Th17 cells and Job's syndrome: a model of skin bacterial translocation

Abstract

Purpose of review

Patients with HIES share with HIV patients a predisposition to infections, including candidiasis in autosomal dominant HIES (AD-HIES) and molluscum contagiousum in autosomal recessive HIES (AR-HIES). This review highlights the underlying pathogenesis of these diseases and their relevance to HIV infection.

Recent findings

Patients with mutations in STAT3, who lack Th17 cells, develop AD-HIES, while AR-HIES may be caused by mutations in Tyk2 or DOCK8, associated with decreased expansion of CD8 T cells. Recent studies on patients with recurrent mucocutaneous candidiasis have led to the discovery of mutations in CARD9 and DECTIN-1, genes key to the production of the Th17-driving cytokines IL-1β, IL-6, and IL-23. Studies of the peripheral blood of HIV+ patients have shown a decreased Th17:Th1 ratio, and Th17 cells were preferentially depleted from the gastrointestinal tract within weeks of SIV infection of rhesus macaques.

Summary

The consequences of inadequate Th17 production in primary immunodeficiency syndromes illustrate the role of Th17 cells in controlling pathogens to which HIV+ individuals are susceptible. Further understanding of the pathogenesis of opportunistic disease in HIV infection will likely require exploring the role of Th17 cells.

Introduction

Autosomal dominant Hyper IgE syndrome (HIES) was initially described in 1966 as Job’s syndrome in several patients who had eosinophilia, eczema and recurrent infections of the skin and pulmonary tract [1]. Six years later, markedly elevated serum IgE was measured in these patients, leading to the title of the Hyper IgE syndrome [2]. Further phenotypic descriptions of skeletal, vascular, dental, neurologic and connective tissue abnormalities solidified the syndrome as a unique multisystem disorder [3–6]. Recently, dominant negative mutations in the gene Signal Transduction and Activation of Transcription (STAT) 3 were identified to account for this syndrome [7–8], providing a unique opportunity to better understand the disease pathogenesis, and to learn more about the roles played by this multifunctional signal transducer and transcription factor. This review will highlight recent findings in the pathogenesis of HIES, its distinction from related disorders, and related studies in STAT3 and Th17 biology, paying specific attention to the mechanisms by which host defense could be compromised by mutations in STAT3.

HIES diagnosis

One of the critical difficulties in understanding AD HIES has been to differentiate it from the myriad of other diseases in which infection and high IgE could be found. The cardinal infectious features of HIES include recurrent cold staphylococcal abscesses, associated with an underlying dermatitis, staphylococcal pneumonia associated with lung cyst formation, oral candiadiasis and onychomycosis. Cardinal non-immunologic findings include joint hyperextensibility, recurrent minimal trauma fractures, and retained childhood dentition with high-arched palate. Of interest, despite high IgE, the rate of allergen-induced atopy such as specific food allergy, allergen-induced wheeze or allergic rhinitis, is not elevated in HIES. A scoring system was proposed which has been useful although not completely accurate, in diagnosing classical HIES [9].

The list of disorders of immunodeficiency associated with high IgE in addition to AD HIES includes Wiskott-Aldrich Syndrome, Omenn’s syndrome, atypical complete DiGeorge syndrome, Netherton’s syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome [10] and a collection of disorders termed autosomal recessive Hyper-IgE Syndrome [11]. Within this last category, mutations in TYK2 [12] and dedicator of cytokinesis 8 (DOCK8) [13*] have been described to cause the phenotype. Tyk2-deficient patients differ from typical HIES in that they lack most of the non-immunologic phenotypes and have pulmonary mycobacterial infections, a phenotype only seen in HIES patients with underlying structural lung defects [14]. Patients with DOCK8 deficiency, in contrast to HIES patients, have multiple specific allergies and a prominence of viral infections, especially of the skin, such as molluscum contagiousum, disseminated varicella, herpes zoster, and others, and they were found to have decreased expansion of activated CD8 T cells in vitro. Skin neoplastic disease is also seen in the DOCK8 deficient patients whereas lymphomas are the only neoplasms noted in HIES.

