Publications by authors named "Stefano Volpi"

70 Publications

Syndrome of Undifferentiated Recurrent Fever (SURF): An Emerging Group of Autoinflammatory Recurrent Fevers.

J Clin Med 2021 May 3;10(9). Epub 2021 May 3.

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.

Syndrome of undifferentiated recurrent fever (SURF) is a heterogeneous group of autoinflammatory diseases (AID) characterized by self-limiting episodes of systemic inflammation without a confirmed molecular diagnosis, not fulfilling the criteria for periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. In this review, we focused on the studies enrolling patients suspected of AID and genotyped them with next generation sequencing technologies in order to describe the clinical manifestations and treatment response of published cohorts of patients with SURF. We also propose a preliminary set of indications for the clinical suspicion of SURF that could help in everyday clinical practice.
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http://dx.doi.org/10.3390/jcm10091963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124817PMC
May 2021

Detection of Tumor DNA in Human Plasma with a Functional PLL-Based Surface Layer and Plasmonic Biosensing.

ACS Sens 2021 06 25;6(6):2307-2319. Epub 2021 May 25.

Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, 95122 Catania, Italy.

Standard protocols for the analysis of circulating tumor DNA (ctDNA) include the isolation of DNA from the patient's plasma and its amplification and analysis in buffered solutions. The application of such protocols is hampered by several factors, including the complexity and time-constrained preanalytical procedures, risks for sample contamination, extended analysis time, and assay costs. A recently introduced nanoparticle-enhanced surface plasmon resonance imaging-based assay has been shown to simplify procedures for the direct detection of tumor DNA in the patient's plasma, greatly simplifying the cumbersome preanalytical phase. To further simplify the protocol, a new dual-functional low-fouling poly-l-lysine (PLL)-based surface layer has been introduced that is described herein. The new PLL-based layer includes a densely immobilized CEEEEE oligopeptide to create a charge-balanced system preventing the nonspecific adsorption of plasma components on the sensor surface. The layer also comprises sparsely attached peptide nucleic acid probes complementary to the sequence of circulating DNA, e.g., the analyte that has to be captured in the plasma from cancer patients. We thoroughly investigated the contribution of each component of the dual-functional polymer to the antifouling properties of the surface layer. The low-fouling property of the new surface layer allowed us to detect wild-type and KRAS p.G12D-mutated DNA in human plasma at the attomolar level (∼2.5 aM) and KRAS p.G13D-mutated tumor DNA in liquid biopsy from a cancer patient with almost no preanalytical treatment of the patient's plasma, no need to isolate DNA from plasma, and without PCR amplification of the target sequence.
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http://dx.doi.org/10.1021/acssensors.1c00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294610PMC
June 2021

Neutrophil Extracellular Traps in Systemic Lupus Erythematosus Stimulate IgG2 Production From B Lymphocytes.

Front Med (Lausanne) 2021 12;8:635436. Epub 2021 Apr 12.

Laboratory of Molecular Nephrology, Division of Nephrology and Transplantation, Scientific Institute for Research, Hospitalization and Health Care (IRCCS) Giannina Gaslini Institute, Genoa, Italy.

Circulating autoantibodies of IgG2 isotype predominate in Systemic Lupus Erythematosus (SLE) and concur to the development of the renal lesions characteristic of Lupus Nephritis (LN). Anti-dsDNA and anti-histones IgG2, together with anti-podocyte proteins (i.e., α-enolase) are the major autoantibodies in serum and renal glomeruli of LN patients. The mechanisms underlying autoantibody formation and isotype switching in SLE and LN are unknown. A major issue is how DNA/histones are externalized from cell nucleus, driving the autoimmune response. Neutrophil Extracellular Traps (NETs) have been recently identified as crucial players in this context, representing the main source of DNA and nucleosome proteins. A second key point is what regulates IgG2 isotype switching: in mouse models, T-bet transcription factor has been described as essential for IgG2a class switch. We hypothesized that, in SLE, NET formation is the key mechanism responsible for externalization of autoantigens (i.e., dsDNA, histones 2,3, and α-enolase) and that T-bet is upregulated by NETs, driving, in this way, immunoglobulin class switch recombination (CSR), with production of IgG2 autoantibodies. The data here presented show that NETs, purified from SLE patients, stimulate IgG2 isotype class switch possibly through the induction of T-bet. Of note, we observed a prominent effect of NETs on the release of soluble IgG2 in SLE patients', but not in healthy donors' B cells. Our results add important knowledge on the mechanisms of IgG2 class switch in SLE and contribute to further elucidate the role of NETs in LN pathogenesis.
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http://dx.doi.org/10.3389/fmed.2021.635436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072216PMC
April 2021

