hold on a ‘seq’: rna for t1d biomarkers

hold on a ‘seq’: rna for t1d biomarkers

By: Hadeel Saab

Biological research was taken to the next level with next-generation sequencing, a technology that allows for analysis of genome expression by looking at RNA. This type of analysis brings huge insight into the pathophysiology and diagnosis of diseases, and researchers have done just that. 

Flare ups

One study used RNA-seq technology to analyze blood samples of four patients with rheumatoid arthritis (RA) over a period of four years. RA is known for being highly erratic — patients are stable one moment and having flares the next. Because of its long-term nature, this study was able to identify consistent changes in the blood transcriptional profiles in the weeks leading up to RA flares. Here’s what they found:

  • Spikes of RNA signatures Antecedent Cluster 2 (AC2) and Antecedent Cluster 3 (AC3) were found in peripheral blood 1-2 weeks before a flare:
    • First came a spike of AC2 transcripts enriched with developmental pathways for naive B-cells and leukocytes, which was in line with other research finding autoreactive naive B-cell activity in RA patients.
    • Second came a spike of AC3 transcripts enriched for cartilage morphogenesis, endochondral bone growth and extracellular matrix organization pathways, suggesting the presence of PRIME (pre-inflammatory mesenchymal) cells. 
  • Put together, the researchers proposed a model in which B-cell immune activation (detected as AC2) acts on PRIME cells (detected as AC3) that move through the blood to the synovial sublining, where they contribute to the inflammatory process.

Another study used unbiased whole blood RNA-seq to understand why some individuals with T1D lose their pancreatic beta cell function more quickly than others. Upon analysis of targeted cell counts, the researchers developed “immunotypes,” or immune phenotypes, to characterize common trends among the patients. 

    • Patients with quicker T1D onset had higher levels of B cells and lower levels of neutrophils.
      • These cell counts were also age-dependent, and specifically B cell levels predicted the rate of progression in young subjects (more B cells meant quicker progression).
  • What does this mean? This supports the idea that B-cell therapy in young patients with high B-cell counts would be effective.
    • In fact, clinical trials of rituximab (to treat RA) did just this, and data supports this treatment option focusing on immunological and age differences in patients.

Overall, RNA sequencing has added to researchers’ understanding of the development and progression of inflammatory diseases. The ability to locate biomarkers of disease heterogeneity and progression will be critical in individualizing treatment options for patients with T1D. 

Sources:

  • Dufort, M. J., Greenbaum, C. J., Speake, C., & Linsley, P. S. (2019). Cell type–specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetes. JCI insight, 4(4).
  • Orange, D. E., Yao, V., Sawicka, K., Fak, J., Frank, M. O., Parveen, S., … & Troyanskaya, O. G. (2020). RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares. New England Journal of Medicine, 383(3), 218-228.
  • Van Vollenhoven, R. F., Emery, P., Bingham, C. O., Keystone, E. C., Fleischmann, R., Furst, D. E., … & Rao, R. (2010). Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials. The Journal of rheumatology, 37(3), 558-567.

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