Early-onset refractory diarrhea due to immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome associated with a novel mutation in the FOXP3 gene: A case report

BACKGROUND Immune dysregulation,polyendocrinopthy,enteropathy,X-linked(IPEX)syndrome is a rare X-linked recessive disease caused by mutations in the forkhead box protein 3(FOXP3)gene,which is a master transcriptional regulator for the development and function of CD4+CD25+regulatory T(Treg)cells.The dysfunction of these cells leads to multiple system autoimmune diseases.We present a case of IPEX due to a mutation not reported in the literature before.CASE SUMMARY We report a male patient with IPEX syndrome who presented with refractory diarrhea and malabsorption leading to failure to thrive,as well as with hypothyroidism and nephrotic syndrome.Laboratory investigation showed increased total IgE and Treg cells,decreased free triiodothyronine(FT3)and free thyroxine(FT4),and proteinuria.Multiple dietary and supportive treatments were introduced but did not improve the diarrhea during his hospital stay.Ultimately,whole exome sequencing revealed that the patient was hemizygous for the exon 5,c.542G>A(p.Ser181Asn)mutation of the FOXP3 gene,which has not been previously reported.The patient remains on prednisone and euthyrox while awaiting hematopoietic stem cell transplantation at the time of the compilation of this case report.CONCLUSION We report a novel FOXP3 gene mutation involved in IPEX.A high level of suspicion should be maintained in an early-onset refractory diarrhea patient.

MicroRNA-663 induces immune dysregulation by inhibiting TGF-β1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus

Mesenchymal stem cells(MSCs)are critical for immune regulation.Although several microRNAs(miRNAs)have been shown to participate in autoimmune pathogenesis by affecting lymphocyte development and function,the roles of miRNAs in MSC dysfunction in autoimmune diseases remain unclear.Here,we show that patients with systemic lupus erythematosus(SLE)display a unique miRNA signature in bone marrow-derived MSCs(BMSCs)compared with normal controls,among which miR-663 is closely associated with SLE disease activity.MiR-663 inhibits the proliferation and migration of BMSCs and impairs BMSC-mediated downregulation of follicular T helper(Tfh)cells and upregulation of regulatory T(Treg)cells by targeting transforming growth factorβ1(TGF-β1).MiR-663 overexpression weakens the therapeutic effect of BMSCs,while miR-663 inhibition improves the remission of lupus disease in MRL/lpr mice.Thus,miR-663 is a key mediator of SLE BMSC regulation and may serve as a new therapeutic target for the treatment of lupus.

Hidradenitis Suppurativa: An Exploration of Genetic Perturbations and Immune Dysregulation

Hidradenitis suppurativa(HS)is a chronic,inflammatory skin condition that poses a significant diagnostic and therapeutic challenge for clinicians,as the underlying etiology and pathogenesis remains unclear.The host of genetic mutations and immune dysfunction has been identified to be involved in the pathogenesis of HS during recent years.These genetic defects,including monogenetic mutations altering subunits ofγ-secretase,a protease that functions through Notch signaling to maintain skin appendages,promote epithelial stability,suppress/terminate innate immune responses(ie,Toll-receptors),further have the propensity to induce aberrant cytokine responses that create to a proinflammatory environment,consequently induce hyperkeratosis and promote expression of pro-inflammatory,locally destructive matrix metalloproteinases.Cytokine-driven inflammation propagates the disease state of HS and contributes to the formation of painful subcutaneous nodules,abscesses,and eventually,fistulas and draining sinus tracts.A closer look at genetic mutations linked to the disease may explain the immune perturbations seen in HS.An understanding of the immune cells and inflammatory markers expressed in affected individuals provides insight into disease pathogenesis and can help identify therapeutic targets.