The spectrum of HIES and HIES-like diseases is broad and, as it becomes more readily diagnosed and recognized, may shed light on the individual pathways, not only the genes, which cause these diseases. Chatila et al reported a large series of cases of patients with infections and high IgE, coupled with a variety of non-immunologic phenotypes [15]. Of interest in their series, the phenotypes of patients with no STAT3 mutations were not significantly different from those who had STAT3 mutations. Furthermore, similar to patients with AD HIES, the STAT3 mutant negative population showed a disruption of Th17 cell production, the key difference being that Th17 cells were inducible in patients with WT STAT3 despite being decreased in the periphery, whereas Th17 cells could not be induced in STAT3 mutant patients. This observation suggests that other abnormalities within the STAT3/TH17 axis might explain some of these diseases. A significant subset of these patients likely has DOCK8 mutations based on the viral infections with which they presented, while others whose clinical phenotypes appear strongly like typical AD-HIES did not have STAT3 mutations. It will be of significant interest to determine how many of these patients have mutations in regions of STAT3 that were not sequenced (such as non-coding regions) or other mutations in the STAT3 pathway, and how many have unrelated pathogeneses.

It also will be important to see the extent to which these pathways contribute to more common atopy. While one study did not detect STAT3 polymorphisms in a large cohort of atopic patients [16], it remains possible that the pathways highlighted by rare diseases of elevated IgE and infection may help better understand common allergic diseases.

HIES Pathogenesis

With the recent identification of dominant negative mutations in STAT3 in patients with AD-HIES, there have been a number of significant advances in understanding the pathophysiology of certain elements of the syndrome.

Markedly decreased Th17 generation has been a hallmark of patients with HIES [17*, 18, 19]. Recent descriptions of patients with recurrent mucocutaneous candidiasis and decreased Th17 production caused by mutations in CARD9 [20*] and DECTIN1 [21*] has added to the evidence that Th17 cells play an important role in antifungal immunity. Coupled with data in mice deficient for the IL-17 receptor suggesting that this receptor is critical for control of oral candidiasis [22], a strong case can be made that the lack of Th17 cells predisposes HIES patients to fungal infections. IL-17 facilitates neutrophil proliferation and recruitment through induction of granulocyte colony stimulating factor (G-CSF) and IL-8 (CXCL8) in epithelial cells [23–26]. Neutrophils are critical for host defense against both Candida and Staphylococcus, killing the organisms by phagocytosis and reactive oxygen burst as well as by neutrophil extracellular traps [27–30]. Neutropenia and neutrophil dysfunction, as in chronic granulomatous disease, are well-recognized risk factors for invasive candidal and severe staphylococcal infections [30–32]. However, candidal and staphylococcal infections in HIES are limited to the skin and lung, suggesting that perhaps the neutrophils are functional but perhaps not trafficking to the site of infection. Indeed, numerous studies have demonstrated defective neutrophil chemotaxis in patients with HIES [33–34]. HIES T-cell supernatant was not able to induce CXCL8 production by human bronchial epithelial cells or keratinocytes but was able to induce its production by fibroplasts and HUVECs, suggesting that in HIES patients, the skin and lung may be preferentially unable to adequately recruit neutrophils in a timely manner [35]. In addition to neutrophils, β-defensins are important in host defense against Candida infections [22]. Mucosal surface β-defensin formation appears to be dependent upon production of IL-22, a Th17-associated cytokine that signals through STAT3 [36]. Indeed HIES T-cell supernatant is not able to induce β-defensins as compared to wild-type. Furthermore, neutralization of IL-17 and IL-22 in normal T-cell supernatants abolishes their capacity to induce defensin expression in keratinocytes and bronchial epithelial cells [35].

However, not all of the disorders of mucocutaneous candidiasis described above and elsewhere [37] to be associated with marked reductions in Th17 cells are themselves associated with bacterial infections. Further complicating our understanding of the direct role of Th17 cells in host defense is the fact that as patients with HIES age, a significant proportion of them have few or no infections of any kind despite continuing to lack peripheral Th17 cells.

One possibility to explain the mucosal bacterial infections is that direct stimulation of defensin expression is impaired due to defective STAT3 signaling (presumably due to IL-22 stimulation) within the target tissues. Direct measurement of defensin expression in HIES will help answer this question. One recent piece of evidence which would suggest a direct role for IL-22 signaling in mucosal defensin production can be found in patients with IL-10 receptor mutations [38]. These patients have a congenital inflammatory bowel disease, likely due to impaired IL-10 signaling which has been shown in mouse models to lead to colitis due to the lack of anti-inflammatory properties of IL-10. One patient was found have a loss of function mutation in IL-10RB, which is significant since this receptor protein is also used by IL-22 for normal signaling. The presence of recurrent folliculitis and pneumonias reported in this patient argues for the critical role of IL-22 in preventing bacterial skin and lung infections, independent of the presence of TH17 cells. It is interesting that despite IL-10 also using STAT3 for signaling, HIES patients have no evidence of inflammatory bowel disease. This may be because STAT3 mutations are hypomorphic in HIES patients allowing for sufficient residual efficacy of IL-10 function, or the use of other STAT proteins by IL-10 in the absence of normal STAT3 function.

