Publications by authors named "Alessandra Pasini"

13 Publications

  • Page 1 of 1

Depletion of circulating IgM memory B cells predicts unfavourable outcome in COVID-19.

Sci Rep 2020 11 30;10(1):20836. Epub 2020 Nov 30.

Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.

Impaired immune responses have been hypothesised to be a possible trigger of unfavourable outcomes in coronavirus disease 2019 (COVID-19). We aimed to characterise IgM memory B cells in patients with COVID-19 admitted to an internal medicine ward in Northern Italy. Overall, 66 COVID-19 patients (mean age 74 ± 16.6 years; 29 females) were enrolled. Three patients (4.5%; 1 female) had been splenectomised and were excluded from further analyses. Fifty-five patients (87.3%) had IgM memory B cell depletion, and 18 (28.6%) died during hospitalisation (cumulative incidence rate 9.26/100 person-week; 5.8-14.7 95% CI). All patients who died had IgM memory B cell depletion. A superimposed infection was found in 6 patients (9.5%), all of them having IgM memory B cell depletion (cumulative incidence rate 3.08/100 person-week; 1.3-6.8 95% CI). At bivariable analyses, older age, sex, number of comorbidities, and peripheral blood lymphocyte count < 1500/µl were not correlated with IgM memory B cell depletion. A discrete-to-marked reduction of the B-cell compartment was also noticed in autoptic spleen specimens of two COVID-19 patients. We conclude that IgM memory B cells are commonly depleted in COVID-19 patients and this correlates with increased mortality and superimposed infections.
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http://dx.doi.org/10.1038/s41598-020-77945-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705651PMC
November 2020

Small Bowel Adenocarcinomas Featuring Special AT-Rich Sequence-Binding Protein 2 (SATB2) Expression and a Colorectal Cancer-Like Immunophenotype: A Potential Diagnostic Pitfall.

Cancers (Basel) 2020 Nov 19;12(11). Epub 2020 Nov 19.

Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Lombardy, Italy.

Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor expressed by colonic cryptic epithelium and epithelial neoplasms of the lower gastrointestinal (GI) tract, as well as by small bowel adenocarcinomas (SBAs), though at a lower rate. Nevertheless, up to now, only small SBA series, often including a very limited number of Crohn's disease-associated SBAs (CrD-SBAs) and celiac disease-associated SBAs (CD-SBA), have been investigated for SATB2 expression. We evaluated the expression of SATB2 and other GI phenotypic markers (cytokeratin (CK) 7 and CK20, caudal type homeobox 2 (CDX2) and alpha-methylacyl-CoA racemase (AMACR)), as well as mismatch repair (MMR) proteins, in 100 SBAs, encompassing 34 CrD-SBAs, 28 CD-SBAs and 38 sporadic cases (Spo-SBAs). Any mutual association and correlation with other clinico-pathologic features, including patient prognosis, were searched. Twenty (20%) SATB2-positive SBAs (4 CrD-SBAs, 7 CD-SBAs and 9 Spo-SBAs) were identified. The prevalence of SATB2 positivity was lower in CrD-SBA (12%) in comparison with both CD-SBAs (25%) and Spo-SBAs (24%). Interestingly, six SBAs (two CD-SBAs and four Spo-SBAs) displayed a full colorectal carcinoma (CRC)-like immunoprofile (CK7-/CK20+/CDX2+/AMACR+/SATB2+); none of them was a CrD-SBA. No association between SATB2 expression and MMR status was observed. Although SATB2-positive SBA patients showed a more favorable outcome in comparison with SATB2-negative ones, the difference did not reach statistical significance. When cancers were stratified according to CK7/CK20 expression patterns, we found that CK7-/CK20- SBAs were enriched with MMR-deficient cases (71%) and patients with CK7-/CK20- or CK7-/CK20+ SBAs had a significantly better survival rate compared to those with CK7+/CK20- or CK7+/CK20+ cancers ( = 0.002). To conclude, we identified a small (6%) subset of SBAs featuring a full CRC-like immunoprofile, representing a potential diagnostic pitfall in attempts to identify the site of origin of neoplasms of unknown primary site. In contrast with data on colorectal carcinoma, SATB2 expression is not associated with MMR status in SBAs. CK patterns influence patient survival, as CK7-/CK20- cancers show better prognosis, a behavior possibly due to the high rate of MMR-deficient SBAs within this subgroup.
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http://dx.doi.org/10.3390/cancers12113441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699330PMC
November 2020

Abnormal post-prandial glucagon-like peptide release in patients with Crohn's disease.