Sepsis-associated liver injury:Mechanisms and potential therapeutic targets

In this editorial,we examined a recent article in the World Journal of Gastroenterology that focused on sepsis-associated liver injury(SLI)and its treatment.SLI is a serious complication of sepsis,primarily caused by microcirculatory disturbances,the gut-liver axis,and inflammatory responses.Specific treatment recommendations for SLI are lacking.The gut-liver axis represents a potential therapeutic target,with metformin showing promise in modulating the gut microbiome and enhancing intestinal barrier function.Although immunomodulatory therapies are being explored,anti-tumor necrosis factor agents and interleukin-1 receptor antagonists have not demonstrated significant clinical benefits.Statins may reduce liver inflammation and prevent injury in sepsis,but their clinical application is limited.Reduced D-related human leucocyte antigen expression on monocytes and lymphocytes suggests immune suppression in patients,indicating that corticosteroids could reverse clinical deterioration in severe infections and address adrenal cortical insufficiency.Current large-scale studies on glucocorticoid therapy for sepsis have yielded mixed results,likely due to inadequate assessment of the immune status of the host.Future research should prioritize the development of personalized immunotherapy tailored to patients’immune profiles,focusing on identifying novel indicators of immune status and advancing immunomodulatory targets and therapeutics for septic patients.

Coronavirus disease 2019 and non-alcoholic fatty liver disease

The coronavirus disease 2019(COVID-19)pandemic may present with a broad range of clinical manifestations,from no or mild symptoms to severe disease.Patients with specific pre-existing comorbidities,such as obesity and type 2 diabetes,are at high risk of coming out with a critical form of COVID-19.Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,and,because of its frequent association with metabolic alterations including obesity and type 2 diabetes,it has recently been re-named as metabolic-associated fatty liver disease(MAFLD).Several studies and systematic reviews pointed out the increased risk of severe COVID-19 in NAFLD/MAFLD patients.Even though dedicated mechanistic studies are missing,this higher probability may be justified by systemic low-grade chronic inflammation associated with immune dysregulation in NAFLD/MAFLD,which could trigger cytokine storm and hypercoagulable state after severe acute respiratory syndrome coronavirus 2 infection.This review focuses on the predisposing role of NAFLD/MAFLD in favoring severe COVID-19,discussing the available information on specific risk factors,clinical features,outcomes,and pathogenetic mechanisms.

Gastrointestinal disease in children with autism spectrum disorders:Etiology or consequence?

Chronic gastrointestinal(GI)symptoms and disorders are common in children with autism spectrum disorder and have been shown to be significantly correlated with the degree of behavioral and cognitive impairment.In this unique population,GI symptoms often arise very early in development,during infancy or toddlerhood,and may be misdiagnosed-or not diagnosed at all–due in part to the challenges associated with recognition of symptoms in a minimally or noncommunicative child.Evidence demonstrating that the gut-brain-axis can communicate gut dysbiosis and systemic immune dysregulation in a bidirectional manner raises the question as to whether an untreated gastrointestinal disorder can directly impact neurodevelopment or,conversely,whether having a neurodevelopmental disorder predisposes a child to chronic GI issues.From the data presented in this mini review,we conclude that the preponderance of available evidence would suggest the former scenario is more strongly supported.

Muco-Cutaneous Changes Following COVID-19 in Children

Coronavirus disease 2019 (COVID-19) is an illness caused by the novel coronavirus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first identified in Wuhan, China, in December 2019, and soon spread all over the world causing a global pandemic. Since the beginning of the pandemic, fewer cases of COVID-19 have been reported in children than in adults. Most cases have been mild and only a small proportion of infected children needed hospitalization. As the pandemic evolved, it was soon evident that immune dysregulation inflicted by the virus, posed children at risk for their lives. It is still hard to predict its effects on children health and well-being. Here are reported a series of cases of muco-cutaneous changes following COVID-19 infection in children. Children ranged from 8 months to ten years. They had a history of a recent COVID-19 infection (1 - 3 months ago), with a RT-PCR for COVID-19 negative, SARS-CoV-2 IgM negative and a positive SARS-Cov-2 IgG. Their presentation was consistent with a late reaction to COVID-19 reaction with muco-cutaneous changes dominating the scenery.

