Rosa Rubicondior: Malevolent Design - The Sneaky Way The Epstein-Barr Virus Can Cause Multiple Sclerosis

Malevolent Design

The Sneaky Way The Epstein-Barr Virus Can Cause Multiple Sclerosis

The Epstein-Barr virus (EBV)

Image: Getty Images

The Epstein-Barr virus (EBV) is very common and can cause glandular fever in young adults.

Image: Getty Images

Genes combined with immune response to Epstein-Barr virus increase MS risk | Karolinska Institutet

To believe in the childish notion of intelligent design by an omniscient, magical designer is to believe two things:

That it created our shoddy immune system that not only fails to protect us from pathogenic organisms such as bacteria, fungi and virus that frequently infect us.
That it also designed those pathogens and gave them the ability to not only evade our immune system but also turn it against us to ensure we suffer the long-term effects of infections, even when we have eliminated the causative parasite from our bodies.

In other words, creationism is to believe the putative designer is incompetent and/or malevolent.

The Epstein Barr virus has recently been implicated in MS. What information do you have on this virus?

Epstein-Barr virus (EBV) is a herpesvirus (human herpesvirus 4) that is best known for causing infectious mononucleosis (glandular fever). However, it has also been linked to several autoimmune diseases and cancers. Recent research has strengthened the case for EBV being a major environmental trigger for multiple sclerosis (MS).

Epstein-Barr Virus Overview

Type: Double-stranded DNA virus in the Herpesviridae family
Transmission: Primarily through saliva, but also through organ transplants and blood transfusions
Infection Sites: Infects B cells and epithelial cells
Latency: EBV establishes lifelong latency in B cells, periodically reactivating
EBV and Multiple Sclerosis (MS)
MS is an autoimmune disorder characterized by the immune system attacking the myelin sheath of neurons. For decades, EBV has been suspected of playing a role in MS, but conclusive evidence was lacking. However, recent large-scale studies provide strong evidence that EBV infection is a necessary precursor to developing MS.

Key Evidence Linking EBV to MS

Longitudinal Studies in Military Personnel (2022)

A landmark study by Harvard researchers analysed data from over 10 million U.S. military personnel.
Those who developed MS had nearly all been infected with EBV before the onset of symptoms.
The risk of MS increased 32-fold after EBV infection.
Other viruses, including cytomegalovirus (CMV), did not show a similar association.

Molecular Mimicry Hypothesis

EBV proteins may mimic myelin proteins, triggering an autoimmune response.
Studies have found that certain EBV proteins, such as EBNA1, share similarities with myelin antigens, leading to immune system cross-reactivity.

B-cell Involvement and Immune Dysregulation

Since EBV primarily infects B cells, it may disrupt immune regulation, leading to aberrant B-cell activation and autoimmunity.
Treatments that deplete B cells (like anti-CD20 therapies) improve MS symptoms, supporting the idea that EBV-infected B cells are involved in the disease.

EBV Reactivation and MS Relapses

MS relapses have been associated with reactivation of EBV, suggesting a role in disease progression.

Other Diseases Linked to EBV

Autoimmune Disorders: Lupus, rheumatoid arthritis, Sjögren’s syndrome
Cancers: Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, gastric cancer
Chronic Fatigue Syndrome (CFS/ME): EBV has been implicated as a possible trigger
Future Research and Potential Treatments

EBV Vaccines: Several vaccines are in development, including mRNA-based approaches.
Anti-EBV Therapies: Monoclonal antibodies and antivirals targeting EBV-infected B cells are being explored.
Early Detection & Prevention: Identifying high-risk individuals based on EBV infection status could help with early intervention strategies.

Conclusion

The evidence now strongly suggests that EBV is a necessary (but not solely sufficient) trigger for MS. This discovery could lead to new treatments and possibly prevention strategies through vaccines or antiviral therapies.

