Session Title: Innate Immunity and Rheumatic Disease: Signaling Mechanisms
Session Type: Abstract Submissions (ACR)
Ibrutinib, a Btk kinase activity inhibitor, is a novel inhibitor under development for autoimmune disease therapy. We have shown that Btk was significantly upregulated in spleen Mɸs of lupus prone BXD2 mice that spontaneously develop high titers of autoantibodies (autoAbs). As loss of control on Btk expression in myeloid cells has been implicated previously to cause mislocation and loss of marginal zone macrophages (MZMs), a critical apoptotic bleb clearance barrier, in the spleen, the purpose of the present study is to determine a possible pathogenic role of autoAbs to disrupt MZM integrity throught upregulating Btk activity in MZMs. The implication of these results in human systemic lupus erythematosus (SLE) was further studied.
Purified polyreactive monoclonal antibodies isolated from the spleen of BXD2 mice were screened for their reactivity to MZM specific scavenger-receptors including MZRCO and SR-A. AutoAbs that are either reactive or non-reactive to anti-MARCO/anti-SR-A were individually administered to recipient B6 mice to evaluate the pathogenic effects on MZMs. Confocal microscope analysis and FACS analysis were carried out to quantitate the percentage of MZMs in the spleen and evaluate the expression of phospho-Btk (pBtk). ELISA was carried out to determine the autoAb titers.
In BXD2 mice, elevated anti-MARCO/anti-SR-A autoAbs in the sera correlated with the loss of MZMs in the spleens. Different purified monoclonal autoAbs were administrated into normal B6 mice. Disruption of MZMs was only observed when recipient mice were administered with polyreactive autoAbs that exhibit high reactivity to both MARCO and SR-A. In these mice, there was gradual induction of pBtk in the MZMs. Increased pBtk was also observed in MZMs of BXD2, and this induction can be efficiently blocked via early global inhibition of endogenous apoptosis using a pan-caspase inhibitor, z-VAD. Delivery of Ibrutinib either systemically or via an Ibrutinib-liposome strategy to target MZM specifically, prevented MZM loss and attenuated autoantibodies mediated glomerulonephritis in autoAb administrated B6 or BXD2 mice. Surprisingly, anti-MARCO/anti-SR-A autoantibody administration also induced the reduction of MZMs in the spleen of Fcγr-/- or C3-/-mice, suggesting that autoAb mediated MZM loss is not related to either antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). In SLE patients, higher serologic levels of anti-MARCO autoAb titers exhibited significant positive correlation with the development of end-stage-renal disease (ESRD). Loss of MZMs was also identified in SLE patient spleens.
The present study suggests a novel autoAb-mediated systemic autoimmune disease mechanism based on the induction of pBtk in MZMs to break a critical barrier that is crucial to clear apoptotic debris in the spleen. The present study further suggests the potential to develop anti-MARCO/anti-SR-A into a novel biomarker for apoptosis clearance defects and development of ESRD in human SLE.
J. C. Edberg,
H. C. Hsu,
J. D. Mountz,
R. P. Kimberly on behalf of PROFILE investigators,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-scavenger-receptor-autoantibodies-disrupted-marginal-zone-macrophage-integrity-via-brutons-tyrosine-kinase/