The challenge of early diagnosis of autoimmune lymphoproliferative syndrome in children with suspected autoinflammatory/autoimmune disorders.

Rheumatology (Oxford) 2021 Apr 28. Epub 2021 Apr 28.

Center for Autoinflammatory diseases and Immunodeficiencies, IRCCS G. Gaslini.

Objectives: To test the usefulness of an extended panel of lymphocyte subsets (LS) in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a pediatric rheumatology center.

Methods: patients referred from 2015 to 2018 to our Rheumatology Unit for an autoimmune or autoinflammatory condition were retrospectively analyzed. Oliveira's required criteria (chronic lymphoproliferation and elevated DNT) were applied as first screening. Flow cytometry study included double negative CD4-CD8-TCR αβ+T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+T cells, B220+T cells, and CD27+B cells. Data were analyzed with an univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated.

Results: 264 patients were included in the study and classified as: i) autoimmune diseases (26); ii) juvenile idiopathic arthritis (JIA) (35) iii) monogenic systemic autoinflammatory disease (SAID) (27); iv) PFAPA syndrome (100); v) systemic undefined recurrent fever (SURF) (45); vi) undetermined-SAID (14); vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαβ+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed 5 clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαβ+B220+lymphocytes.

Conclusions: Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαβ+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to pediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS.
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http://dx.doi.org/10.1093/rheumatology/keab361DOI Listing
April 2021

Collapsing Glomerulopathy as a Complication of Type I Interferon-Mediated Glomerulopathy in a Patient With RNASEH2B-Related Aicardi-Goutières Syndrome.

Am J Kidney Dis 2021 Apr 17. Epub 2021 Apr 17.

Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence; Medical Genetics Unit, Meyer Children's Hospital, Florence; Nephrology and Dialysis Unit, Meyer Children's Hospital, Florence. Electronic address:

Aicardi-Goutières syndrome (AGS) is a well-characterized monogenic type I interferonopathy presenting with prominent neurologic manifestations. Among extraneurologic features, renal involvement has been described in only 1 patient with an IFIH1 mutation in whom membranous nephropathy developed. The pathogenic role of augmented interferon (IFN) signaling in tissues other than the central nervous system remains to be elucidated. We report a case of collapsing glomerulopathy in a 15-year-old girl affected by AGS with RNASEH2B mutation (an alanine-to-threonine change at amino acid 177), which led to kidney failure. The patient had no lupus-like features and lacked the APOL1 G1 and G2 risk alleles. Kidney biopsy showed findings consistent with collapsing glomerulopathy. MxA, a protein involved in antiviral immunity and induced by type I IFNs, was selectively expressed in CD133-positive parietal epithelial cells (PECs) but not in podocytes that stained for synaptopodin or in other glomerular cells. MxA also colocalized within pseudocrescents with CD44, a marker of PEC activation involved in cellular proliferation, differentiation, and migration and in glomerular scarring. Our findings suggest that collapsing glomerulopathy can be a complication of the type I interferonopathy AGS and that a constitutively enhanced type I IFN response in CD133-positive PECs can drive collapsing glomerulopathy.
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http://dx.doi.org/10.1053/j.ajkd.2021.02.330DOI Listing
April 2021

Neutrophil Extracellular Traps in the Autoimmunity Context.

