Disorder Of Immune Regulation Research Articles

Trichinella spiralis alleviates LPS-induced acute lung injury by modulating the protective Th2 immune response

Sepsis is a disorder of immune regulation caused by pathogenic microorganisms. A large number of inflammatory factors and inflammatory mediators are released, resulting in systemic inflammatory response disorder and acute lung injury (ALI). Helminths infection activate Th2 cytokines and immunomodulatory pathways, which have the function of anti-infection effector molecules. The early infection of Trichinella spiralis (T. spiralis) was mainly intestinal phase. In this study, we explored the effect of intestinal phase infection of T. spiralis on LPS-induced ALI. Compared with control mice, the serum and lung tissues of T. spiralis infected mice had a significant decrease of Th1 inflammatory cytokines, a significant increase of Th2 anti-inflammatory cytokines, and a significant decrease of inflammatory cell infiltration in lung tissue. These results suggest that T. spiralis during the intestinal phase can act on distal organs (lung) and reduce LPS-induced lung inflammation, providing evidence for a potential new pathway for immune-mediated disease in helminths and a possible role for intestinal worms in the gut-lung axis.

169 Long Term Management of Transplanted Patients with Chronic Granulomatous Disease, Wiskott-Aldrich Syndrome, and Primary Immune Regulatory Disorders: A PIDTC Survey

169 Long Term Management of Transplanted Patients with Chronic Granulomatous Disease, Wiskott-Aldrich Syndrome, and Primary Immune Regulatory Disorders: A PIDTC Survey

13 Long-Term Medical Management of Patients with Chronic Granulomatous Disease, Wiskott-Aldrich Syndrome, and Primary Immune Regulatory Disorders: A Primary Immune Deficiency Treatment Consortium Survey

13 Long-Term Medical Management of Patients with Chronic Granulomatous Disease, Wiskott-Aldrich Syndrome, and Primary Immune Regulatory Disorders: A Primary Immune Deficiency Treatment Consortium Survey

Targeted treatments for immune dysregulation in inborn errors of immunity

Primary immune regulatory disorders (PIRDs) constitute a subset of inborn errors of immunity and are characterized by lymphoproliferation, autoimmunity, malignancy, and infection. Unlike classical primary immune deficiencies, initial symptoms of PIRDs can manifest as autoimmunity such as cytopenias or enteropathy, which can often prove resistant to conventional treatments and occur years prior to the onset of infectious complications. Raising awareness about PIRDs among specialists and adopting a multidisciplinary approach is crucial for early diagnosis, intervention, and potential prevention of severe organ damage. Significant progress has been made in identifying several PIRDs, which has contributed to a more comprehensive comprehension of their underlying immunological mechanisms. This knowledge has paved the way for targeted therapies focusing on specific molecules, which tend to offer superior disease control compared to traditional immunosuppressants. This review, informed by the latest literature, explores prevalent PIRDs, detailing their clinical manifestations and recent advancements in treatment modalities.

Primary immune regulatory disorders (PIRD): expanding the mutation spectrum in Turkey and identification of sixteen novel variants.

