Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed RA

[AndyPR]

Thought this might be interesting, especially in light of Mark Davis' recent talk on T cells. Please note though that I have no real understanding of what I'm reading here.

Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis

Abstract
Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.

Open access at https://www.nature.com/articles/ncomms15869

 

[Philipp]

Serious question: What does the 'somatic' modifier do there? Is it to distinguish from 'genetic' or something (i.e., a somatic mutation being something that has 'manifested as tissue' or whatever)?

 

[melihtas]

Wikipedia

Somatic mutations

A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a somatic cell genetic mutation or acquired mutation.

Somatic mutations are not inherited because this type of mutation does not affect the reproductive cells (sperm and egg) but it can affect any other type of cell. These types of mutations are usually prompted by environmental causes, such as ultraviolet radiation or any exposure to certain harmful chemicals. This type of mutation can cause various diseases; a common one is cancer.

 

[lansbergen]

Serious question: What does the 'somatic' modifier do there? Is it to distinguish from 'genetic' or something (i.e., a somatic mutation being something that has 'manifested as tissue' or whatever)?

It is an aquired mutation not present in every cell.

 

[RogerBlack]

It is an aquired mutation not present in every cell.

However certain cells in the body (t-cells) for example, are cloned from one prototype cell - this is how much of the immune system that reacts to specific things works.

So, a mutation can be significant to the patient, because it can end up massively multiplied.
This happens in cancer, though in that case, the multiplication is not intended by the body, which causes seperate issues.

 

[melihtas]

However certain cells in the body (t-cells) for example, are cloned from one prototype cell - this is how much of the immune system that reacts to specific things works.

So, a mutation can be significant to the patient, because it can end up massively multiplied.
This happens in cancer, though in that case, the multiplication is not intended by the body, which causes seperate issues.

As far as I understand, according to the paper, the mutations are not present in the original t cells, they are created during clonal expansion, so, something in the serum must be causing it like Ron Davis said.

Figure 6: Hypothesis for the accumulation of somatic mutations.

​

Mature T cells undergo thymic selection, and during the expansion phase after antigen stimulation, mutation(s) occur (1st mutation). When the cell population continues to grow, additional mutations may arise in the same clone, thereby resulting in different VAFs in the same clonal population. In our patient cohort, CD4+ cells presented a more equally distributed T-cell repertoire than did CD8+ T cells (analysed with flow cytometry), and we did not find any somatic variants in CD4+ cells. APC, antigen-presenting cell; DN, double negative; DP, double positive; SP, single positive; MHC, major histocompatibility complex.