Human Leukocyte Antigen Variation Links Multiple sclerosis and Localized scleroderma (Morphea)
What do Multiple sclerosis and Localized scleroderma share? There’s the obvious association in their names: they’re both a type of sclerosis (or hardening), but the similarities seem to stop there. One is a brain disease and one is a skin disease. Yet, they share a striking thing: the association with Human Leukocyte Antigen (HLA) variation HLA DRB1*15:01. This is a Class II variation, which means that it appears on antigens (molecules that antibodies can react to) on Antigen Presenting Cells only, like B cells, a type of white blood cell called a lymphocyte.
I started the week wanting to learn more about the association between the Localized scleroderma sub-type, Generalized morphea, and a genetic variation that, according to one study, could be specific to this one sub-type of Localized scleroderma: HLA DRB1*15:01. To learn more about Scleroderma, systemic sclerosis and Localized scleroderma, you can read it’s work-in-progress Diagnosis Description here. I’ve now ended the week at self-antibodies directed against Myelin Basic Protein (MBP), found in both Localized scleroderma (Morphea) and Multiple sclerosis. Myelin is the fatty sheath covering nerves throughout the body to fast track messages throughout the brain and body (not all nerves are covered by this fatty sheath, by design, but many are). When myelin is damaged, nerve signals slow down, which can cause lack of coordination in Multiple sclerosis, or possibly pain in Localized scleroderma (Morphea). Each study on this winding road was revelatory.
Generalized Morphea Is Associated with HLA-DRB1*15:01
It’s enough to know that the alphabet soup of HLA-DRB1*15:01 is simply the name for a specific genetic variant that controls the structure of an antigen on Antigen Presenting Cells. And this study was able to associate this variant specifically with one sub-type of Localized scleroderma: Generalized morphea. This is important for two reasons: 1. it suggests that Generalized morphea is genetically distinct from other Localized scleroderma sub-types and 2. it could aid in the diagnosis of this sub-type.
(Jacobe et. al, 2014)
What’s Been Studied in Connection with HLA-DRB1*15:01?
Multiple sclerosis. This study considers HLA-DRB1*15:01 to be the strongest genetic risk factor for Multiple sclerosis. It set out to study the connection between the strongest genetic risk factor (HLA-DRB1*15:01) for the development of Multiple sclerosis and the strongest environmental risk factor (Epstein-Barr virus) for the development of Multiple sclerosis. A graphic from the study (pictured below) illustrates how the Epstein-Barr virus more efficiently enters a B cell, which is a type of Antigen Presenting Cell (Class II cell), with the help of HLA-DRB1*15:01. Once the Epstein-Barr virus enters the cell, it uses the B cell’s structures to replicate more virus cells, which then go on to enter more B cells, further proliferating the virus in the body.
(Menegatti et. al, 2021)
You may have noticed that “CD21” also appears as an antigen on the B cell’s surface. That’s because this is a receptor that was already known to aid the Epstein-Barr virus with its entrance into the B cell. It was also previously known that HLA-DR, -DQ, and/or –DP Class II molecules were used for binding of Epstein-Barr virus. What was not known was whether HLA DRB1*15:01, specifically, is used as a co-receptor for Epstein-Barr’s entrance into a cell. I like to think of these co-receptors as a kind of multi-factor authentication. The faster and more efficient the multi-factor authentication is completed, then the faster and more efficiently the virus can replicate in the body. Some genetically determined B-cell antigens are slow and inefficient when Epstein-Barr virus tries to bind to them—the equivalent of trying to log into your bank account on your laptop when your phone is on another floor of the house. This inefficiency slows viral replication, buying time for an effective immune response. Some genetically determined B-cell receptors are fast and efficient—the equivalent of logging into your bank account on your laptop with your phone in your pocket. This efficiency allows the virus to replicate and spread quickly.
To control the number of variables, this experiment used a lab cell line of immature human B cells that already have CD21, then the researchers added HLA DRB1*15:01 to the surface of the immature B cells, then introduced Epstein-Barr virus (virus replication graphed in bottom right hand corner). For comparison, they also introduced Epstein-Barr virus to the B cells that only had CD21 (seen in the upper left hand corner in the graphs below), B cells that had CD21 and an empty vector added (seen in the upper right hand corner; think of the vector as a genetically inactive tube that is used to contain the genetic material added to a cell), and a CD21 B cell with HLA-DRB1*01:01 added to it (lower left hand corner). The top two graphs show that CD21-only cells and empty vector cells were not able to be infected with Epstein-Barr virus—no multi-factor authentication was possible. Interestingly, HLA-DRB1*01:01, used as a comparison, was thought to be protective against Multiple sclerosis. Even so, it’s easy to see that replication is faster and more efficient with HLA-DRB1*15:01 as a co-receptor to CD21 compared to HLA-DRB1*01:01. The graphs below represent just 3 days of viral replication.
(Menegatti et. al, 2021. GFP=the molecular change they made to the Epstein-Barr virus to make it fluorescent, so it could be detected in their analysis)
Now Back to Generalized Morphea
The results above are fascinating in and of themselves, but also in the context of Generalized morphea’s association with HLA-DRB1*15:01. If this particular genetic susceptibility is shared between Generalized morphea and Multiple sclerosis, then what determines which disease develops? My first thought was type of triggering infection. Perhaps for Generalized morphea, it’s not the confluence of genetic variation HLA-DRB1*15:01 and Epstein-Barr virus that contributes to disease, but the confluence of HLA-DRB1*15:01 and Lyme disease that contributes to disease development. There is a loose association between Localized scleroderma and Lyme disease documented sparsely in the literature. For Localized scleroderma, the type of infection that confers the most susceptibility is unclear—there are a number of entrenched reasons that the infections associated with Localized scleroderma is unclear, so as of the timing of this post, infection type is a bit of a dead end comparison.
