Autosomal Dominant Hyper IgE Syndrome, a STAT3 Mutation
Lydia Sofia Moutsiou, W1574096
Hyper-immunoglobulin E syndrome (HIES), is a rare primary immunodeficiency characterized by elevated serum levels of IgE, pneumonia, recurrent eczema, eosinophilia, and staphyloccocal skin infections. It is estimated to affect 1:100,00 and it can inherited by be either an autosomal dominant (AD) mutation in STAT3 gene, or autosomal recessive mutation in DOCK8 gene (Grimbacher, Holland, & Puck, Hyper-IgE syndromes, 2005).
History
The autosomal dominant HIES was first described in 1966 by Davis, Schaller and Wedgwood. They investigated a rare case of two red-haired girls with recurrent eczema, pneumonia and staphylococcal skin infections and referred to it as Job’s syndrome (Davis, Schaller, & Wedgwood, 1966). Later on, in 1972, Buckley et al. worked on a case of two boys presenting the same symptoms as well as eosinophilia, severe dermatitis and elevated serum IgE levels and referred to it as Buckley’s syndrome (Buckley, Wray BB, & Belmaker, 1972). Further research in the first case of the two girls confirmed that they also had high serum IgE levels and abnormalities in neutrophil chemotaxis suggesting that both Davis and Buckley were describing the same syndrome (Hill, et al., 1974). For many years the condition was only associated with the immune system. In 1999, Grimbacher et al., proved that autosomal dominant HIES also affects the skeletal and connective tissue in a study involving 30 patients with hyper-IgE syndrome and 70 of their relatives. The majority of the patients were presented with either recurrent bone fractures, scoliosis or hyperextensible joints (Grimbacher B. , et al., 1999). Even though the symptoms had been investigated the underlying cause of the condition was still unknown. In 2006, a case of a patient with mild HIES was investigated and showed that it was associated with Tyk2 deficiency (Minegishi Y, 2006). However, the absence of certain symptoms suggested further investigation. In 2007, it was identified that AD-HIES was due to heterozygous mutations in STAT3 gene locus on chromosome 17 (Holland, DeLeo, Elloumi, & Hsu, 2007).
JAK/STAT Family of Proteins
The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway is responsible for transmitting messages from outside the cell into the nucleus and DNA in response to cytokines and growth factors. This results in transcription of DNA and activation of cellular responses such as proliferation, differentiation, migration and apoptosis suggesting an important role in both innate and adaptive immunity (Aaronson & Horvath, 2002) (O’Shea & Plenge , 2012). Therefore, many primary immunodeficiencies have been associated with mutations that interfere with the JAK-STAT pathway.
In 1994, Darnel et al. were the first to talk about the JAK-STAT signaling pathway while in search of interferon signal transduction pathway (Heim, 1999). JAK family comprise four proteins (JAK1, JAK2, JAK3 and Tyk2) whereas STAT has seven members (STAT 1, 2, 3, 4, 5a, 5b, 6). JAKs are tyrosine kinases with a primary role of binding on the intercellular domain of cytokine receptors in order to activate a cascade of events that forms the pathway. On the other hand STATs are transcription factors with a similar conformation to JAKs (Aaronson & Horvath, 2002). Different cytokines activate different combinations of JAKs and STATs. For instance, interferon gamma (IFNγ) activates JAK1 and 2 proteins and STAT1 whereas interleukin 6 (IL6) activates JAK1 and 2 and STAT3.
STAT3 signaling pathway
As mentioned above, mutations in the STAT3 gene are responsible for AD-HIES. STAT3 was first discovered in 1994 and its association with IL6 was confirmed by Akira and her colleagues (Akira S, 1994). It is associated with many cellular functions as well regulation of the skeletal system, immune system, and inflammation. It is located on the long arm of chromosome 17 and more precisely at position 21.31 (Genetics Home Reference, 2015).
Many different cytokines and growth factors can trigger STAT3 activation such as IL6, IL10, IL22, IL23 etc. Upon binding of the cytokine and activation its receptor a cascade of events takes place starting with the recruitment of JAK2 and Tyk2 intracellularly. Phosphorylation of JAK2/Tyk2 opens the SH2 domain where STAT3 is positioned. Phosphorylation of STAT3 follows on the domain Tyr705 resulting in either homodimerazation, involving two STAT3 molecules, or heterodimerization, involving a STAT3 molecule and either STAT1 or STAT5. The dimer is translocated to the nucleus where it binds to the ISRE/GAS complex and transcription is activated (O’Shea & Plenge , 2012) (Mogensen, 2013). STAT3 is responsible for the activation of transcription of a wide variety of genes and upregulation of different cytokines and growth factors including IL6, IL10, TGFβ, IL22 and IL17. Furthermore, it also induces downregulation of pro-inflammatory molecules such as tumor necrosis factor (TNF) α, IL12 and IFNγ (O’Shea & Plenge , 2012). Its importance in regulation and cellular survival is apparent and therefore mutations can negatively affect important processes and put the organism in danger.
Genotype, Phenotype and Pathogenesis of Hyper IgE Syndrome
Genotype: As mentioned above, in 2006 Holland and his colleagues identified that HIES was due to mutations in STAT3 in a study that involved 50 patients with HIES and 48 of their family members. Abnormalities in the signalling of IL6 as well as increased responses of the immune system were observed. It was finaly identified that misense mutations and in-frame deletions in the STAT3 gene locus on chromosome 17 gave rise to the syndrome (Holland et al., 2007). Minegishi et al. further investigated this and found that the mutation were dominant negative and consequently abolished the functions of the wild type protein. Moreover, the mutations were located in the DNA and SH2 binding domains (Minegishi et al., 2007). Although mutations on STAT3 have been idenitified the specific mechanism is not clearly understood. A cohort study of 11 Mexican patients with AD-HIES evaluated the signalling functions of STAT3 in an attempt to identify the exact mutations. Two mutations were found, Asn395Tyr and Asn425Tyr, in some of the patients but there wasn’t exact correlation between the defective genes and HIES (Alcantara-Montiel, et al., 2015).
