients with a well defined genetic etiology documented to date had a recurrence of HSE (with documented viral replication in only one case). To our knowledge, no child with three or more episodes of HSE with viral replication has ever been reported. Our preliminary data suggest that other defects in the TLR3 pathway may account for HSE in other children.

Collectively, these results indicate that the TLR3-dependent production of anti-viral IFNs in the CNS is essential for protective immunity to HSV-1 in the course of primary infection in childhood. Conversely, it seems to be redundant for prolonged immunity to latent HSV-1, although the occurrence of relapses indicates that this balance is fragile and may be disrupted.

Are there other PIDs associated with a narrow range of infections that also display this feature? EV is clearly a chronic disease, associated with susceptibility to multiple HPV of the B1 type[69,70]. Once the patient is infected with HPV, the warts spread and recur until the patient eventually dies of skin cancer. Two genetic forms of XLP are known, SAP and XIAP deficiency. Both predispose affected patients to severe disease caused by EBV[71–73]. It is difficult to assess recurrence, as clinical illness may follow various courses: an acute course with hemophagocytosis, requiring hematopoi- etic stem cell transplantation, a chronic course with hypogammaglobulinemia or, more rarely, the disease may manifest as late-onset lymphoma. XR properdin and AR complement membrane attack complex deficiencies are associated with recurrent Neisseria infections [74]. Thus, each of the three groups of diseases considered here may be seen as paradigm-shifting, as they contrast with other previously described PIDs. MSMD in patients with mutations in IL12B or IL12RB1 is typically characterized by a single episode of childhood-onset mycobacterial disease, caused by

BCG or any of the more than 100 known species of EM. IPD is often recurrent in patients with mutations in IRAK4 or MYD88, but it is unclear whether the same serotype is responsible for different episodes of disease and, in any case, IPD episodes cease to occur once the patient reaches adolescence, even in the absence of prophylaxis. Finally, HSE did recur once, in two of the four patients with mutations in UNC93B1 or TLR3, but HSE recurrence is generally rare and new defects in the TLR3 and other pathways will probably soon provide us with a clearer picture of the risk of recurrence as a function of genetic etiology. In conclusion, at least three PIDs manifest as susceptible to primary infection, but not to the reactivation of infection or secondary infectious diseases. These findings pave the way to the description of new PIDs underlying sporadic infectious diseases of childhood. They suggest that new PIDs impairing protective immunity to primary, but not to secondary or latent infections will be deciphered by focusing on children with both rare and common severe infectious diseases.

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