Front Med (Lausanne) 2021 22;8:614829. Epub 2021 Mar 22.

Laboratory of Molecular Nephrology, Scientific Institute for Research and Health Care, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

The formation of neutrophil extracellular traps (NETs) is a strategy utilized by neutrophils for capturing infective agents. Extracellular traps consist in a physical net made of DNA and intracellular proteins externalized from neutrophils, where bacteria and viruses are entrapped and killed by proteolysis. A complex series of events contributes to achieving NET formation: signaling from infectious triggers comes first, followed by decondensation of chromatin and extrusion of the nucleosome components (DNA, histones) from the nucleus and, after cell membrane breakdown, outside the cell. NETs are composed of either DNA or nucleosome proteins and hundreds of cytoplasm proteins, a part of which undergo post-translational modification during the steps leading to NETs. There is a thin balance between the production and the removal of circulating NETs from blood where digestion of DNA by circulating DNases 1 and IL3 has a critical role. A delay in NET removal may have consequences for autoimmunity. Recent studies have shown that circulating NET levels are increased in systemic lupus erythematosus (SLE) for a functional block of NET removal mediated by anti-DNase antibodies or, in rare cases, by DNase IL3 mutations. In SLE, the persistence in circulation of NETs signifies elevated concentrations of either free DNA/nucleosome components and oxidized proteins that, in some cases, are recognized as non-self and presented to B-cells by Toll-like receptor 9 (TLR9). In this way, it is activated as an immunologic response, leading to the formation of IgG2 auto-antibody. Monitoring serum NET levels represents a potential new way to herald the development of renal lesions and has clinical implications. Modulating the balance between NET formation and removal is one of the objectives of basic research that are aimed to design new drugs for SLE. The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).
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http://dx.doi.org/10.3389/fmed.2021.614829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019736PMC
March 2021

Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus.

J Exp Med 2021 May;218(5)

Department of Pathology, New York University Grossman School of Medicine, New York, NY.

Antibodies to double-stranded DNA (dsDNA) are prevalent in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis, yet the nature and regulation of antigenic cell-free DNA (cfDNA) are poorly understood. Null mutations in the secreted DNase DNASE1L3 cause human monogenic SLE with anti-dsDNA autoreactivity. We report that >50% of sporadic SLE patients with nephritis manifested reduced DNASE1L3 activity in circulation, which was associated with neutralizing autoantibodies to DNASE1L3. These patients had normal total plasma cfDNA levels but showed accumulation of cfDNA in circulating microparticles. Microparticle-associated cfDNA contained a higher fraction of longer polynucleosomal cfDNA fragments, which bound autoantibodies with higher affinity than mononucleosomal fragments. Autoantibodies to DNASE1L3-sensitive antigens on microparticles were prevalent in SLE nephritis patients and correlated with the accumulation of cfDNA in microparticles and with disease severity. DNASE1L3-sensitive antigens included DNA-associated proteins such as HMGB1. Our results reveal autoantibody-mediated impairment of DNASE1L3 activity as a common nongenetic mechanism facilitating anti-dsDNA autoreactivity in patients with severe sporadic SLE.
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http://dx.doi.org/10.1084/jem.20201138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020718PMC
May 2021

Inborn errors of immunity with atopic phenotypes: A practical guide for allergists.

World Allergy Organ J 2021 Feb 22;14(2):100513. Epub 2021 Feb 22.

Department of Pediatrics, Giovanni XXIII Pediatric Hospital, Bari, Italy.