Phenotype and Pathogenesis: The phenotype of HIES can be categorized into immunological and somatic. The primary characteristic of the disease is extensive inflammation on the skin. The defective gene blocks signal transduction of STAT3 that leads to upregulation of the cytokines TNFα and IFNγ and reduced production of pro- and anti-inflammatory cytokines such as IL6, IL10, IL17, IL21 and IL22 as well as reduced neutrophil chemotaxis making the organism prone to infections by Staphyloccus aureus. In turn such infections are the cause of skin and lung abseccess, eczema and in some instances eosinophilia. Most cases are also affected by chronic mucocutaneous candidiasis (Davis et al., 1966). Regulation of epithelial cell barriers, which is also abnormal in patients with HIES, is due to impaired signalling of Il22 (Sonnenberg et al., 2011). Lung infections in severe cases, along with increased matrix metalloprotease activity, may lead to the formation of pneumatoceles; making the organism more prone to infections from another bacterium, Pseudomonas aeruginosa (Sowerwine et al., 2012).
It has been proved in patients with the syndrome that mutations in STAT3 result in loss of ability to differentiate into Th17 cells making the organism more sensitive in infections such as chronic mucocutaneous candidiasis (Milner et al., 2008) (Puel et al., 2012). Proliferation and chemotaxis of neutrophils are also affected due to downregulation of IL17 playing a key role in the phenomenon of recurrent lung and skin infections. IL17 along with IL22 also play a role in the production of peptides that fight microbial infections; which are disturbed in the case of the syndrome (Ong et al., 2002). Furthermore, impaired signaling on IL21 receptors results in increased IgE serum levels, which was proved in mice that lacked IL21 receptor, as well as B cell lymphoma if it comes along with disturbed B cell differentiation. Rare infections by fungi such as Cryptococcus, Coccidioides and Histoplasma may result in gastrointestinal infections (Sowerwine et al., 2012).
Non-immunological manifestations are also evident in patients suffering from HIES. As mentioned above, craniofacial abnormalities, hyperextensibility and retention of childhood teeth are some features of the somatic phenotype (Smithwick et al., 1978) (O’Connell et al., 2000). Furthermore, cases of scoliosis and osteoporosis as well as fractures not related trauma have been identified [ (Grimbacher B. , et al., 1999) ]. Studies on mice showed that STAT3 destruction is also associated with osteoclastogenesis and osteopenia (Zhang et al., 2005). Due to problematic signaling, downregulation of TGFβ signaling, along with TNFα production cause problems in the cardiovascular system including changes in the flexibility of the arteries and hypertension (Freeman et al., 2011). Finally, certain cancer types, especially of the malignant type, such as non-Hodgkin lymphoma are very prone to patients with hyper IgE syndrome (Leonard et al., 2004).
Diagnosis and Treatment of HIES
Most of the symptoms or conditions associated with HIES are also present in many other diseases, so in order to make a correct diagnosis a new system has been considered. If the patient is presented with elevated IgE serum levels, chronic mucocutaneous candidiasis or staphylococcal lung and skin infections a ‘’genetic analysis of STAT3’’ is performed. (Takeda et al., 1997) (Mogensen, 2013). However, it is important to bear in mind that conditions of this disease may lead to a different diagnosis. For example, increased IgE serum levels may be associated with allergies or parasitic infections, as well as conditions such as Omenn syndrome, dysregulation of the immune system and atypical complete DeGeorge syndrome. The same problem is evident in other conditions such as staphylococcal infections and chronic mucocutaneous candidiasis.
When it is established that a patient is suffering from AD-HIES the aim is to manage the symptoms. Antibiotics, such as sulfamethoxazole, are used to prevent infections from Staphylococcus aureus (Ghoreschi et al., 2009). To reduce the effects of eczema anti-staphyloccocal oral therapy is recommended and in the case of pneumatocule the antibiotic itraconazole is prescribed (Sowerwine et al., 2012). In 2015 a breakthrough in the future treatment of AD-HIES was made by Patel et al., who were successful in fully treating the AD-HIES by transplating haploidentical donor haematopoietic stem cells resulting in restoration and normal function of STAT3 in an adolescent suffering from the condition. The cells transplated were obtained from the father of the patient and twenty four months after the transplant her IgE serum levels were normal and did not produce any skin infections (Patel et al., 2015).
Conclusion
AD-HIES is a very rare and complex primary immunodeficiency with both immunological and non-immunological consequences. Over the past ten years great progress has been made in understanding the disease and its causes. The identification of mutations in Tyk2 in patients with some of the symptoms set the roots and led to the discovery of mutations in STAT3 gene on chromosome 17 as the main cause of the disease. This helped in the understanding of the signaling pathway and the functions of STAT3 protein. Consequently, the pathophysiology of both the immunological and somatic phenotypes was understood and questions regarding recurrent staphylococcal infections and extensive inflammation on the skin and lungs have been resolved. Even though there was no treatment to overcome a syndrome as whole, just treatments to alleviate the symptoms separately, great progress has been made with transplantation of haploidentical donor haematopoietic stem cells, which restored IgE serum levels in the patient affected. Even though particular mutations still need to be identified in order to produce an effective gene therapy the future seems promising and hopeful.
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