Clin Res Hepatol Gastroenterol 2020 Oct 7:101533. Epub 2020 Oct 7.

First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy. Electronic address:

Background And Aims: Glucagon-like peptide GLP-1 and -2 have been shown to regulate immune responses in immune-mediated disorders, including Crohn's disease (CD). Our aim was to investigate post-prandial GLP release and its potential link to chronic inflammation, insulin secretion/sensitivity and body composition changes in CD patients.

Methods: Fifteen patients with CD, 15 healthy controls (HC) and 15 patients with metabolic syndrome (MS) were recruited. All patients underwent assessment of body composition by means of bio-impedance followed by a meal tolerance test (MTT). Only one CD patient did not tolerate the MTT and was excluded.

Results: Basal GLP-1 levels were up-regulated in CD, however, as compared to HC, stimulated GLP-1 secretion was significantly reduced in CD (-31 %, p < 0.05) as in MS (-52 %, p < 0.003). Similarly, basal GLP-2 levels were comparable to that of HC, while response to MTT in CD was virtually absent (p < 0.05). Similar fasting insulin sensitivity, estimated 1 and 2 phase insulin secretion and insulinogenic index were found in CD and in HC. Post-prandial GLP secretion was positively correlated to insulin secretion indices, both in CD and MS. In CD, high-sensitive C reactive protein levels (hsCRP) and extra-cellular to intra-cellular water ratio (ECW/ICW), an index of cellular inflammation, were inversely correlated with stimulated GLP-1 (p < 0.05 and p < 0.01, respectively) levels.

Conclusion: CD is characterized by abnormal fasting and post-prandial GLP levels. Circulating GLP influences subclinical inflammation and glucose metabolism in CD patients, but not their body composition parameters.
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http://dx.doi.org/10.1016/j.clinre.2020.08.011DOI Listing
October 2020

Intestinal expression of genes implicated in iron absorption and their regulation by hepcidin.

Clin Nutr 2017 10 30;36(5):1427-1433. Epub 2016 Sep 30.

Department of Internal Medicine, University of Pavia Medical School, and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy. Electronic address:

Background & Aims: Through inhibition of iron absorption and iron mobilization from tissue stores, hepcidin exerts a negative control on iron homeostasis. Hepcidin, in fact, promotes the degradation of ferroportin (Fpn1), the iron exporter molecule expressed on the membrane of hepatocytes and macrophages, thus preventing iron release from cells to plasma. Hepcidin effects on enterocytes, however, are less clear. Aim of the present study was to further investigate the regulation of iron absorption by hepcidin.

Methods: The transcriptional response of human duodenal mucosa to hepcidin was investigated using organ cultures of duodenal biopsies perendoscopically collected from healthy controls. Biopsies were cultured for 4 h with or without hepcidin-25 and were then assayed for the expression of iron-related genes.

Results: In samples that had not been exposed to hepcidin, correlations were found between the expression of genes involved in iron absorption: DMT1, Fpn1, Dcytb and HCP1. In ex vivo experiments hepcidin down-regulated mRNA levels of the iron transporters Fpn1, and DMT1, of the ferric reductase Dcytb, of the ferroxidase hephaestin, and of the putative heme carrier protein HCP1.

Conclusions: Through the reported transcriptional changes hepcidin can modulate several steps of the iron absorption process, including the reduction of dietary iron by Dcytb, its uptake by enterocytes through DMT1, the mucosal uptake of heme iron by HCP1, and enterocyte iron release to plasma by Fpn1 in conjunction with hephaestin.
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http://dx.doi.org/10.1016/j.clnu.2016.09.021DOI Listing
October 2017

Innate and adaptive immunity in self-reported nonceliac gluten sensitivity versus celiac disease.

Dig Liver Dis 2016 Jul 7;48(7):745-52. Epub 2016 Apr 7.

Department of Internal Medicine, San Matteo Hospital, University of Pavia, Pavia, Italy.

Background: Immune mechanisms have been implicated in nonceliac gluten sensitivity (NCGS), a condition characterized by intestinal and/or extraintestinal symptoms caused by the ingestion of gluten in non-celiac/non-wheat allergic individuals.

