Clinical and MRI disease activity in multiple sclerosis are associated with reciprocal fluctuations in serum and cerebrospinal fluid levels of soluble HLA class I molecules

Fainardi, Enrico; Granieri, Enrico; Tola, Maria Rosaria; Melchiorri, Loredana; Vaghi, Luca; Rizzo, Roberta; Castellazzi, Massimiliano; Ceruti, Stefano; Paolino, E.; Baricordi, Olavio R.

doi:10.1016/s0165-5728(02)00348-x

Cited by 18 publications

(21 citation statements)

References 34 publications

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“…g/ml) NK cells produce a higher amount of IFN-+ leading to a sustained activation of several lymphocyte subsets and antigen-presenting cells. The serum levels of sHLA-I significantly increase in several pathological conditions such as in patients affected by autoimmune diseases (SLE, RA, multiple sclerosis), or infections or during severe graft-versus-host disease following allogeneic bone marrow transplantation [9][10][11]20]. Indeed, it has been reported that sHLA-I levels in sera of healthy volunteers are usually less than 1 ?…”

Section: Discussionmentioning

confidence: 99%

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IFN‐γ production in human NK cells through the engagement of CD8 by soluble or surface HLA class I molecules

et al. 2003

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The engagement of CD8 on NK cell surface by either surface or soluble HLA class I (sHLA-I) molecules induces synthesis and secretion of IFN-+ . HLA-I-mediated effects were inhibited by the covering of CD8 with specific anti-CD8 monoclonal antibodies, indicating a direct interaction of HLA-I and CD8. That CD8 ligation induces IFN-+ production was further supported by the finding that cross-linking of CD8 led to release of IFN-+ at similar levels to those obtained with HLA-I. The sHLA-I-induced IFN-+ production via CD8 was strongly down-regulated by the engagement of the inhibitory isoforms of either CD94/NKG2 complex by sHLA-I-non-(A,B,C,G) (putative sHLA-E) or CD158b by sHLA-I-Cw3 allele. Ligation of CD8 did not elicit, different from other activating NK cell surface molecules such as CD16 or CD69, triggering of NK cell-mediated cytolysis. Cyclosporin A, but not concanamycin A, an H + -ATPase vacuolar inhibitor which affects perforin and granzyme release, strongly reduced the sHLA-I-mediated CD8-dependent IFN-+ production but did not affect cytolytic activity of NK cells, suggesting that different biochemical pathways are involved. Altogether, these findings indicate that CD8 engagement by sHLA-I activates a cyclosporin A-dependent pathway leading to production and secretion of IFN-+ which may play a role in the regulation of innate immune responses in humans.

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Section: Discussionmentioning

confidence: 99%

“…g/ml while sHLA-I levels in sera of patients affected by inflammatory disorders are higher than 2 ? g/ml [20]. Thus, it is likely that sufficient amounts of sHLA-I, able to induce IFN-+ production by NK cells, are present in sera of autoimmune patients and may play a role in maintaining chronic inflammation [9][10][11]20].…”

Section: Discussionmentioning

confidence: 99%

IFN‐γ production in human NK cells through the engagement of CD8 by soluble or surface HLA class I molecules

et al. 2003

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“…We provided additional information in a recent paper, which included an evaluation of CSF and serum levels of sHLA-I in a group of patients with RR, SP, and PP MS, other inflammatory neurological disorders (OIND), and noninflammatory neurological disorders (NIND) [59]. By means of enzyme-linked immunosorbent assay (ELISA) based on the use of W6/32 monoclonal antibody as the capture antibody, we reported that a local production of sHLA-I within the CSF compartment, detected by specific sHLA-I index according to the IgG Index [60], was more frequent in MS patients than in controls, as well as in clinically and MRI-active MS compared with clinically and MRI-stable MS.…”

