Antibody-Independent Thrombocytopenia in Lactate Dehydrogenase-Elevating Virus-Infected Mice

Su, Dan; Musaji, Andrei; Legrain, Sarah; Detalle, Laurent; Kaa, Jos van der; Verbeek, J. Sjef; Ryffel, Bernhard; Coutelier, Jean‐Paul

doi:10.1128/jvi.00745-12

Cited by 5 publications

(6 citation statements)

References 13 publications

(13 reference statements)

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“…FccRI/II/III/IV quadruple KO mice have been used in previous studies and will be described elsewhere (manuscript in preparation, J.S. Verbeek) [36][37][38].…”

Section: Micementioning

confidence: 99%

Enhanced uptake of blood coagulation factor VIII containing immune complexes by antigen presenting cells

Hartholt

Wroblewska

Herczenik

et al. 2017

Journal of Thrombosis and Haemostasis

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Background A major complication in the treatment of hemophilia A is the development of inhibitory antibodies targeting coagulation factor VIII (FVIII). Eradication of these inhibitors can be established by immune tolerance induction (ITI), which consists of daily administration of high dosages of FVIII. FVIII immune complexes (FVIII-IC) could be formed following FVIII infusion in patients with pre-existing anti-FVIII antibodies. Objectives Here we studied endocytosis of FVIII-IC by bone marrow-derived dendritic cells (BMDCs). Methods BMDCs were pulsed with FVIII/FVIII-IC and uptake was assessed by flow cytometry and confocal imaging. Results BMDCs were able to efficiently internalize FVIII-IC in a dose-dependent manner, 3-4-fold more efficiently when compared with equimolar concentrations of non-complexed FVIII. Uptake of FVIII-IC, but not FVIII alone, could be inhibited with anti-Fcγ receptor (FcγR) antibody 2.4G2, indicating functional involvement of FcγR. No internalization of FVIII-IC was observed in BMDCs lacking FcγRI, FcγRIIb, FcγRIII and FcγRIV. Genetic ablation of FcγRIIb, FcγRIII or FcγRIV individually did not affect the ability of anti-FVIII IgG to promote the uptake of FVIII. BMDCs lacking FcγRI showed lower FVIII-IC uptake levels when compared with other single FcγR null BMDCs. Expression of the inhibitory FcγRIIb alone was sufficient to internalize FVIII-IC more efficiently than FVIII. Conclusions FcγR are critical in the internalization of FVIII-IC by BMDCs and multiple FcγR can contribute independently to this process. Our findings provide a basis for future studies to address whether the outcome of ITI is dependent on the interplay between FVIII-IC and inhibitory and activating FcγR.

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“…FccRI/II/III/IV quadruple KO mice have been used in previous studies and will be described elsewhere (manuscript in preparation, J.S. Verbeek) [36][37][38].…”

Section: Micementioning

confidence: 99%

Enhanced uptake of blood coagulation factor VIII containing immune complexes by antigen presenting cells

Hartholt

Wroblewska

Herczenik

et al. 2017

Journal of Thrombosis and Haemostasis

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“…IgM-mediated thrombocytopenia could not arise in those animals, either uninfected or infected with LDV, whereas the Ab-independent, but phagocytosisdependent thrombocytopenia that is triggered by the virus alone (29) was not impaired. Thus, in this model of autoimmune thrombocytopenia, Fca/mR expression is required for the development of IgM-mediated disease.…”

Section: Discussionmentioning

confidence: 82%

Involvement of Fcα/μ Receptor in IgM Anti-Platelet, but Not Anti–Red Blood Cell Autoantibody Pathogenicity in Mice

Legrain

Breukel

et al. 2015

The Journal of Immunology

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IgM anti-mouse platelet autoantibodies cause thrombocytopenia by mediating uptake of opsonized thrombocytes, whereas IgM anti-erythrocyte autoantibodies induce anemia through a phagocytosis-independent cell destruction. In this article, we show that infection with lactate dehydrogenase–elevating virus, a benign mouse arterivirus, exacerbates the pathogenicity of IgM anti-platelet, but not anti-erythrocyte autoantibodies. To define the role of Fcα/μ receptor (Fcα/μR) in IgM-mediated thrombocytopenia and anemia, we generated mice deficient for this receptor. These animals were resistant to IgM autoantibody-mediated thrombocytopenia, but not anemia. However, the lactate dehydrogenase–elevating virus–induced exacerbation of thrombocytopenia was not associated with enhanced Fcα/μR expression on macrophages. These results indicate that Fcα/μR is required for the pathogenicity of IgM anti-platelet autoantibodies but is not sufficient to explain the full extent of the disease in virally infected animals.

