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January 2006 - May 2015
Publications
Publications (86)
Most autoinflammatory diseases are caused by mutations in innate immunity genes. Previously, four variants in the RHO GTPase CDC42 were discovered in patients affected by syndromes generally characterized by neonatal-onset of cytopenia and auto-inflammation, including hemophagocytic lymphohistiocytosis and rash in the most severe form (NOCARH syndr...
Objective
The aim of this study is to report the safety and efficacy of CD19‐targeting chimeric antigen receptor (CAR) T cells in a child with refractory juvenile dermatomyositis (JDM).
Methods
We describe a 12‐year‐old White male with severe, chronically active JDM refractory to multiple immunosuppressive treatment lines, including B cell depleti...
Objectives
Fibrodysplasia ossificans progressiva (FOP) is one of the most catastrophic forms of genetic heterotopic ossification (HO). FOP is characterized by severe, progressive inflammatory flare-ups, that often lead to HO. The flare-ups are associated with increased inflammatory cytokine production, suggesting auto-inflammatory features driven b...
Cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene that encodes cystinosin, a ubiquitous lysosomal cystine/H⁺ antiporter. The hallmark of the disease is progressive accumulation of cystine and cystine crystals in virtually all tissues. At the kidney level, human cystinosis is characterized by the development of r...
Background: Perinatal hypoxia triggers the release of cytokines and chemokines by neurons, astrocytes and
microglia. In response to hypoxia–ischemia resting/ramified microglia proliferate and undergo activation, producing
proinflammatory molecules. The brain damage extension seems to be related to both the severity of
hypoxia and the balance betwee...
Infectious peritonitis is a leading cause of peritoneal functional impairment and a primary factor for therapy discontinuation in peritoneal dialysis (PD) patients. Although bacterial infections are a common cause of peritonitis episodes, emerging evidence suggests a role for viral pathogens. Toll-like receptors (TLRs) specifically recognize conser...
TLR7 recognizes pathogen-derived single-stranded RNA (ssRNA), a function integral to the innate immune response to viral infection. Notably, TLR7 can also recognize self-derived ssRNA, with gain-of-function mutations in human TLR7 recently identified to cause both early-onset systemic lupus erythematosus (SLE) and neuromyelitis optica. Here, we des...
Most autoinflammatory diseases are caused by mutations in innate immunity genes. Recently, four variants in the RHO GTPase CDC42 were discovered in patients affected by syndromes generally characterized by neonatal-onset of cytopenia and auto-inflammation, including hemophagocytic lymphohistiocytosis and rash in the most severe form (NOCARH syndrom...
Background
Systemic juvenile idiopathic arthritis (sJIA) is a rare autoinflammatory disease of unknown etiology. Several uncontrolled studies showed that early treatment with anakinra is associated with a better outcome, according to the “window of opportunity” hypothesis. However, very limited scientific evidence is available on withdrawal strateg...
Background
Macrophage Activation Syndrome (MAS) and Secondary Hemophagocytic Lymphohistiocytosis (sHLH) are hyperinflammatory conditions, in which IFNγ plays a pivotal role. Prompt recognition and early treatment are essential to improve the outcome and the mortality rate.
Objectives
This is a retrospective multicenter study. We correlated traditi...
Background
Macrophage activation syndrome (MAS) is a life-threatening complication of different rheumatic diseases, particularly of systemic juvenile idiopathic arthritis (sJIA).
Objectives
We report the case of 17-year-old girl with sJIA complicated by recurrent severe MAS episodes.
Methods
Patient received emapalumab (anti-IFNg antibody) in two...
Background & Objective. Perinatal hypoxia acutely triggers the release of cytokines and chemokines from neurons, astrocytes and microglia. In response to hypoxia-ischemia resting/ramified microglia proliferate and undergo activation, with the production of proinflammatory molecules. The brain damage extension seems to be related with both the sever...
Purpose
Interferonopathies are conditions characterized by excessive production of type 1 interferon. Several diseases, autoinflammatory or autoimmune, are classified as type1 interferonopathies such as Aicardi-Goutieres, Sting associated vasculopathy with onset in Infancy, monogenic Systemic lupus erythematosus (SLE) and Dermatomyositis. The aim o...
