Team: Pathogenic ANCA, aka “The Most Villainous Protein (MVP)”
Region: Ab Workout
Base Article: Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002;110(7):955-963. doi:10.1172/JCI15918. PMID 12370273.
Authors: University of North Carolina Rheumatology Fellowship Program; Katherine Yates, MD, First Year Rheumatology Fellow; Prarthana Jain, DO, MPH, First Year Rheumatology Fellow; Astia Allenzara, MD, Second Year Rheumatology Fellow
While teamwork makes the dreamwork, it never hurts to have a most villainous protein (MVP) on the team. The Most Villainous Protein team is lucky enough to have recruited an anti-MPO protein. This antibody has revolutionized the game by providing evidence that antineutrophil cytoplasmic antibodies (ANCAs) are directly pathogenic in crescentic glomerulonephritis and small vessel vasculitis1. Some have compared this protein’s impact to that of Michael Jordan’s last second, National Championship game winning jumper in 1982; legendary.
It has been known for quite some time that the anti-MPO antibody was an important player. Further tape review, however, has revealed just how impactful this protein can be. This is similar to how the most valuable player of all time, Michael Jordan, was an outstanding player during this time at UNC, but the full extent of his talent was not observed until further observations were made as he played in the NBA. The film to which we are referring is the definitive evidence, meeting all 8 Bradford Hill criteria, that anti-MPO antibodies cause glomerulonephritis and small vessel vasculitis. The Most Villainous Protein team has demonstrated through knockout mice lacking functioning B and T lymphocytes that the addition of anti-MPO antibodies results in the development of crescentic glomerulonephritis within days1. This effect was dose dependent, with mice that received more anti-MPO developing necrotizing glomerulonephritis, hemorrhagic pulmonary capillaritis and granulomatous inflammation1. Anti-MPO’s absence on the court is also noticeable: when anti-MPO was on the bench, anti-BSA splenocytes and anti-BSA IgG were unable to induce the same glomerular crescents1.
Anti-MPO is an impactful player, but talent is not enough to win championships. What separates this protein on the assay is how this antibody also inspires its teammates. Just as Michael Jordan was known to push his UNC teammates, anti-MPO knows how to inspire and motive its teammates. Prime examples of this skill occurred during big games against several rival teams (immune complex glomerulonephritis or anti-GBM glomerulonephritis), where anti-MPO demonstrated the ability to bring the team together and activated both neutrophils and monocytes to win the games. Anti-MPO has been known to stimulate neutrophils to release injurious oxygen metabolites, proteases, and proinflammatory cytokines and allow neutrophiles to hold on tight and thwart its endothelial cell opponents2,3,4. Anti-MPO’s presence on the court also encourages monocytes to undergo a respiratory burst, releasing a wave of proteinases and cytokines5. All this goes to show that The Most Villainous Protein team not only has the MVP, but also includes several other players that will likely go on to be inducted into the hall of fame.
Impact on Rheumatology
While anti-MPO has been known to be involved in causing glomerular and vascular inflammation, this team has provided definitive evidence for its pathogenic role. This exciting development is a game changer.
Knowing that anti-MPO antibodies have a pathogenic role has resulted in the study and development of new treatment strategies, including a reduced dose glucocorticoid regimen over a standard dose regimen and Rituximab over Cyclophosphamide for induction for active severe ANCA-associated vasculitis6. One could say that this discovery has rewritten the rule book.
Recently, there has been more attention paid to how anti-MPO influences its neutrophil and monocyte teammates. This increased focus will likely improve our understanding of other rheumatologic diseases and has the potential to inspire novel treatment strategies.
Chances in the Tournament
Anti-MPO is felt to be a top runner for the overall tournament MVP award as this protein presents a threat on multiple fronts including a definitive pathological role in inducing glomerulonephritis and vasculitis as well as stimulating its neutrophil and monocyte teammates. Any opponent will need to be prepared to withstand bursts of injurious oxygen metabolites, proteinases, and proinflammatory cytokines.
The Most Villainous Protein team has a formidable opponent in the first round with CCP & Enolase, but the more definitive role of anti-MPO will allow this MVP to roll over its first challenger in this tournament. Anti-MPO’s impact will likely be enough to carry The Most Villainous Protein team through the Ab Workout region, but it will be this protein’s inspiration and influence on its neutrophil and monocyte teammates that will help to carry the team through to the championship.
The Blue-Ribbon Panel will appreciate the application of the Bradford Hill criteria to prove anti-MPO antibodies’ causation of glomerulonephritis and vasculitis. The phenomenal demonstration of this pathogenic role is awe inspirating and has a significant impact on our understanding of the pathogenesis of ANCA glomerulonephritis and vasculitis and has led to the development of new treatment strategies. Furthermore, this discovery has the potential to continue to provide insights into pathogenesis and revolutionize management as more is learned about the role of neutrophils and monocytes.
Next scouting report: CYC for PAN
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See the Q&A on theMednet.org for the Ab Workout Region: How do you approach follow up in patients with isolated positive ANA, but no current clinical signs or symptoms of systemic lupus erythematosus?
- Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. Journal of Clinical Investigation. 2002;110(7):955-963. doi:10.1172/JCI15918
- Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proceedings of the National Academy of Sciences. 1990;87(11):4115-4119. doi:10.1073/pnas.87.11.4115
- Charles LA, Caldas MLR, Falk RJ, Terrell RS, Jennette JC. Antibodies Against Granule Proteins Activate Neutrophils In Vitro. Journal of Leukocyte Biology. 1991;50(6):539-546. doi:10.1002/jlb.50.6.539
- Ewert BH, Jennette JC, Falk RJ. Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney International. 1992;41(2):375-383. doi:10.1038/ki.1992.52
- Casselman BL, Kilgore KS, Miller BF, Warren JS. Antibodies to neutrophil cytoplasmic antigens induce monocyte chemoattractant protein-1 secretion from human monocytes. J Lab Clin Med. 1995;126(5):495-502.
- Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis. Arthritis & Rheumatology. 2021;73(8):1366-1383. doi:10.1002/art.41773