The hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Since the ...prototypical HIES description 55 years ago, areas of significant progress have included description of key disease-causing genes and differentiation into clinically distinct entities. The first two patients reported had what is now understood to be HIES from dominant-negative mutations in signal transduction and activator of transcription 3 (STAT3-HIES), conferring a broad immune defect across both innate and acquired arms, as well as defects in skeletal, connective tissue, and vascular function, causing a clinical phenotype including eczema, staphylococcal and fungal skin and pulmonary infection, scoliosis and minimal trauma fractures, and vascular tortuosity and aneurysm. Due to the constitutionally expressed nature of STAT3, initial reports at treatment with allogeneic stem cell transplantation were not positive and treatment has hinged on aggressive antimicrobial prophylaxis and treatment to prevent the development of end-organ disease such as pneumatocele. Research into the pathophysiology of STAT3-HIES has driven understanding of the interface of several signaling pathways, including the JAK-STAT pathways, interleukins 6 and 17, and the role of Th17 lymphocytes, and has been expanded by identification of phenocopies such as mutations in IL6ST and ZNF341. In this review we summarize the published literature on STAT3-HIES, present the diverse clinical manifestations of this syndrome with current management strategies, and update on the uncertain role of stem cell transplantation for this disease. We outline key unanswered questions for further study.
STAT3 transcription factor signaling in specific T helper cell differentiation has been well described, although the broader roles for STAT3 in lymphocyte memory are less clear. Patients with ...autosomal-dominant hyper-IgE syndrome (AD-HIES) carry dominant-negative STAT3 mutations and are susceptible to a variety of bacterial and fungal infections. We found that AD-HIES patients have a cell-intrinsic defect in the number of central memory CD4
+ and CD8
+ T cells compared to healthy controls. Naive T cells from AD-HIES patients had lower expression of memory-related transcription factors
BCL6 and
SOCS3, a primary proliferation defect, and they failed to acquire central memory-like surface phenotypes in vitro. AD-HIES patients showed a decreased ability to control varicella zoster virus (VZV) and Epstein-Barr virus (EBV) latency, and T cell memory to both of these viruses was compromised. These data point to a specific role for STAT3 in human central memory T cell formation and in control of certain chronic viruses.
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► Patients with AD-HIES have reduced number of central memory CD4 and CD8 T cells ► The reduction of central memory T cell numbers is T cell intrinsic ► Naive T cells from patients express decreased memory-related transcription factors ► HIES patients have an increased incidence of shingles and EBV viremia
Introduction: The transcription factors signal transducer and activator of transcription (STAT) 1 and STAT3 fulfill fundamental functions in nonimmune and immune cells. The description and follow-up ...of patients with germline mutations that result in either loss-of-function or gain-of-function have contributed to our understanding of the pathophysiology of these regulators. Depending on the type of mutations, clinical symptoms are complex and can include infection susceptibility, immune dysregulation as well as characteristic nonimmune features.
Areas covered: In this review, we provide an overview about mechanistic concepts, clinical manifestations, diagnostic process, and traditional as well as innovative treatment options aiming to help the clinical immunologist to better understand and manage these complex and rare diseases. Clinical and research papers were identified and summarized through PubMed Internet searches, and expert opinions are provided.
Expert commentary: The last several years have seen an explosion in the clinical descriptions and pathogenesis knowledge of the diseases caused by GOF and LOF mutations in STAT1 and STAT3. However, harmonization of laboratory testing and follow-up in international cohorts is needed to increase our knowledge about the natural history of these disorders as well as the development of curative or supportive targeted therapies.
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus ...reactivation and subsequent onset of autoimmune diseases
. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge
and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases
. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions
, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK-STAT signaling pathway as a potential target. We further showed that central memory CD4
T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK-STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine.
Hyper-IgE syndrome update Sowerwine, Kathryn J.; Holland, Steven M.; Freeman, Alexandra F.
Annals of the New York Academy of Sciences,
February 2012, Letnik:
1250, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Autosomal dominant hyper‐IgE syndrome (AD‐HIES) or Job's syndrome is a primary immunodeficiency with a wide array of clinical features caused by dominant negative mutations in STAT3. In recent years, ...not only the clinical phenotype of the disease has been expanded with recognition of features such as arterial aneurysms, but also our understanding of the pathogenesis of the disease has greatly improved.
Summary
DOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in ...featuring (a) profound susceptibility to virus infections of the skin, with associated skin cancers, and (b) severe food allergies. The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination‐mediated somatic DNA repair. Residual DOCK8 protein contributes to the variable disease phenotype. The severe virus infections of the skin, and probably also VZV‐associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues. Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets. Recent work has uncovered the roles for DOCK8 in dendritic cell responses that can also help explain the virus susceptibility, as well as in regulatory T cells that might help explain autoimmunity in a minority of patients. Fortunately, hematopoietic stem cell transplantation cures the eczema and infection susceptibility of DIDS, but not necessarily the other disease manifestations including food allergies.
Hyper-IgE Syndromes and the Lung Freeman, Alexandra F; Olivier, Kenneth N
Clinics in chest medicine,
09/2016, Letnik:
37, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Elevated serum IgE has many etiologies including parasitic infection, allergy and asthma, malignancy, and immune dysregulation. The hyper-IgE syndromes caused by mutations in STAT3, DOCK8, and PGM3 ...are monogenic primary immunodeficiencies associated with high IgE, eczema, and recurrent infections. These primary immunodeficiencies are associated with recurrent pneumonias leading to bronchiectasis; however, each has unique features and genetic diagnosis is essential in guiding therapy, discussing family planning, and defining prognosis. This article discusses the clinical features of these primary immunodeficiencies with a particular focus on the pulmonary manifestations and discussion of the genetics, pathogenesis, and approaches to therapy.
There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of ...developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.
We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.
An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.
We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.
This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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