Current understanding of ELF4 deficiency:a novel inborn error of immunity

Background ELF4 deficiency has been recently recognized as a novel disorder within the spectrum of inborn errors of immunity(IEIs),specifically categorized as a“disease of immune dysregulation.”Cases of this condition,reported by our team and others,are very limited worldwide.As such,our current knowledge of this new disease remains preliminary.This review aims to provide a brief overview of the clinical manifestations,pathogenesis,and treatment strategies for this novel IEI.Data sources A comprehensive review was conducted after an extensive literature search in the PubMed/Medline database and websites concerning transcriptional factor ELF4 and reports concerning patients with ELF4 deficiency.Our search strategy was“ELF4 OR ETS-related transcription factor Elf-4 OR EL4-like factor 4 OR myeloid Elf-1-like factor”as of the time of manuscript submission.Results The current signature manifestations of ELF4 deficiency disorder are recurrent and prolonged oral ulcer,abdominal pain,and diarrhea in pediatric males.In some cases,immunodeficiency and autoimmunity can also be prominent.Targeted Sanger sequencing or whole exome sequencing can be used to detect variation in ELF4 gene.Western blotting for ELF4 expression of the patient’s cells can confirm the pathogenic effect of the variant.To fully confirm the pathogenicity of the variant,further functional test is strongly advised.Glucocorticoid and biologics are the mainstream management of ELF4 deficiency disorder.Conclusions Pediatric males presenting with recurring ulcerations in digestive tract epithelium with or without recurrent fever should be suspected of DEX.When atypical presentations are prominent,variations in ELF4 gene should be carefully evaluated functionally due to the complex nature of ELF4 function.Experience of treating DEX includes use of glucocorticoid and biologics and more precise treatment needs more patients to identify and further mechanistic study.

Unveiling the nexus:Decoding interactions between regulated cell death and systemic lupus erythematosus pathogenesis for innovative therapeutic avenues

Systemic lupus erythematosus(SLE)is characterized by disruptions in cell death pathways and impaired clearance of apoptotic cells,resulting in immune dysregulation and tissue damage.This review explores the complex interplay of regulated cell death(RCD)mechanisms,including apoptosis,necroptosis,pyroptosis,NETosis,autophagy,and ferroptosis,in the pathogenesis of SLE.These pathways release autoantigens and danger signals,triggering autoimmune reactions and inflammation.Six various RCDs have mutual associates to support immune dysregulation and are associated with SLE.Apoptosis intrinsically induces immune tolerance by packaging dying cells into immunologically inert fragments.Deficiencies in apoptotic clearance will result in impaired tolerance.Necroptosis,pyroptosis,NETosis,and ferroptosis lead to cell membrane destruction,production of intracellular immunostimulatory components,and triggering a strong inflammatory immune reaction.Abnormal autophagic activity affects the development,differentiation,function,and metabolism of many immune cell subpopulations.Investigating the interconnections between cell death pathways and SLE sheds light on the disease's underlying mechanisms and provides opportunities for novel therapeutic interventions.The convergence of precision medicine and innovative strategies targeting these intricate pathways holds promise for expanding the landscape of SLE treatment.

Cell-in-cell:an emerging player in COVID-19 and immune disorders

Cell-in-cell is a unique phenomenon mostly documented in human cancer tissues.A recent study demonstrated that cell-in-cell might promote lymphopenia by internalizing and killing immune cells in COVID-19,which implicates cell-in-cell as an emerging player in a broader spectrum of pathological processes,such as immune dysregulation.

The pathogenesis and diagnosis of sepsis post burn injury

Burn is an under-appreciated trauma that is associated with unacceptably high morbidity and mortality.Although the survival rate after devastating burn injuries has continued to increase in previous decades due to medical advances in burn wound care,nutritional and fluid resuscitation and improved infection control practices,there are still large numbers of patients at a high risk of death.One of the most common complications of burn is sepsis,which is defined as“severe organ dysfunction attributed to host’s disordered response to infection”and is the primary cause of death in burn patients.Indeed,burn injuries are accompanied by a series of events that lead to sepsis and multiple organ dysfunction syndrome,such as a hypovolaemic state,immune and inflammatory responses and metabolic changes.Therefore,clear diagnostic criteria and predictive biomarkers are especially important in the prevention and treatment of sepsis and septic shock.In this review,we focus on the pathogenesis of burn wound infection and the post-burn events leading to sepsis.Moreover,the clinical and promising biomarkers of burn sepsis will also be summarized.