Another explanation for the infectious predilection in HIES has been defective antibody production. Indeed memory B-cells numbers are decreased in HIES [39], and antibody responses to vaccines can be variable [40]. However IVIG is not routinely used or needed in HIES, despite a number who are on it. One might have anticipated that T-follicular helper cell, CD4+ T-cells responsible for germinal center formation and normal B-cell help, might be impaired in HIES, given the dependence of TFH cells upon stat3 [41, 42] and bcl-6 [43–45] for TFH formation. However CXCR5+ cells are at normal frequencies in HIES [18], and recent data has shown that human T-cells can upregulate BCL-6 and other markers and functions of the T-follicular helper cells lineage in response to IL-12 via STAT4 [46, 47].

Similarities between HIES and HIV

The infections with which HIV-infected patients present overlap substantially with those of patients with HIES and HIES-like diseases. Persistent or recurrent mucocutaneous candidiasis is recognized as one of the most common opportunistic infections in HIV+ patients [48]. HIV infection increases the risk of Staphylococcus aureus bacteremia 17-fold [49]), and methicillin-resistant Staphylococcus aureus skin abscesses by 18-fold, with a high rate of recurrence [50, 51]. Furthermore, as in patients with DOCK8 mutations, HIV-infected patients are predisposed to severe herpes simplex, herpes zoster, human papillomavirus, and molluscum contagiosum infections [48]. In addition, some rare infections of HIES patients are seen in HIV patients, such as pneumonia caused by Streptococcus [52] or Pneumocystis jiroveci [53].

HIV-infected individuals have lower Th17:Th1 CD4 T cell ratios in the peripheral blood and preferential loss of Th17 cells from the gastrointestinal tract [54**]. Studies of SIV-infected rhesus macaques have revealed that the frequency of Th17 cells in healthy macaques is actually higher in the GI tract than in the periphery, and Th17 cells but not Th1 cells are depleted from the GI tract within the first several weeks of SIV infection. Furthermore, the frequency of Th17 cells in mucosal sites is inversely correlated with the SIV viral load [55**]. Cells from the terminal ileum of SIV-infected rhesus macaques fail to upregulate IL-17, IL-22, and IL-8 expression in response to Salmonella typhimurium infection and have higher bacterial loads in the mesenteric lymph nodes than SIV-uninfected macaques, suggesting that the infected monkeys have decreased local control of infection [56*]. Consistent with the finding of poor local control of bacteria is the presence of elevated LPS levels in the plasma of patients with HIV without active bacterial infections [57]. Th17 cells may also be essential for defense against both Streptococcus pneumoniae and Pneumocystis jiroveci, as administration of an anti-IL-17 neutralizing antibody leads to impairment of bacterial clearance in the former and increased fungal burden in the latter in mouse models [58, 59]. Treatment with antiretrovirals can restore CD4 T cells, including Th17 cells, in the GALT [60*], decrease LPS levels in the plasma [57], and decrease the frequency of opportunistic infections [48]. Thus, decreased peripheral Th17 cell frequencies or a decreased systemic Th17:Th1 ratio may predispose HIV-infected patients to certain infections, including some of the same pathogens to which HIES patients are susceptible.

Conclusion

Since Job’s syndrome was first described over 40 years ago, significant advances have been made in understanding the pathogenesis of this disease. Patients with HIV infection share immunologic and infectious manifestations of both AD HIES, caused by STAT3 mutations, and AR HIES associated with DOCK8 mutations and potentially inadequate CD8 T cell expansion. The Th17 deficiency seen in AD HIES likely predisposes these individuals to infections with Candida and Staphylococcus via impairment of neutrophil chemotaxis and defensin production. A similar phenomenon may explain the predilection for recurrent mucocutaneous candidiasis and staphylococcal infections, and other bacterial and fungal infections, in HIV-infected individuals. Similarly, HIES patients with DOCK8 mutations have inadequate control of usually latent viral infections, likely due to defects in CD8 T cell function. Given recent data demonstrating important roles for IL-21 [61–63], a cytokine that uses STAT3 for signaling, and blimp-1 [64–66], a STAT3 target, in CD8 memory functions, it is likely that continued study of both the STAT3 and DOCK8 mutations seen in HIES patients will shed more light on the mechanisms underlying both CD4 and CD8 T-cell memory functions in humans.