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Uncovering the mechanisms behind autoimmunity in Down’s syndrome

A study, recently published in Nature, has revealed the mechanisms underpinning autoimmune susceptibility in individuals with Down’s syndrome. The researchers identified chronic expression of certain immune cells, particularly those that can be described as “autoimmune-prone”.

Trisomy 21

Down’s syndrome, or trisomy 21, is caused by the presence of an extra copy of chromosome 21 and the 200 genes it encodes. It is the most common chromosomal aberration globally and is thought to affect around 1 in 700 infants. The condition is characterised by various symptoms including learning difficulties. However, a lesser known (yet often severe) aspect of Down’s syndrome is an increased susceptibility to infectious diseases and autoimmune conditions. Despite research in recent years identifying some drivers of immune dysfunction in individuals with Down’s syndrome, the puzzle remains incomplete.

To address this, a team of researchers from the Icahn School of Medicine assessed plasma samples from individuals with Down’s syndrome. In their analysis, they identified rogue immune cells that may explain the phenomenon of increased autoimmune susceptibility.

Heightened immunity

The first stage of the study was an analysis of the immune landscape in those with Down’s syndrome at the basal level, in the absence of any infections. A cytokine array of 29 markers revealed that many of the individuals had widespread, increased cytokine levels. The researchers then measured the levels in samples from patients with respiratory viruses, revealing that in many individuals with Down’s syndrome, basal levels were often similar or higher than in patients suffering from COVID-19. This implies some level of constant immune response, regardless of the presence of any disease.

Subsequently, the team identified increased proportions of activated immune cells in the Down’s syndrome group, particularly IL-6 activated T-cells and CD11c+ cells. The latter is a subset of B-cells that arise via cytokine and T-cell stimulation. They have been previously implicated in other autoimmune conditions, specifically lupus. Consequently, the team chose to further investigate the presence of CD11c+ cells in individuals with Down’s syndrome.

The CD11c+ cells derived from both the Down’s syndrome cohort and the control group had longer CDR3 lengths than other memory cells, a feature that is associated with autoimmunity. However, as there is an increased proportion of CD11c+ cells in individuals with Down’s syndrome, this would imply a heightened level of CD11c+-derived autoimmunity. In addition, the cells derived from the Down’s syndrome group were seen to express genes more closely associated with self-reactivity than those from the control group. These two features led the researchers to the conclusion that cytokine and T-cell mediated activation of CD11c+ cells was likely a major driver of increased inflammatory responses and autoimmunity in those with Down’s syndrome.

Figure 1. Graphical abstract showing the mechanism of autoimmunity in Down’s syndrome. Increased cytokine levels and activation of T-cells leads to the presence of CD11c+ cells and autoreactive antibodies. Taken from Malle et al., 2023.

Hope for the future

Despite extensive research into immune dysfunction in individuals with Down’s syndrome, the drivers behind autoimmunity have remained largely unknown. With an understanding of the underlying cause, there is now potential for autoimmune conditions in those with Down’s syndrome to be addressed at the source, rather than simply treating the symptoms. The researchers believe that existing treatments that have not yet been explored for use in Down’s syndrome could be utilised. Lead author Dusan Bugnovich stated: “Available drugs such as tocilizumab and a variety of JAK inhibitors could potentially tame this inflammation. And in patients who have elevated autoimmune prone B cells, there is an opportunity to develop therapies targeting this cell type specifically.”