Mechanistic insights into how Rituximab attenuates Arthritis: Rituximab (brand name: Ritusan), used to treat bone-related disorders, increases IL-9 levels, augments proliferation of ILC2s (type 2 innate lymphoid cells) and regulatory T (Treg) cells, promotes resolution of inflammation, attenuates cartilage destruction, decreases bone loss, and inhibits pathological features associated with arthritis, via up-regulation of its target genes, 13/August/2019, 12.24 am

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Introduction: What they say

A study from Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany shows that “Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells.” This research paper was published, in the 17 July 2017 issue of the journal “Nature Medicine” [One of the best research journals in General Medicine with an I.Fs of 30.357], by Prof. Andreas Ramming, Rauber S and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that:  Mechanistic insights into how Rituximab attenuates Arthritis: Rituximab (brand name: Ritusan), used to treat bone-related disorders, increases IL-9 levels, augments proliferation of ILC2s (type 2 innate lymphoid cells) and regulatory T (Treg) cells, promotes resolution of inflammation, attenuates cartilage destruction, decreases bone loss, and inhibits pathological features associated with arthritis, via up-regulation of its target genes

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From the significance of the study to Public health relevance:

Given that: (1) Rheumatoid arthritis (RA) has caused 49,000 deaths globally in 2010; and it is likely that death due to RA may increase in the coming years; (2) RA approximately affects between 0.5% to 1% of adults in the developing world; (3) between 5 and 50 per 100, 000 people develop RA each year; (3) Women are three to five times more affected by RA than men; (4) most of the drugs that are in use today, to treat RA, treats only the symptoms, not the root cause of the disease; (5) RA is characterized by chronic joint pains; and (6) the global economic cost spent in the treatment of RA is enormous, there is an urgent need to find: (i) molecular mechanisms and the components involved in bio-pathways leading to RA; (ii) a cheaper alternative to the existing expensive drugs; and (iii) a side-effect-free Natural product-based drug that alleviates not only Rheumatoid arthritis (RA) pain, but also cures RA.


What is known?

Prof.Andreas Ramming‘s research team has recently shown that: (1) interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as mediators of chronic inflammation; (2) the lack of IL-9 production culminates in: (a) defective ILC2 proliferation and activation of regulatory T (Treg) cells; (b) arthritis; (c) excessive cartilage destruction; and (d) bone loss; (3) treatment with IL-9 results in a) resolution of inflammation; and b) protection of bone; and (4) increased numbers of IL-9+ILC2s in joints and the circulation of patients, in remission stage of rheumatoid arthritis, suggesting that IL-9-mediated ILC2 activation is a method of treatment for chronic inflammation, such as arthritis, as it promotes resolution of inflammation rather than suppression of inflammatory mediators.


From research findings to Therapeutic opportunity:

Earlier, a study from the University College London, London, United Kingdom had published its research findings stating that Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.” This study was published, in the 17 June 1994 issue of of the prestigious journal N Engl J Med. (NEJM) (Impact factor: 79.258+),  by  Prof. Shaw MT, Edwards JC and others.  This study suggests that Rituximab, a mononclonal antibody that targets CD20 on the surface of B-cells, ameliorates clinical symptoms associated with Rheumatoid arthritisHowever, the precise mechanism of action of the antibody Rituximab remains largely unclear. 

The study presented here substantiates and supports the aforementioned study’s claim by providing detailed mechanistic insights into how Rituximab may aid in attenuating Rheumatoid arthritis and other inflammatory diseases.

Rituximab, which is commonly used to treat bone-related disorders, by increasing the expression of its target gene, it may increase the expression of IL-9 (Interleukin-9) and its down stream target genes (Figs. 1-2). Thereby, it may: (1) increase the proliferation of ILC2s cells; (2) promote activation of Treg cells; (3) promote resolution of inflammation; (4) suppress cartilage destruction; (5) inhibit bone loss and strengthen bone structure; and (6) inhibit arthritis progression (Figs 2-5).

Figure 1. Mechanistic insights into how Rituximab, by increasing the expression of its target genes, increases IL-9 levels, promotes proliferation/activation of ILC2s/Treg cells, enhances the resolution of inflammation, stifles cartilage destruction and inhibits bone loss.

Figure 2.  Rituximab may attenuate inflammation, rheumatoid/psoriatic arthritis and ulcerative colitis through up-regulation of IL-9

Figure 3. While it has been shown that activation of IL-9 producing type 2 innate lymphoid cells prevents inflammatory diseases, including rheumatoid arthritis, this study suggests for the first time that Rituximab may attenuate bone loss and prevent osteo/rheumatoid/psoriatic-arthritis through up-regulation of IL-9.

Figure 4. While it has been shown that Rituximab (the study depicted in the fig.4 above) attenuates rheumatoid arthritis,  the mechanism of action remains unclear. This study suggests for the first time that Rituximab  attenuates rheumatoid/psoriatic arthritis and prevents bone loss through up-regulation of IL-9.

Figure 5. While it has been shown that Rituximab (the study depicted in the fig.5 above) attenuates rheumatoid arthritis,  the mechanism of action remains unclear. This study suggests for the first time that Rituximab  attenuates rheumatoid/psoriatic arthritis and prevents bone loss through up-regulation of IL-9.

Together, this study suggests that a pharmacological mixture encompassing “Rituximab or its functional equivalents”, either alone or in combination with other drugs, will: a) prevent bone loss in postmenopausal women under 60 years of age; and b) attenuate the progression of rheumatoid/psoriatic  arthritis. 


Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.

Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/

Amount: $ 500#

Undisclosed mechanistic information: How Rituximab increases IL-9 levels, activates ILC2 proliferation and regulatory T (Treg) cells, inhibits cartilage destruction, suppresses bone loss and improves arthritis.

# Research cooperation

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References:

Web: http://genomediscovery.org or http://newbioideas.com

Citation: Boominathan, L., Mechanistic insights into how Rituximab attenuates Arthritis: Rituximab (brand name: Ritusan), used to treat bone-related disorders, increases IL-9 levels, augments proliferation of ILC2s (type 2 innate lymphoid cells) and regulatory T (Treg) cells, promotes resolution of inflammation, attenuates cartilage destruction, decreases bone loss, and inhibits pathological features associated with arthritis, via up-regulation of its target genes, 13/August/2019, 12.23 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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