Human Inborn Errors of Immunity (IEIs) encompass a clinically and genetically heterogeneous group of disorders, ranging from mild cases to severe, life-threatening types. Among these, Primary Immune Regulatory Disorders (PIRDs) constitute a subset of IEIs characterized by diverse clinical phenotypes, prominently featuring severe atopy, autoimmunity, lymphoproliferation, hyperinflammation, autoinflammation, and susceptibility to malignancies. According to the latest report from the International Union of Immunological Societies (IUIS), PIRDs arise from mutations in various genes including LYST, RAB27A, AP3B1, AP3D1, PRF1, UNC13D, STX11, STXBP2, FAAP24, SLC7A7, RASGRP1, CD70, CTPS1, RLTPR, ITK, MAGT1, PRKCD, TNFRSF9, SH2DIA, XIAP, CD27 (TNFRSF7), FAS (TNFRSF6), FASLG (TNFSF6), CASP10, CASP8, FADD, LRBA, STAT3, AIRE, ITCH, ZAP70, TPP2, JAK1, PEPD, FOXP3, IL2RA, CTLA4, BACH2, IL2RB, DEF6, FERMT1, IL10, IL10RA, IL10RB, NFAT5, TGFB1, and RIPK1 genes. We designed a targeted next-generation sequencing (TNGS) workflow using the Ion AmpliSeq™ Primary Immune Deficiency Research Panel to sequence 264 genes associated with IEIs on the Ion S5™ Sequencer. In this study, we report the identification of 38 disease-causing variants, including 16 novel ones, detected in 40 patients across 15 distinct PIRD genes. The application of next-generation sequencing enabled rapid and precise diagnosis of patients with PIRDs.

Imbalance of cell differentiation clusters associated with contamination of biological media by lanthanides in workers of the titanium and rare metals recovery and distillation workshop

The professional activity of a person, depending on the working conditions, modifies the regulation of a single homeostatic mechanism, ultimately forming a breakdown of adaptation associated with an imbalance of immunological 
 parameters.
 The study aims to evaluate changes in the surface molecules of leukocytes of the immune system specifically induced by the presence of lanthanides in workers in the production environment.
 The authors examined 88 people working in the metallurgical industry. The observation group consisted of 24 people with an average work experience of 7.4±0.9 years, the comparison group included 64 people with an average work experience of 7.3±0.9 years. The scientists determined the identification of membrane markers (CD11a, CD277+, CD304+) by flow cytometry, and they also identified specific IgG to lanthanides by allergosorbent testing.
 Excessive concentrations of lanthanides in the blood are formed in workers of the titanium and rare metals recovery and distillation workshop, which are reliably associated with indicator indicators of cellular differentiation of immune regulation clusters: inhibition of expression of immunological phenotypes CD11a, CD304+, CD277+, hyperproduction of specific IgG class reagins to lanthanides. The established immunological scenario is characteristic of the phenotypic characteristics of classical dendritic cells involved in autoimmune inflammatory reactions during the formation of vascular disorders of the central nervous system in workers in these production conditions.
 The results obtained indicate that under conditions of industrial exposure to rare earth metals (lanthanides), workers in the workshop for the recovery and distillation of titanium and rare metals form maladaptive processes of disorders of immune regulation and expression of mediators of cellular differentiation, the markers of which include inhibition of cellular immunity associated with neurovascular mediators (CD11a, CD277+, CD304+), hyperproduction of specific IgG to lanthanides.
 Ethics. The study was approved by the Ethics committee of Federal Scientific Center for Medical and Preventive Health Risk Management Technologies. All patients were informed about the purpose of the study, and voluntary informed consent was obtained.

Genetic aetiologies of acute liver failure.

Acute liver failure (ALF) is a rare, rapidly evolving, clinical syndrome with devastating consequences where definitive treatment is by emergency liver transplantation. Establishing a diagnosis can be challenging and, historically, the cause of ALF was unidentified in up to half of children. However, recent technological and clinical advances in genomic medicine have led to an increasing proportion being diagnosed with monogenic aetiologies of ALF. The conditions encountered include a diverse group of inherited metabolic disorders each with prognostic and treatment implications. Often these disorders are clinically indistinguishable and may even mimic disorders of immune regulation or red cell disorders. Rapid genomic sequencing for children with ALF is, therefore, a key component in the diagnostic work up today. This review focuses on the monogenic aetiologies of ALF.

Infections in Disorders of Immune Regulation.

