Regulation of cGAS and STING signaling during inflammation and infection.

Stimulator of interferon genes (STING) is a sensor of cyclic dinucleotides including cyclic GMP-AMP, which is produced by cyclic GMP-AMP synthase (cGAS) in response to cytosolic DNA. The cGAS-STING signaling pathway regulates both innate and adaptive immune responses, as well as fundamental cellular functions such as autophagy, senescence, and apoptosis. Mutations leading to constitutive activation of STING cause devastating human diseases. Thus, the cGAS-STING pathway is of great interest because of its role in diverse cellular processes and because of the potential therapeutic implications of targeting cGAS and STING. Here, we review molecular and cellular mechanisms of STING signaling, and we propose a framework for understanding the immunological and other cellular functions of STING in the context of disease.

Autoinflammatory Diseases Due to Defects in Degradation or Transport of Intracellular Proteins.

The number of human inborn errors of immunity has now gone beyond 430. The responsible gene variants themselves are apparently the cause for the disorders, but the underlying molecular or cellular mechanisms for the pathogenesis are often unclear. In order to clarify the pathogenesis, the mutant mice carrying the gene variants are apparently useful and important. Extensive analysis of those mice should contribute to the clarification of novel immunoregulatory mechanisms or development of novel therapeutic maneuvers critical not only for the rare monogenic diseases themselves but also for related common polygenic diseases. We have recently generated novel model mice in which complicated manifestations of human inborn errors of immunity affecting degradation or transport of intracellular proteins were recapitulated. Here, we review outline of these disorders, mainly based on the phenotype of the mutant mice we have generated.

Imaging findings of COPA Syndrome.

BACKGROUND: Autosomal dominant mutations in the coatomer-associated protein alpha (COPA) gene cause an immune dysregulation disorder associated with pulmonary hemorrhage, lymphoid hyperplasia, arthritis, and glomerulonephritis. OBJECTIVE: To describe the thoracic, musculoskeletal, and renal imaging findings of COPA syndrome with a focus on the evolution of the pulmonary findings. MATERIALS AND METHODS: With approval of the Institutional Review Board, consensus retrospective review of findings on chest radiography and computed tomography (CT), musculoskeletal radiography and magnetic resonance imaging (MRI), and renal ultrasound (US) was performed for pediatric COPA syndrome patients. COPA syndrome patients < 18 years of age presenting between 1992 and 2019 were identified from an institutional rheumatology registry. RESULTS: Twelve pediatric COPA syndrome patients (mean age of 6.5 years at first imaging exam; 6 females) were identified. Imaging exams available for review included 45 chest CT exams on 12 patients, 37 musculoskeletal exams on 4 patients, and 10 renal US exams on 5 patients. All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12). Nine had at least one follow-up chest CT, which showed improvement in nodules (7/9), ground-glass opacities (4/9), and lymphadenopathy (9/9), but worsening of septal thickening (3/9), cyst formation (3/9), and fibrosis (3/9). Four had musculoskeletal imaging revealing synovitis (2/4), bone erosions (1/4), tenosynovitis (1/4), enthesitis (1/4), and subcutaneous nodules (1/4). Five had at least one renal US, revealing renal size abnormalities (4/5) and cortical hyperechogenicity (3/5). CONCLUSION: The most prevalent imaging finding of COPA syndrome is diffuse lung disease related to early childhood-onset recurrent pulmonary hemorrhage and lymphoid hyperplasia that may progress to pulmonary fibrosis. Other imaging findings manifesting later in childhood or adolescence relate to arthritis and glomerulonephritis.

A toddler with an unusually severe polyarticular arthritis and a lung involvement: a case report.