How Else Could the Same Genetic Variant Be Associated with the Development of Different Sclerotic Diseases?
Remember the study authors from 2014, who connected Generalized morphea to the HLA-DRB1*15:01 variant? In 2022, many of the same authors went on to study self-antibodies against Myelin Basic Protein (MBP) in Localized scleroderma (Morphea). Self-antibodies against Myelin Basic Protein were already well-known in Multiple sclerosis. These authors used serum samples from a registry of patients, known as the Morphea in Adults and Children (MAC) cohort. Based on their inclusion criteria, their study consisted of 70 participants. They found:
50 out of 70 (71.4%) had self-antibodies to Myelin Basic Protein
24 out of the 50 participants with self-antibodies to Myelin Basic Protein carried a diagnosis of Generalized morphea
Linear morphea was the next most common sub-type with self-antibodies to Myelin Basic Protein, although at 20 participants, there must be some participants with multiple sub-type diagnoses, and I wish this was broken out in the table
Lesion pain was more common in participants with self-antibodies to Myelin Basic Protein, which makes sense with increased nerve damage
Serum from Localized scleroderma (Morphea) participants with self-antibodies to Myelin Basic Protein caused inflammation around nerves in human Morphea tissue samples (non-brain) and in mouse brain tissue
Distinct bio-signatures of Localized scleroderma (Morphea) self-antigens to Myelin Basic Protein were not present in healthy controls or controls with Systemic sclerosis: “Of all the morphea cases, 71.4% exhibited increased MBP autoantibodies compared to 20% of healthy controls and 6.7% of systemic sclerosis cases”
Target epitopes—the small pieces of the Myelin Basic Protein that self-antibodies react to—were different for Localized scleroderma (Morphea) compared to Multiple sclerosis. That is, self-antibodies are attacking different parts of Myelin Basic Protein in Localized scleroderma and Multiple sclerosis, respectively.
(Zhu et. al, 2022)
Last, but not least, I wanted to know if there was documentation of Localized scleroderma (Morphea) and Multiple sclerosis co-occurring in study participants. Except for one case study of a patient with pre-existing Multiple sclerosis developing Morphea after an injection of interferon, I found nothing.
Why It Matters
For the diagnosis of Localized scleroderma, these studies advance the possibility of finding unique genetic and self-antibodies that differentiate Generalized morphea, particularly, from other diseases, including Systemic sclerosis. This makes definitive diagnostic testing closer to a reality. These studies provide yet more evidence that Systemic sclerosis is a distinct entity.
The genetic connection between Localized scleroderma (Morphea) and Multiple sclerosis provides a point of comparison and the opportunity for contrast. They don’t appear to overlap clinically, so building a body of evidence of the differences between them will help to define both diseases. And better define how genetic susceptibility interacts with environmental factors for all autoimmune disease.
For those who are new to AutoimmuneDx, I am currently writing posts based on reader-requests for more information and analysis on particular autoimmune diagnoses. I base my posts on the questions, concerns and—yes, feelings—that come up while completing a Diagnosis Description (you can read more about what goes into a Diagnosis Description here). Diagnosis Descriptions are designed to be a catalog of information that effectively describes and organizes the scientific evidence on autoimmune disease for people without a medical background. If you would like me to take a closer look at a particular diagnosis, please leave a comment below. If you don’t feel comfortable commenting publicly, email me at autoimmunedx@gmail.com. Because I have a curious mind and a medical background, I sometimes get too wrapped up in the weeds of autoimmune disease, so if you would like me to clarify a post, a concept, a word, or anything in-between, please don’t hesitate to leave a comment or send an email.
References
Condie D, Grabell D, Jacobe H. Comparison of outcomes in adults with pediatric-onset morphea and those with adult-onset morphea: a cross-sectional study from the morphea in adults and children cohort. Arthritis Rheumatol. 2014 Dec;66(12):3496-504. doi: 10.1002/art.38853. PMID: 25156342; PMCID: PMC4245331.
Jacobe H, Ahn C, Arnett FC, Reveille JD. Major histocompatibility complex class I and class II alleles may confer susceptibility to or protection against morphea: findings from the Morphea in Adults and Children cohort. Arthritis Rheumatol. 2014 Nov;66(11):3170-7. doi: 10.1002/art.38814. Erratum in: Arthritis Rheumatol. 2015 Mar;67(3):751. PMID: 25223600; PMCID: PMC4211936.
Menegatti J, Schub D, Schäfer M, Grässer FA, Ruprecht K. HLA-DRB1*15:01 is a co-receptor for Epstein-Barr virus, linking genetic and environmental risk factors for multiple sclerosis. Eur J Immunol. 2021 Sep;51(9):2348-2350. doi: 10.1002/eji.202149179. Epub 2021 Jun 3. PMID: 34019695.
Zhu JL, Paniagua RT, Chen HW, Florez-Pollack S, Kunzler E, Teske N, Rainwater YB, Li QZ, Hosler GA, Li W, Ramirez DMO, Monson NL, Jacobe HT. Autoantigen microarrays reveal myelin basic protein autoantibodies in morphea. J Transl Med. 2022 Jan 24;20(1):41. doi: 10.1186/s12967-022-03246-5. PMID: 35073943; PMCID: PMC8785566.