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

Autism spectrum disorder(ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones.

The Implication and Significance of Beta 2 Microglobulin： A Conservative Multifunctional Regulator

Objective： This review focuses on the current knowledge on the implication and significance of beta 2 microglobulin （β2M）, a conservative immune molecule in vertebrate.Data Sources： The data used in this review were obtained from PubMed up to October 2015.Terms of β2M, immune response, and infection were used in the search.Study Selections： Articles related to β2M were retrieved and reviewed.Articles focusing on the characteristic and function of β2M were selected.The exclusion criteria of articles were that the studies on β2M-related molecules.Results： β2M is critical for the immune surveillance and modulation in vertebrate animals.The dysregulation of β2M is associated with multiple diseases, including endogenous and infectious diseases.β2M could directly participate in the development of cancer cells, and the level of β2M is deemed as a prognostic marker for several malignancies.It also involves in forming major histocompatibility complex （MHC class Ⅰ or MHC Ⅰ） or like heterodimers, covering from antigen presentation to immune homeostasis.Conclusions： Based on the characteristic of β2M, it or its signaling pathway has been targeted as biomedical or therapeutic tools.Moreover, β2M is highly conserved among different species, and overall structures are virtually identical, implying the versatility of β2M on applications.

IL-10-Producing Type 1 Regulatory T Cells and Allergy

As an important subset of regulatory T （Treg） cells, IL-10-producing type 1 regulatory T cells （Trl）, have some different features to thymic-derived naturally occurring CD4^＋CD25^＋Foxp3^＋ Treg cells（nTreg cells）. Similar to nTreg cells, Trl also play important roles in the control of allergic inflammation in several ways. There is a fine balance between Trl and Th2 responses in healthy subjects. Skewing of allergic-specific effctor T cells to a Trl phenotype appears to be a critical event in successful allergen-specific immunotherapy and glucocorticoids and β2-agonists treatment. Trl suppress Th2 cells and effector cells of allergic inflammation, such as eosinophils, mast cells, basophils, through producing IL-10, and perhaps TGF-β. Understanding of Trl may be helpful in developing new strategies for treatment of allergic diseases.

Emerging roles of spliceosome in cancer and immunity

Precursor messenger RNA(pre-mRNA)splicing is cat-alyzed by an intricate ribonucleoprotein complex called the spliceosome.Although the spliceosome is consid-ered to be general cell"housekeeping"machinery,mutations in core components of the spliceosome fre-quently correlate with cell-or tissue-specific pheno-types and diseases.In this review,we expound the links between spliceosome mutations,aberrant splicing,and human cancers.Remarkably,spliceosome-targeted therapios(STTs)have become efficient anti-cancer strategies for cancer patients with splicing defects.We also highlight the links between spliceosome and immune signaling.Recent studies have shown that some spliceosome gene mutations can result in immune dysregulation and notable phenotypes due to mis-splicing of immune-related genes.Furthermore,several core spliceosome components harbor splicing-inde-pendent immune functions within the cell,expanding the functional repertoire of these diverse proteins.

Dysregulated immunity in PID patients with low GARP expression on Tregs due to mutations in LRRC32

Immune dysregulation diseases are characterized by heterogeneous clinical manifestations and may have severe disease courses.The identification of the genetic causes of these diseases therefore has critical clinical implications.We performed whole-exome sequencing of patients with immune dysregulation disorders and identified two patients with previously undescribed mutations in LRRC32,which encodes glycoprotein A repetitions predominant(GARP).These patients were characterized by markedly reduced numbers and frequencies of regulatory T cells(Tregs).Tregs with mutated LRRC32 exhibited strongly diminished cell-surface GARP expression and reduced suppressor function.In a model of conditional Garp deficiency in mice,we confirmed increased susceptibility to inflammatory diseases once GARP expression on Tregs was decreased.Garp deficiency led to an unstable Treg phenotype due to diminished Foxp3 protein acetylation and stability.Our study reinforces the understanding of the immunological mechanisms of immune dysregulation and expands the knowledge on the immunological function of GARP as an important regulator of Treg stability.