Inborn errors of immunity (IEI) are a heterogeneous group of disorders, mainly resulting from mutations in genes associated with immunoregulation and immune host defense. These disorders are characterized by different combinations of recurrent infections, autoimmunity, inflammatory manifestations, lymphoproliferation, and malignancy. Interestingly, it has been increasingly observed that common allergic symptoms also can represent the expression of an underlying immunodeficiency and/or immune dysregulation. Very high IgE levels, peripheral or organ-specific hypereosinophilia, usually combined with a variety of atopic symptoms, may sometimes be the epiphenomenon of a monogenic disease. Therefore, allergists should be aware that severe and/or therapy-resistant atopic disorders might be the main clinical phenotype of some IEI. This could pave the way to target therapies, leading to better quality of life and improved survival in affected patients.
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http://dx.doi.org/10.1016/j.waojou.2021.100513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907539PMC
February 2021

Efficacy of early anti-inflammatory treatment with high doses of intravenous anakinra with or without glucocorticoids in patients with severe COVID-19 pneumonia.

J Allergy Clin Immunol 2021 04 6;147(4):1217-1225. Epub 2021 Feb 6.

IRCCS G. Gaslini, Genoa, Italy. Electronic address:

Background: IL-1 plays a pivotal role in the inflammatory response during cytokine storm syndromes.

Objective: Our aim was to analyze the efficacy and safety of early anti-inflammatory treatment (AIT) with intravenous anakinra with or without glucocorticoids in coronavirus disease 2019 (COVID-19) pneumonia.

Methods: We performed a retrospective single-center cohort study of patients admitted for COVID-19 pneumonia from February 26 to April 29, 2020, to assess the efficacy of early AIT with intravenous anakinra (100 mg every 8 hours for 3 days, with tapering) alone or in combination with a glucocorticoid (intravenous methylprednisolone, 1-2 mg/kg daily, with tapering). The standard of care (SOC) treatment was hydroxychloroquine and/or azithromycin with or without antivirals and anticoagulants. Late rescue AIT with anakinra or tocilizumab was also evaluated. Treatment effect on overall survival was assessed by a propensity score-adjusted Cox model.

Results: A total of 128 patients were analyzed; 63 patients received early AIT (30 received anakinra alone and 33 received anakinra plus a glucocorticoid) at admission, and 65 patients did not receive early AIT and were used as controls; of the latter 65 patients, 44 received the SOC treatment alone and 21 received the SOC treatment plus late rescue AIT. After adjustment for all the unbalanced baseline covariates, early AIT reduced the hazard of mortality by 74% (adjusted hazard ratio [HR] = 0.26; P < .001). The effect was similar in patients receiving anakinra alone (adjusted HR = 0.28; P = .04) and anakinra plus a glucocorticoid (adjusted HR = 0.33; P = .07). Late rescue treatment did not show a significant advantage over SOC treatment alone (adjusted HR = 0.82; P = .70).

Conclusions: This study suggests, on a larger series of patients with COVID-19 pneumonia, the potential efficacy and safety of the early use of high doses of intravenous anakinra with or without glucocorticoids.
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http://dx.doi.org/10.1016/j.jaci.2021.01.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865089PMC
April 2021

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation.

Front Immunol 2020 7;11:604206. Epub 2021 Jan 7.

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

A growing number of monogenic immune-mediated diseases have been related to genes involved in pathways of actin cytoskeleton remodeling. Increasing evidences associate cytoskeleton defects to autoinflammatory diseases and primary immunodeficiencies. We reviewed the pathways of actin cytoskeleton remodeling in order to identify inflammatory and immunological manifestations associated to pathological variants. We list more than twenty monogenic diseases, ranging from pure autoinflammatory conditions as familial Mediterranean fever, mevalonate kinase deficiency and PAPA syndrome, to classic and novel primary immunodeficiencies as Wiskott-Aldrich syndrome and DOCK8 deficiency, characterized by the presence of concomitant inflammatory and autoimmune manifestations, such as vasculitis and cytopenia, to severe and recurrent infections. We classify these disorders according to the role of the mutant gene in actin cytoskeleton remodeling, and in particular as disorders of transcription, elongation, branching and activation of actin. This expanding field of rare immune disorders offers a new perspective to all immunologists to better understand the physiological and pathological role of actin cytoskeleton in cells of innate and adaptive immunity.
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http://dx.doi.org/10.3389/fimmu.2020.604206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817698PMC
June 2021

Submonomeric Strategy with Minimal Protection for the Synthesis of C(2)-Modified Peptide Nucleic Acids.