Aims: We investigated innate and adaptive immunity in self-reported NCGS versus celiac disease (CD).

Methods: In the supernatants of ex vivo-cultured duodenal biopsies from 14 self-reported NCGS patients, 9 untreated and 10 treated CD patients, and 12 controls we detected innate cytokines - interleukin (IL)-15, tumor necrosis factor-α, IL-1β, IL-6, IL-12p70, IL-23, IL-27, IL-32α, thymic stromal lymphopoietin (TSLP), IFN-α-, adaptive cytokines - interferon (IFN)-γ, IL-17A, IL-4, IL-5, IL-10, IL-13-, chemokines - IL-8, CCL1, CCL2, CCL3, CCL4, CCL5, CXCL1, CXCL10-, granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF).

Results: Mucosal innate and adaptive cytokines, chemokines and growth factors did not differ between self-reported NCGS, treated CD and controls. On the contrary, IL-6, IL-15, IL-27, IFN-α, IFN-γ, IL-17A, IL-23, G-CSF, GM-CSF, IL-8, CCL1 and CCL4 were significantly higher in untreated CD than in self-reported NCGS, treated CD and controls, while TSLP was significantly lower in untreated CD than in self-reported NCGS, treated CD and controls.

Conclusion: In our hands, patients with self-reported NCGS showed no abnormalities of the mucosal immune response.
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http://dx.doi.org/10.1016/j.dld.2016.03.024DOI Listing
July 2016

Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease.

Gut 2016 10 4;65(10):1670-80. Epub 2015 Sep 4.

First Department of Internal Medicine, St Matteo Hospital, University of Pavia, Pavia, Italy.

Objective: The short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn's disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals.

Design: TSLP isoforms-long and short-and receptors-TSLPR and interleukin (IL)-7Rα-were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed.

Results: Mucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies.

Conclusions: Reduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD.
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http://dx.doi.org/10.1136/gutjnl-2014-308876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036244PMC
October 2016

Increase in neuroendocrine cells in the duodenal mucosa of patients with refractory celiac disease.

Am J Gastroenterol 2014 Feb 7;109(2):258-69. Epub 2014 Jan 7.

First Department of Medicine, Celiac Centre, St. Matteo Hospital, University of Pavia, Pavia, Italy.

Objectives: Several immune-mediated gastrointestinal disorders, including celiac disease (CD), are associated with neuroendocrine cell hyperplasia. However, neuroendocrine cells have never been explored in refractory CD (RCD).

Methods: Serial duodenal sections from 17 patients with RCD (6 type 1 and 11 type 2), 16 uncomplicated CD patients before and after gluten-free diet, 14 patients with potential CD, 27 patients with non-CD villous atrophy, i.e., common variable immunodeficiency (n=12), Whipple's disease (n=10) and giardiasis (n=5), and 16 healthy subjects were processed for the immunohistochemical detection of chromogranin A (CgA), serotonin, and somatostatin. Mucosal tryptophan hydroxylase (TpH)-1 and serotonin-selective reuptake transporter (SERT) transcripts were measured by quantitative reverse transcription-PCR. Serum CgA and 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) were assessed. Biopsies from treated CD patients were cultured with serotonin or peptic tryptic digest of gliadin (PT-gliadin), and interferon (IFN)-γ was detected by ELISA in culture supernatants.

Results: Epithelial cells positive for CgA and serotonin, but not somatostatin, were significantly increased in RCD. Raised mucosal transcripts of TpH-1, but not SERT, were found in RCD. On biopsies from treated CD patients, serotonin upregulated IFN-γ production at levels comparable to those induced by PT-gliadin. Serum CgA, but not urine 5-HIAA, was increased in RCD. No significant difference was found between RCD type 1 and type 2 in terms of neuroendocrine cells, mucosal TpH-1 transcripts, and serum CgA.

Conclusions: Serotonin-producing neuroendocrine cells are increased in RCD mucosa. IFN-γ upregulation induced by serotonin suggests that this monoamine may have a role in sustaining the local inflammatory response in CD.
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http://dx.doi.org/10.1038/ajg.2013.426DOI Listing
February 2014

Serum hepcidin in inflammatory bowel diseases: biological and clinical significance.

