Epitope Spreading
How do you pin a wave upon the sand?
Understanding Epitope Spreading
My understanding of this theory audibly clicked, simultaneously with The Sound of Music song How do you solve a problem like Maria? playing repeatedly in my head. How do you solve a problem like autoimmunity? For all of my (legitimate) criticisms of the clinical care provided to autoimmune symptom sufferers, I have a healthy amount of admiration for the clinicians and researchers publishing information on concepts like Epitope Spreading. I was introduced to Epitope Spreading while researching and writing about Multiple autoimmune syndrome. There was just one tantalizing sentence addressing it in the study I was reading at the time, and I set it aside for further research:
epitope spreading, in which an immune response is modified over time and the changes are associated with changes in the clinical picture [41, 42]. (Mena-Vázquez et. al, 2020)
Okay, what specific modifications are they talking about? How have those modifications been associated with changes in the clinical picture? What do their references reveal about Epitope Spreading?
Wait, what’s an epitope again?
An antigen is a molecule, whether self or foreign, that can react with an antibody. An epitope is the “precise area of the molecule that is recognized” by the antibody. So, the antigen may be a much larger molecule that only contains a small piece (the epitope), to which the antibody reacts. (Heuther & McCance, 2008)
How do Epitopes Spread?
The term “Epitope Spreading” appears in several publications researching Anti-Ro/SSA and Anti-La/SSB autoantibodies. These may be familiar to some readers because these are common autoantibodies used to diagnose patients with Sjogren’s syndrome, Systemic lupus erythematous, and other systemic autoimmune diseases. I learned that Ro and La stand for the names of the patients these antigens were first found in (the naming convention also used for the antigens of Antisynthetase syndrome). Separately, another researcher(s) identified two antigens in Sjogren’s syndrome and named them SSA and SSB. It was later determined that Ro and SSA are the same antigen and that La and SSB are the same antigen. So, these two different naming origins are combined with a slash—the scientifically haphazard version of the hyphenated last name. I also learned that Ro and La are part of a class of antigens called extractable nuclear antigens, which are found in the nucleus of a cell, but also in the cytoplasm of a cell (the gel-like filling). There are over 100 (as of 2012) identified extractable nuclear antigens. In other words, antigens that can be scientifically studied, and used for testing for disease, although only a handful are used routinely in lab testing for autoimmune disease. (Yoshimi et. al, 2012)
Ro/SSA and La/SSB are ribonucleic proteins that are responsible for suppressing (down-regulating) immune responses. An immune system that destroys these proteins becomes an immune system with fewer checks and balances on its actions in the body. (Yoshimi et. al, 2012)
In their review of what is known about Ro/SSA autoantibody systems, Yoshimi et. al touch briefly on Epitope Spreading in autoimmunity in their summary of the results of a single Australian study from 1995 that was, disappointingly, conducted on mice. I specify Epitope Spreading in autoimmunity because it is also a concept used in cancer research. In the 1995 study, researchers injected healthy mice (without autoimmune disease) with recombinant (from different sources) mouse La/SSB antigens. The previously healthy mice then developed their own autoantibodies to La/SSB antigens. The autoantibodies the mice produced initially attacked a specific epitope on La/SSB, but then began attacking two other, nearby epitopes, of the La antigen. The mice were tested every ten days to study autoantibody activity against antigens. When healthy mice were injected with a specific La/SSB epitope, the mice developed autoantibodies that attacked multiple epitopes of La/SSB that were not side-by-side. When they injected healthy mice with mouse or human La/SSB, the mice also developed autoantibodies to Ro/SSA. When healthy mice were injected with Ro/SSA antigens, the mice developed their own autoantibodies that attacked epitopes on Ro/SSA antigens. The autoantibodies then diversified to attack La/SSB antigens as well.
These findings show that the development of autoantibodies to multiple components of the La/Ro ribonucleoprotein complex may follow initiation of immunity to a single component. In addition, the data reveal the incomplete nature of immune tolerance to La and Ro despite their endogenous expression in all nucleated cells. These observations are likely to account for the coexistence of anti-La/Ro antibodies in autoimmune disease and suggest a general explanation for the appearance of mixed autoantibody patterns in systemic autoimmune disorders. (Topfer et. al, 1995)
It’s easy to see why a study that induces autoimmunity can only be conducted on mice. It’s also obvious that a lot more research is needed to further characterize and scientifically prove this theory. It might already be out there, but I couldn’t find it under the name Epitope Spreading. It may not be a widely accepted or used term.
Why It Matters
I’m used to considering autoimmune signs and symptoms as difficult-to-define, difficult-to-predict, and hard to track. Epitope Spreading, right down to the amino acid level, shows how the attack on a single epitope can expand to include neighboring epitopes on a particular antigen, distant epitopes on a particular antigen, and then different epitopes on different antigens. If serial testing of humans with autoimmune disease were studied, I can imagine that disease progression could be tracked, and perhaps staged, at the epitope level. Associated clinical signs and symptoms could be studied at the epitope level. If it can be tracked at this level, maybe it can be treated at this level, with different treatments having different levels of effectiveness depending on the epitope stage of the disease. For people with risk factors for developing autoimmune disease, testing for Epitope Spreading has the potential to catch and treat disease in its earliest stages. And that’s how Epitope Spreading has brought me dangerously close to the magnetic possibility of autoimmune disease prevention. This could be how you solve a problem like autoimmunity.
References
Huether, S. E., & Mccance, K. L. (2008). Understanding pathophysiology. Mosby.
Mena-Vázquez N, Fernández-Nebro A, Pego-Reigosa JM, Galindo M, Melissa-Anzola A, Uriarte-Isacelay E, Olivé-Marqués A, Aurrecoechea E, Freire M, Tomero E, García-Villanueva MJ, Stoye C, Salas-Heredia E, Bernal-Vidal JA, Salgado E, Blanco R, Javier Novoa F, Ibáñez-Barcelo M, Torrente-Segarra V, Narvaez J, Calvet J, Moriano Morales C, Ramon Vazquez-Rodriguez T, Garcia de la Peña P, Bohórquez C, Andreu-Sánchez JL, Cobo-Ibañez T, Bonilla G, Lozano-Rivas N, Montilla C, Toyos FJ, De la Fuente JLM, Expósito L, Ruiz-Lucea ME, Vals E, Manero-Ruiz J, Bernal-Vidal JA, Rua-Figueroa I. Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry. Rheumatology (Oxford). 2020 Aug 1;59(8):2043-2051. doi: 10.1093/rheumatology/kez562. PMID: 31808534; PMCID: PMC7382602.
Topfer F, Gordon T, McCluskey J. Intra- and intermolecular spreading of autoimmunity involving the nuclear self-antigens La (SS-B) and Ro (SS-A). Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):875-9. doi: 10.1073/pnas.92.3.875. PMID: 7846070; PMCID: PMC42723.
Yoshimi R, Ueda A, Ozato K, Ishigatsubo Y. Clinical and pathological roles of Ro/SSA autoantibody system. Clin Dev Immunol 2012; 2012:1.