The study documented 205 cetacean stranding events involving 281 animals during 2023. This was more than 15 times the average of approximately 18.5 stranded cetaceans recorded annually in Chile between 2014 and 2022, when two unusually large events involving 373 sei whales in 2015 and 124 pilot whales in 2016 were excluded. The animals represented at least 19 species, with long-beaked common dolphins the most frequently recorded at 56, followed by Burmeister’s porpoises at 40, dusky dolphins at 33, Chilean dolphins at 18, bottlenose dolphins at 17 and sei whales at 16. Most events involved one animal: 171 were single strandings, while 34 involved between two and nine animals.

Of the 281 stranded animals, 271 were found dead and 10 were alive when reported. Eight of the live animals subsequently died, while two were successfully released from entanglement. Most carcasses, 248, were described as being in normal body condition, whereas 33 showed clear emaciation. Sixty-six were in an advanced state of decay and could not be classified to species level. Cases occurred in 14 of Chile’s 15 administrative coastal regions, with Arica, the northernmost region, accounting for 152 cases. The study’s spatial analysis identified two high-risk clusters in northern Chile, where cetacean strandings and HPAIV-positive wild birds overlapped in time and geography, but neither cluster was statistically significant at p greater than 0.05.

Investigators sampled 27 stranded cetaceans from 13 species at 26 locations across 11 administrative regions. Selection was constrained by carcass freshness, location, logistical capacity and, in some cases, concerns about human health risk; it was not a random or population-representative sample. Swabs were collected from the spiracle, genital area and/or rectum, pooled for each animal in viral transport medium and initially tested for generic influenza A virus with a commercial diagnostic kit. Investigated results were then examined through real-time reverse-transcription PCR assays designed to detect H5 viruses of clade 2.3.4.4, determine their pathogenic classification and identify the N1 subtype. The sample represented less than one-tenth of all 281 animals recorded during the year.

Four of the 27 sampled cetaceans, or 18.5%, were positive for HPAIV H5N1 in swabs. They were two of five Burmeister’s porpoises sampled in northern Chile and two of five Chilean dolphins sampled in south-central Chile, with each positive animal coming from a different location. This amounted to a positivity rate of approximately 40% within each of those two species groups. The other swabbed animals were negative. Cycle-threshold values for generic influenza A detection ranged from 17.9 to 25, while the clade-specific, pathotyping and N1-subtyping assays produced values in the ranges of 18–27, 21–24 and 17–30, respectively. These findings represented the first reported detections of HPAIV H5N1 in Burmeister’s porpoises and Chilean dolphins.

The fifth infected cetacean was a long-beaked common dolphin initially found alive but which died shortly after stranding. Its carcass was recovered two days later because of logistical limitations and was moderately decomposed. Gross examination showed trauma associated with the stranding, including subcutaneous hemorrhages, as well as lung congestion and alveolar edema. No parasites or other major abnormalities were found in the thorax or abdomen, and no viral RNA was detected in the available swabs. After H5N1 was detected in tissue, investigators examined formalin-fixed, paraffin-embedded sections by histology and immunohistochemistry and used PCR and sequencing to examine archived tissue. The animal’s exact cause of death was not established.

PCR detected HPAIV H5N1 in two of eight tissue samples from the common dolphin: one lung section, with a cycle threshold of 37, and a brain section, with a value of 29. Sequencing of an approximately 150-base-pair amplicon identified the H5 subtype of clade 2.3.4.4b. The resulting partial consensus sequence showed 96.05% identity with avian sequences from Chile, Peru, Brazil and Texas, and 95.39% identity with avian sequences and South American sea lion sequences from Chile and Brazil. The researchers emphasized that this limited sequence was obtained to confirm viral presence and was not a comprehensive genetic analysis of the virus circulating in cetaceans. The available evidence therefore did not resolve how the virus reached individual animals or whether cetaceans played a broader role in transmission.