Primary immune regulatory disorders (PIRDs) constitute a spectrum of inborn errors of immunity (IEIs) that are primarily characterized by autoimmunity, lymphoproliferation, atopy, and malignancy. In PIRDs, infections are infrequent compared to other IEIs. While susceptibility to infection primarily stems from antibody deficiency, it is sometimes associated with additional innate immune and T or NK cell defects. The use of immunotherapy and chemotherapy further complicates the immune landscape, increasing the risk of diverse infections. Recurrent sinopulmonary infections, particularly bacterial infections such as those associated with staphylococcal and streptococcal organisms, are the most reported infectious manifestations. Predisposition to viral infections, especially Epstein-Barr virus (EBV)-inducing lymphoproliferation and malignancy, is also seen. Notably, mycobacterial and invasive fungal infections are rarely documented in these disorders. Knowledge about the spectrum of infections in these disorders would prevent diagnostic delays and prevent organ damage. This review delves into the infection profile specific to autoimmune lymphoproliferative syndrome (ALPS), Tregopathies, and syndromes with autoimmunity within the broader context of PIRD. Despite the critical importance of understanding the infectious aspects of these disorders, there remains a scarcity of comprehensive reports on this subject.

CYP1A1 (RS4646421) gene polymorphism and peculiarities of immune profile in children under aerogenic exposure to benzo(a)pyrene

Introduction. The benzo(a)pyrene exposure forms the special phenotype of the immune profile in children. The study of immune system features associated with the polymorphism of detoxification genes is relevant in the conditions of health risks linked with environmental pollution.
 Materials and methods. There was performed clinical and laboratory examination of four hundred seventy nine children aged of 3–6 years. The observation group consisted of 308 children living in conditions of aerogenic exposure to benzo(a)pyrene. The comparison group included 171 children from a relatively clean territory. Determination of benzo(a)pyrene concentration in an atmospheric air and in blood was carried out by HPLC. The study of polymorphism of CYP1A1 (rs4646421) gene was carried out by real-time PCR. CD3+CD4+-lymphocyte phenotyping was performed by flow cytometry, IgG to benzo(a)pyrene – by allergosorbent testing.
 Results. Aerogenic exposure to benzo(a)pyrene at an average daily dose of 8.76•10–2 µg/(kg•day) causes an increase in the level of blood contamination with PAH, forms an imbalance of the immune profile (IgG to benzo(a)pyrene hyperproduction, CD3+CD4+-lymphocyte expression deficiency and CD4+/CD8+decrease) associated with T-allele and CT-genotype of the CYP1A1 gene (rs4646421) (OR(CI)=2.35–6.65; p<0.05). Children with the CT-genotype of the CYP1A1 gene (rs4646421) are characterized by the most pronounced changes in the immune profile (excess IgG to benzo(a)pyrene; reduction of CD3+CD4+ and CD4+/CD8+ against the background of maximum blood contamination with benzo(a)pyrene in relation to other genotypic groups (OR(CI)=1.64–3.08; p<0.05). 
 Limitations. The limitations are related to the need to increase the sample and verify the results obtained in subsequent observations.
 Conclusion. The peculiarities of the immune profile in CT-genotype carriers of the CYP1A1 (rs4646421) gene under the conditions of aerogenic exposure to benzo(a)pyrene at a dose of 8.76•10–2 mcg/(kg•day) should include the formation of specific sensitization to benzo(a)pyrene, deficiency of cellular differentiation clusters: CD3+CD4+-lymphocytes, CD4+/CD8+ reduction associated with blood contamination with benzo(a)pyrene, which indicate the likelihood of hereditary predisposition realization and the formation of immune regulation disorders associated with exposure to benzo(a)pyrene.

