A multifaceted disease: The stats of STAT3 GOF

There is a growing list of genes in which differing variants, often in the same regions, can lead to differing clinical presentations depending on whether the variants lead to gain-of-function (GOF) or dominant negative (DN) disease, or are somatic changes. STAT3 is one such gene, initially with DN variants described to cause autosomal dominant hyper-IgE syndrome, followed by somatic changes leading to large granular lymphocyic leukemia.1Holland S.M. DeLeo F.R. Elloumi H.Z. Hsu A.P. Uzel G. Brodsky N. et al.STAT3 mutations in the hyper IgE syndrome.N Engl J Med. 2007; 357: 1608-1619Crossref PubMed Scopus (956) Google Scholar, 2Minegishi Y. Saito M. Tsuchiya S. Tsuge I. Takada H. Hara T. et al.Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.Nature. 2007; 448: 1058-1062Crossref PubMed Scopus (818) Google Scholar, 3Koskela H.L. Eldfors S. Ellonen P. van Adrichem A.J. Kuusanmäki H. Andersson E.I. et al.Somatic STAT3 mutations in large granular lymphocytic leukemia.N Engl J Med. 2012; 366: 1905-1913Crossref PubMed Scopus (592) Google Scholar Finally, in 2014, STAT3 GOF was described as a multisystem disease that is now classified as being on the growing list of primary immune regulatory disorders (PIRDs).4Chan A.Y. Torgerson T.R. Primary immune regulatory disorders: a growing universe of immune dysregulation.Curr Opin Allergy Clin Immunol. 2020; 20: 582-590Crossref PubMed Scopus (35) Google Scholar, 5Haapaniemi E.M. Kaustio M. Rajala H.L. van Adrichem A.J. Kainulainen L. Glumoff V. et al.Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.Blood. 2015; 125: 639-648Crossref PubMed Scopus (203) Google Scholar, 6Milner J.D. Vogel T.P. Forbes L. Ma C.A. Stray-Pedersen A. Niemela J.E. et al.Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.Blood. 2015; 125: 591-599Crossref PubMed Scopus (373) Google Scholar PIRDs are a recently described group of inborn errors of immunity (IEIs), which present with primarily immune-related pathology such as autoimmunity and lymphoproliferation, as opposed to the classic primary immunodeficiencies, which typically present with infections. Within the PIRDs, both STAT1 and STAT3 GOF disease have been classified as Tregopathies owing to the degree of autoimmunity that can be seen in addition to other clinical features.4Chan A.Y. Torgerson T.R. Primary immune regulatory disorders: a growing universe of immune dysregulation.Curr Opin Allergy Clin Immunol. 2020; 20: 582-590Crossref PubMed Scopus (35) Google Scholar However, like STAT1 GOF disease, autoimmunity is just one of the many clinical complications that is observed. Also similar to STAT1 GOF disease, STAT3 GOF has a much more varied phenotype than the phenotypes seen in the DN diseases, with disease phenotype ranging from asymptomatic or minimally symptomatic to multisystem disease with early mortality.7Tsilifis C. Freeman A.F. Gennery A.R. STAT1 Hyper-IgE syndrome-an update and unanswered questions.J Clin Immunol. 2021; 41: 864-880Crossref PubMed Scopus (37) Google Scholar Genotype-phenotype predictions have been difficult, and much remains to be understood for these STAT GOF diseases. In the study “Monogenic early-onset lymphoproliferation and autoimmunity: The natural history of STAT3 GOF disease” in this issue of the Journal of Allergy and Clinical Immunology, Leiding et al present the clinical features, genetic variants, immunologic laboratory data, and therapies provided for 191 patients (76 previously published) from 33 countries.8Leiding J.W. Vogel T.P. Santarlas V.G.J. Mhaskar R. Smith M.R. Alexandre Carisey A. et al.Monogenic early-onset lymphoproliferation and autoimmunity: natural history of STAT3 gain-of-function syndrome.J Allergy Clin Immunol. 2023; 151: 1081-1095Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The publication greatly broadens the clinical information available for this disease and reinforces its clinical variability. It is not unexpected that STAT3 GOF disease would be a multisystem disease on account of the ubiquitous expression of STAT3 and its critical role in so many cellular functions. This is clearly demonstrated in STAT3 DN, in which in addition to eczema and infections, there are connective tissues, skeletal, brain, vascular, and gastrointestinal changes, with a natural history evolving as the patients age.7Tsilifis C. Freeman A.F. Gennery A.R. STAT1 Hyper-IgE syndrome-an update and unanswered questions.J Clin Immunol. 