Histology revealed mild, multifocal leptomeningitis in the dolphin’s brain, with lymphoplasmacytic and histiocytic inflammation, occasional neutrophils and leukocytosis. The pattern was considered compatible with a leptomeningoencephalitis, but common alternative infectious causes—including cetacean morbillivirus, Toxoplasma gondii and Brucella species—were excluded by molecular testing. The observed infiltrates were therefore judged more likely to be related to HPAIV H5N1 in conjunction with the positive tissue PCR results, but they were nonspecific. The authors also noted the absence of perivascular cuffing and neuronal necrosis in the gray matter of the cerebral hemispheres, two pathological features commonly associated with avian influenza infection of the central nervous system. More severe lesions might also have been present in regions that were not sampled.

Immunohistochemistry found no influenza A viral antigen in the examined tissues. The investigators said this could reflect the sensitivity limits of the method in formalin-fixed material, a viral load below its detection threshold, severe lesions in unsampled regions or differences between molecular and antigen-based testing. The brain inflammation might be compatible with neurological impairment that contributed to the dolphin’s live stranding, and video evidence suggested possible neurological involvement, but the pathological findings were too mild to establish the cause of death. The authors therefore retained an inconclusive interpretation for both the stranding and death, emphasizing that the dolphin also had trauma and that histopathology could not directly connect H5N1 infection with neurological signs.

Spatial analysis found two nonsignificant high-risk clusters in northern Chile where cetacean strandings overlapped geographically and temporally with HPAIV-positive wild birds. Because both clusters had p values greater than 0.05, the analysis did not demonstrate a causal relationship or a statistically robust concentration of mortality. The correspondence nevertheless supports the possibility that the virus circulated in coastal marine ecosystems while cetaceans were stranding at an elevated rate. Wild birds are considered a plausible infection source because large numbers of seabirds tested positive during the outbreak, while surface feeding and shared coastal habitats could provide opportunities for environmental exposure. The available evidence did not directly establish transmission from birds to any of the cetaceans. HPAIV H5N1 had previously been reported in a bottlenose dolphin in Florida, a long-beaked common dolphin in Peru and a harbor porpoise in Sweden, but the Chilean findings extended detection to two additional species and provided the first evidence in this outbreak across several cetacean taxa.

The investigation had important constraints. Restrictions on access to stranding sites, concerns about the virus’s zoonotic potential, shortages of personnel and the scale of the seabird mortality emergency sharply curtailed sampling. In addition, necropsies were prohibited during the outbreak except when performed through public services, leaving only one cetacean available for detailed pathological investigation. The 18.5% positivity rate among the constrained sample cannot represent infection prevalence among all stranded cetaceans, nor does it show that H5N1 was responsible for the overall increase in strandings. Environmental contamination, unusual mortality events associated with harmful algal blooms, vessel collisions, fishing or aquaculture gear and other known causes of cetacean mortality also remained relevant. The study was therefore an epidemiological field report rather than a controlled test of viral pathogenicity, and its findings document an emerging cross-species exposure while leaving the causes of Chile’s unusual 2023 stranding increase unresolved.

Subject of Research: Epidemiological detection of HPAIV H5N1 in stranded cetaceans during Chile’s 2023 outbreak

Article Title: Highly pathogenic avian influenza virus H5N1 infection in stranded porpoises and dolphins in Chile

Article References: Ulloa, M., Neira, V., Sierra, E., Colom-Rivero, A., Muñoz, G., Johow, M., Lillo, F., Rojas, D., Ortega, R., Alegría-Morán, R., & Fernández, A. (2026). Highly pathogenic avian influenza virus H5N1 infection in stranded porpoises and dolphins in Chile. Frontiers in Veterinary Science, 13, 1969182. https://doi.org/10.3389/fvets.2026.1969182