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Information Continually updated

A stunning example of a reputedly intelligently-designed virus causing unnecessary suffering, especially in young adults, is the recent discovery of a strong association between infection with the common Epstein-Barr virus and multiple sclerosis (MS). This was the recent subject of a paper by a team of researchers from the Karolinska Institutet, in Proceeding of the National Association of Sciences (PNAS), as explained in a Karolinska Insitutet News release:

Genes combined with immune response to Epstein-Barr virus increase MS risk
In multiple sclerosis (MS), antibodies to the common Epstein-Barr virus can accidentally attack a protein in the brain and spinal cord. New research shows that the combination of certain viral antibodies and genetic risk factors can be linked to a greatly increased risk of MS. The study has been published in the journal PNAS and led by researchers at Karolinska Institutet, Sweden, and Stanford University School of Medicine, USA.
An estimated 90 to 95 percent of adults are carriers of the Epstein-Barr virus (EBV) and have formed antibodies against it. Many become infected as children with few or no symptoms, but in young adults, the virus can cause glandular fever. After infection, the virus remains in the body in a dormant (latent) phase without active virus production.

Attacking a protein in the brain

Everyone affected by the neurological disease MS, where the immune system attacks the brain and spinal cord, is a carrier of EBV. However, the mechanisms behind the association are not fully understood.

Now, researchers at Karolinska Institutet and Stanford Medicine have confirmed that antibodies to an EBV protein called EBNA1 can inadvertently react with a similar protein in the brain called GlialCAM, which probably contributes to the development of MS. The new study also shows how different combinations of antibodies and genetic risk factors for MS contribute to the risk increase.

A better understanding of these mechanisms may ultimately lead to better diagnostic tools and treatments for MS.

Professor Tomas Olsson, co-corresponding author
Neuroimmunology Unit
Department of Clinical Neuroscience
Karolinska Institutet, Stockholm , Sweden.
The researchers analysed blood samples from 650 MS patients and 661 healthy people. They compared the levels of antibodies directed against the viral protein EBNA1 and the levels of misdirected antibodies against GlialCAM and two other proteins in the brain, ANO2 and CRYAB, which are also similar to EBNA1.

Increased levels of antibodies

Elevated levels of all these antibodies were detected in people with MS. High antibody levels in combination with a genetic risk factor for MS (HLA-DRB1*15:01) were associated with a further increase in risk. The absence of a protective gene variant (HLA-A*02:01) in combination with any of the antibodies against proteins in the brain was also associated with a strong increase in risk.

The new findings provide another piece of the puzzle that adds to our understanding of how genetic and immunological factors interact in MS.

Professor Lawrence Steinman, co-corresponding author
Department of Neurology and Neurological Sciences
Beckman Center for Molecular Medicine
Stanford University School of Medicine, Stanford, CA, USA.

Biomarker potential

Researchers at Karolinska Institutet now plan to analyse samples collected before MS disease development to see when these antibodies appear.

If they are already present before the onset of the disease, they may have the potential to be used as biomarkers for early diagnosis.

Professor Tomas Olsson.

Publication
Neda Sattarnezhad, Ingrid Kockum, Olivia G. Thomas, Yicong Liu, Peggy P. Ho, Alison K. Barrett, Alexandros I. Comanescu, Tilini U. Wijeratne , Paul J. Utz, Lars Alfredsson, Lawrence Steinman, William H. Robinson, Tomas Olsson, Tobias V. Lanz.
Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls
PNAS (Proceedings of the National Academy of Sciences), online 10 March 2025, doi: 10.1073/pnas.2424986122.

Significance

Multiple sclerosis (MS) is an autoimmune disease of the brain and spinal cord, leading to disability in young adults. Infection with Epstein–Barr virus (EBV) is a prerequisite for developing the disease. We previously demonstrated that antibody responses against the virus protein EBV nuclear antigen 1 (EBNA1) cross-react with brain proteins of MS patients and contribute to the disease. Here, we confirm in a large cohort of MS patients and controls that the presence of these antibodies increases the risk for MS, and we correlate them with the major genetic risk factor for MS. A combination of multiple antibodies and the genetic risk factor increases the risk for MS in an additive fashion.

