Use of monoclonal antibodies to dissect specificity and pathogenesis of antiphospholipid antibodies

Abstract

Monoclonal antiphospholipid antibodies (aPL) have been utilized to dissect the relationship between their sequence, structure, binding and biological properties relevant to the pathogenesis of the antiphospholipid syndrome. In particular, sequence analysis of aPL has highlighted the clustering of certain amino acid residues in the antigen contact sites of their heavy and light chains. Therefore, these sequence motifs are likely to be important in determining aPL binding properties and their pathogenic effects. Experiments, however, using monoclonal aPL engineered to contain specific point mutations in their sequence which alter their ability to bind relevant antigens have shown that these alterations in binding are not directly mirrored by their pathogenic effects. In this review we focus on work carried out by others and ourselves using monoclonal antibodies with specific binding properties to extend our knowledge of the non-linear structure-binding-function relationship of aPL.

Gene expression profiling identifies distinct molecular signatures in thrombotic and obstetric antiphospholipid syndrome

“…Genes such as TLR4, Annexin II, VEGF, TGFβ, C3R, PKC, PKN, BCL2 as well as many genes involved in mitochondrial function and oxidative stress like MPO, GPX3, DUOX1, UCP3 were common to both our results and the previous studies of Lopez-Pedrera's group [8,12]. In addition, we confirmed our previous findings comparing the intracellular effects of VT+/PM- and VT-/PM+ IgG in monocytes [7]. This microarray analysis found the regulation of MAPKK kinase signalling and cell communication through Ikappa kinase/NF-kappa-B cascade to be a distinctive feature of VT+/PM- IgG.…”

“…A few studies found differences in the effects of aPL from patients with and without thrombosis upon various signalling pathways in target cells [[4], [5], [6], [7]]. Proteomic analyses of monocytes isolated from patients with APS [8] and healthy monocytes treated with APS-IgG [9] have shown that the monocyte proteome is differentially regulated by IgG from obstetric compared to thrombotic APS.…”