Broad Spectrum of IVIG Targets, Non-Specificity Could Be Key to Efficacy in Various Diseases

Using systems biology approaches and machine learning, researchers have found that intravenous immunoglobulin’s (IVIG) broad spectrum of targets and non-specificity could be the key to its efficacy in very different diseases, according to a study published by Frontiers in Immunology.

IVIG is used for several autoimmune and inflammatory conditions, although researchers have not fully understood its specific mechanisms. Because of this, the study authors used machine learning and systems biology to establish the differences in the pathophysiological pathways of autoimmune and inflammatory conditions that show diverse responses to IVIG treatment. They also aimed to determine the targets of IVIG involved in the best treatment response of the diseases they evaluated.

The beneficial effect of IVIG is explained by mechanisms involving either its F(ab’)2 or Fc domain, or both. The immunomodulatory effects are complex, but IVIG has been proven to modulate B and T cells, phagocytosis, complement activity, cytokine production, and the properties of dendritic cells, among many others. This wide range of targets can trigger pleiotropic effects in the immune system.

In the study, investigators selected and classified a range of diseases, characterized them molecularly, and characterized the target profile of IVIG. Algorithms were then created and used to explore the relationships between IVIG targets and the molecular definition of each disease.

A set of 26 autoimmune and inflammatory conditions was selected and previously reported IVIG response categories were used. Potential benefits of IVIG were grouped into 4 categories: definitely beneficial, probably beneficial, may provide benefit, and unlikely to provide benefit.

The findings suggest that diseases within each IVIG response cluster shared similar pathophysiological processes, particularly within the “definitely beneficial” and “unlikely to provide benefit” clusters. Identifiable differences between the clusters could be found and a chi-squared test showed that there was dependency between pathological processes and disease classification based on IVIG response.

In particular, diseases assigned to the definitely beneficial cluster were positively associated with B cell-mediated processes and complement system. However, innate immunity and inflammatory processes were frequently associated with the “may provide benefit” and “unlikely to provide benefit” categories.

Based on the analyses, the researchers found that diseases in the “definitely beneficial” cluster were found to be mainly characterized by deregulated processes in B cells and the complement system. Additionally, IVIG targets related to B cell and complement system pathways seemed to be involved in the clinical response.

However, targets related to other immune processes may also play an important role in the IVIG response, supporting its wide range of action through a variety of mechanisms. The investigators also noted that 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.

The findings also support further research into the role of IVIG in diseases in which B cells and the complement system are relevantly involved and for which there is little or inconclusive evidence (i.e. diseases classified as “probably beneficial” and “may provide benefit”).

Finally, because the level of relationship varied between proteins in the “definitely beneficial” cluster and different diseases, IVIG appeared to have a pleiotropic effect that may involve the collaboration of several topics. The weight of each target in treatment efficacy may vary for each condition, which suggests that the broad spectrum of IVIG targets could be vital for its efficacy in a wide range of diseases.

REFERENCE

Segu-Verges C, Cano S, Calderon-Gomez E, Bartra H, et al. 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. News release. Front Immunol 2022;13:901872.