Org Lett 2021 02 8;23(3):902-907. Epub 2021 Jan 8.

Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 17/A, Parma, 43123, Italy.

A novel synthesis of C(2)-modified peptide nucleic acids (PNAs) is proposed, using a submonomeric strategy with minimally protected building blocks, which allowed a reduction in the required synthetic steps. N(3)-unprotected, d-Lys- and d-Arg-based backbones were used to obtain positively charged PNAs with high optical purity, as inferred from chiral GC measurements. "Chiral-box" PNAs targeting the G12D point mutation of the gene were produced using this method, showing improved sequence selectivity for the mutated- vs wild-type DNA strand with respect to unmodified PNAs.
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http://dx.doi.org/10.1021/acs.orglett.0c04116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880566PMC
February 2021

HAPLOIDENTICAL α/β T-CELL AND B-CELL STEM CELL TRANSPLANTATION IN SEVERE MEVALONATE KINASE DEFICIENCY.

Rheumatology (Oxford) 2021 Jan 7. Epub 2021 Jan 7.

Centro Malattie Auto-infiammatorie e Immunodeficienze, Istituto G Gaslini, Genova, Italy.

Objective: Mevalonic aciduria (MA) represents the most severe of mevalonate kinase deficiency (MKD). Patients with MA have an incomplete response even to high doses of anti-cytokine drugs as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease.

Methods: We report the first two children affected by severe MKD who received haploidentical (haplo) α/β T cell and B cell depleted SCT. Both patients received treosulfan based conditioning regimen and one received a second haplo-SCT for secondary rejection of the first.

Results: Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high in post transplant in the absence of any inflammatory signs.

Conclusion: Haploidentical α/β T cell and B cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT.
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http://dx.doi.org/10.1093/rheumatology/keaa912DOI Listing
January 2021

Multifunctional Delivery Systems for Peptide Nucleic Acids.

Pharmaceuticals (Basel) 2020 Dec 25;14(1). Epub 2020 Dec 25.

Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy.

The number of applications of peptide nucleic acids (PNAs)-oligonucleotide analogs with a polyamide backbone-is continuously increasing in both in vitro and cellular systems and, parallel to this, delivery systems able to bring PNAs to their targets have been developed. This review is intended to give to the readers an overview on the available carriers for these oligonucleotide mimics, with a particular emphasis on newly developed multi-component- and multifunctional vehicles which boosted PNA research in recent years. The following approaches will be discussed: (a) conjugation with carrier molecules and peptides; (b) liposome formulations; (c) polymer nanoparticles; (d) inorganic porous nanoparticles; (e) carbon based nanocarriers; and (f) self-assembled and supramolecular systems. New therapeutic strategies enabled by the combination of PNA and proper delivery systems are discussed.
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http://dx.doi.org/10.3390/ph14010014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823687PMC
December 2020

Serum IgG2 antibody multicomposition in systemic lupus erythematosus and lupus nephritis (Part 1): cross-sectional analysis.

Rheumatology (Oxford) 2021 Jul;60(7):3176-3188

Division of Nephrology and Dialysis, University of Brescia and Ospedale di Montichiari, Brescia.

Objectives: Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis.

Methods: A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques.

Results: The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low-medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0-12 months), and high levels at T0-1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions.

Conclusion: Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients.

Trial Registration: The Zeus study was registered at https://clinicaltrials.gov, NCT02403115.
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http://dx.doi.org/10.1093/rheumatology/keaa767DOI Listing
July 2021

Serum IgG2 antibody multi-composition in systemic lupus erythematosus and in lupus nephritis (Part 2): prospective study.