BACKGROUND: COPA syndrome is a rare hereditary inflammatory disease caused by mutations in the gene encoding the coatomer protein subunit alpha, causing excessive production of type I interferon. This case is a reminder for the general paediatrician, highlighting the relevance of the association between arthritis and lung involvement in toddlers. CASE PRESENTATION: We report the case of a 2-year-old girl with intermittent limping and joint pain. Her family history was relevant for a Still disease with lung involvement in the mother. Physical examination showed moderate wrist swelling. Laboratory findings on admission showed an increase in inflammatory markers, positive rheumatoid factor, antibodies antinuclear antibody (ANA) and cyclic citrullinated peptide (anti-CCP). Wrists' ultrasound documented synovial thickening, and chest X-rays showed an unexpected severe interstitial pneumopathy. Genetic testing confirmed the diagnosis of a heterozygous mutation of the COPA gene in c.841C > T (p.R281W). Janus kinase treatment was started (baricitinib, 4 mg daily per os) with a remarkable improvement in limping and joint pain after two weeks. CONCLUSIONS: In cases of recurrent arthritis with family history and multiple involvement organs, a genetic disorder should be suspected and genetic testing should be performed. Furthermore, this case suggests that therapy with jak inhibitors may be effective and safe in interferonopathies.

Type I interferon pathway activation in COPA syndrome.

Mutations of the COPA gene cause an immune dysregulatory disease characterised by polyarticular arthritis and progressive interstitial lung disease with pulmonary haemorrhages. We report the case of a young girl that presented at age 3 with polyarticular arthritis, chronic cough and high titer rheumatoid factor. Radiologic imaging showed interstitial lung disease with tree-in-a-bud nodules and air-filled cysts. Targeted genetic analysis of COPA gene showed the reported c.698G>A mutation. The patient was lost to follow up for 3years during which therapy was discontinued with the development of joint damage and deformities. Analysis of peripheral blood showed activation of type 1 interferon pathway, which was also confirmed in 4 previously reported COPA patients. Our observations underline the importance of early treatment in COPA disease to avoid loss of joint function. Furthermore, our results suggest a role for type 1 interferon in disease pathogenesis opening the possibility for targeted therapeutic approaches.

Imaging findings of Copa syndrome in a 12-year-old boy.

Copa syndrome is a newly described autosomal dominant autoinflammatory disease that presents as pulmonary hemosiderosis and polyarticular arthritis. Twenty-one cases from five families have been reported to date. We present chest computed tomography (CT) and temporomandibular joint magnetic resonance (MR) findings of a 12-year-old boy presenting with dyspnea on exertion, fatigue and clubbing. Additional findings included a restrictive pattern of pulmonary involvement and positive inflammatory markers and autoantibodies. Genetic testing revealed a p.W240R variant of the COPA gene confirming the diagnosis of Copa syndrome. CT of the chest showed a nonspecific interstitial pneumonia pattern distributed mainly in the lower lobes. MR of the temporomandibular joints and follow-up CT three years later are also described.

COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA.

BACKGROUND: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance. CASE PRESENTATION: Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein. CONCLUSIONS: This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome.

COPA syndrome caused by a novel p.Arg227Cys COPA gene variant.

BACKGROUND: COPA syndrome is a recently described and rare monogenic autosomal dominant disease caused by heterozygous missense mutations in the Coatomer Protein Subunit alpha (COPA) gene that encodes the alpha subunit of coat protein complex I (COPI). Its main clinical manifestations are inflammatory lung disease, arthritis, and renal disease. The development of inflammation in COPA syndrome maybe due to abnormal autophagic response and abnormal activation of type I interferon pathway. To date, 59 cases of COPA have been reported worldwide. METHODS: In this case, Trio-whole exome sequencing was employed in the proband and her parents to identify the underlying genetic cause. COPA variant were detected and the clinical presentation of the patient was described. RESULTS: Herein, we report a case of a 5-year-old girl with COPA syndrome who presented with symptoms of arthritis combined with Anti-neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV), and progressive renal decline with minimal pulmonary involvement. Trio-whole exome sequencing was performed which revealed a novel heterozygous likely pathogenic variation in the COPA gene (c.679C>T,p.Arg227Cys), which was maternally inherited. Her mother was a heterozygote, but she had no phenotypic manifestations. No other mutations associated with the clinical phenotype were identified. CONCLUSION: The present identification and characterization of a novel mutation expands the genotypic spectra of the COPA syndrome and provide reference data to guide future clinical diagnosis and treatment of COPA syndrome.

Case report: COPA syndrome with interstitial lung disease, skin involvement, and neuromyelitis spectrum disorder.