2021; 41: 864-880Crossref PubMed Scopus (37) Google Scholar Leiding et al8Leiding J.W. Vogel T.P. Santarlas V.G.J. Mhaskar R. Smith M.R. Alexandre Carisey A. et al.Monogenic early-onset lymphoproliferation and autoimmunity: natural history of STAT3 gain-of-function syndrome.J Allergy Clin Immunol. 2023; 151: 1081-1095Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar paint a similar picture for STAT3 GOF disease, with more disease manifestations emerging with increasing recognition and diagnosis (Fig 1). Highlights of the article by Leiding et al include the detailed genetic information, novel clinical presentations, and insights into therapeutics.8Leiding J.W. Vogel T.P. Santarlas V.G.J. Mhaskar R. Smith M.R. Alexandre Carisey A. et al.Monogenic early-onset lymphoproliferation and autoimmunity: natural history of STAT3 gain-of-function syndrome.J Allergy Clin Immunol. 2023; 151: 1081-1095Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The genetic variants span the STAT3 gene, but the majority of patients have variants in the transactivation, DNA binding, and coiled-coil domains, as compared with STAT3 DN disease with concentration in the SH2 and DNA binding domains. As expected for a GOF disease, the vast majority of variants are missense. The main clinical features, occurring in at least half of the patients, were lymphoproliferation, infections, autoimmune cytopenias, skin disease, and growth failure (frequently with enteropathy). Newly described features include characteristic facial features, vascular disease, renal disease, and brain disease (including enhancing subcortical and cortical lesions). Of interest, about 60% of patients had eczema, clinically overlapping with STAT3 DN disease, and the finding of bronchiectasis was fairly frequent. Immunologic abnormalities were common but variable between patients and not assessed throughout the cohort. These included increased double-negative T cells in 82% of those checked; hypogammaglobulinemia in about half of those checked; and consistent with the autoimmunity seen, decreased numbers of regulatory T cells and increased numbers of TH17 cells in 39% and 27% of those checked, respectively. To predict worse survival, many features were investigated, with the use of at least 5 treatments and progressive oxygen-dependent lung disease (typically interstitial lung disease and/or bronchiectasis) being most predictive of poor survival. Similar to what is seen with many IEIs, earlier diagnosis is likely key to instituting therapies to improve morbidity and mortality. Leiding et al reported a median time of about 10 years between onset of symptoms and diagnosis (range 2.3-12 years).8Leiding J.W. Vogel T.P. Santarlas V.G.J. Mhaskar R. Smith M.R. Alexandre Carisey A. et al.Monogenic early-onset lymphoproliferation and autoimmunity: natural history of STAT3 gain-of-function syndrome.J Allergy Clin Immunol. 2023; 151: 1081-1095Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar In part, this delay in diagnosis is due to the more recent identification of STAT3 GOF disease, but early recognition remains an issue for this disease and other IEIs. It is hoped that genetic testing will become more available in both resource-rich and resource-poor countries and education about these important diseases will continue to be undertaken. But, Leiding et al also note the concern of siloing in these multisystem disorders, in which case the patient may be followed by subspecialities without an eye for the larger multisystem disorder. Multidisciplinary teams are essential for these complex diseases, with the focus for STAT3 GOF disease on immunology, infectious diseases, hematology, pulmonary, endocrine, gastroenterology, and hepatology. The strength of the report by Leiding et al resides in the number of affected patients and the comprehensive clinical features reported8Leiding J.W. Vogel T.P. Santarlas V.G.J. Mhaskar R. Smith M.R. Alexandre Carisey A. et al.Monogenic early-onset lymphoproliferation and autoimmunity: natural history of STAT3 gain-of-function syndrome.J Allergy Clin Immunol. 2023; 151: 1081-1095Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar; however, further work will need to be done to really delve into the details of some of these complications. For instance, there were 2 patients reported to have had liver transplants and 2 reported to have had lung transplants, as well as the infrequent finding of significant brain disease. Compiling pathology from these difficult cases could add insight into the pathogenesis, with the goal of precision medicine therapies. Also, infections were reported in about three quarters of the patients, including in patients taking immune suppressants such as corticosteroids, but further description of the pathogens can assist in guiding the ideal infection monitoring and prophylaxis. Leiding et al8Leiding J.W. Vogel T.P. Santarlas V.G.J. Mhaskar R. Smith M.R. Alexandre Carisey A. et al.Monogenic early-onset lymphoproliferation and autoimmunity: natural history of STAT3 gain-of-function syndrome.J Allergy Clin Immunol. 