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Role of innate immunity in the pathogenesis of autoimmune diseases

Final Report Summary - RIISPAD (Role of innate immunity in the pathogenesis of autoimmune diseases)

In this final report of Dr Mavilio's proposal (RIISPAD project; Grant Agreement No 204188) submitted for the 2007 Marie Curie International Reintegration Grants (IRGs), we summarise the achievements obtained in the past 2 years. Since the project has been divided in work packages, this report provides a short description for each session of this proposal of translational medicine:

WP1: Role of natural killer (NK) cells in the lymphomagenesis associated to autoimmune diseases

Overall, our results did not find any substantial aberrancies of circulating NK cells during the course of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) in those patients that resulted naïve for immunosuppressive therapy. Indeed, we could detect the presence of CD56neg / CD16neg NK cells (as indicated in the previous periodic report) in those SLE and RA patients in therapy with either immunosuppressive drugs or corticosteroids. Therefore, we excluded these patients from our projects. In contrast, we found aberrancies of NK and B cells during the course of primary Sjögren's syndrome (pSS). In particular, pSS patients showed significant alterations in circulating B and NK cell compartments, possibly associated with the high levels of serum BLys and aberrancies of cell homeostasis at tissue gland level. Moreover, we found that the reduced numbers of NK cells and some aberrancies in their receptor repertoire was associated with an impaired ability of NK cells to kill Burkitt lymphoma cell line (RAJI) (as also stated by our preliminary results summarised in the previous report). This phenomenon was much more pronounced in pSS carrying either MESA or mucosa-associated lymphoid tissue (MALT)-type lymphoma in the parotid glands. These results confirmed that NK cells likely play an important role in the lymphomagenesis during pSS. We also analysed the frequency, the distribution and the phenotype of NK cells in the parotid glands. We did this by both using a human ex vivo model (biopsies of human parotid glands of pSS patients either with or without lymphomas) and an in vivo mouse model of syaloadenitis compatible with pSS. Our preliminary results confirmed than NK infiltrates the parotid glands especially in the early phases of the diseases and highly contribute to its pathogenesis. Interestingly, we found less NK cell infiltrate in the parotids of pSS patients carrying either MESA or MALT-type lymphoma compared to that of pSS individuals without any histological sigh of tumours. This suggests that defects in NK cells trafficking in peripheral tissues might leads to the onset of cancer lesions in the glands. This last part of the project is still ongoing and we are currently looking for some potential mechanisms involved in these defective NK cell infiltrations in the parotid glands of pSS patients also co-affected by lymphomas. We are currently writing a manuscript related to the findings briefly summarised in this WP1.

WP2: NK cells and autoimmune arthritis: identification of novel biomarkers for an early diagnosis and clinical follow up

Due the difficulties in the recruitment program, we did not get access to a reasonable amount (in terms of volumes) and numbers of patients donating synovial fluid from the joints affected by RA, psoriatic arthritis (PA) and juvenile arthritis (JA). One of the highest limitations was that, although without a definitive diagnosis, the vast majority of patients who had access to our outpatient clinic presented a long history of arthritis and were in therapy with immunosuppressant and/or anti-inflammatory drugs (mostly corticosteroids given either locally in the joints or systemically (oral of intravenously)). This created a strong bias in the interpretation of the data, since we could not really determine if the changes in gene modulation, cell trafficking / migration to inflamed joints and cell phenotype and functions (of both circulating and joint NK cells) were associated with the diseases or with the therapy. Not even the patients sometimes could detail their medical history and the type and dose of drug previously administered to them. Given this heterogeneous recruitment program and considering our restraints in data interpretation, we were forced to close the recruitment programme and early terminate WP2 without performing the planned experiments of this part of the project.

Since Dr Mavilio experienced some unexpected difficulties in performing WP2 included in the original experimental plan, he initiated or implemented other projects of translational medicine. Given the fact that this Marie Curie Reintegration Grant allowed Dr Mavilio to go back to his home country and open a new research unit, he took advantage of this possibility to develop and / or implement other lines of research considered as a part of this proposal.