This report describes a case of a 22 months Chinese boy with COPA syndrome bearing the c.715G > C (p.A239P) genotype. In addition to interstitial lung diseae, he also suffered from recurrent chilblain-like rashes, which has not been previously reported, and neuromyelitis optica spectrum disorder (NMOSD), which is a very rare phenotype. Clinical manifestations expanded the phenotype of COPA syndrome. Notably, there is no definitive treatment for COPA syndrome. In this report, the patient has achieved short-term clinical improvement with sirolimus.

COPA Syndrome from Diagnosis to Treatment: A Clinician's Guide.

COPA syndrome is a recently described autosomal dominant inborn error of immunity characterized by high titer autoantibodies and interstitial lung disease, with many individuals also having arthritis and nephritis. Onset is usually in early childhood, with unique disease features including alveolar hemorrhage, which can be insidious, pulmonary cyst formation, and progressive pulmonary fibrosis in nonspecific interstitial pneumonia or lymphocytic interstitial pneumonia patterns. This review explores the clinical presentation, genetics, molecular mechanisms, organ manifestations, and treatment approaches for COPA syndrome, and presents a diagnostic framework of suggested indications for patient testing.

Chronic limping in childhood, what else other than juvenile idiopathic arthritis: a case series.

BACKGROUND: Limping is a common clinical symptom in childhood; different clinical conditions may lead to limping and the diagnosis of the underlying cause may often be a challenge for the pediatrician. CASE PRESENTATION: We describe the clinical manifestations, radiological pictures and disease course of other causes of limping in childhood, through a case series of seven cases and a brief discussion of each disease. CONCLUSIONS: although trauma is the most common cause of acute limping, when there is no history of traumatic events and the limping has a chronic course, Juvenile Idiopathic Arthritis is usually the most likely clinical diagnosis. However, other some rare conditions should be taken into account if JIA is not confirmed or if it presents with atypical clinical picture.

Allograft dysfunction after lung transplantation for COPA syndrome: A case report and literature review.

Coatomer subunit alpha (COPA) syndrome is an autoinflammatory disease with autoimmune and autoinflammatory manifestations affecting lungs, joints, and kidneys. COPA syndrome is caused by heterozygous loss-of-function mutations in COPA gene, encoding α subunit of coatmer protein complex I (COP-I) coated vesicles. Mutant COPA induces constitutive activation of stimulator of interferon genes, leading to systemic inflammation and elevated type I interferon response. We have previously reported a Japanese family of COPA syndrome with a novel V242G mutation. Two out of four patients required lung transplantation due to intractable interstitial lung disease and respiratory failure. Both of them deceased after lung transplantation, one due to sepsis and the other due to allograft dysfunction possibly caused by the reccurent interstitial lung disease. The literature review indentified unfavorable outcome of the solid organ transplant in COPA syndrome and its related disease, however, precise clinico-pathological description of these cases has been scarce. Here, we report in detail the clinical course of our cases to clarify the pathophysiology of allograft dysfunction in COPA syndrome and propose potential therapeutic approaches to improve post-transplant graft survival.

Dysregulation of the cGAS-STING Pathway in Monogenic Autoinflammation and Lupus.

One of the oldest mechanisms of immune defense against pathogens is through detection of foreign DNA. Since human DNA is compartmentalized into the nucleus, its presence in the cytosol heralds a potential threat. The cGAS-STING pathway is one of the most important cytosolic DNA sensing pathways and leads to interferon signaling, inflammasome activation, autophagy, and cell death. While STING signaling is protective at physiologic levels, chronic activation of this pathway can instead drive autoinflammation and autoimmunity. Here we discuss several monogenic disorders of the STING pathway that highlight its impact on both innate and adaptive immunity in the progressive loss of tolerance. The potential relevance of STING signaling in systemic lupus erythematosus is then discussed with a focus on future avenues for monitoring and targeting this pathway.

IL-6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome.