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), which is linked to Epstein–Barr virus (EBV) infection, preceding the disease. The molecular mechanisms underlying this connection are only partially understood. We previously described molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and three human CNS proteins: anoctamin-2 (ANO2), alpha-B crystallin (CRYAB), and glial cellular adhesion molecule (GlialCAM). Here, we investigated antibody responses against EBNA1 and GlialCAM in a large cohort of 650 MS patients and 661 matched population controls and compared them to responses against CRYAB and ANO2. We confirmed that elevated IgG responses against EBNA1 and all three CNS-mimic antigens associate with increased MS risk. Blocking experiments confirmed the presence of cross-reactive antibodies and molecular mimicry between EBNA1 and GlialCAM, and accompanying antibody responses against adjacent peptide regions of GlialCAM suggest epitope spreading. Antibody responses against EBNA1, GlialCAM, CRYAB, and ANO2 are elevated in MS patients carrying the main risk allele HLA-DRB1*15:01, and combinations of HLA-DRB1*15:01 with anti-EBNA1 and anti-GlialCAM antibodies increase MS risk significantly and in an additive fashion. In addition, antibody reactivities against more than one EBNA1 peptide and more than one CNS-mimic increase the MS risk significantly but modestly. Overall, we show that molecular mimicry between EBNA1 and GlialCAM is likely an important molecular mechanism contributing to MS pathology.
Multiple sclerosis (MS) is the most common cause of nontraumatic disability in young adults. It is an autoimmune demyelinating disorder, where aberrantly activated B and T cells from the adaptive arm of the immune system, and macrophages from the innate arm of the immune system, attack the myelin sheaths in the central nervous system (CNS). Demyelination is followed by neuronal loss and widespread activation of the brain’s glial cells. While tremendous progress has been made in controlling disease activity and delaying progression of disability, much of the pathophysiology of MS remains to be elucidated (1). The ubiquitous herpesvirus Epstein–Barr virus (EBV) is strongly associated with MS and is considered a prerequisite for developing the disease (2). However, a conundrum arises because only a small percentage of individuals infected with EBV develop MS. Thus, additional genetic and environmental factors are involved before clinical disease appears. In addition to EBV infection, symptomatic infectious mononucleosis (IM) and highly elevated titers of serum antibodies against EBV nuclear antigen 1 (EBNA1) are additional independent risk factors for MS (3, 4). Other risk factors include low vitamin D levels, smoking, and carrying MS risk genes, including the human leukocyte antigen (HLA) class II allele HLA-DRB1*15:01, the most significant risk gene for MS. Most of the environmental/lifestyle factors interact with MS HLA risk genes, leading to substantially increased Odds ratios (ORs). Since HLA class II genes regulate CD4+ T cells, the interactions with such genes argue for mechanisms of the environmental factors acting through adaptive immunity, just as MS risk genes (5–7).

On a molecular level, the link between EBV and MS is incompletely understood. Studies found evidence for several mechanisms, including altered anti-EBV T cell responses in MS patients (8–11), unstable EBV latency in infected B cells (12), and dysregulation of genes associated with autoimmunity, largely mediated by the EBV transcription factor EBNA2 (13). We and others described molecular mimicry between the EBV transcription factor EBNA1 and CNS antigens, including anoctamin 2 (ANO2), glial cellular adhesion molecule (GlialCAM), Alpha-B crystallin (CRYAB), and myelin basic protein (MBP) (14–17). The pathogenic relevance of several of these mimics was supported by animal models of MS (14, 15). In most instances, striking sequence homology between EBNA1 and the respective CNS mimic was identified. Interestingly, most mimics are concentrated in a narrow region on EBNA1 between the second glycine-arginine repeat region and the C-terminal DNA binding domain (amino acid residues ~AA380–450). Elevated antibody reactivities against this region are strongly associated with MS (2, 18–21).

