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- Mathsson, Linda, 1977-
(författare)
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Immune Complex Regulated Cytokine Production in Rheumatic and Lymphoproliferative Diseases
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Immune complexes (ICs) are produced during normal immune responses and facilitate clearance of foreign antigens. ICs not efficiently cleared from the circulation can cause tissue damage. This might happen if ICs are formed with autoantibodies and autoantigens. Well described effects of ICs are neutralization of antigen, classical complement activation or FcR-mediated phagocytosis, whereas cytokine inducing effects of ICs in human clinical settings are less well described. I have investigated cytokine-inducing properties in vitro of ICs from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and cryoglobulinemia in association with lymphoproliferative diseases. Cryoglobulin (CG)-induced cytokine production varied with changes in temperature and ionic strength in parallel to CG precipitation. IgG CG-induced cytokine production was also mediated via FcγIIa on monocytes. Blockade of the complement system, resembling the in vivo situation of complement consumption in CG-associated diseases, increased IgG CG induced IL-10 and decreased TNF-α production. This represents hitherto not described mechanisms for CG-associated inflammation. ICs from SLE patients induced IL-10 and IL-6 production from PBMC cultures via FcγRIIa. Occurrence of anti-SSA autoantibodies and signs of in vivo complement activation contributed to increased levels of circulating ICs in SLE patients, corresponding to increased amounts of IC-induced IL-10 in vitro. This represents a possible vicious cycle that might perpetuate antibody dependent pathology in SLE, and put anti-SSA in a new pathological context. RF-associated ICs from RA joints and ICs formed with antibodies against collagen type II from RA serum induced pro-inflammatory cytokine production from monocytes via FcγRIIa, showing how specific autoantibodies might induce or perpetuate joint inflammation in RA. I have described how ICs can induce significant amounts of pathophysiologically important monocyte-derived cytokines in three major IC-dependent diseases. Blockade of FcγRIIa and suppression of monocytes/macrophages might be a means of reducing pathogenic IC-induced cytokine production in these diseases.
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| 2. |
- Mullazehi, Mohammed, 1966-, et al.
(författare)
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Anti-type II collagen-IC-induced production of IL-1β and TNF-α, stimulate production of matrix met-alloproteinases from monocytes/rheumatoid arthritis synovial fibroblast co-cultures
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: To establish an in vitro model that might explain the association between early joint destruction and the appearance of collagen type II (CII) antibodies in early Rheumatoid Arthritis (RA) patients. This RA pannus tissue model utilizes immune complexes (IC) containing CII-antibodies as stimulus and monocytes and synovial fibroblastsas responder cells. Methods: Peripheral blood mononuclear cells (PBMC) and RA synovial fibroblasts (RASF) were stimulated with IC individually as well in co-cultures. Monocytes were depleted to define the responder cells, and TNF-α and IL-1β were neutralized to study the effect on MMP production. TNF-α, IL-1β, MMP-1, MMP-8 and MMP-13 were measured in cell culture super-natants using ELISA.Results: Anti-CII-containing IC induced production of TNF-α, IL-1β and MMP-1 in PBMC cultures, and TNF-α, IL-1β, MMP-1 and MMP-8 in PBMC/fibroblast co-cultures, in a dose-dependent manner. IC-induced MMP-1 responses were stronger and more associated with induced produc-tion of IL-1β as compared to MMP-8 responses. Baseline production of IL-1β and MMP-1 increased significantly in co-cultures as compared to indi-vidual cultures, whereas this was not the effect for TNF-α and MMP-8. Monocyte depletion decreased TNF-α, IL-1β and MMP-1 production, while the effect on MMP-8 production was variable. Cytokine neutralization re-vealed that IL-1β was a stronger inducer of MMP-1 than was TNF-α.Conclusion:Synergistic actions between RASF and PBMC result in enhanced anti-CII IC-induced production of IL-1β and MMP-1. IL-1β and MMP-1 are regu-lated in parallel as anti-CII IC-induced IL-1β supports the production of MMP-1. MMP-8 seems to be regulated by other means. Anti-CII IC-induced TNF-α seems to be inferior to IL-1β concerning MMP-1 induction. The fact that IC stimulated synovial macrophages and fibroblasts to produce MMP, which are the first enzymes to cleave the interstitial collagens may explain the anti-CII-associated joint destruction apparent in early RA.
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| 4. |
- Wenink, Mark H., et al.
(författare)
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The inhibitory Fc gamma IIb receptor dampens TLR4-mediated immune responses and is selectively up-regulated on dendritic cells from rheumatoid arthritis patients with quiescent disease
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 183:7, s. 4509-4520
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and premature death. Although a role for FcgammaRs and TLRs is accepted, their precise involvement remains to be elucidated. FcgammaRIIb is an inhibitory FcR important in the maintenance of tolerance. We hypothesized that the inhibitory FcgammaRIIb inhibits TLR responses on monocyte-derived dendritic cells (DC) and serves as a counterregulatory mechanism to dampen inflammation, and we surmised that this mechanism might be defective in RA. The expression of the inhibitory FcgammaRIIb was found to be significantly higher on DCs from RA patients having low RA disease activity in the absence of treatment with antirheumatic drugs. The expression of activating FcgammaRs was similarly distributed among all RA patients and healthy controls. Intriguingly, only DCs with a high expression of FcgammaRIIb were able to inhibit TLR4-mediated secretion of proinflammatory cytokines when stimulated with immune complexes. In addition, when these DCs were coincubated with the combination of a TLR4 agonist and immune complexes, a markedly inhibited T cell proliferation was apparent, regulatory T cell development was promoted, and T cells were primed to produce high levels of IL-13 compared with stimulation of the DCs with the TLR4 agonist alone. Blocking FcgammaRIIb with specific Abs fully abrogated these effects demonstrating the full dependence on the inhibitory FcgammaRIIb in the induction of these phenomena. This TLR4-FcgammaRIIb interaction was shown to dependent on the PI3K and Akt pathway.
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