OBJECTIVE: COPA syndrome is a genetic disorder of retrograde cis-Golgi vesicle transport that leads to upregulation of pro-inflammatory cytokines (mainly IL-1ß and IL-6) and the development of interstitial lung disease (ILD). The impact of COPA syndrome on post-lung transplant (LTx) outcome is unknown but potentially detrimental. In this case report, we describe progressive allograft dysfunction following LTx for COPA-ILD. Following the failure of standard immunosuppressive approaches, detailed cytokine analysis was performed with the intention of personalising therapy. METHODS: Multiplexed cytokine analysis was performed on serum and bronchoalveolar lavage (BAL) fluid obtained pre- and post-LTx. Peripheral blood mononuclear cells (PMBCs) obtained pre- and post-LTx were stimulated with PMA, LPS and anti-CD3/CD28 antibodies. Post-LTx endobronchial biopsies underwent microarray-based gene expression analysis. Results were compared to non-COPA LTx recipients and non-LTx healthy controls. RESULTS: Multiplexed cytokine analysis showed rising type I/II IFNs, and IL-6 in BAL post-LTx that decreased following treatment of acute rejection but rebounded with further clinical deterioration. In vitro stimulation of PMBCs suggested that myeloid cells were driving deterioration, through IL-6 signalling pathways. Tocilizumab (IL-6 receptor antibody) administration for 3 months (4 mg kg-1, monthly) effectively suppressed IL-6 levels in BAL. Mucosal gene expression profile following tocilizumab suggested greater similarity to normal. CONCLUSION: Clinical effectiveness of IL-6 receptor blockade was not observed. However, we identified IL-6 upregulation associated with graft injury, effective IL-6 suppression with tocilizumab and evidence of beneficial effect on molecular transcripts. This mechanistic analysis suggests a role for IL-6 blockade in post-LTx care that should be investigated further.

A Novel Mutation c.841C>T in COPA Syndrome of an 11-Year-Old Boy: A Case Report and Short Literature Review.

COPA syndrome is a rare autosomal dominant disorder with auto-immune and auto-inflammatory abnormalities. This disease is caused by mutations of COPα, a protein that functions in the retrograde transport from the Golgi to the ER. Here we report the first COPA case of an 11-year-old boy with c.841C>T, p.R281W mutation. The arginine at position 281 was located in a highly evolutionary-conserved region. Immunosuppressive drugs and corticosteroids might not improve the long-term outcome of COPA patients. For patients with pulmonary disease, polyarthritis and/or kidney disorder, and suspected of COPA, genetic analysis should be conducted promptly for early diagnosis.

STING Operation at the ER/Golgi Interface.

DNA is present in the nucleus and mitochondria of eukaryotic cells. There are, however, certain instances in which DNA emerges in the cytosol. The two major sources of cytosolic DNA are self DNA that is leaked out from the nucleus or mitochondria, and non-self DNA from DNA viruses. The cytosolic DNA triggers the host immune response. Recent studies have identified two key molecules, cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) in this immune response. STING is an endoplasmic reticulum (ER) protein. After STING binding to cGAMP, STING exits the ER and translocates to the Golgi, where STING triggers the type I interferon- and proinflammatory responses through the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB). STING also activates other cellular responses including cell senescence, autophagy, and cell death. In this review, we focus on emerging issues regarding the regulation of STING by membrane traffic, with a particular focus on the retrograde membrane traffic from the Golgi to the ER. The retrograde membrane traffic is recently shown by us and others to be critical for silencing the STING signaling pathway and the defect in this traffic underlies the pathogenesis of the COPA syndrome, a monogenic autoinflammatory disease caused by missense mutations of coatomer protein complex subunit α (COP-α).

Lymphocytic interstitial pneumonia and follicular bronchiolitis in children: A registry-based case series.

