Team: Clonal Selection, aka “the Forbidden Clones.”
Region: Mechanism Madness
Authors: Vanderbilt University Medical Center Rheumatology Fellowship Program. Meridith Balbach, fourth year medical student; Robert Corty, MD PhD, first year rheumatology fellow; Ganiat Adeogun, MD, first year rheumatology fellow; Catherine Deffendall, MD, first year rheumatology fellow; Erin Chew, MD, second year rheumatology fellow; Sarah Luebker, DO, second year rheumatology fellow; Tyler Reese, MD, assistant professor of medicine; Kevin Byram, MD, assistant professor of medicine; Narender Annapureddy, MD, MSCI, associate professor of medicine; Leslie Crofford, MD, professor of medicine, Vanderbilt University Medical Center
Basketball coaches have long debated team-building strategy. The “Wooden school” recruits malleable players with potential and teaches them to play a winning system. The “Calipari school” simply recruits such highly skilled players that victories occur without much further training. In the 1950s, immunologists engaged in a similar debate on the mechanism by which the immune system produces antibodies.
The Lamarckian “instructive school” held that an antibody-producing cell ingests an antigen that “impresses its character” onto its respective antibody, coaching it so that it might make it into the big leagues of peripheral circulation.1,2 Building on Ehrlich’s side chain theory (1898) and Jerne’s natural selection theory (1955), however, Coach MacFarlane Burnet stepped onto the court in 1957 with his Darwinian theory of clonal selection.3,4 He posited that the immune system produces a diversity of candidates and subsequently recruits the most capable among them into the periphery, generating an all-star lineup.5
In this 1959 monograph, Burnet applies clonal selection theory to provide a working approach to autoimmune disease.6 He states that a high degree of mutability during the embryonic stage of development generates a diversity of antibody-producing cells, akin to Jerne’s preexisting repertoires while satisfying the newfound central dogma. From there, cells that react with self-antigen are eliminated by a homeostatic mechanism—now known as central tolerance.
The understanding that the “breakdown in that information service” which differentiates between self and non-self allows the emergence of self-reactive antibody or immunologically active cells is a slam dunk—one that revolutionizes our understanding of adaptive immunity. Burnet recognized that making a team from players with existing talents left the floor wide open for Forbidden Clones when that central tolerance is lost, predisposing to autoimmune disease.
Impact on Rheumatology
Incorporating clonal selection theory into our understanding of autoimmune disease represented a major paradigm shift in the 20th century—and is sparking game-changing plays once again. An enhanced understanding of adaptive immunity spurred numerous innovations. Clonal selection theory contributed to the production of the first monoclonal antibody in 1975, now a cornerstone of treatment in numerous rheumatic diseases.7 It guided selection of antigens capable of eliciting a memory response in vaccine development, including the crowd-pleasing COVID-19 inoculations we now use to protect our most vulnerable patients.8 In parallel, it set a pick for understanding T cell selection—the importance of which is not lost on our oncology colleagues leveraging these principles with CAR T-cell therapy—or, increasingly, in refractory systemic lupus erythematosus.9,10 Furthermore, it shifted the spotlight from antigen to antibody, prepping the rheumatology community to better understand the presence of autoantibodies prior to disease onset in lupus, rheumatoid arthritis, systemic sclerosis, and more.11-13
Incredibly, the applications of Burnet’s seminal work, particularly understanding Forbidden Clones as opponents in rheumatic disease, is only growing—just take a look at the 2022 American College of Rheumatology Convergence meeting. Drs. Peter Campbell and Joanne Reed incorporated Forbidden Clones into their playbooks, directly citing Burnet’s work.14-16 Both put forth somatic mutation as a key mechanism by which autoantibodies arise and become increasingly pathogenic, highlighting these cells as playmakers in autoimmune diseases such as Sjogren’s syndrome and vasculitis. This research exploring the evolution from benign seropositivity to antibody-driven pathology may yield a treatment targeting those Forbidden Clones.
