Plasmin immunization preferentially induces potentially prothrombotic IgG anticardiolipin antibodies in MRL/MpJ mice

Ede, Kaleo; Hwang, Kwan‐Ki; Wu, Chen-Ching; Wu, Mei‐Fang; Yang, Yao‐Hsu; Lin, Wei‐Shiang; Chien, Daniel; Chen, Pei-Chih; Tsao, Betty P.; McCurdy, Deborah; Chen, Pojen P.

doi:10.1002/art.24818

Cited by 3 publications

(3 citation statements)

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“…Rheumatoid factor (RF, anti-IgG2a a ) was determined by ELISA, as described [29], using serum samples diluted at 1:250 and the secondary antibody, AP-conjugated goat-anti mouse kappa at 1:1,000 dilution. Anti-CL antibodies were detected as previously described [30]. In brief, ELISA plates were coated with CL Ag (5 μg/ml, ≥97% TCL, Sigma, St. Louis, MO, USA) in 200-proof ethyl alcohol (Daigger, Vernon Hills, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

Germline deletion of β2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus

et al. 2013

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Introductionβ2-microglobulin (β2m) is required for the surface expression of MHC class I and class I-like proteins such as CD1d, Qa1 and neonatal Fc receptor (FcRn), all of which may impact the development of autoimmunity. Since CD1d is known to bind and present phospholipid antigens to T cells, we asked if the deficiency of β2m or CD1d will impact the development of anti-phospholipid antibodies as compared to other aspects of lupus autoimmunity.MethodsWe introgressed the β2m-null genotype onto the NZB and NZW backgrounds for 12 to 14 generations to generate genetically lupus-susceptible (NZB/NZW)F1 (BWF1) mice that are β2m-deficient (β2m°). Circulating immunoglobulins (Ig), rheumatoid factor (RF), anti-DNA and anti-cardiolipin (anti-CL) antibodies, and renal disease were analyzed in these and CD1d-deficient (CD1d°) BWF1 mice that we had previously generated.ResultsWhereas β2m° BWF1 mice had reduced serum IgG, they had increased mortality, nephritis, serum IgG anti-DNA antibody and RF as compared to heterozygous and wild-type littermates. These effects were recapitulated in CD1d° BWF1 mice, except that they also had increased serum IgG as compared to control littermates. Intriguingly, both β2m° and CD1d° mice had lower serum anti-CL antibody levels than in control littermates. Such CD1d dependence of anti-CL antibody production is not mediated by CD1d/glycolipid-reactive iNKT cells, as these cells reduced the production of RF and anti-DNA antibodies but had no effect on anti-CL antibodies.ConclusionsWe report a novel dichotomous role of β2m and CD1d, whereby these molecules differently regulate autoimmunity against phospholipid versus non-phospholipid autoantigens.

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Section: Methodsmentioning

confidence: 99%

Germline deletion of β2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus

et al. 2013

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“…Next, we assessed whether the B6 mouse is appropriate as the control of MRL/lpr and whether the genetic background affected the expression of miR-200a-3p. Age-and sex-matched MRL/MPJ (Fas +/+ ) mice that present late and mild autoimmune phenotype (23,24) were in- cluded to control for the genetic background. As shown in Fig.…”

Section: Mir-200a-3p Is Downregulated In Murine Lupus Cd4 + T Cellsmentioning

confidence: 99%

Downregulation of miR-200a-3p, Targeting CtBP2 Complex, Is Involved in the Hypoproduction of IL-2 in Systemic Lupus Erythematosus–Derived T Cells

Katsuyama

Yan

Watanabe

et al. 2017

The Journal of Immunology

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Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB)1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4 T cells from MRL/lpr- mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4 T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element A was significantly upregulated after PMA/ionomycin stimulation in lupus CD4 T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.

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“…В подтверждение этого недавно было продемонстрировано, что иммунизация мышей линии MRL/MpJ плазмином человека сопровождалась образованием аКЛ и анти-2-ГП1 в высоких титрах. Некоторые моноклональные антитела, полученные от этих животных, взаимодействовали также с тромбином и фXа, что указывало на возможный механизм их протромботического действия [40]. В целом приведенные данные показывают, что плазминоген и плазмин могут быть аутоантигенами у больных с АФС и антиплазминовые антитела способны оказывать протромботическое действие прямо, ингибируя фибринолитический эф-О с н о в н ы е к о м п о н е н т ы с и с т е м ы ф и б р и н о л и з а фект плазмина, или косвенно -через перекрестные иммунологические реакции с гомологичными белками каскада свертывания крови.…”

Section: система фибринолизаunclassified

The antiphospholipid syndrome and the fibrinolytic system

Ostryakova¹,

Patrushev²,

Решетняк³

2011

rsp

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Plasmin immunization preferentially induces potentially prothrombotic IgG anticardiolipin antibodies in MRL/MpJ mice

Cited by 3 publications

References 34 publications

Germline deletion of β2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus

Germline deletion of β2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus

Downregulation of miR-200a-3p, Targeting CtBP2 Complex, Is Involved in the Hypoproduction of IL-2 in Systemic Lupus Erythematosus–Derived T Cells

The antiphospholipid syndrome and the fibrinolytic system

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