Rheumatology (Oxford) 2021 Jul;60(7):3388-3397

Nephrology and Dialysis Unit, University of Messina and G Martino Hospital, Messina, Italy.

Objectives: Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes.

Methods: Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques.

Results: LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T0 and presented the maximal decrement within 12 months.

Conclusions: Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN.

Trial Registration: The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).
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http://dx.doi.org/10.1093/rheumatology/keaa793DOI Listing
July 2021

Immunological basis of virus-host interaction in COVID-19.

Pediatr Allergy Immunol 2020 11;31 Suppl 26:75-78

Department of Pediatrics, Giovanni XXIII Pediatric Hospital, Bari, Italy.

COVID-19 is a complex new viral disease, in which a strict balance between anti-viral immune response and the ensuing organ inflammation has a critical role in determining the clinical course. In adults, compelling evidence exists indicating that an uncontrolled inflammatory response ("cytokine storm") is pivotal in determining disease progression and mortality. Children may rarely present with severe disease. Modulating factors related to the host's genetic factors, age-related susceptibility, and the capability to mount appropriate immune responses might play a role in control virus load at an early stage and regulating the inflammatory reaction. Elucidating these mechanisms seems crucial in developing target therapies according to patient's age, immunologic status, and disease evolution in COVID-19.
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http://dx.doi.org/10.1111/pai.13363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753582PMC
November 2020

Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients.

J Allergy Clin Immunol Pract 2021 02 18;9(2):803-818.e11. Epub 2020 Nov 18.

Pediatric Pulmonology Department and Reference Center for Rare Lung Disease RespiRare, Trousseau University Hospital, AP-HP Sorbonne Université, Paris, France.

Background: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).

Objective: To describe a cohort of patients with SAVI.

Methods: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.

Results: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.

Conclusion: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
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http://dx.doi.org/10.1016/j.jaip.2020.11.007DOI Listing
February 2021

Spontaneous pregnancy after hematopoietic stem cell transplantation for chronic granulomatous disease.

Pediatr Blood Cancer 2021 Apr 28;68(4):e28783. Epub 2020 Oct 28.

Hematopoietic Stem Cell Transplant Unit, Department of Hematology and Oncology, IRCCS Istituto Giannina Gaslini, Genova, Italy.

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http://dx.doi.org/10.1002/pbc.28783DOI Listing
April 2021

Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction.

Am J Hum Genet 2020 11 5;107(5):882-894. Epub 2020 Oct 5.

Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China. Electronic address:

Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a "CC" end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674998PMC
November 2020

Dysregulation in B-cell responses and T follicular helper cell function in ADA2 deficiency patients.

Eur J Immunol 2021 01 28;51(1):206-219. Epub 2020 Aug 28.

Unità Operativa Semplice Dipartimentale Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Adenosine deaminase 2 deficiency (DADA2) is an autoinflammatory disease characterized by inflammatory vasculopathy, early strokes associated often with hypogammaglobulinemia. Pure red cell aplasia, thrombocytopenia, and neutropenia have been reported. The defect is due to biallelic loss of function of ADA2 gene, coding for a protein known to regulate the catabolism of extracellular adenosine. We therefore investigated immune phenotype and B- and T-cell responses in 14 DADA2 patients to address if ADA2 mutation affects B- and T-cell function. Here, we show a significant decrease in memory B cells, in particular class switch memory, and an expansion of CD21 B cells in DADA2 patients. In vitro stimulated B lymphocytes were able to secrete nonfunctional ADA2 protein, suggesting a cell intrinsic defect resulting in an impairment of B-cell proliferation and differentiation. Moreover, CD4 and CD8 T cells were diminished; however, the frequency of circulating T follicular helper cells was significantly increased but they had an impairment in IL-21 production possibly contributing to an impaired B cell help. Our findings suggest that ADA2 mutation could lead to a B-cell intrinsic defect but also to a defective Tfh cell function, which could contribute to the immunodeficient phenotype reported in DADA2 patients.
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http://dx.doi.org/10.1002/eji.202048549DOI Listing
January 2021

Monogenetic causes of chilblains, panniculitis and vasculopathy: the Type I interferonopathies.

