Scientists have long queried the causes of immune disorders in only one of two identical twins with identical genes. New research from the Wellcome Sanger Institute, the Josep Carreras Leukaemia Research Institute in Spain, and collaborators, has found the answer lies in both alterations in immune cell-cell communication and the epigenome, the host of biological processes that regulate how our genes function.

Their newly reported work represents what is claimed to be the first cell atlas to categorize common variable immunodeficiency (CVID) at the single-cell resolution. Researchers found that “communication problems” resulting from defects in B cells and other immune cell types impaired immune response, highlighting a number of pathways that are promising targets for epigenetic treatments. In addition, they also identified major defects in the epigenome.

Javier Rodríguez-Ubreva, PhD, a research scientist from the Josep Carreras Leukaemia Research Institute, explained, “The human immune system is not a static entity and communication between immune cells is vital for it to work effectively. We can see in healthy individuals how cells talk to each other and from there identify where communication breaks down in individuals with CVID. In the immune system this cell-to-cell communication is critical to define the ability of B cells to mature and produce antibodies.”

Rodríguez-Ubreva is lead author of the team’s paper in Nature Communications, which is titled, “Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses.” In their paper, the team stated, “Our data indicate prevalent and widespread alterations affecting DNA methylation and chromatin accessibility of memory B cells, and provide evidence that these changes impact the transcriptome of these cells following activation.”

CVID encompasses a range of immune disorders that are caused by a reduced ability to produce protective antibodies, leaving the individual vulnerable to persistent or repeated infection. People with CVID usually have low immunoglobulin levels due to problems with the B cells that create them. “A high proportion of CVID patients have a low frequency of memory B cells,” the authors wrote. “In fact, CVID is mainly considered to be a humoral immunodeficiency, although several immune cell types might be affected.”

CVID is usually detected sporadically in patients with no family history of immunodeficiency, but for about 10% of patients a close family member may also be hypogammaglobulinemic, or exhibit selective IgA deficiency, the team noted. Moreover, they pointed out, “the existence of a genetic component in CVID has been recognized for decades, and next-generation sequencing has revealed a number of pathogenic genes.”

Even so, the researchers continued, “CVID pathogenesis remains largely unexplained … The absence of mutations for a high proportion of CVID patients together with the incomplete disease penetrance for those harboring mutations suggest the operation of additional, as yet undefined, mechanisms (e.g., polygenic, epigenetic, and environmental contributors) that help determine the CVID clinical phenotype.”

Around 20% of CVID cases can be attributed to a defect in a gene associated with the condition. But with four in five cases remaining largely unexplained, scientists have predicted that other factors must be involved. This was confirmed by a recent study, which linked CVID to DNA methylation, an epigenetic process that turns the level of a particular gene up or down.

Though identical twins share the same genome, most will be born with a small number of genetic and epigenetic differences and the number of variations will increase over their lifetime. But where one twin experiences a health problem that their sibling does not, in most cases genetic differences alone cannot explain why this has occurred. “Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease,” the investigators pointed out.

For the newly reported study, the investigators generated single-cell data to investigate epigenetic factors involved in CVID. Samples were taken from a pair of identical twins, only one of whom suffered from CVID, as well as a wider group of CVID patients and healthy individuals.

Analysis of the identical twin participants found that not only did the sibling with CVID have fewer B cells, but that B cell defects resulted in epigenetic problems with DNA methylation, chromatin accessibility, and transcriptional defects in memory B cells themselves. In addition, researchers found massive defects in the cell-to-cell communication required for the immune system to function normally. “Our findings demonstrate that the transcriptional program of activated B cells is compromised in the CVID twin and that CVID-associated epigenetic alterations might contribute to transcriptional perturbations that occur during B-cell response,” the investigators noted.

The researchers compared the epigenetic changes and cell-to-cell communication problems found in the twin suffering from CVID against a wider CVID cohort and found that the problems were the same, providing a solid model for characterizing the disease. The challenge now will be to use these insights to develop new treatments.

“Our data indicate prevalent and widespread alterations affecting DNA methylation and chromatin accessibility of memory B cells, and provide evidence that these changes impact the transcriptome of these cells following activation,” the authors concluded. “These epigenetic and transcriptional alterations show defective immune cell-cell communication, which may explain the impaired immune responses observed in these patients.”

Senior study author Esteban Ballestar, PhD, a group leader at the Josep Carreras Leukaemia Research Institute, said: “This is the first of many studies that will look at CVID and other primary immunodeficiencies in the attempt to identify new therapies for treating these disorders. We already have viable options, such as immunoglobulin replacement therapy, which I would hope can be adapted to address the specific B cell defects that we have identified here.”

As well as immunoglobulin replacement therapy, epigenetic drugs can also be used to treat immune disorders and the findings of this study highlight a number of biological pathways worthy of further investigation for new drug targets.

Roser Vento-Tormo, PhD, a senior author of the study and group leader from the Wellcome Sanger Institute, said: “This is the first cell atlas to categorize common variable primary immunodeficiencies and will be a valuable contribution to the Human Cell Atlas initiative to map every cell type in the human body. What this study in particular shows is how quickly cell atlas data can be applied to better understand specific health challenges and open up new avenues of treatment.”

The authors further stated, “Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.”

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