The hyper‐inflammatory response, also known as multisystem inflammatory syndrome in children (MIS‐C), represents a major concern in children with SARS‐CoV‐2 infection. We report bone marrow features of three patients with MIS‐C who were diagnosed during the first wave of the SARS‐CoV‐2 pandemic. A bone marrow evaluation was performed at onset of th...
CD8+ T-cell activation has been demonstrated to distinguish patients with primary and infection-associated hemophagocytic lymphohistiocytosis (pHLH and iaHLH) from patients with early sepsis. We evaluated the activation profile of CD8+ T cells in patients with various forms of secondary HLH (sHLH), including macrophage activation syndrome (MAS). Fl...
Haploinsufficiency of A20 (HA20) is an inflammatory disease caused by mutations in the TNFAIP3 gene classically presenting with Behcet’s-like disease. A20 acts as an inhibitor of inflammation through its effect on NF-kB pathway. Here we describe four consanguineous patients (three sisters and their mother) with a predominantly autoimmune phenotype,...
The activation of several inflammatory pathways has recently been documented in patients and different cellular and animal models of nephropathic cystinosis. Upregulated inflamma-tory signals interact with many pathogenic aspects of the disease, such as enhanced oxidative stress, abnormal autophagy, inflammatory cell recruitment, enhanced cell deat...
Interferon-γ (IFNγ) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFNγ underlies several, potentially fatal, hyperinflammatory or immune-mediated diseases. Several data from animal models and/or from translational research in patients point to a role of IFNγ in hy...
Objective
To evaluate the impact of early treatment and IL1RN genetic variants on the response to anakinra in systemic juvenile idiopathic arthritis (JIA).
Methods
Response to anakinra was defined as achievement of clinically inactive disease (CID) at 6 months without glucocorticoid treatment. Demographic, clinical, and laboratory characteristics...
Objective
To investigate the activation of the IFNγ signaling pathway in monocytes of patients with secondary hemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) and to evaluate whether levels of phosphorylated STAT1 represent a biomarker for the identification of patients at early stages of the disease.
Methods
Fresh wh...
We describe a 2 year old boy with two previously undescribed frameshift mutations in the interferon (IFN)α/β receptor 2 (IFNAR2) gene presenting with hemophagocytic lymphohistiocytosis (HLH) following measles-mumps-rubella vaccination. Functional analyses show the absence of response to type I IFN in the patient’s cells, as revealed by the lack of...
Perinatal asphyxia triggers an acute inflammatory response in the injured brain. Complement activation and neuroinflammation worsen brain damage after a systemic ischemia/reperfusion insult. The increase of mannose binding lectin (MBL) during asphyxia may contribute to the brain damage, via activation of the complement lectin pathway. The possible...
Background and objective
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the MEFV gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is c...
Background:
Nephropathic cystinosis, a hereditary lysosomal storage disorder caused by dysfunction of the lysosomal cotransporter cystinosin, leads to cystine accumulation and cellular damage in various organs, particularly in the kidney. Close therapeutic monitoring of cysteamine, the only available disease-modifying treatment, is recommended. Wh...
Background:
Fibrodysplasia ossificans progressiva (FOP) is the most catastrophic form of heterotopic ossification, due to ongoing intracellular signaling through the bone morphogenic protein pathway. The paroxysmal appearance of inflammatory lumps and elevated inflammatory markers during flares, suggest that FOP is an auto-inflammatory disease. Ba...
Aim of this study was to investigate the activation of the IFNγ pathway in the affected liver and in the blood of patients with secondary hemophagocytic lymphohistiocytosis (sHLH). To this purpose, the mRNA expression levels of IFNG and IFNγ-inducible genes as well as Tyrosine (701)-phosphorylated signal transducer and activator of transcription 1...
Nod-like Receptor Pyrin domain containing proteins (NLRPs) expressed by resident renal cells may contribute to the pathogenesis of multiple renal diseases. Cystinosis is a genetic disorder that affects kidney and particularly proximal tubular epithelial cells (PTEC). Here, we investigated the expression of NLRP family members in human control and c...
Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematolog...
Background
Use of NGS in patients with unclassifiable disease lies a possible approach to the identification of novel disease causing genes.
Objectives
We report a patient with an early onset inflammatory bowel disease with granulomatous lesions and recurrent HLH episodes carrying a missense mutation in the WNT6 gene.
Methods
A trio based Whole E...