Primary Immune Regulatory Disorders (PIRDs) That Amplify mTOR Signaling Share a T Cell Exhaustion-like Process

Background: Primary Immune Regulatory Disorders (PIRDs) are a complex and challenging-to-treat subset of Inborn Errors of Immunity (IEI), which are characterized by immune dysregulation leading to recurrent infections, lymphoproliferation, and autoimmunity including refractory cytopenias. Since many ultra-rare monogenic PIRDs exist, it is not feasible to design targeted therapies for each. An alternate strategy is to identify shared aspects of T cell dysfunction and strategies targeting them. We have focused our studies on PIRDs that chronically amplify T cell receptor (TCR) signaling, mimicking chronic infection. Under conditions of chronic inflammation and antigen presentation, seen during chronic infections, CD8 T cell exhaustion (Tex) can result and is characterized by increased inhibitory receptor expression, altered transcriptional networks, epigenetic poise, and impaired T cell functions including cytokine production. Here, we have evaluated CD8 T cell dysfunction in PIRDs, including the potential for Tex. Methods: Deep immune phenotyping and T cell functional analyses were performed using CyTOF and spectral flow cytometry, in addition to single cell RNA-sequencing and CITE-seq from untreated PIRD and healthy control PBMCs. Finally, CRISPR/Cas9 editing in healthy control CD8 T cells was used to create a cellular disease model. Results: We identified a Tex-like process in activated PI3 kinase delta syndrome (APDS), CTLA-4 haploinsufficiency, and Ras-associated Autoimmune Leukoproliferative Disease (RALD), which share increased mTOR activation. We identified increased PD-1, CD39, TIGIT and TOX expression on CD8 T cells consistent with a Tex-like phenotype. We also found impaired CD8 T cell cytokine and proliferation consistent with Tex. Lastly, a cellular model of CTLA-4 haploinsufficiency was created for perturbation studies to evaluate best available therapies and target novel therapeutics in these rare disorders. Conclusion: By identifying shared patterns of CD8 T cell dysfunction in these ultra-rare disorders, we may both identify novel therapeutic strategies and increase our understanding of CD8 T cell function, including cytokine production.

Too much of a good thing: a review of primary immune regulatory disorders.

Primary immune regulatory disorders (PIRDs) are inborn errors of immunity caused by a loss in the regulatory mechanism of the inflammatory or immune response, leading to impaired immunological tolerance or an exuberant inflammatory response to various stimuli due to loss or gain of function mutations. Whilst PIRDs may feature susceptibility to recurrent, severe, or opportunistic infection in their phenotype, this group of syndromes has broadened the spectrum of disease caused by defects in immunity-related genes to include autoimmunity, autoinflammation, lymphoproliferation, malignancy, and allergy; increasing focus on PIRDs has thus redefined the classical 'primary immunodeficiency' as one aspect of an overarching group of inborn errors of immunity. The growing number of genetic defects associated with PIRDs has expanded our understanding of immune tolerance mechanisms and prompted identification of molecular targets for therapy. However, PIRDs remain difficult to recognize due to incomplete penetrance of their diverse phenotype, which may cross organ systems and present to multiple clinical specialists prior to review by an immunologist. Control of immune dysregulation with immunosuppressive therapies must be balanced against the enhanced infective risk posed by the underlying defect and accumulated end-organ damage, posing a challenge to clinicians. Whilst allogeneic hematopoietic stem cell transplantation may correct the underlying immune defect, identification of appropriate patients and timing of transplant is difficult. The relatively recent description of many PIRDs and rarity of individual genetic entities that comprise this group means data on natural history, clinical progression, and treatment are limited, and so international collaboration will be needed to better delineate phenotypes and the impact of existing and potential therapies. This review explores pathophysiology, clinical features, current therapeutic strategies for PIRDs including cellular platforms, and future directions for research.

The double-edged sword role of hydrogen sulfide in hepatocellular carcinoma.