WP3: Differentiation of human peripheral blood Vdelta1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells

The success of cancer immunotherapy depends on productive tumour cell recognition by killer lymphocytes. Gamma-delta T cells are a population of innate-like lymphocytes endowed with strong, MHC-unrestricted cytotoxicity against tumour cells. We identified and characterised a novel Vdelta1+ PBL subset capable of targeting ematological tumours highly resistant to fully-activated Vgamma9Vdelta2 PBLs. We show that this Vdelta1+ population owes its specialised killer function to induced expression of natural cytotoxicity receptors (NCRs), which have been mostly regarded as NK-specific markers. This experimental evidence disclosing an unanticipated antiviral function of NCRpos Vdelta1 T-cells opens new avenues for understanding the pathogenic role and for manipulating the function of gamma-liledelta T-cells in human immunodeficiency virus (HIV)-1 infection. This study has been recently published in 2011 and the support of this grant that has been acknowledged in the manuscript.

WP4: Role of NK cells in the pathogenesis of HIV-1 infection. Since Dr Mavilio has been historically investigating on the role of NK cells in the pathogenesis of HIV-1 infection, he wrote a comprehensive review summarising his last results over the past 5 years. This was also possible to the support of this grant that has been acknowledged in the manuscript published in 2010.

WP5

RET is the gene mainly involved in the pathogenesis of Hirschsprung disease (HSCR), a rare and severe neonatal anomaly of the enteric nervous system leading to the onset of severe inflammatory symptoms and signs. We fully characterised the phenotypic distribution of RET receptor on human peripheral blood mononuclear cells (PBMCs) and we demonstrate that its increased surface expression on immune cell subsets from HSCR patients correlates with the presence of loss of function RET mutations. The present study linking several genetic features of HSCR with its immunological counterparts also demonstrates that the engagement of RET on PBMCs induces the modulation of genes involved in inflammation (i.e. chemokines such as CCL20, CCL2, CCL3, CCL4, CCL7, CXCL1, cytochine such as IL-1b, IL-6 and IL-8, chemochine / cytokine receptors such as CCR2 and IL8-Ra). Moreover, we identified another small set of genes that, regardless of stimulation of RET with its ligand and co-receptor, are differently regulated in healthy donors versus HSCR patients. Amongst these RET-independent genes there are CSF-1R, IL1-R1, IL1-R2 and TGFb-1. These results demonstrate that immune system actively participates in the physiopathology of HSCR disease by inducing an inflammatory program that is either dependent or independent from RET. The related manuscript entitled 'Induction of both a RET dependent and independent pro-inflammatory programme in human PBMCs from Hirschprung patients' is currently under submission and the support of this grant that has been acknowledged in the manuscript. We partially deviated in part from the original experimental plan because we were not able to complete the WP2, as detailed above. Given the fact that the current Marie Curie Reintegration Grant allowed Dr Mavilio to go back to his home country and open a new research unit, he took advantage of this possibility to develop other lines to of research (WP3, WP4 and WP5) that are considered as a part of this awarded support. Indeed, the opportunity given by this granted proposal substantially helped Dr Mavilio to establishing European and international networks, to set up clinical facilities / administrative procedures and to start several collaborations needed to perform these projects. This represented a remarkable step forward for Dr Mavilio's scientific and clinical career back in his home country, where he undertook programs of translational medicine on the basis of his past experience at the National Institutes of Health, Bethesda, Maryland, United States of America.

Domenico Mavilio, M.D. Ph.D.
Principal Investigator
Unit of Clinical and Experimental Immunology
Istituto Clinico Humanitas
Via Manzoni 56, 20089 Rozzano (Milano), Italy
Phone: +39 02 8224 5157, Fax: +39 02 8224 5191
email: domenico.mavilio@humanitas.it
Webpages: (Italian): http://www.humanitas.it/hur/cms/la_nostra_squadra/laboratori/ and (English): http://www.humanitas.it/hur/cms/english/activities/lab/index.html