2023; 151: 1081-1095Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar noted that the rate of malignancy was not as high as may have been expected, but the reported patient cohort remains younger than the general population, and with increased STAT3 activity reported in common cancers such as breast cancer, closer monitoring of these patients over time will allow more accurate assessment of incidence.9Ma J.-H. Qin L. Li X. Role of STAT3 signaling pathway in breast cancer.Cell Commun Signal. 2020; 18: 33Crossref PubMed Scopus (127) Google Scholar Malignancy screening may need to be increased in this population if solid organ cancers are increasingly found in addition to lymphomas. Much work on the optimal therapies for STAT3 GOF disease remains, and it was remarkable that the majority of patients in the study by Leiding et al required at least 5 therapies to control disease manifestations.8Leiding J.W. Vogel T.P. Santarlas V.G.J. Mhaskar R. Smith M.R. Alexandre Carisey A. et al.Monogenic early-onset lymphoproliferation and autoimmunity: natural history of STAT3 gain-of-function syndrome.J Allergy Clin Immunol. 2023; 151: 1081-1095Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Although Janus kinase inhibitors and IL-6 inhibitors make sense for treatment and are showing great promise both in this report and in previous studies, questions remain about the durability of these therapies as well as about the indication as to when to start therapy.10Forbes L.R. Vogel T.P. Cooper M.A. Castro-Wagner J. Schussler E. Weinacht K.G. et al.Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations.J Allergy Clin Immunol. 2018; 142: 1665-1669Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar With the phenotypic variation, at diagnosis some affected individuals are asymptomatic at diagnosis (and their disease is detected only as a result of family history) or minimally symptomatic—would therapy prevent possible long-term complications? Those patients for whom dual therapy is indicated as opposed to either Janus kinase inhibition or IL-6 inhibitors remains unclear. Controlled treatment studies are planned and necessary despite the rarity of the disease. The role of hematopoietic stem cell transplantation (HSCT) also needs further consideration. The current overall poor survival rate of 62% of those with HSCT is, in part, likely due to the end-organ disease that develops in these patients over time, but it is also potentially due to the inflammatory milieu at the time of HSCT. Further information is needed to tease this out and be able to predict who will do poorly in so variable a disease and should therefore consider HSCT before end-organ disease develops. As seen in STAT3 DN disease, there were no variant domain-phenotype correlations to predict at diagnosis the disease course to propose HSCT. In addition, as these are activating mutations, the best approaches to conditioning to achieve appropriate chimerisms is essential. Finally, with HSCT, which manifestations of the disease would be corrected needs further investigation. We know from STAT3 DN disease that STAT3 is expressed broadly, leading to multiple organ systems involved, and that HSCT can improve only some manifestations.7Tsilifis C. Freeman A.F. Gennery A.R. STAT1 Hyper-IgE syndrome-an update and unanswered questions.J Clin Immunol. 2021; 41: 864-880Crossref PubMed Scopus (37) Google Scholar Multicontinent studies such as the study by Leiding et al8Leiding J.W. Vogel T.P. Santarlas V.G.J. Mhaskar R. Smith M.R. Alexandre Carisey A. et al.Monogenic early-onset lymphoproliferation and autoimmunity: natural history of STAT3 gain-of-function syndrome.J Allergy Clin Immunol. 2023; 151: 1081-1095Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar are needed to really understand these rare IEIs, and it is hoped that we will continue to see multicenter collaborations to truly understand the natural history of such rare diseases to help guide choosing therapies, ideally with multidisciplinary teams. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndromeJournal of Allergy and Clinical ImmunologyVol. 151Issue 4PreviewIn 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Full-Text PDF