Background
Systemic juvenile idiopathic arthritis (sJIA) is a polygenic autoinflammatory disease. Innate immune mechanisms appear to play a central role in the pathogenesis of the disease. Nevertheless, a better understanding of the pathophysiology of sJIA is still needed to identify patients responsive to IL-1 or IL-6 targeted therapies.
Objectiv...
Background
The NLRC4 inflammasome activation is essential in host defence, particularly against enteric pathogens. Gain-of-function mutations in NLRC4 are associated with a distinct autoinflammatory syndrome characterized by enterocolitis and recurrent HLH.
Objectives
To report safety and efficacy of faecal microbiota transplantation (FMT) in a pa...
Background
Despite continuous advances in the identification of novel causative genes, several patients with a clinical autoinflammatory phenotype remain unclassifiable Objectives: to describe a novel hematological and autoinflammatory disorder in three unrelated patients caused by a de novo missense mutation of CDC42
Methods
Whole exome sequencin...
Purpose of review:
IL-18 is a pleiotropic cytokine involved in the regulation of innate and adaptive immune responses. IL-18 pro-inflammatory activities are finely regulated in vivo by the inhibitory effects of the soluble IL-18-binding protein (IL-18BP). The elevation of circulating levels of IL-18 has been described in children with systemic juv...
Background
Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory condition that presents with fever, rash and arthritis. At onset systemic features are predominant and the diagnosis may be a challenge. Secondary hemophagocytic lymphohistiocytosis (sHLH) forms may be associated with different disorders, including rheumatic diseases, and t...
Objective
To identify the role of mature nerve growth factor (mNGF), its immature form proNGF and their receptors in arthritis inflammation.
Methods
Real-time PCR, western blot and ELISA were performed to evaluate NGF, proNGF, their receptor and cytokine expression in synovial tissue and cells of patients with juvenile idiopathic arthritis (JIA) a...
Background:
The pathogenesis of macrophage activation syndrome (MAS) is not clearly understood: a large body of evidence supports the involvement of mechanisms similar to those implicated in primary hemophagocytic lymphohistiocytosis.
Objective:
To investigate the pathogenic role of interferon-γ (IFNγ) and the therapeutic efficacy of IFNγ neutra...
Background:
An increasing number of infants are diagnosed with food protein induced enterocolitis syndrome (FPIES), a non-IgE-mediated food allergy. Until now, T-cell, food-specific mechanisms have been hypothesized.
Methods:
16 children (11M, 5F), affected by FPIES from cow's milk, wheat, fruit, rice and others, experienced 25 acute episodes ma...
The mannose-binding lectin (MBL) is a member of the collectin family, belonging to the innate immunity system. Genetic, biologic, and clinical properties of MBL have been widely investigated throughout the last decades, although some interesting aspects of its potential clinical relevance are still poorly understood. Low circulating concentrations...
Background
Macrophage activation syndrome (MAS) is a severe complication of rheumatic disease in childhood, particularly in systemic Juvenile Idiopathic Arthritis (sJIA). It is characterize by an uncontrolled activation and proliferation of T lymphocytes and macrophages. Main contentMAS is currently classified among the secondary or acquired forms...
Significance
Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by more than 310 mutations in the gene MEFV , which encodes Pyrin. Pyrin recently was shown to trigger inflammasome activation in response to Rho GTPase-modifying bacterial toxins. Here we report that Clostridium difficile infection and intoxication with its enter...
Objectives Interferon-γ (IFNγ) is the pivotal mediator in murine models of primary haemophagocytic lymphohistiocytosis (pHLH). Given the similarities between primary and secondary HLH (sec-HLH), including macrophage activation syndrome (MAS), we investigate the involvement of the IFNγ pathway in MAS by evaluating levels of IFNγ and of the induced c...
Frequently fatal, primary hemophagocytic lymphohistiocytosis (HLH) occurs in infancy resulting from homozygous mutations in natural killer (NK) and CD8 T cell cytolytic pathway genes. Secondary HLH presents after infancy and may be associated with heterozygous mutations in HLH genes. We report 2 unrelated teenagers with HLH and an identical heteroz...
Frequently fatal, primary hemophagocytic lymphohistiocytosis (HLH) occurs in infancy resulting from homozygous mutations in NK and CD8 T cell cytolytic pathway genes. Secondary HLH presents after infancy and may be associated with heterozygous mutations in HLH genes. We report two unrelated teenagers with HLH and an identical heterozygous RAB27A mu...
