Systems biology and artificial intelligence analysis highlights the pleiotropic effect of IVIg therapy in autoimmune diseases with a predominant role on B cells and complement system

Abstract

Intravenous immunoglobulin (IVIg) is used as treatment for several autoimmune and inflammatory conditions, but its specific mechanisms are not fully understood. Herein, we aimed to evaluate, using systems biology and artificial intelligence techniques, the differences in the pathophysiological pathways of autoimmune and inflammatory conditions that show diverse responses to IVIg treatment. We also intended to determine the targets of IVIg involved in the best treatment response of the evaluated diseases. Our selection and classification of diseases was based on a previously published systematic review, and we performed the disease characterization through manual curation of the literature. Furthermore, we undertook the mechanistic evaluation with artificial neural networks and pathway enrichment analyses. A set of 26 diseases was selected, classified, and compared. Our results indicated that diseases clearly benefiting from IVIg treatment were mainly characterized by deregulated processes in B cells and the complement system. Indeed, our results show that proteins related to B-cell and complement system pathways, which are targeted by IVIg, are involved in the clinical response. In addition, targets related to other immune processes may also play an important role in the IVIg response, supporting its wide range of actions through several mechanisms. Although B-cell responses and complement system have a key role in diseases benefiting from IVIg, protein targets involved in such processes are not necessarily the same in those diseases. Therefore, IVIg appeared to have a pleiotropic effect that may involve the collaborative participation of several proteins. This broad spectrum of targets and ‘non-specificity’ of IVIg could be key to its efficacy in very different diseases.

Study on the Treatment of ITP Mice with IVIG Sourced from Distinct Sex-Special Plasma (DSP-IVIG)

“…First, the proteomics data obtained from spleen and plasma in mice suggested that IVIG treatment for ITP should primarily focus on modulating the differentiation of T cell lines, T-cell receptor binding, IL-17 signaling pathway, FcγRs mediated phagocytosis, cytokines, chemokines, etc. These findings were consistent with the work of Wang et al [45], Ding et al [46], and Segú-Vergés et al [47]. In addition, Wang et al reported that ITP samples exhibited higher counts of macrophages and Th cells compared to normal…”

“…Concerning complement activation, Cristina Segú-Vergés et al found that diseases with good therapeutic effect of IVIG were characterized by an imbalance of B cells and complements system, suggesting a close relationship between IVIG and complement system [47]. Increasing evidence indicates that complement inhibition is a key anti-inflammatory mechanism of IVIG.…”

Low-dose intravenous immunoglobulin for children with newly diagnosed immune thrombocytopenia: protocol of a systematic review and meta-analysis

“…Since then, IVIg has been applied to treating ITP. Studies on the pharmacological mechanism of IVIg have indicated that IVIg inhibits Fc-mediated phagocytosis of antibody-coated platelets by the reticuloendothelial system to protect platelets, promotes the development or activation of regulatory T cells, and regulates B-cell function and survival 40 41…”

Antibody diversity in IVIG: Therapeutic opportunities for novel immunotherapeutic drugs

“…Depending on the pathophysiology of a select disease, different MoAs may act in concert (15, 34), yet distinct mechanisms may prevail (Figure 1). Indeed, a recent analysis based on artificial intelligence supports the notion that IVIG exerts pleiotropic effects, while distinct pathways, such as involving B cells or complement, were found to be more relevant for specific disorders (35). The inherent pluripotency of polyclonal IVIG and SCIG preparations might explain their efficacy in a magnitude of autoimmune and inflammatory diseases despite their heterogenous pathogenetic background.…”