Inflamm Bowel Dis 2013 Sep;19(10):2166-72

Department of Internal Medicine, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Background: Hepcidin, a peptide produced by hepatocytes, regulates body iron homeostasis. Inflammation increases serum hepcidin, and its determination can be useful in the differential diagnosis of anemias during inflammatory diseases.

Methods: We measured serum hepcidin-25 and hepcidin-20 isoforms in 54 patients with inflammatory bowel diseases (IBD) and 54 reference subjects (36 healthy controls and 18 anemic patients without inflammation or renal failure). Disease activity, blood counts, iron status, and erythropoiesis-related parameters were obtained for all study subjects.

Results: In IBD hepcidin-25, the peptide bioactive isoform correlated positively with C-reactive protein and serum ferritin; an inverse correlation was observed with transferrin, the soluble transferrin receptor, and the soluble transferrin receptor to Log(ferritin) ratio. Similar correlations were found in reference subjects. Patients with anemia of inflammation had higher hepcidin-25 levels than those with iron deficiency anemia or a combination of iron deficiency anemia and inflammation (P = 0.0061). In patients with inflammation and serum ferritin concentration 100 to 200 ng/mL, hepcidin-25 was low, suggesting that these patients had iron deficiency. A serum hepcidin-25 concentration below 2.0 nM differentiated 85% of patients with iron deficiency anemia (with or without inflammation) from patients with anemia of inflammation. In IBD, hepcidin-20 correlated with both hepcidin-25 and C-reactive protein.

Conclusions: In IBD, iron stores, inflammation, and iron requirement for erythropoiesis influence serum hepcidin-25. Hepcidin-25 determination can be useful in the differential diagnosis of IBD-associated anemias. Serum hepcidin-20 is linked to hepcidin-25, but inflammation has an independent regulatory role on its concentration, indicating that hepcidin-20 may have a biological function.
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http://dx.doi.org/10.1097/MIB.0b013e31829a6e43DOI Listing
September 2013

The role of interleukin 17 in Crohn's disease-associated intestinal fibrosis.

Fibrogenesis Tissue Repair 2013 Jul 8;6(1):13. Epub 2013 Jul 8.

Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK.

Background: Interleukin (IL)-17A and IL-17E (also known as IL-25) have been implicated in fibrosis in various tissues. However, the role of these cytokines in the development of intestinal strictures in Crohn's disease (CD) has not been explored. We investigated the levels of IL-17A and IL-17E and their receptors in CD strictured and non-strictured gut, and the effects of IL-17A and IL-17E on CD myofibroblasts.

Results: IL-17A was significantly overexpressed in strictured compared with non-strictured CD tissues, whereas no significant difference was found in the expression of IL-17E or IL-17A and IL-17E receptors (IL-17RC and IL-17RB, respectively) in strictured and non-strictured CD areas. Strictured CD explants released significantly higher amounts of IL-17A than non-strictured explants, whereas no difference was found as for IL-17E, IL-6, or tumor necrosis factor-α production. IL-17A, but not IL-17E, significantly inhibited myofibroblast migration, and also significantly upregulated matrix metalloproteinase (MMP)-3, MMP-12, tissue inhibitor of metalloproteinase-1 and collagen production by myofibroblasts from strictured CD tissues.

Conclusions: Our results suggest that IL-17A, but not IL-17E, is pro-fibrotic in CD. Further studies are needed to clarify whether the therapeutic blockade of IL-17A through the anti-IL-17A monoclonal antibody secukinumab is able to counteract the fibrogenic process in CD.
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http://dx.doi.org/10.1186/1755-1536-6-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733737PMC
July 2013

Altered expression of type-1 and type-2 cannabinoid receptors in celiac disease.

PLoS One 2013 19;8(4):e62078. Epub 2013 Apr 19.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

Anandamide (AEA) is the prominent member of the endocannabinoid family and its biological action is mediated through the binding to both type-1 (CB1) and type-2 (CB2) cannabinoid receptors (CBR). The presence of AEA and CBR in the gastrointestinal tract highlighted their pathophysiological role in several gut diseases, including celiac disease. Here, we aimed to investigate the expression of CBR at transcriptional and translational levels in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also biopsies from treated celiac patients cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our data show higher levels of both CB1 and CB2 receptors during active disease and normal CBR levels in treated celiac patients. In conclusion, we demonstrate an up-regulation of CB1 and CB2 mRNA and protein expression, that points to the therapeutic potential of targeting CBR in patients with celiac disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631143PMC
November 2013

Effect of tumor necrosis factor-α blockade on mucosal addressin cell-adhesion molecule-1 in Crohn's disease.