Image Credits: AI Generated

DOI: 10.3389/fvets.2026.1969182

Keywords: HPAIV H5N1, Chile, cetacean strandings, Burmeister’s porpoises, Chilean dolphins, common dolphins, avian influenza, wildlife surveillance, marine mammals, viral pathogenesis, Highly, pathogenic

A new study led by researchers from the U.S. Geological Survey, the University of Georgia’s Southeastern Cooperative Wildlife Disease Study, the U.S. Fish and Wildlife Service, and the California Waterfowl Association offers a detailed portrait of infection and immunity in the waterfowl and waterbirds of northern California’s Sacramento National Wildlife Refuge Complex (SNWRC). Published in Frontiers in Cellular and Infection Microbiology, the research leveraged ongoing capture efforts for movement ecology studies between October 2022 and July 2025 to sample wild birds for both active viral infection and serological evidence of previous exposure. The results reveal a population largely carrying the immunological fingerprints of H5N1 exposure, alongside surprising evidence that some sympatric waterbird species may be far less engaged with the virus than their duck and goose neighbors.

The SNWRC spans roughly 70,000 acres of managed wetlands in the Sacramento Valley and serves as critical habitat for migratory and wintering waterfowl in the Pacific Flyway. Sacramento National Wildlife Refuge alone has historically hosted an estimated 16 percent of California’s wintering ducks, or 10 to 15 percent of the Pacific Flyway’s population. This extraordinary density of birds makes the complex a natural laboratory for avian influenza surveillance—and a place where the consequences of HPAI incursion have been painfully visible. A mortality event from June 2022 through January 2023 killed an estimated 100 Snow Geese, with smaller losses among Mallards, Gadwall, Canada Geese, and even American White Pelicans. A subsequent outbreak from December 2023 through January 2024 killed over 1,100 Snow Geese and 200 Ross’s Geese. Beyond mortality, some infected Snow Geese have failed to migrate or delayed their departure, extending the ecological footprint of the virus.

Between October 2022 and July 2025, the team captured assorted waterbirds—ducks, geese, coots, and stilts—using rocket nets and air boats with dip nets during targeted sampling windows in July, October, and December. Each bird received a federal metal band, and paired oropharyngeal and cloacal swabs were collected using sterile polyester-tipped applicators and placed in cold virus transport medium. When study parameters allowed, blood was drawn from the jugular vein, centrifuged to separate serum, and archived for antibody testing. All birds appeared healthy at the time of processing, with no clinical signs typical of HPAI infection. Laboratory work proceeded on two fronts: viral RNA was extracted from swabs and screened by real-time reverse transcriptase PCR targeting the influenza A virus matrix gene and the clade 2.3.4.4b H5 hemagglutinin, while serum samples were heat-inactivated and tested with a commercial blocking enzyme-linked immunosorbent assay (bELISA) for antibodies to influenza A viruses (IAVs).

The scale of the effort was substantial: 384 swab samples and 204 sera from assorted waterfowl and waterbird species were analyzed. Yet active HPAI H5N1 infection was confirmed in only three individuals—two Snow Geese and one Greater White-fronted Goose—all asymptomatic at capture. The National Veterinary Services Laboratory confirmed all three detections as clade 2.3.4.4b HPAI H5N1. A B3.6 genotype virus was isolated from the Greater White-fronted Goose sample, while the Snow Goose samples failed to meet the cycle threshold at which virus isolation is attempted. The near absence of detectable infection across three years of sampling, in a refuge that has experienced repeated HPAI mortality events, immediately raised the question of what the serological data might explain.

