Multiple sclerosis has long been recognized as a disease of extraordinary variability. Some patients lose the ability to walk within a decade of diagnosis, while others remain ambulant for decades. Under the microscope, the variability is just as striking: some brains are riddled with actively inflamed demyelinated lesions, while others show mostly burned-out, inactive scars. For years, this heterogeneity has frustrated efforts to draw clean lines between what pathologists see in post-mortem tissue and what clinicians observed in the patient while alive. The new research argues that the missing link may lie in donor-specific pathological features—persistent, recurring characteristics of an individual’s inflammatory and reparative biology that color everything the disease does in that person’s brain.

The research team, led by Lukas Lütje and J. Q. Alida Chen along with colleagues including Jörg Hamann, Joost Smolders, Inge Huitinga, and Aletta M. R. van den Bosch, systematically assessed brain tissue from 287 donors with confirmed MS pathology, collected between 1990 and 2021. The scale of the sampling effort is remarkable: on average, nearly 22 tissue blocks and more than 35 lesions were dissected per donor, taken from standardized locations in the brainstem, with lesions identified macroscopically or guided by post-mortem magnetic resonance imaging. Each tissue block was formalin-fixed and paraffin-embedded, then subjected to double immunostaining for human leukocyte antigen proteins (HLA-DP-DR-DQ) and proteolipid protein (PLP)—a technique that simultaneously reveals activated microglia and macrophages, the inflammatory workhorses of the disease, and the myelin they attack. Iron deposition was visualized using a DAB-enhanced Turnbull Blue staining method, adding another layer of pathological detail.

The four donor-specific features at the heart of the study each capture a different dimension of MS biology. Perivascular cuffs are exaggerated accumulations of lymphocytes—both B and T cells—crowding into the perivascular spaces of the brain, visible when at least one such space shows the hallmark buildup in any examined tissue block. Microglial nodules are small clusters of at least four ramified microglia, the brain’s resident immune cells, appearing in tissue that otherwise looks normal—the so-called normal-appearing white matter. Broad rim lesions, or BRLs, are a particularly dramatic subtype of chronic active lesion, defined by a hypercellular HLA-positive rim at least one millimeter wide surrounding a hypocellular, fully demyelinated core. And remyelination efficiency divides donors into efficient remyelinating donors and poorly remyelinating donors, based on the proportion of lesions showing repair, with a threshold set at a remyelinated lesion proportion of at least 0.27.

When the researchers crossed these pathological features with the donors’ genetic profiles, striking associations emerged. Carriers of the HLA-DRB115:01 allele—by far the strongest known genetic risk factor for multiple sclerosis, tagged by the SNP rs3135388—showed a higher prevalence of both perivascular cuffs and microglial nodules. This finding is biologically provocative: HLA-DRB115:01 encodes a molecule that presents antigens to T cells, and its association with lymphocytic cuffing suggests that the classic genetic gateway to MS risk may shape the very character of the inflammatory infiltrates in the brain decades later. Meanwhile, carriers of a severity-associated variant in the DYSF–ZNF638 locus (rs10191329), which prior genome-wide studies have linked to faster disability progression, showed enrichment of both broad rim lesions and perivascular cuffs—hinting that genetic determinants of severity may act partly by promoting more aggressive, more heavily inflamed lesion architectures.

The clinical correlations were equally revealing. Perivascular cuffs were associated with an increased microglia/macrophage activation score across the brain and with a younger age at death, suggesting that donors whose brains harbored these lymphocyte accumulations died earlier and with more widespread innate immune activation. Microglial nodules in the normal-appearing white matter—the tissue that appears spared at first glance—were associated with a higher proportion of actively inflamed lesions elsewhere, implying that these subtle clusters of immune cells may be a harbinger of a brain in which inflammatory lesion formation remains in full swing. The presence of these nodules may thus serve as an indicator of ongoing, brain-wide inflammatory activity even in regions that would never be flagged as lesions on conventional examination.

Broad rim lesions carried perhaps the weightiest clinical associations of all. Donors with BRLs showed increased proportions of both active and mixed active/inactive lesions, a higher lesion rate in the brainstem, and—a crucial finding—a higher age-related Multiple Sclerosis Severity Score, a metric that adjusts disability for age to capture how aggressively the disease has progressed. The broad rim itself is thought to represent a smoldering zone of myelin-phagocytosing macrophages at the lesion edge, and the new data reinforce the idea that these structures are engines of ongoing damage rather than passive scars. The association with brainstem lesions is particularly notable, as brainstem involvement often correlates with severe, disabling disease courses.