Chances in the Tournament
Avoid making Forbidden Clones’ first-round opponent “NRLP3 in gout” your bracketbuster—it will be nothing but net as the Forbidden Clones take the “Mechanism Madness” region. Treatment implications of their base paper are reliant on understanding Forbidden Clones—just consider the need for concomitant methotrexate administration with pegloticase in gout to prevent the rise of a specific type of forbidden clone—that is, anti-pegloticase antibodies.17,18
In the following round, they will take on the winner of the Ab Workout region. This is sure to be a tough matchup, but the Forbidden Clones will win big if the Blue Ribbon Panel considers that this base paper establishes the mechanistic underpinnings of how any potential opponent from the Ab Workout region might emerge. Our MVP (& Nobel Prize Winner) Burnet will guide his team to victory, just as he’s guided immunology and rheumatology over the last 60+ years.
Although the previous panels have traditionally focused on clinical practicality, they may be more focused on the fundamentals this year given the theme of the tournament. If the panel employs this logic, the Forbidden Clones have an excellent chance to cut down the nets. Just remember, Forbidden Clones don’t play by the rules— just as they bypass central tolerance, you may find yourself rooting for them as they bypass the competition.
Next scouting report: MSU & NLRP3
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- F B, F H. Chemische Untersuchung des Prazipitates aus Hamoglobin und Anti-Hamoglobin-Serum und Bemerkungen uber die Natur der Antikorper. Physiol Chem. 1930;192(45)doi:https://doi.org/10.1515/bchm2.1930.192.1-3.45
- Pauling L. A Theory of the Structure and Process of Formation of Antibodies*. J. Am. Chem. Soc.; 1940. p. 2643–2657.
- Ehrlich P. Croonian Lecture: On Immunity with Special Reference to Cell Life. Proceedings of the Royal Society of London; 1900. p. 424-448.
- Jerne NK. THE NATURAL-SELECTION THEORY OF ANTIBODY FORMATION. Proc Natl Acad Sci U S A. Nov 15 1955;41(11):849-57. doi:10.1073/pnas.41.11.849
- Burnet FM. A modification of Jerne’s theory of antibody production using the concept of clonal selection. Australian Journal of Science. 1957;20:67-69.
- BURNET M. Auto-immune disease. I. Modern immunological concepts. Br Med J. Oct 10 1959;2(5153):645-50. doi:10.1136/bmj.2.5153.645
- Liu JK. The history of monoclonal antibody development – Progress, remaining challenges and future innovations. Ann Med Surg (Lond). Dec 2014;3(4):113-6. doi:10.1016/j.amsu.2014.09.001
- Clem AS. Fundamentals of vaccine immunology. J Glob Infect Dis. Jan 2011;3(1):73-8. doi:10.4103/0974-777X.77299
- Bernard N. When humoral became cellular. Nature Immunology. 2016;17(9)doi:https://doi.org/10.1038/ni.3604
- Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. Oct 2022;28(10):2124-2132. doi:10.1038/s41591-022-02017-5
- Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. Oct 16 2003;349(16):1526-33. doi:10.1056/NEJMoa021933
- Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. Feb 2004;50(2):380-6. doi:10.1002/art.20018
- Burbelo PD, Gordon SM, Waldman M, et al. Autoantibodies are present before the clinical diagnosis of systemic sclerosis. PLoS One. 2019;14(3):e0214202. doi:10.1371/journal.pone.0214202
- Campbell P. Somatic mutations in normal & autoimmune lymphocytes 2022:
- Reed J. Somatic Mutations Shape Autoantibody Response 2022:
- Singh M, Jackson KJL, Wang JJ, et al. Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody. Cell. Mar 05 2020;180(5):878-894.e19. doi:10.1016/j.cell.2020.01.029
- Lipsky PE, Calabrese LH, Kavanaugh A, et al. Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout. Arthritis Res Ther. Mar 04 2014;16(2):R60. doi:10.1186/ar4497
- Botson JK, Tesser JRP, Bennett R, et al. Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR). J Rheumatol. May 2021;48(5):767-774. doi:10.3899/jrheum.200460