With an increasing worldwide prevalence, hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver in the world. It is also the primary reason for cancer-related death in the world. The pathogenesis of HCC is complex, such as DNA methylation changes, immune regulatory disorders, cell cycle disorders, chromosomal instability, and so on. Although many studies have been conducted on HCC, the molecular mechanisms of HCC are not completely understood. At present, there is no effective treatment for HCC. Hydrogen sulfide (H2S) has long been regarded as a toxic gas with the smell of rotten eggs, but recent studies have shown that it is an important gasotransmitter along with carbon monoxide (CO) and nitric oxide (NO). Increasing evidence indicates that H2S has multiple biological functions, such as anti-inflammation, anti-apoptosis, anti-oxidative stress, and so on. Recently, a lot of evidence has shown that H2S has a "double-edged sword" effect in HCC, but the mechanism is not fully understood. Here, we reviewed the progress on the role and mechanism of H2S in HCC in recent years, hoping to provide a theoretical reference for future related research.

Clinical utility of measuring CD4+ T follicular cells in patients with immune dysregulation

Mechanistic studies of autoimmune disorders have identified circulating T follicular helper (cTfh) cells as drivers of autoimmunity. However, the quantification of cTfh cells is not yet used in clinical practice due to the lack of age-stratified normal ranges and the unknown sensitivity and specificity of this test for autoimmunity. We enrolled 238 healthy participants and 130 patients with common and rare disorders of autoimmunity or autoinflammation. Patients with infections, active malignancy, or any history of transplantation were excluded. In 238 healthy controls, median cTfh percentages (range 4.8%–6.2%) were comparable among age groups, sexes, races, and ethnicities, apart from a significantly lower percentages in children less than 1 year of age (median 2.1%, CI: 0.4%–6.8, p < 0.0001). Among 130 patients with over 40 immune regulatory disorders, a cTfh percentage exceeding 12% had 88% sensitivity and 94% specificity for differentiating disorders with adaptive immune cell dysregulation from those with predominantly innate cell defects. This threshold had a sensitivity of 86% and specificity of 100% for active autoimmunity and normalized with effective treatment. cTfh percentages exceeding 12% distinguish autoimmunity from autoinflammation, thereby differentiating two endotypes of immune dysregulation with overlapping symptoms and different therapies.

Frequency of HLA-DR+CD38hi T cells identifies and quantifies T-cell activation in hemophagocytic lymphohistiocytosis, hyperinflammation, and immune regulatory disorders

Quantifying T-cell activation is essential for the diagnosis and evaluation of treatment response in various hyperinflammatory and immune regulatory disorders, including hemophagocytic lymphohistiocytosis. Plasma soluble IL-2 receptor (sIL-2R) is a well-established biomarker for evaluating systemic T-cell activation. However, the limited availability of sIL-2R testing could result in delayed diagnosis. Furthermore, high sIL-2R levels may not always reflect T-cell activation. To address these limitations, this study investigated whether cell surface markers of T-cell activation, HLA-DR, and CD38, as assessed by flow cytometry, could be used to quantify systemic T-cell activation in a variety of inflammatory disease states and examine its correlation with sIL-2R levels. Results for sIL-2R, CXCL9, and ferritin assays were obtained from patient's medical records. Frequency of HLA-DR+CD38high(hi) T-cells was assessed in different T-cell subsets using flow cytometry. In this study's cohort, activation in total CD8+ T (r=0.65; P< .0001) and CD4+ (r= 0.42; P< .0001) T-cell subsets significantly correlated with plasma sIL-2R levels. At the disease onset, the frequency of HLA-DR+CD38hi T cells in CD8+ T (r= 0.65, P< .0001) and CD4+ T (r= 0.77; P< .0001) effector memory (TEM) compartments correlated strongly with sIL-2R levels. Evaluation of T-cell activation markers in follow-up samples also revealed a positive correlation for both CD4+ TEM and CD8+ TEM activation with sIL-2R levels; thus, attesting its utility in initial diagnosis and in evaluating treatment response. The frequency of HLA-DR+CD38hi T-cells in the CD8+ TEM compartment also correlated with plasma CXCL9 (r= 0.42; P= .0120) and ferritin levels (r= 0.32; P=.0037). This study demonstrates that flow cytometry-based direct T-cell activation assessed by HLA-DR+CD38hi Tcells accurately quantifies T-cell activation and stronglycorrelates with sIL-2R levels across a spectrum ofhyperinflammatory and immune dysregulation disorders.