The antibody results were striking. Of 164 waterfowl tested, 107 (65 percent) tested positive for antibodies to IAVs; among 40 additional waterbirds, 12 (30 percent) were positive. Antibodies were detected in all duck and goose species sampled, and the majority of positive samples also carried antibodies specific to both the H5 hemagglutinin and the N1 neuraminidase—the two surface proteins of the circulating H5N1 strain. In ducks sampled during October, the proportion of IAV antibody-positive birds carrying both H5 and N1 antibodies remained high and relatively constant, at 64 percent in 2023 and 80 percent in 2024. A remarkable 88 percent of ducks sampled in July 2025 also carried antibodies to both proteins. This pattern indicates a population-level history of substantial exposure to H5N1 and subsequent survival, consistent with findings from numerous duck species in the Mississippi Flyway, where H5 and N1 antibodies increased dramatically following the 2.3.4.4b incursion.

The study also reports the first known observation of H5 antibodies in the American Coot (Fulica americana), a waterbird species not traditionally associated with influenza A virus circulation. However, both overall IAV seroprevalence and H5-specific antibodies in coots were notably lower than in sympatric waterfowl: IAV antibody prevalence fell from 54 percent in 2023 to 24 percent in 2024, and only 14 to 20 percent of antibody-positive coots carried both H5 and N1 antibodies. Black-necked Stilts showed similarly minimal antibody detection, though sampling was especially limited for this species. The disparity between coots and the ducks and geese sharing the same aquatic habitats cannot be directly explained by the data, but the authors suggest two possibilities: coots may have lower innate susceptibility to infection, or they may exhibit behaviors that limit exposure. A survivorship bias—in which most exposed individuals died—seems unlikely given the low number of American Coot mortalities reported during the outbreak.

Translating antibody prevalence into population immunity is complicated, but experimental studies offer a framework. Sequential challenges with low pathogenic (LP) and highly pathogenic (HP) IAVs have shown that previous exposure can reduce infection, mortality, and viral shedding during subsequent infections with both LP and HP H5 viruses. The relatively high level of subtype-specific immunity observed in ducks—up to 80 percent carrying both H5 and N1 antibodies—may partially explain the near absence of detectable HPAI H5N1 infection during the study years. The authors caution, however, that the serologic techniques used cannot determine whether H5 or N1 antibodies result solely from HP H5N1 exposure; they likely represent a history of exposure to both HP and LP H5 viruses, and LP H5 viruses are known to circulate commonly in these wetlands, potentially maintained locally by non-migratory waterfowl. Cross-reactive antibodies and antigenic imprinting may also mask antigenic differences between LP and HP H5 viruses, preventing definitive estimation of specific exposure history.

The findings also validate the bELISA screening threshold used in the study. A serum-to-negative control absorbance ratio below 0.7 proved an effective guide for further serotyping: while some individuals above the threshold tested positive for H5 and N1 antibodies, this represented only a small percentage of samples. The authors note that test sensitivity may vary over time and among testing formats, and that the timing of infection before sampling cannot be known, but the threshold should not introduce significant error in detecting subtype-specific antibodies. This methodological validation matters for surveillance programs considering serology as a complementary tool to the U.S. national active surveillance strategy, which focuses on viral detection in waterfowl and does not include species such as coots.

Overall, the study underscores the value of serologic surveillance as a supportive strategy for informing HPAI H5N1 risk management in wild birds. The high level of IAV immunity in waterfowl suggests, based on experimental evidence, a reduced potential for widespread or seasonally concentrated mortality in these populations. Results from coots and stilts highlight the species differences that exist in exposure and potential risk at a given site and time—and the possibility that some species remain essentially immunologically naïve and susceptible, even when the virus circulates intensively among sympatric waterfowl. The authors emphasize that additional sampling across subsequent seasons is needed to understand how these immunological baselines shift, but the data provide a critical portrait of the years immediately following the clade 2.3.4.4b incursion in the Pacific Flyway. As HPAI H5N1 continues to evolve and expand its host range across North America, studies like this one—integrating virology, serology, and ecology in a single surveillance framework—will be essential for anticipating where the virus will strike next and which species will bear the burden.