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“…Immunomodulatory effects of LDV infection include nonspecific polyclonal activation of B cells, immunoglobulin secretion, acute lymphopenia, chronic lymphocytosis, and abnormal interferon and natural killer (NK) cell responses. [2][3][4]6,19,20 Reported impacts of LDV infection on other mouse models include increased susceptibility to LPSinduced septic shock, 21,22 suppression of immune-mediated islet cell injury in non-obese diabetic (NOD) mice by interfering with function of 1a-positive macrophages, 23 and antibodymediated thrombocytopenia, 24 among others.…”

Section: Discussionmentioning

confidence: 99%

Degenerative Myelopathy and Neuropathy in NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (NSG) Mice Caused by Lactate Dehydrogenase–Elevating Virus (LDV)

et al. 2022

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Following implantation of patient-derived xenograft (PDX) breast carcinomas from three separate individuals, 33/51 female NOD. Cg-Prkdc scid Il2rg tm1Wjl/SzJ (NSG) mice presented with progressive, unilateral to bilateral, ascending hindlimb paresis to paralysis. Mice were mildly dehydrated, in thin to poor body condition, with reduced to absent hindlimb withdrawal reflex and deep pain sensation. Microscopically, there was variable axonal swelling, vacuolation, and dilation of myelin sheaths within the ventral spinal cord and spinal nerve roots of the thoracolumbar and sacral spinal cord, as well as within corresponding sciatic nerves. Results of PCR screening of PDX samples obtained at necropsy and pooled environmental swabs from the racks housing affected animals were positive for lactate dehydrogenase–elevating virus (LDV). LDV is transmitted through animal-animal contact or commonly as a contaminant of biologic materials of mouse origin. Infection is associated with progressive degenerative myelopathy and neuropathy in strains of mice harboring endogenous retrovirus (AKR, C58), or in immunosuppressed strains (NOD-SCID, Foxn1nu), and can interfere with normal immune responses and alter engraftment and growth of xenograft tumors in immunosuppressed mice. This is the first reported series of LDV-induced poliomyelitis in NSG mice and should be recognized as a potentially significant confounder to biomedical studies utilizing immunodeficient xenograft models.

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Antibody-Independent Thrombocytopenia in Lactate Dehydrogenase-Elevating Virus-Infected Mice

Cited by 5 publications

References 13 publications

Enhanced uptake of blood coagulation factor VIII containing immune complexes by antigen presenting cells

Enhanced uptake of blood coagulation factor VIII containing immune complexes by antigen presenting cells

Involvement of Fcα/μ Receptor in IgM Anti-Platelet, but Not Anti–Red Blood Cell Autoantibody Pathogenicity in Mice

Degenerative Myelopathy and Neuropathy in NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (NSG) Mice Caused by Lactate Dehydrogenase–Elevating Virus (LDV)

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Antibody-Independent Thrombocytopenia in Lactate Dehydrogenase-Elevating Virus-Infected Mice

Cited by 5 publications

References 13 publications

Enhanced uptake of blood coagulation factor VIII containing immune complexes by antigen presenting cells

Enhanced uptake of blood coagulation factor VIII containing immune complexes by antigen presenting cells

Involvement of Fcα/μ Receptor in IgM Anti-Platelet, but Not Anti–Red Blood Cell Autoantibody Pathogenicity in Mice

Degenerative Myelopathy and Neuropathy in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) Mice Caused by Lactate Dehydrogenase–Elevating Virus (LDV)

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Degenerative Myelopathy and Neuropathy in NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (NSG) Mice Caused by Lactate Dehydrogenase–Elevating Virus (LDV)