Improving Access to Therapy for Patients With Inborn Errors of Immunity: A Call to Action.

Breakthroughs in sequencing technology, targeted immunotherapy, and immune reconstituting treatment have increased the pool of patients with inborn errors of immunity, requiring expertise from clinical immunologists. A growing category of immunodeficiency, presenting as primary immune regulatory disorder and secondary immunodeficiency due to targeted immune therapy for cancer and autoimmunity, has added to the growing burden of patients needing access to immune-supportive therapy. The confluence of a growing population of patients needing a clinical immunologist, complex payer structures, and inadequate health care representation will exacerbate current problems with access to therapy. Patients, health care providers, researchers, public and private payers, and industry must come together to find solutions to improve access to therapy. In this article, we reviewed the major topics regarding access to therapy for patients with immunodeficiency.

Inborn Errors of Immunity and Autoimmune Disease.

Autoimmunity may be a manifestation of inborn errors of immunity (IEI) specifically as part of the subgroup of primary immunodeficiency (PID) known as primary immune regulatory disorders (PIRD). However, while making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes and inheritance of autoimmunity associated with PIRD, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunological features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. Additionally, there will be a review of autoimmunity in non-genetically defined PID such as common variable immunodeficiency (CVID), and of instances where primary autoimmunity can result in clinical phenocopies of IEI.

The utility of HLA-DR+CD38high expression in quantifying the amplitude of T cell activation in HLH and immune dysregulation disorders

IntroductionIdentifying T-cell activation, the hallmark of multiple hyperinflammatory diseases like HLH and immune dysregulation disorders (IDS) like LRBA deficiency, is critical for diagnosis, management, and monitoring treatment response for patients with immune activation driven disease processes. Soluble Interleukin 2 Receptor (sIL2R) is an established systemic marker for T-cell activation but the clinical availability of sIL2R testing is limited. sIL2R is also not a reliable marker of T-cell activation in patients with eosinophilia or T-cell lymphoma. A recent study by Chaturvedi et.al has demonstrated the utility of flow-based T-cell activation assessment in differentiating HLH from sepsis. However, its utility in defining and quantifying T-cell activation across the hyperinflammatory spectrum and its correlation with sIL2R has not yet been established. MethodsA total of 125 samples were collected either at disease onset (n = 81) or at follow-up (n = 44) from 85 human subjects. Paired plasma sIL2R and T-cell activation markers were prospectively evaluated in patients with suspected HLH (n = 79) or IDS (n = 46). Flow cytometry-based T-cell activation was evaluated in different T-cell sub-compartments by the coexpression of HLA-DR and CD38 surface markers. ResultsEvaluation of T-cell activation measured by HLADR+CD38high in healthy controls (HCs) and different hyperinflammatory/ immune regulatory disorders revealed that HCs have less than 8% of T-cell activation in CD8 + Teffector memory (TEM) and less than 4% for activation in the CD4+ TEM compartments. In patients with suspected hyperinflammatory/ immune regulatory disorders, we identified significant correlation of direct T-cell activation with plasma sIL2R level in different T-cell subsets, CD3 (r = 0.44, p < 0.0001), CD4 (r = 0.41, p < 0.0001), CD8 (r = 0.45, p < 0.001), CD4 TEM (Teffector memory) (r = 0.53, p < 0.001), and CD8 TEM (r = 0.53, p < 0.0001).The strongest correlation between HLADR+CD38high with sIL2R level was noted in CD4+ TEM and CD8+ TEM compartments (Figure 1). [Display omitted] [Display omitted] ConclusionsFlow cytometry-based direct assessment of HLADR+ CD38high in T cells subsets can reliably quantify T-cell activation and strongly correlate with sIL2R level across a spectrum of different hyperinflammatory and immune dysregulation disorders.