Macrophage activation syndrome is a term used to identify hemophagocytic lymphohistiocytosis secondary to rheumatic diseases (rheuHLH). It is a severe, potentially fatal condition that occurs in the context of rheumatic diseases, particularly systemic juvenile idiopathic arthritis. It is part of secondary HLH forms, that are clinically and biochemi...
The NLRP12 related autoinflammatory disorder (NLRP12-RD) is a rare autosomal dominant disease, caused by mutations in the NLRP12 gene, a member of NLRs family involved in negative regulation of NF-kB pro-inflammatory pathways. At present, few cases have been reported, although novel NLRP12 variants have recently been described.
Objective. Systemic juvenile idiopathic arthritis (s-JIA) is associated with high levels of Interleukin-6 (IL-6) in serum and in synovial fluid. Also, impairment of natural killer (NK) cell function is often observed. Our aim was to evaluate a possible link between these two biological findings, as well as with the development of macrophage activat...
The identification of early noninvasive biochemical markers of disease is a crucial issue of the current scientific research, particularly during the first period of life, since it could provide useful and precocious diagnostic information when clinical and radiological signs are still silent. The ideal biomarker should be practical and sensitive i...
The role of Interleukin(IL)-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (s-JIA) has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone o...
Systemic juvenile idiopathic arthritis (s-JIA) is associated with high levels of Interleukin-6 (IL-6) in serum and in synovial fluid. Also, impairment of natural killer (NK) cell function is often observed. Our aim was to evaluate a possible link between these two biological findings, as well as with the development of macrophage activation syndrom...
Background:
As described in animal models, the lectin-complement pathway is central to the propagation of ischemia-reperfusion injuries in many tissues, including the brain. Similarly, it might affect the genesis of brain damage in preterm infants. MBL2 gene single-nucleotide polymorphisms (SNPs), regulating mannose-binding lectin (MBL) serum leve...
Background
This study aims to investigate the inflammasome response in peripheral blood mononuclear cells (PBMCs) and the expression of inflammasome components in bone biopsies from patients with chronic recurrent multifocal osteomyelitis (CRMO).
Methods
The expression of inflammasome components mRNAs was evaluated in PBMCs isolated from 15 CRMO p...
Nerve growth factor (NGF) levels are highly increased in inflamed tissues, but their role is unclear. We show that NGF is part of a regulatory loop in monocytes: inflammatory stimuli, while activating a proinflammatory response through TLRs, upregulate the expression of the NGF receptor TrkA. In turn, NGF, by binding to TrkA, interferes with TLR re...
Intralysosomal cystine crystal accumulation, due to mutations in the CTNS gene, is a hallmark of nephropathic cystinosis, but the role of these crystals in disease pathogenesis remains unclear. We hypothesized that, similar to other host-derived crystalline moieties, cystine crystals can induce IL-1β production through inflammasome activation. Thus...
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by heterozygous mutations of CIAS1/NLRP3 gene. Affected patients may present three different phenotypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome and CINCA syndrome. Common symptoms include sporadic or cold-induced non pruritic urticari...
Systemic juvenile idiopathic arthritis (sJIA) accounts for 10-20% of all patients with JIA. The clinical features include fever, evanescent rash, arthralgia and arthritis, myalgia, lymphadenopathy, hepatomegaly, splenomegaly and serositis. Interleukin 1 (IL-1) has been shown to be a major mediator of the inflammatory cascade that underlies sJIA (1)...
Nephropathic cystinosis is a rare autosomal recessive disorder caused by a mutation in the CTNS gene, which encodes for cystinosin. It is characterized by the lysosomal accumulation of cystine, which leads to the formation of cystine crystals within various organs, including kidneys, brain, cornea, intestine and bone marrow. The exact role of intra...
Cryopyrin-associated periodic syndromes (CAPS) comprise a spectrum of distinct, rare, autosomal dominant autoinflammatory disorders of increasing severity caused by NLRP3 gene mutations.
We describe a 13-year-old female who presented, in the initial phase of the disease, recurrent episodes of high fever, pericarditis, arthralgia, arthritis of the k...
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among premature infants. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that has been implicated in the pathophysiology of inflammatory bowel diseases. The MIF promoter contains a functionally relevant single nucleotide polymorphism (SNP) G→C...