Subject of Research: Highly pathogenic H5N1 avian influenza infection and exposure in waterfowl and waterbirds of the Sacramento National Wildlife Refuge Complex, 2022-2025

Article Title: Highly pathogenic H5N1 avian influenza infection and exposure in waterfowl and waterbirds of the Sacramento National Wildlife Refuge Complex, 2022-2025

Article References: Sullivan, J. D., Poulson, R. L., Casazza, M. L., Matchett, E. L., D’Errico, M., Bundy, A., Chappell, J., Mackell, D., Mott, A., Overton, C. T., Stallknecht, D. E., & Prosser, D. J. (2026). Highly pathogenic H5N1 avian influenza infection and exposure in waterfowl and waterbirds of the Sacramento National Wildlife Refuge Complex, 2022-2025. Frontiers in Cellular and Infection Microbiology, 16, Article 1993811. https://doi.org/10.3389/fcimb.2026.1993811

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1993811

Keywords: Highly, pathogenic, H5N1, avian, influenza, infection, exposure, waterfowl, waterbirds, Sacramento, National, Wildlife

The SLC29A3 gene encodes equilibrative nucleoside transporter 3, or ENT3, a protein essential for shuttling nucleosides across lysosomal and mitochondrial membranes. When biallelic mutations disrupt this transporter, the result is a multisystem disorder historically described under separate names, including H syndrome, Faisalabad histiocytosis, pigmented hypertrichosis with insulin-dependent diabetes, and familial Rosai-Dorfman disease. These entities are now recognized as a single clinical spectrum characterized by overlapping features such as histiocytic infiltration, lymphadenopathy, hyperpigmentation, hypertrichosis, and endocrine dysfunction. The clinical phenotype is remarkably diverse, with significant variability both between and within families, which often leads to delayed diagnosis, particularly in adults.

Born to first-degree cousin parents, the patient presented with a lifelong history of recurrent severe lower respiratory tract infections requiring multiple hospitalizations since childhood. She also suffered from chronic vomiting and recurrent nephrolithiasis, having previously undergone ureteroscopic lithotripsy and double-J stent placement. On physical examination, she exhibited significant growth failure, with height and weight below the 3rd percentile for her age. She had microcephaly, dysmorphic facial features, long and dense eyelashes, and generalized hirsutism. Skeletal findings included bilateral hallux valgus and mild flexion contractures of the fingers. Notably, her cognitive development was fully preserved.

Laboratory investigations revealed severe hypogammaglobulinemia, with IgG below 320 mg/dL against a reference range of 700 to 1600 mg/dL, IgA below 25 mg/dL against a reference of 70 to 400 mg/dL, and IgM below 25 mg/dL against a reference of 40 to 230 mg/dL. Hematologic evaluation showed microcytic anemia associated with iron deficiency. Liver function tests showed mildly elevated transaminases. Endocrine evaluation confirmed severe vitamin D deficiency with secondary hyperparathyroidism, although diabetes screening, including fasting blood glucose and HbA1c, was normal at the time of presentation. Chest computed tomography demonstrated chronic post-infectious small-airway changes, minimal bronchiectasis, and segmental consolidation in the right middle lobe. Abdominal imaging revealed right ureteric stones with associated hydronephrosis and a chronically small right kidney.

Genetic testing via whole-exome sequencing identified a homozygous missense variant in SLC29A3: c.1309G>A, resulting in the amino acid substitution p.Gly437Arg. The variant was classified as pathogenic according to American College of Medical Genetics and Genomics criteria and confirmed by Sanger sequencing. Parental segregation analysis was not performed because the parents were unavailable for testing. Copy-number variant analysis using an internally validated pipeline yielded no additional significant findings, establishing a diagnosis within the SLC29A3-related disorder spectrum.

The p.Gly437Arg variant identified in this patient is a known pathogenic allele frequently reported in Palestinian and Arab populations. In the original gene-discovery study, the variant was identified in several geographically clustered Arab families, and haplotype analysis showed a shared disease-associated haplotype among the analyzed families, consistent with a shared origin of the variant. Despite carrying a recurrent variant, this patient’s phenotype is notable for several reasons that expand the known clinical spectrum of the disease.