G Ital Dermatol Venereol 2020 Oct 2;155(5):590-598. Epub 2020 Jul 2.

Autoinflammatory Diseases and Immunodeficiencies Center, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Type I interferonopathies are a clinically heterogeneous group of inherited disorders of the innate immune system characterized by constitutive activation of the type I interferon signaling pathway. Cutaneous vasculopathy, lipodystrophy, interstitial lung disease and brain calcifications are the typical manifestations characterizing affected patients. The pathogenic mechanism commonly underlying these disorders is the abnormal activation of immune pathways involved in recognition of non-self-oligonucleotides. These natural defenses against virus consent humans to survive the infections. Target therapies capable of inhibiting type I interferon signaling pathway seem effective in these patients, albeit with possible incomplete responses and severe side effects.
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http://dx.doi.org/10.23736/S0392-0488.20.06709-7DOI Listing
October 2020

Recent Insight into SARS-CoV2 Immunopathology and Rationale for Potential Treatment and Preventive Strategies in COVID-19.

Vaccines (Basel) 2020 May 14;8(2). Epub 2020 May 14.

Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy.

As the outbreak of the new coronavirus (SARS-CoV-2) infection is spreading globally, great effort is being made to understand the disease pathogenesis and host factors that predispose to disease progression in an attempt to find a window of opportunity for intervention. In addition to the direct cytopathic effect of the virus, the host hyper-inflammatory response has emerged as a key factor in determining disease severity and mortality. Accumulating clinical observations raised hypotheses to explain why some patients develop more severe disease while others only manifest mild or no symptoms. So far, Covid-19 management remains mainly supportive. However, many researches are underway to clarify the role of antiviral and immunomodulating drugs in changing morbidity and mortality in patients who become severely ill. This review summarizes the current state of knowledge on the interaction between SARS-CoV-2 and the host immune system and discusses recent findings on proposed pharmacologic treatments.
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http://dx.doi.org/10.3390/vaccines8020224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349555PMC
May 2020

On the Alert for Cytokine Storm: Immunopathology in COVID-19.

Arthritis Rheumatol 2020 07 10;72(7):1059-1063. Epub 2020 May 10.

Boston Children's Hospital, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.
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http://dx.doi.org/10.1002/art.41285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262347PMC
July 2020

Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality.

J Allergy Clin Immunol 2020 08 10;146(2):429-437. Epub 2020 Mar 10.

University Department of Pediatrics, Unit of Immune and Infectious Diseases, Bambino Gesù Children's Hospital, University of Rome Tor Vergata, and the Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Background: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce.

Objective: Our aim was to describe the natural history of XLA.

Methods: A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base.

Results: Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease.

Conclusions: This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians.
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http://dx.doi.org/10.1016/j.jaci.2020.03.001DOI Listing
August 2020

Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production.

J Exp Med 2020 02;217(2)

Immunity and Inflammatory Diseases, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.

Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.
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http://dx.doi.org/10.1084/jem.20191336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041712PMC
February 2020

Probing the determinants of porosity in protein frameworks: co-crystals of cytochrome c and an octa-anionic calix[4]arene.

Org Biomol Chem 2020 01;18(2):211-214

School of Chemistry, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland.

Sulfonato-calix[n]arenes (sclxn) are promising tools to generate crystalline protein frameworks. We report, for the first time, a lower rim functionalised octa-anionic calix[4]arene (sclx4mc) in complex with proteins. Two crystal structures of sclx4mc bound to yeast or horse heart cytochrome c (cytc) are described. Highly porous honeycomb or tubular assemblies were obtained with yeast or horse cytc, respectively. Related frameworks were obtained previously with sclx8 and sclx6 but not with sclx4, suggesting that the ligand charge is a determining factor.
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http://dx.doi.org/10.1039/c9ob02275aDOI Listing
January 2020
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