Inflamm Bowel Dis 2013 Feb;19(2):259-64

Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK.

Background: Mucosal addressin cell-adhesion molecule (MAdCAM)-1, which is overexpressed on gut endothelium in active Crohn's disease (CD), promotes intestinal recruitment of integrin α(4)β(7)(*) T cells that sustain chronic inflammation. As tumor necrosis factor alpha (TNF)-α, a cytokine centrally involved in CD, modulates gut endothelial adhesion molecules, we here explored the in vivo and ex vivo effects of TNF-α blockade on MAdCAM-1 expression in CD.

Methods: MAdCAM-1 was determined by immunoblotting in colonic biopsies collected before and 10 weeks after either infliximab or adalimumab treatment in CD patients, and in CD biopsies incubated with either infliximab or adalimumab or control IgG(1). Integrin β(7)(*) circulating T cells were analyzed by flow cytometry.

Results: MAdCAM-1 significantly decreased after either infliximab or adalimumab treatment in responder but not in nonresponder patients. In parallel, an increase of circulating β(7)(*) T cells was found in responder patients only. A marked downregulation of MAdCAM-1 was observed in CD biopsies cultured with either infliximab or adalimumab in comparison to IgG(1)-treated biopsies.

Conclusions: Our findings showing that MAdCAM-1 is downregulated by TNF-α blockade point to a novel mechanism of action of anti-TNF-α antibodies in CD.
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http://dx.doi.org/10.1097/MIB.0b013e31828100a4DOI Listing
February 2013

Abnormal anandamide metabolism in celiac disease.

J Nutr Biochem 2012 Oct 29;23(10):1245-8. Epub 2011 Dec 29.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

The endocannabinoid system has been extensively investigated in experimental colitis and inflammatory bowel disease, but not in celiac disease, where only a single study showed increased levels of the major endocannabinoid anandamide in the atrophic mucosa. On this basis, we aimed to investigate anandamide metabolism in celiac disease by analyzing transcript levels (through quantitative real-time reverse transcriptase-polymerase chain reaction), protein concentration (through immunoblotting) and activity (through radioassays) of enzymes responsible for anandamide synthesis (N-acylphosphatidyl-ethanolamine specific phospholipase D, NAPE-PLD) and degradation (fatty acid amide hydrolase, FAAH) in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also, treated celiac biopsies cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our in vivo experiments showed that mucosal NAPE-PLD expression and activity are higher in untreated celiac patients than treated celiac patients and controls, with no significant difference between the latter two groups. In keeping with the in vivo data, the ex vivo activity of NAPE-PLD was significantly enhanced by incubation of peptic-tryptic digest of gliadin with treated celiac biopsies. On the contrary, in vivo mucosal FAAH expression and activity did not change in the three groups of patients, and accordingly, mucosal FAAH activity was not influenced by treatment with peptic-tryptic digest of gliadin. In conclusion, our findings provide a possible pathophysiological explanation for the increased anandamide concentration previously shown in active celiac mucosa.
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http://dx.doi.org/10.1016/j.jnutbio.2011.06.017DOI Listing
October 2012

Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process.

J Neuroimmunol 2009 May;210(1-2):73-9

Laboratory for Research on Neurodegenerative Disorders, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.

In this work we show that patients with sporadic amyotrophic lateral sclerosis exhibit immunological alterations in their blood, with respect to healthy controls, such as: i) increased levels of CD4+ cells and decreased levels of CD8+ T lymphocytes, the latter due to the reduced expression of the anti-apoptotic molecule Bcl-2; ii) significantly reduced CD4+CD25+ regulatory T (Treg) cells and monocytes (CD14+) levels in patients at a less severe stage of disease, suggesting their early recruitment towards the CNS area of primary neurodegeneration; iii) reduced expression of HLA-DR and CCR2 expression, as markers of activation, in monocytes. Since resident microglia partially derives from circulating activated monocytes and Treg cells are known to interact with the local microglia, this study strengthens the hypothesis of an involvement of the adaptive immune system associated with a neuroinflammatory process in the pathobiology of ALS.
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http://dx.doi.org/10.1016/j.jneuroim.2009.02.012DOI Listing
May 2009