First, the severity of the immunologic phenotype is exceptional. While immunodeficiency and recurrent infections are recognized features of the SLC29A3-related disorder spectrum, the degree of hypogammaglobulinemia observed here, with nearly undetectable IgA and IgM and severely low IgG, is unusual. This raises the possibility that ENT3 deficiency may influence B-cell maturation or function, although the underlying mechanism remains unclear. Second, the associated renal manifestations, specifically recurrent nephrolithiasis and a small kidney, are noteworthy. Renal involvement has been reported in approximately 6 percent of cases within the spectrum, including hydronephrosis and renal asymmetry. It remains unclear whether these findings are a direct consequence of ENT3-related metabolic dysfunction or secondary to chronic inflammation and infection.

Following the diagnosis, a multidisciplinary management plan was initiated. Immunoglobulin replacement therapy was recommended and initiated, leading to a reduction in the frequency of respiratory infections during the initial six months of follow-up. The patient also received vitamin D supplementation and was referred to nephrology for management of recurrent stones and to endocrinology for ongoing diabetes surveillance. Comparison with previously reported cases of the same variant reveals significant phenotypic heterogeneity. While some patients present with predominant cutaneous and endocrine features, others exhibit a more severe immunologic and skeletal phenotype, suggesting the influence of genetic modifiers or environmental factors.

This case underscores the importance of considering the SLC29A3-related disorder spectrum in adults with longstanding multisystem disease. The combination of growth failure, skeletal anomalies, and immunodeficiency should prompt genetic evaluation even in the absence of the classic cutaneous hyperpigmentation often seen in H syndrome. Early genetic diagnosis using whole-exome sequencing is crucial for establishing a unifying diagnosis and guiding targeted multidisciplinary care, including immunoglobulin replacement therapy, which may substantially reduce infection-related morbidity, and vigilant surveillance for endocrine and renal complications. As a single case report, the study is limited by the absence of parental segregation analysis, functional studies of ENT3 activity, extended immune phenotyping, and detailed renal metabolic evaluation. Future studies are needed to determine whether nephrolithiasis is a primary metabolic manifestation of ENT3 deficiency or an incidental finding.

Subject of Research: Adult presentation of SLC29A3-related disorder spectrum with marked hypogammaglobulinemia due to a recurrent homozygous pathogenic variant (G437R): a case report

Article Title: Adult presentation of SLC29A3-related disorder spectrum with marked hypogammaglobulinemia due to a recurrent homozygous pathogenic variant (G437R): a case report

Article References: Ishqair, M. A., Masalma, A. K. H., Saleh, M., Awad, F., Khalili, A., Ishqair, A. A., Salah, S., & Saleh, A.-R. N. (2026). Adult presentation of SLC29A3-related disorder spectrum with marked hypogammaglobulinemia due to a recurrent homozygous pathogenic variant (G437R): a case report. Frontiers in Genetics, 17, Article 1904219. https://doi.org/10.3389/fgene.2026.1904219

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1904219

Keywords: Adult, presentation, SLC29A3-related, disorder, spectrum, marked, hypogammaglobulinemia, recurrent, homozygous, pathogenic, variant, G437R

The structures in question are known as artery tertiary lymphoid organs, or ATLOs. Unlike the classical lymph nodes and spleen, which develop during embryogenesis and serve the entire body, tertiary lymphoid organs arise postnatally in response to chronic inflammation at affected tissues. In atherosclerosis, they form in the adventitia, the outermost layer of the arterial wall, adjacent to plaques rich in immune cells. Previous work had established that these structures contain germinal centers, the specialized microenvironments where B cells proliferate, mutate their antibody genes, and undergo selection for increasingly potent antigen binding. What remained unknown was what these germinal centers were actually targeting, and whether the antibodies they produced mattered for disease.

