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| Identifier |
338844 |
| Title |
Ο ρόλος της μη ειδικής ανοσίας στην παθογένεια της νεφρίτιδας του συστηματικού ερυθηματώδους λύκου |
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Author
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Παπαδημητράκη, Εύα
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Thesis advisor
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Μπούμπας, Δημήτριος
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Reviewer
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Καρδάσης, Δημήτριος
Τσατσάνης, Χρήστος
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| Abstract |
Systemic lupus erythematosus (SLE) is the prototype systemic autoimmune disorder, characterized by an abnormal T-cell driven - B-cell mediated production of pathogenic autoantibodies against nuclear auto-antigens. Whereas the role of adaptive immune response has been extensively studied, the role of innate immune response in initiating and / or perpetuating the abnormal autoimmune phenomena, has not been thoroughly investigated in SLE. Toll-like receptors (TLRs) are pattern associated receptors of innate immunity that may be involved in the recognition of self antigens and the production of autoantibodies. In the present study we investigated the expression and function of TLR-2, -3, -4 and -9 in peripheral blood and bone marrow cell subpopulations of patients with SLE. The expression of TLR-9 was further examined in renal biopsies from SLE patients. Toll-like receptor 9 (TLR-9), which may recognize hemi-methylated self-DNA, exhibits a disturbed expression pattern in the peripheral blood and the bone marrow of patients with high disease activity compared with patients with lower disease activity and healthy individuals. More specifically, an increased proportion of B-cells and monocytes expresses TLR-9 among patients with active SLE (49.5 ± 24.4% and 30.7 ± 24.1% respectively) compared to patients with inactive disease (22.8 ± 19.6%, p=0.02 and 14.3 ± 8.4%, p=0.03 respectively). Among B-cells, increased proportions of plasmacytoid cells and memory B-cells (the putative autoantibody producing cells), but not naïve B-cells, express TLR-9 in patients with active SLE. Increased percentages of TLR-9 expressing B-cells correlate with the presence of anti-dsDNA antibodies (p=0.007) in active SLE patients.Of interest, increased proportions of TLR-9 expressing plasmacytoid cells are present in the bone marrow of SLE patients with high disease activity compared with their peripheral counterparts. Enhanced TLR-9 expression is accompanied by an enhanced proliferative and antigen presenting capacity of B-cells from active SLE patients, as evidenced by an enhanced proliferative response and an increased HLA-DR induction on these cells after stimulation of TLR-9 with its specific ligand ODN 2006. On the contrary, the production of cytokines IL-6, IL-10 and TNF-a upon ODN 2006 treatment does not differ among groups under study. The culture of B-cells derived from healthy individuals in the presence of active SLE serum results in the increase of both, the number of peripheral plasmacytoid B cells and of the percentage of these cells that express TLR-9. The addition in the culture medium of hydroxychloroquine, an agent that is widely used for the treatment of SLE, abrogates this effect of SLE serum in the expression pattern of TLR-9. Regarding monocytes, TLR-9 expression does not to influence their capacity to produce interferon-α -an important immune modulating cytokine in lupus- as shown indirectly by the lack of enhanced induction of interferon inducible genes upon ΤLR-9 stimulation of total PBMCs of active lupus patients. Ιmmunohistochemical analysis of renal TLR-9 expression revealed an enhanced glomerular ΤLR-9 expression in patients with active proliferative or membranous lupus nephritis compared to patients suffering from non SLE nephritis, other immune mediated glomerulonephritis or healthy controls. Diffuse tubulointersistial ΤLR-9 expression does not dignificantly differ among groups under study. Taken together these results, implicate innate immunity pathways –predominantly via TLR-9- both, in the initiation of autoreactivity and in the amplification of the glomerular injury in lupus patients.
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| Language |
Greek |
| Subject |
Lupus Erythematosus, Systemic |
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Λύκος ερυθηματώδης, Συστηματικός |
| Issue date |
2006-08-04 |
| Collection
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School/Department--School of Medicine--Department of Medicine--Doctoral theses
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Type of Work--Doctoral theses
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| Permanent Link |
https://elocus.lib.uoc.gr//dlib/4/2/6/metadata-dlib-2006papadimitraki.tkl
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| Views |
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