DISCUSSION
RA is a systemic autoimmune inflammatory disease that leads to painful joint destruction and disability [11]. IVIG with good proven beneficial and safety profile, is one of the first biological therapies which was introduced already in 1981 by Imbach I et al, for immune thrombocytopenic purpura (ITP) [11] . Since then, IVIG was employed successfully in wide range of conditions such as immune deficiency, sepsis, autoimmunity (e.g specific subgroups of RA patients, juvenile chronic arthritis (JCA), Still’s disease, Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy occurring in the context of rheumatic disease, as well as in SLE, idiopathic inflammatory myopathies, systemic sclerosis, and ANCA-associated vasculitides, Still’s disease and more ) [13-24].
We show herein a beneficial effect of IVIG in the treatment in established murine CIA. IVIG inhibited the arthritis clinical score, inflammatory condition, exemplified by reduced the levels of circulating inflammatory cytokines. IVIG prevent infiltration of immune cells by histopathological examination inhibit joints destruction, as compared with the untreated or PBS subjected CIA mice. The lower clinical score was accompanied by reduced levels of anti-collagen antibodies (P <0.001). Likewise, the diminished levels of circulating inflammatory cytokines (IFNγ, IL-1β, IL-6, IL-17, TNFα) were recorded, P <0.001. Our data support and strength our previous observation that prophylactic treatment with IVIG inhibited the severity of disease inflammation in murine CIA. In that study, IVIG affinity purified on curillin peptides (ACPA-specific IVIG) and more significantly citrullinated-peptides specific IVIG was found to be 200 times more efficient in the reduction of CIA inflammation activity, inhibiting the inflammatory cytokines production ex-vivo by spleen cells and enhanced expansion of spleen T regulatory cells as compared to regular IVIG treatment [35]. Moreover , the immunomodulatory makeup of IVIG in this study was attributed to its anti-idiotypic activity via the Fab portion of the molecules, although we can’t exclude the Fc contribution via elevation of T regulatory cells number.
Lee SY et al, using a prophylactic protocol for the IVIG treatment in CIA mice, showed that IVIG inhibited the development of disease score in CIA mice, reduce the number of Th17 cells in the spleen, expansion of spleen T-regulatory cells and inflammatory cytokines in the joints [38] . Similarly, IVIG up-regulated IL-10 and Fcγ receptor IIB expression by spleen cells (38). It is worth mentioning that in our current study, IVIG was found to abrogate the course of disease, even when the treatment started when the mice have already an arthritis score of 2-3, as compared to the prophylactic treatment of (name of group).. Passive transfer of sera from RA patients to K/BxN mice is an additional murine model of arthritis [39]. IVIG given in a prophylactic protocol or recombinant IgG1 Fc hexamer (Fc-μTP-L309C), resulted in attenuation of arthritis score in the artherogenic K/BXN mice [40].
IVIG mode of action encompass numerous biological functions related in part to the F(ab)2 of the molecule and/or to the Fc activities. The anti-inflammatory activity of IVIG is based on the following activities: a) Neutralization of inflammatory cytokines since IVIG targets at least 13 different cytokines or cytokine-inhibitors [41-45]. Due to the fact that IVIG has anti-inflammatory cytokine activities, it was shown that IVIG is an efficient therapy in the cytokine storm in cases of catastrophic antiphospholipid syndrome, severe influenza, and also currently in COVID-19 [43-48]. IVIG bind specifically the spike protein on RS-Cov-2 as well as the receptor binding protein (personal data) ;b) IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin , limiting the production of inflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation in-vitro [49].c) IVIG can function through the Fc portion thus contributing to the expansion of T regulatory cells , Fc receptor blocking including the sialic acid content of the Fc portion of the antibodies and the interaction with ITAM-bearing Fc receptors [50,51]. Of note, and as opposed to some common assumptions in the medical scientific community, IVIG was found to have less side effects as compared to current biological treatments which might cause severe side effect and loss of efficacy in the long-term. Moreover, IVIG might be even cheaper than current expansive biological agents, therefore it might change the financial burden of biological treatment in RA and other inflammatory/autoimmune diseases.