Here, we follow up on our initial data that described cross-reactivity between EBNA1 and GlialCAM. We utilized a bead-based assay to screen for IgG reactivity against EBNA1 and GlialCAM in a large cohort that included plasma samples of 650 MS patients and 661 sex- and age-matched population-based controls (Table 1). EBNA1 and GlialCAM proteins were included, as well as individual peptides spanning the regions of interest, and differential levels of reactivities and the individual relationships between reactivities against each region were evaluated. The data corroborate our prior studies in that MS risk is associated with elevated antibody levels against EBNA1 AA386-405 and GlialCAM AA370-389 and the adjacent regions of both proteins. Antibody reactivities against the broader regions of both proteins are strongly associated with each other. Anti-GlialCAM reactivity against the initially described peptide epitope GlialCAM AA370-389 can be blocked with the EBNA1 peptide AA386-405, confirming the presence of cross-reactive antibodies. However, the antibody response against GlialCAM extends beyond this narrow region and encompasses adjacent peptide regions, likely generated by epitope spreading (22, 23).

In addition, we correlate antibody reactivity with allele dose of HLA-DRB1*15:01, the strongest MS risk allele. HLA-DRB1*15:01 conveys a fourfold (heterozygous) and eightfold (homozygous) increased risk for developing MS (6). The allele shapes the adaptive immune response by enabling preferential presentation of certain peptide antigens on antigen-presenting cells (APC). B cells are effective APCs for their cognate antigens and can promote autoreactive CD4 T cell responses. CD4 T cell help, in turn, promotes maturation of B cells and secretion of antibodies. Enhanced binding of myelin antigens and CD4 T cell responses against CNS antigens have been shown (24, 25), and recent data suggest that the HLA-DRB1*15:01 allele facilitates cross-presentation of intracellular EBV antigens in EBV-infected B cells to be presented on HLA class II (26). HLA-DRB1*15:01 could be an important factor that facilitates the development of molecular mimicry from an anti-EBNA1 antibody response toward GlialCAM. We show that positive HLA-DRB1*15:01 status together with elevated antibody reactivity against EBNA1 and either GlialCAM, CRYAB, or ANO2 synergistically increases the risk for MS.

N. Sattarnezhad, I. Kockum, O.G. Thomas, Y. Liu, P.P. Ho, A.K. Barrett, A.I. Comanescu, T.U. Wijeratne, P.J. Utz, L. Alfredsson, L. Steinman, W.H. Robinson, T. Olsson, & T.V. Lanz (2025)
Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls
Proc. Natl. Acad. Sci. U.S.A. 122 (11) e2424986122, https://doi.org/10.1073/pnas.2424986122.

Copyright: © 2025 The authors.
Published by the National Academy of Sciences of the USA. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

Creationists often attempt to explain the existence of harmful pathogens like the Epstein-Barr virus (EBV) by invoking "genetic entropy"—a scientifically baseless concept rooted in the equally meaningless notion of "devolution," popularized by Michael J. Behe. By suggesting that "sin" allows genetic entropy to degrade an originally perfect genome, they inadvertently reveal the religious underpinnings of Intelligent Design (ID), despite years of insisting otherwise.

However, in the case of multiple sclerosis (MS), the real issue isn’t the virus itself but the immune system’s response to it. From an Intelligent Design perspective, this presents a problem: it’s not just the supposed designer of the virus that appears malevolent, but the designer of the immune system that seems profoundly incompetent. Why would an intelligently designed immune system attack the body’s own nervous tissue in response to a common virus?

Of course, the ID movement avoids these questions because they expose the flaws in their ideology. Instead, "Cdesign Proponentists" would rather insist on a bungling or cruel designer than acknowledge that the scientific theory of evolution provides a far more coherent explanation—one rooted in natural processes rather than theological rationalizations.

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