On the repair side of the ledger, poor remyelination efficiency painted its own distinctive portrait. Donors classified as poorly remyelinating showed a higher proportion of mixed active/inactive and inactive lesions and, tellingly, a shorter disease duration. The link with shorter disease duration is intriguing and suggests that inefficient repair may accelerate the trajectory toward severe disability and death, compressing the disease course. It may also reflect a vicious cycle in which active inflammation impairs oligodendrocyte precursor cells’ ability to rebuild myelin sheaths, leaving lesions unrepaired and vulnerable axons exposed to further injury. The loss of the protective, insulating myelin sheath ultimately leads to neurodegeneration, and the study’s authors and their predecessors have consistently shown that inflammatory lesion activity persists until death and correlates closely with that neurodegeneration.

The lesion classification system underpinning the work is itself a technical achievement. Lesions in white matter and deep grey matter were categorized by integrating innate inflammatory activity, assessed through HLA staining, with myelin status assessed by PLP staining. Reactive sites—aggregates of microglia and macrophages without demyelination—were distinguished from active lesions with dense microglial accumulation and partial myelin loss, mixed lesions with a rim of myeloid cells surrounding a quiescent core, inactive hypocellular lesions, and remyelinated lesions showing sparse inflammation and partial myelination restoration. Cortical lesions were classified by anatomical location as leukocortical, intracortical, or subpial. Against this standardized backdrop, the donor-specific features stand out as modifiers—variables that reshape the statistical landscape of lesion types and clinical outcomes rather than merely adding noise.

What makes this study transformative is its implication for how post-mortem MS research is conducted and interpreted. Rather than treating all donors with MS as members of a single pathological population, the findings argue for a stratified approach in which cuff status, nodule status, BRL presence, and remyelination efficiency are recorded alongside lesion classifications. Two donors with identical lesion loads could, in this framework, represent fundamentally different biological states—one with brisk lymphocyte-driven inflammation tied to HLA risk alleles, the other with smoldering broad-rimmed lesions tied to severity loci and a failing repair program. Pooling such donors in a typical case-control analysis would wash out precisely the signals that matter most for understanding disease mechanisms and for designing targeted therapies.

The work also resonates with the broader movement in MS research toward recognizing the disease as a spectrum of interacting pathological dimensions rather than a single entity. Prior analyses from the same cohort demonstrated that lesion load, the proportion of mixed active/inactive lesions, and microglial activation scores associate with clinical severity while also varying enormously between individuals. By showing that this inter-individual variability has genetic roots and clinical consequences, the new study closes the loop: it connects the genome to the lesion microenvironment to the bedside. Patients carrying risk or severity alleles may be pre-programmed, in a sense, to build different kinds of lesions and to repair them differently, with predictable consequences for how their disease unfolds.

For the estimated 2.9 million people worldwide living with multiple sclerosis, the clinical translation of such findings remains on the horizon rather than at hand—autopsy tissue, by definition, comes from those who have died, and the features studied here cannot yet be visualized reliably in living patients. But the biological logic they reveal is actionable. Therapies aimed at enhancing remyelination, for example, may need to be tailored differently for patients whose reparative capacity is genetically or immunologically compromised, while anti-inflammatory strategies might be stratified by whether a patient’s pathology is dominated by lymphocytic cuffing or by smoldering myeloid rims. Biomarker development, too, could take cues from these pathological dimensions, seeking surrogate markers in blood or advanced imaging that recapitulate what the microscope sees.

In the end, the study’s message is one of biological individuality made rigorous. The 287 donors of the Netherlands Brain Bank, through their extraordinary gift, have shown that multiple sclerosis is not one disease stamped identically upon every brain it touches, but a process profoundly shaped by each person’s genetic inheritance and intrinsic inflammatory and reparative character. Reading those individual signatures in the tissue—and understanding how they link risk variants, lesion architecture, and clinical fate—may finally provide the framework needed to explain, and one day to predict, why this disease takes such different courses in different lives.

Latin America has been shaped by centuries of population admixture, predominantly between Native American Indian groups and populations from Europe, along with a lesser influence from African ancestry. This rich tapestry of genetic diversity in Latin America might play a critical role in the epidemiology of MS, potentially influencing both susceptibility to the disease and its clinical manifestations among affected individuals. The interaction between genetic predispositions and environmental exposures could help to elucidate the underlying mechanisms contributing to this regional disparity in MS prevalence.