Section: Shla-g and Ms: First Evidencementioning

confidence: 99%

Potential role of soluble human leukocyte antigen-G molecules in multiple sclerosis

et al. 2009

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“…This can suggest that in sera with high levels of sHLA-I (2-4µg/ml) NK cells produce a higher amount of IFN-γ leading to a sustained activation of several lymphocyte subsets and antigen presenting cells. The serum levels of sHLA-I significantly increase in several pathological conditions such as in patients affected by auto-immune diseases (SLE, RA, multiple sclerosis), or infections or during severe graft-versus-host disease following allogeneic bone marrow transplantation [19][20][21][22]36]. Indeed, it has been reported that the sHLA-I in sera of healthy volunteers is usually less than 1µg/ml while in those affected by inflammatory disorders is more than 2µg/ml [36].…”

Section: Soluble Hla-i Triggers Ifn-γ Release Through the Engagement mentioning

confidence: 99%

“…The serum levels of sHLA-I significantly increase in several pathological conditions such as in patients affected by auto-immune diseases (SLE, RA, multiple sclerosis), or infections or during severe graft-versus-host disease following allogeneic bone marrow transplantation [19][20][21][22]36]. Indeed, it has been reported that the sHLA-I in sera of healthy volunteers is usually less than 1µg/ml while in those affected by inflammatory disorders is more than 2µg/ml [36]. Thus, it is likely that sufficient amounts of sHLA-I, able to induce IFN-γ production by NK cells, are present in sera of auto-immune patients and may play a role in maintaining chronic inflammation [19][20][21][22]36].…”

Section: Soluble Hla-i Triggers Ifn-γ Release Through the Engagement mentioning

confidence: 99%

Triggering of Apoptosis and Pro-Inflammatory Cytokines in NK Cells: Regulation by Cyclosporin A

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Poggi

2005

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Human natural killer (NK) cells are effectors of innate immunity, capable of killing transformed or virusinfected cells and producing pro-inflammatory cytokines, once activated in a non-HLA-dependent fashion. NK cells express receptors for HLA-I molecules, including CD8, or members of the Inhibitory Receptor Superfamily (IRS), such as the Killer Ig-like receptor (KIR) or C-Lectin type Inhibitory Receptor (CLIR). Soluble molecules of HLA-I (sHLA-I) are significantly increased in the serum of patients affected by auto-immune or infectious diseases.We reported that upon interaction of sHLA-I with either CD8 or IRS activating isoforms (AR), NK cells produced and released FasL which elicited NK cell apoptosis by interacting with Fas at the NK cell surface. CD94/NKG2A or KIR2DL, both inhibiting isoforms of IRS, exerted an inhibitory effect on sHLA-I-mediated apoptosis and secretion of FasL induced via CD8, suggesting that IRS can function as survival receptors. Moreover, large amounts of IFN-γ were detectable in culture supernatant of either CD8 + or AR + NK cells incubated with the appropriate sHLA-I ligand. In chronic diseases, sHLA could amplify inflammation and, at the same time, eliminate effectors of innate immunity, thus favouring infections. On the other hand, this could represent a mechanism of down-regulation of NK-mediated functions as well, which ultimately contributes to limit self-reaction. Importantly, cyclosporin A (CsA) blocks both AR-or CD8-mediated apoptosis and IFN-γ production, without affecting AR-mediated activation of cytolysis. This would indicate that CsA, although being an immunosuppressive drug, can downregulate inflammation maintaining NK cell-dependent innate immunity, further supporting CsA treatment in autoimmune diseases.

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Clinical and MRI disease activity in multiple sclerosis are associated with reciprocal fluctuations in serum and cerebrospinal fluid levels of soluble HLA class I molecules

Cited by 18 publications

References 34 publications

IFN‐γ production in human NK cells through the engagement of CD8 by soluble or surface HLA class I molecules

IFN‐γ production in human NK cells through the engagement of CD8 by soluble or surface HLA class I molecules

Potential role of soluble human leukocyte antigen-G molecules in multiple sclerosis

Triggering of Apoptosis and Pro-Inflammatory Cytokines in NK Cells: Regulation by Cyclosporin A

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