To answer those questions, the research team, led by Zihao Zhang, Yue Zhang, Shu Ran, Ying Wang and colleagues, combined single-cell transcriptomic profiling with B cell receptor sequencing of germinal center B cells harvested from artery tertiary lymphoid organs. Single-cell transcriptomics allows researchers to capture the complete gene expression program of individual cells, revealing their identity, activation state, and developmental trajectory. B cell receptor sequencing, meanwhile, reads out the rearranged antibody genes carried by each B cell, providing a molecular fingerprint of the antigen-binding receptor that defines the cell’s specificity. By layering these two datasets on top of one another, the investigators could reconstruct, at unprecedented resolution, the population of B cells being educated within the arterial wall itself.

The analysis revealed a clonally expanded population of autoreactive B cells within the ATLO germinal centers, indicating that these cells had undergone the canonical process of somatic hypermutation and antigen-driven selection that normally refines antibody responses during infection or vaccination. From this population, the team cloned a monoclonal antibody, designated A6, and demonstrated that it binds with high affinity to histone 2B, or H2B, one of the core histone proteins around which DNA is wrapped in every cell nucleus. Histones are potent immunological stimuli, well known to activate innate immune pathways, but the identification of a germinal center-derived, high-affinity antibody specific for H2B within the artery wall was unexpected and mechanistically significant.

The pathogenic relevance of the finding was established through two complementary lines of experimentation. First, the researchers tested H2B vaccination: when animals were immunized with histone 2B, the resulting immune response markedly accelerated the progression of atherosclerosis, confirming that a targeted anti-H2B response is sufficient to worsen disease. Second, and more directly, the team performed adoptive transfer of the anti-H2B A6 monoclonal antibody itself. Simply delivering the purified antibody into circulation was enough to significantly speed plaque development, demonstrating that the antibody is not merely a marker of the disease process but an active driver of it.

These results carry substantial mechanistic weight because they close a causal loop. Earlier studies had documented that tertiary lymphoid organs appear in the arterial adventitia as atherosclerosis advances, and that their germinal centers become more prominent with disease severity. But correlation is not causation, and it remained possible that the local immune structures were protective, attempting to contain plaque inflammation, or merely incidental. By identifying a specific autoantibody-autoantigen pair encoded within these structures and showing that the antibody accelerates disease when transferred, the study establishes that ATLOs are not passive observers but productive factories of pathogenic humoral immunity.

The technical achievement underlying the discovery deserves emphasis. Germinal center B cells are notoriously difficult to study because they are short-lived, rapidly dividing, and spatially restricted within organized lymphoid tissue. Extracting them from the arterial wall, dissociating the tissue into single cells while preserving RNA quality, and obtaining paired heavy- and light-chain B cell receptor sequences from each cell requires meticulous single-cell handling. The successful cloning of a functional monoclonal antibody from this dataset, one that retains its specificity and pathogenic activity when expressed recombinantly, validates the entire pipeline and opens the door to systematically cataloging the full repertoire of antigens targeted within atherosclerotic ATLOs.

The identification of H2B as the target antigen also connects atherosclerosis to a broader theme in autoimmunity. Anti-histone antibodies are hallmarks of several systemic autoimmune diseases, most notably drug-induced lupus, where they bind nuclear components released by dying cells. In atherosclerotic plaques, cell death is abundant: foam cells undergo apoptosis, necrotic cores accumulate, and nuclear debris is released into the plaque microenvironment. It is plausible that this ongoing cell death provides a continuous supply of histone antigen, which drains to the adjacent adventitial lymphoid structures and drives the affinity maturation of autoreactive B cells. The new findings suggest that atherosclerosis may therefore share fundamental immunological machinery with classical autoimmune diseases, a concept that reframes how the field thinks about cardiovascular inflammation.