Various environmental aspects specific to the Southern Hemisphere may further contribute to the reduced incidence of MS observed in Latin America. Factors such as sunlight exposure, which is known for its association with vitamin D levels, could be pivotal. Vitamin D plays a critical

The Epstein-Barr virus is widely recognized, as it is estimated that around 90 to 95 percent of the adult population are carriers. While numerous individuals contract EBV during childhood with minimal or no symptoms, young adults may experience glandular fever. This latent phase of infection means the virus persists in the body without causing active disease, raising questions about its role in neurodegenerative disorders such as MS.

One of the standout findings of the study is the identification of the specific EBV protein EBNA1. The researchers demonstrated that antibodies generated against EBNA1 could mistakenly bind to GlialCAM, a protein found in the brain that ensures the proper functioning of neuronal support cells. This unintended immune response may be a crucial player in the autoimmune attack that characterizes multiple sclerosis, indicating that the immune system’s aggressive actions could be misdirected due to molecular mimicry.

Moreover, the research does not stop at uncovering the antibodies’ misdirected behavior, but it also explores the intersection of genetic predisposition and immune responses. The study reveals that individuals carrying the HLA-DRB1*15:01 genetic variant, commonly associated with an increased risk of developing MS, exhibit heightened risks when coupled with elevated antibody levels against EBNA1 and GlialCAM. This dual factor appears to amplify the susceptibility to MS, highlighting the complex interplay between genetics and immunological responses in disease onset.

Another significant aspect of the research is the investigation of additional proteins that share structural similarities with EBNA1. The study included assessments of antibodies aimed at other proteins like ANO2 and CRYAB, which have analogous traits to EBNA1. High levels of these antibodies were also found in MS patients, reinforcing the notion that a broader array of misdirected immune responses could be at play in the landscape of multiple sclerosis.

Elevated antibody levels against these proteins were noted in MS patients as compared to healthy controls, reinforcing the concept of an underlying immune dysregulation. The absence of protective alleles, such as HLA-A*02:01, further compounds the situation by increasing the risk when any of the antibodies against the aforementioned brain proteins are present. This nuanced understanding may pave the way for new therapeutic approaches targeting these specific immune interactions, aiming to regulate or redirect the immune response in MS patients.

In light of these findings, researchers at Karolinska Institutet are embarking on further investigations, aiming to examine blood samples collected prior to any clinical manifestation of MS. By determining when these antibodies first emerge, the researchers could potentially identify biomarkers that herald the onset of the disease. Early detection of MS is crucial for effective intervention, as it holds the promise of mitigating disease progression and refining therapeutic strategies.

Understanding the mechanistic nuances of how EBV interacts with the immune system offers a tantalizing glimpse into potential diagnostic avenues. If the antibodies discovered in this research are found to be present before the onset of MS symptoms, they could serve as critical biomarkers for pre-symptomatic detection, fundamentally changing how the disease is monitored and managed.

In the landscape of autoimmune diseases, the link between infections and subsequent immune dysfunction has been of increasing interest. Previous research has suggested that viral infections can serve as triggers for autoimmune dysregulation, a theory that finds new support in the context of EBV and MS. The current study not only reinforces this theory but also underscores the importance of investigating viral etiology in neurodegenerative diseases.

Furthermore, the study’s outcomes emphasize the pressing need for a paradigm shift in how we regard the initiation of MS. With roughly 90 percent of the global population being EBV carriers, understanding the factors that differentiate between healthy individuals and those progressing to autoimmune conditions could hold the key to prevention strategies.

The insights gleaned from this research hold significant implications for clinical practice; healthcare providers could leverage this information to screen at-risk populations more effectively and leverage personalized medicine approaches in MS treatment and intervention. Additionally, the collaborative efforts of renowned institutions demonstrate the power of interdisciplinary research in tackling complex health challenges that have long puzzled the scientific community.

Ultimately, the findings pave the way for future research initiatives aimed at disarming the autoimmune responses that plague MS patients. As the interaction between EBV, genetic susceptibility, and the autoimmune response is further elucidated, the potential for groundbreaking diagnostic and therapeutic tools emerges, promising to transform the trajectory of multiple sclerosis management.

Subject of Research: Human tissue samples related to multiple sclerosis and the association with Epstein-Barr virus antibodies.

Article Title: Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls.

News Publication Date: March 10, 2025.

Web References: DOI link to article

References: Neda Sattarnezhad et al., PNAS (Proceedings of the National Academy of Sciences)

Image Credits: Not available.

Keywords: Multiple sclerosis, Epstein-Barr virus, antibodies, genetic risk factors, biomarkers, autoimmune disorders, neuroscience, immunology, viral infections, human brain, neurodegeneration, MS research.