Manipulating the complement system via Therapeutic plasmapheresis: Is there any therapeutic role?

The complement system was discovered over a 100 years ago and now seems more sophisticated than originally thought. Complements have a role beyond innate immunity. Early complement components intervene on the rapid uptake of debris while inducing a tolerogenic profile and also increase immune complex clearance via the liver. Deficiency in early complement components may lead to autoimmune disease. However, the complement system also has an important role in anaphylaxis (C3a, C5a), bacterial opsonization (C3b), and bacterial killing by forming membrane attack complexes (C5bC9). Deficiency in late complement components may cause recurrent bacterial infections. Moreover, the complement system has important roles in T-cell activation, reducing the threshold of B-cell activation and antigen processing and recall. Finally, it has complex interactions with the coagulation and fibrinolysis pathways. Nowadays, the pathogenic role of complement system in many diseases is better elucidated and is not limited merely to those clinical settings associated with low plasma complement levels. Interestingly, among most of the diseases for which plasma exchange is considered to have a therapeutic role, the complement system seems to play an important role in pathogenesis of disease. Its role in myasthenia gravis, catastrophic antiphospholipid disease, antineutrophil cytoplasmic antibody (ANCA)associated vasculitis, antiglomerular basemen membrane disease and chronic inflammatory demyelination polyneuropathy is highlighted by the efficacy of anticomplement treatments like Eculizumab or Avacopan. Xiao et al. elucidated the importance of complements in ANCA-associated vasculitis by showing that, in mice depleted of complements, there was no crescent formation after injecting antimyeloperoxidase ANCA. Moreover, atypical hemolytic uremic syndrome, previously considered as category 1, is now treated primarily by Eculizumab (not readily available in many parts of the world where therapeutic plasma exchange still remains the first line of treatment). Many questions about the complement system and the role of therapeutic plasma exchange in altering complement components remain unanswered. The true halflives of some components are unknown. Moreover, many components circulate as oligomers. For example, properdin has a molecular weight of 55 kD but circulates in plasma in dimeric (110 kD), trimeric (165 kD), and tetrameric (200 kD) forms. Importantly, the tetrameric form is 10 times more potent than the monomeric form. Besides half-life, the molecular weight and the size of complement components are very important when using double filtration plasmapheresis (DFPP) because the clearance of substances in DFPP depends on pore size of second filter. On the other hand, the site of complement system activity can be far from plasma that we often search for it. For instance, while dendritic cells present antigens to naïve T cells in the context of major histocompatibility complex and costimulatory molecules, complements are important for proliferation and preventing apoptosis or may be highly active in the tissues whereas their activity cannot be found in plasma. This may explain the discordance between C5BC9 deposits on cell membranes and circulating C5BC9. Besides all these complexities in the study of the complement system, alterations in complement plasma components can vary by applying different procedures of therapeutic plasmapheresis, from single plasma exchange to DFPP or by using adsorption techniques. In addition, it should also be noted that not all these techniques are available everywhere, such as DFPP, which does not have an FDA authorization in the United States. Few data are available in this field. Defendi et al. studied the effect of immunoadsorption (IA) combined with membrane filtration on properdin and mannose-binding lectin (MBL). They found that percentages of MBL and properdin removal were significantly higher with combinations of membrane filtration (MF) and IA compared to IA alone. Another Interesting finding of their study was that properdin and MBL had increased to baseline 7 days after the procedure only in the group that had undergone MF + IA whereas, in those who underwent IA first, properdin and MBL remained significantly lower than baseline. This finding may have an important clinical impact as higher risk of infection but also a protective role in preventing ischemia-reperfusion during organ transplantation. This Received: 26 May 2022 Revised: 15 July 2022 Accepted: 18 July 2022