Therapeutically, the work suggests several possible avenues, though the researchers are careful to note that translation from experimental models to human patients will require further validation. If comparable anti-H2B responses are confirmed in human atherosclerotic arteries, the autoantibody could serve as a biomarker for identifying patients whose disease is driven by autoreactive immunity. More ambitiously, the pathways that organize and sustain artery tertiary lymphoid organs, including the lymphotoxin and chemokine networks that recruit and retain lymphocytes in the vessel wall, could become targets for interventions designed to quiet local antibody production without globally suppressing protective immunity. Given that atherosclerosis remains the leading cause of death worldwide despite aggressive lipid-lowering therapy, any mechanism that explains residual cardiovascular risk in patients is of enormous clinical interest.

The study also raises fundamental questions about how immune tolerance breaks down inside the artery. Germinal centers normally enforce stringent selection against self-reactive B cells, yet the ATLO germinal centers clearly nurtured a high-affinity autoreactive clone to maturity. Understanding why the arterial environment licenses this breach, whether through the character of the antigens presented, the cytokine milieu, or the absence of regulatory cell networks found in conventional lymphoid tissue, may reveal general principles applicable to other chronic inflammatory diseases in which tertiary lymphoid structures arise, from rheumatoid arthritis to organ transplant rejection. For now, the demonstration that a single cloned antibody targeting a nuclear protein can measurably accelerate the arterial disease that kills more people than any other stands as a vivid reminder that the immune system, in the wrong context, can be as dangerous as any traditional risk factor.

The adventitia, where these lymphoid structures take root, has long been treated as a largely passive scaffold of collagen, vasa vasorum, and resident fibroblasts. The demonstration that it can host affinity-matured humoral responses repositions this outer arterial layer as an immunologically active compartment. It also helps explain earlier observations that immune-cell clusters in the adventitia expand in parallel with plaque burden and that lymphatic vessels draining the arterial wall become more prominent as disease advances, providing a plausible route by which plaque-derived antigens reach the local immune structures.

Histone 2B belongs to a family of proteins that are normally sequestered inside the nucleus, where they package DNA into nucleosomes. When cells die, particularly through the inflammatory forms of cell death common in plaques, histones can escape into the extracellular space, where they act as damage-associated molecular patterns that stimulate innate receptors. The new work shows that this same nuclear material can also serve as a target for affinity-matured adaptive responses, linking innate danger signaling and autoreactive antibody production within a single tissue site.

The adoptive transfer result is especially informative, because it separates the antibody itself from the cells that produce it. Accelerated plaque development following antibody delivery alone indicates that circulating anti-H2B immunoglobulin is sufficient to promote disease, pointing future mechanistic studies toward how the antibody engages antigens within the vessel wall and what effector pathways it recruits once bound.

Subject of Research: Artery tertiary lymphoid organs encode a pathogenic high-affinity autoantibody−autoantigen pair in atherosclerosis

Article Title: Artery tertiary lymphoid organs encode a pathogenic high-affinity autoantibody−autoantigen pair in atherosclerosis

Article References: Zhang, C., Zhang, X., Ran, Y., Wang, Z., Li, L., Wang, S., Zheng, J., Zhang, Y., Sun, T., Li, Y., Lu, S., Hong, M., Ma, Z., Steffens, S., Hristov, M., Blanchet, X., Zhu, J., Dou, X., Deng, X., … Yin, C. (2026). Artery tertiary lymphoid organs encode a pathogenic high-affinity autoantibody−autoantigen pair in atherosclerosis. Nature Cardiovascular Research, 5(9), 869-890. https://doi.org/10.1038/s44161-026-00864-w

Image Credits: AI Generated

DOI: 10.1038/s44161-026-00864-w

Keywords: Artery, tertiary, lymphoid, organs, encode, pathogenic, high-affinity, autoantibody, autoantigen, pair, atherosclerosis, scientific research