Amplified STAT3 signaling alters expression of CD39 in STAT3 gain-of-function (STAT3 GOF) and in healthy donor CD8 +T cells

Abstract It is still unknown whether primary immune regulatory disorders (PIRD) due to genetic variants that amplify T cell receptor and/or inflammatory cytokine signaling yield T cell exhaustion. Here, we investigate the impact of dysregulated cytokine signaling on CD8 +T cells in STAT3 gain-of-function (STAT3 GOF) patients. Immune profiling via 43-parameter CyTOF reveals altered CD8 +T cell differentiation, including loss of naïve cells, increased frequency of effector memory and T EMRAcells, and downregulation of markers of stemness (i.e., TCF-1 and CD127) in STAT3 GOF. Additionally, STAT3 GOF CD8 +T cells demonstrate decreased IL-2 production and proliferation. We identify increased expression of the ecto-enzyme, CD39, which has been reported on exhausted cells and hydrolyzes extracellular ATP, on CD8 +T cells from STAT3 GOF patients and in a mouse model of STAT3 GOF. To identify the signals regulating CD39, healthy donor CD8 +T cells were cultured with STAT3-activating cytokines alone but did not upregulate CD39. However, TCR engagement led to robust CD39 expression which was further augmented with STAT3-activating cytokines. Specifically, CD39 upregulation occurs in pSTAT3 Y705+cells. Finally, sorted CD39 +CD8 +T cells hydrolyzed ATP and suppressed effector CD8 +T cell proliferation compared to CD39 −CD8 +T cells. These data suggest that STAT3 signaling may play a role in regulating CD39 levels and thus contribute to CD8 +T cell exhaustion, which will be explored in future work. Understanding how dysregulated STAT3 signaling impacts T cell function in these rare patients can improve our understanding of this complex disease and may yield insights into shared aspects of T cell dysfunction found in more common inflammatory diseases. HHMI Gilliam Fellowship for Advanced Studies (GT15736) Penn Presidential Fellowship PIDTC (Henrickson Lab) IDF (Henrickson Lab) NIH NIAD K08AI135091 (Henrickson Lab) Burroughs Wellcome Fund CAMS (Henrickson Lab)

STAT3 gain-of-function syndrome.

STAT3 gain-of-function (GOF) syndrome is a multi-organ primary immune regulatory disorder characterized by early onset autoimmunity. Patients present early in life, most commonly with lymphoproliferation, autoimmune cytopenias, and growth delay. However, disease is often progressive and can encompass a wide range of clinical manifestations such as: enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, and rarely neurologic disease, vasculopathy, and malignancy. Treatment of the autoimmune and immune dysregulatory features of STAT3-GOF patients relies heavily on immunosuppression and is often challenging and fraught with complications including severe infections. Defects in the T cell compartment leading to effector T cell accumulation and decreased T regulatory cells may contribute to autoimmunity. While T cell exhaustion and apoptosis defects likely contribute to the lymphoproliferative phenotype, no conclusive correlations are yet established. Here we review the known mechanistic and clinical characteristics of this heterogenous PIRD.

Rare immune diseases paving the road for genome editing-based precision medicine.

Clustered regularly interspaced short palindromic repeats (CRISPR) genome editing platform heralds a new era of gene therapy. Innovative treatments for life-threatening monogenic diseases of the blood and immune system are transitioning from semi-random gene addition to precise modification of defective genes. As these therapies enter first-in-human clinical trials, their long-term safety and efficacy will inform the future generation of genome editing-based medicine. Here we discuss the significance of Inborn Errors of Immunity as disease prototypes for establishing and advancing precision medicine. We will review the feasibility of clustered regularly interspaced short palindromic repeats-based genome editing platforms to modify the DNA sequence of primary cells and describe two emerging genome editing approaches to treat RAG2 deficiency, a primary immunodeficiency, and FOXP3 deficiency, a primary immune regulatory disorder.