Anti‐La/SSB antibodies transported across the placenta bind apoptotic cells in fetal organs targeted in neonatal lupus

Abstract

Objective. To determine whether La and/or Ro epitopes on apoptotic cells in fetal organs that are targeted in neonatal lupus syndrome (NLS) are accessible for binding by autoantibodies in vivo, we traced the fate of transplacental autoantibodies in a murine passive transfer model.Methods. Pregnant mice at day 15 of gestation (E15) were injected intraperitoneally with human antiRo/La-positive sera or control sera, and transplacental transfer of human autoantibodies was tested by enzymelinked immunosorbent assay with recombinant antigens. Multiple cryostat sections at the level of the heart of E17 fetuses were visualized simultaneously for human IgG binding and apoptosis (TUNEL) under confocal microscopy. Serial paraffin sections of E17 and E19 fetuses were examined for histologic evidence of inflammation.Results. Human IgG anti-52-kd Ro, anti-60-kd Ro, and anti-La autoantibodies were transported efficiently into the fetal circulation. Human IgG-apoptotic cell complexes were detected in the heart (atrial trabeculae and atrioventricular node), skin, liver, and newly forming bone of fetuses from mothers injected with anti-Ro/La sera but not control sera. The IgG binding was fetal-specific and organ-specific; transplacental autoantibodies did not bind to apoptotic cells in the fetal thymus, lung, brain, or gut. The complexes were not associated with an inflammatory reaction. Injection of mothers with affinity-purified anti-La autoantibodies (but not anti-Ro/La Ig depleted of anti-La) revealed an identical location of IgG binding to apoptotic cells in the fetuses.Conclusion. This is the first study to demonstrate that transplacental anti-La autoantibodies bind specifically to apoptotic cells in selected fetal organs in vivo, similar to the organ involvement in NLS. We hypothesize that additional factors are required to promote proinflammatory clearance of IgG-apoptotic cell complexes and subsequent tissue damage.

Neonatal Lupus Erythematosus

“…Similar to other NLS manifestation rhizomelic chondrodysplasia punctata occurs as a result of IgG-apoptotic cell complexes presented in the zones of newly forming fetal bones initiating an immune complex-mediated inflammation at growth plates [12].…”

“…Maternal autoantibodies mediate fetal autoimmune disease through formation of antibody complexes with apoptotic antigens in the skin, liver, heart and newly forming bone which when phagocytosed and opsonized initiate proinflammatory process that results in immune-mediated damage to fetal tissues [12,13].…”

The consequences of apoptosis in autoimmunity

“…[70] [17] [69] [74] Systemic lupus erythematosus (SLE) The pathogenesis of SLE is strongly associated with C1q deficiency, it has been demonstrated that C1q does not bind apoptotic cells isolated from SLE patients. The pathogenic role of the complement in SLE is still unclear, but it seems to be linked to impairment of apoptotic cell removal.…”

Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model

“…Although La is a relatively low abundance protein sequestered primarily in cell nuclei, it is likely to be accessible to autoreactive lymphocytes under certain circumstances, such as apoptosis of cells (13,33,34), since hLa peptides appear to be constitutively presented by B cells in hLa Tg mice (7). Despite this Ag exposure, splenic autoreactive hLa-specific B cells were not deleted in hLa ϫ anti-hLa double-Tg mice, but instead were present in numbers equivalent to those of naive hLa-specific B cells from single-Tg anti-hLa littermates.…”