OBJECTIVES: Pediatric lymphocytic interstitial pneumonia (LIP) and follicular bronchiolitis (FB) are poorly characterized lymphoproliferative disorders. We present and quantify demographics, radiological and histopathologic patterns, treatments and their responses, and outcomes in non-HIV-infected children with LIP and FB. METHODS: This structured registry-based study included a retrospective chart review, blinded analysis of imaging studies and lung biopsies, genetic testing, and evaluation of treatments and outcomes. RESULTS: Of the 13 patients (eight females) studied, eight had FB, four had combined LIP/FB, and one had isolated LIP; diagnoses were highly concordant between the pathologists. Most patients became symptomatic during the first 2 years of life, with a mean lag time to diagnosis of 4 years. The most common symptoms were coughing and respiratory infections (11 out of 13 each), dyspnea (10 out of 13), and wheezing (eight out of 13). Autoantibodies were found in eight out of 13 patients. In three patients, disease-causing mutations in the COPA gene were identified. CT revealed hilar lymphadenopathy (five out of 12), ground-glass opacity (eight out of 12), consolidation (five out of 12), and cysts (four out of 13). Systemic steroids as intravenous pulses (11 out of 13) or oral intake (10 out of 13) were the main treatments and showed high response rates of 100% and 90%, respectively. Within the mean observation period of 68 months, all children had chronic courses, eight out of 13 had severe diseases, two died, and one worsened. CONCLUSIONS: Children with LIP/FB have chronic diseases that occurred in early childhood and were commonly associated with immune dysregulation as well as high morbidity and mortality. Early diagnosis and treatment may be crucial to improve the outcome.

An unprecedented COPA gene mutation in two patients in the same family: comparative clinical analysis of newly reported patients with other known COPA gene mutations.

INTRODUCTION: The COPA syndrome is a newly recognized monogenic, autosomal dominant autoimmune disease presenting mostly presenting in childhood. Clinical features include inflammation of the lungs, kidneys, and joints. Approximately twenty-six patients with COPA syndrome worldwide have been investigated all originating from eight families. Patients with this syndrome exhibit heterozygous monogenic missense mutations in the WD40 domain. This domain is a functionally-significant area of the alpha subunit of coatomer-associated protein (COPα) which encodes the coat protein complex I (COPI). The COPI dysfunction is also associated with autoantibody expansion. We report two patients with COPA syndrome. METHODS: All testing and molecular genetic analysis were performed after obtaining the informed consent of both the patient and parents. A retrospective chart review was carried out on both the patients. Demographic, clinical and laboratory findings were abstracted from outpatient and inpatient encounters. Pulmonary function tests (PFTs), chest computed tomography (CT) scans, and lung biopsy histopathology reports were also reviewed and summarized. RESULTS: The index case and the father of the child both demonstrated a unique inflammatory pulmonary, arthritis, and renal disease triad starting in early childhood including pulmonary hemorrhage. The two patients had a novel COPA mutation previously undescribed. CONCLUSIONS: To date, only four pathological, genetic mutations have been reported that are compatible with COPA syndrome. We here report two patients with COPA syndrome within the same family with a novel COPA gene mutation different than the heterozygous monogenic missense mutations in the WD40 domain and distinct from the clinical phenotypes reported in the literature so far.

Genetics of COPA syndrome.

Inborn errors of immunity usually not only result in immunodeficiency but may also manifest as immune dysregulation in the form of autoinflammation, autoimmunity, or sometimes malignancy. One of the most recently discovered monogenic disorder of immune dysregulation is COPA syndrome. COPA syndrome is an inherited autoimmune disorder caused by mutations in COPA gene. COPA gene encodes for α subunit of the COP1 protein, which is involved in the reverse vesicular protein transport from Golgi apparatus to the endoplasmic reticulum (ER). The inheritance pattern of COPA syndrome is autosomal dominant, and the patients typically present with interstitial lung disease with pulmonary hemorrhage and subsequently develop arthritis. Immunological features involve autoantibody formation, elevated expression of IL-1ß and IL-6, and increase in the number of Th17 cells. Molecular pathophysiology of COPA syndrome is not clearly understood. However, it is known that accumulation of unfolded proteins in ER leads to ER stress, which is an indirect result of aberrant vesicular transport of proteins from Golgi apparatus to ER and defective cellular autophagy. ER stress induces inflammation and is responsible for pathogenesis of a large number of chronic inflammatory diseases. Unfolded protein response process responds to improperly folded proteins and defends against stress in ER to ensure the fidelity of the protein folding. It maintains the expression of stress-response genes and causes initiation of inflammatory signaling pathways essential for the innate immunity. Mutation in COPA gene associated with defective protein sorting to ER has unearthed a new primary immunodeficiency disease with a unique clinical phenotype. This review highlights the clinical and molecular aspects of COPA syndrome.