Why do immune cells attack the joints, leading to rheumatoid arthritis?

Despite the important role of T cells in rheumatoid arthritis, it is not known why T cells attack joints and not other organs. Helena Soares and her group,Immunobiology & Pathogenesis, joined the clinical investigation, with the participation of 120 patients with rheumatoid arthritis from the Hospital Egas Moniz in Lisbon, collaborating with the groups of Jaime Branco and Fernando Pimentelas well, all from CEDOC-NMS.


We spoke with Helena and Daniela Saraiva, the first author of the study, to reveal the main results of this work.

What discoveries led you to the research described in your publication?

We identified a subset of T cells, a type of white blood cell, that is expanded in rheumatoid arthritis patients. What distinguishes these T cells is the fact that they express a receptor, TLR4, that is common in innate immune cells but not so much in T cells. As in innate immune cells TLR4 senses bacterial infections and tissue damage, we thought that TLR4 could be playing an important role in guiding T cells to release cytokines, proteins involved in inflammation, selectively in the joints. Reinforcing our hypothesis T cells with TLR4 (TLR4+) were enriched in the joints when compared to the blood. Mechanistically, we found that TLR4+ T cells balance an antibody producing versus a tissue balance program depending on the environmental cues that they receive through TLR4.

What were you trying to understand and what is the main discovery of this work?

Our main question was actually a very simple one. We were trying to understand how joint specificity is achieved. Meaning, we wanted to identify the cues that instructs T cells to deploy their inflammatory program at the joints. If you think about it, immune cells and T cells in particular are everywhere in the body, but in rheumatoid arthritis the main (and first) damage is to the joints. We wanted to understand how this tissue targeting occurred, at a molecular level.

Why is this important?

It is important on a very broad level because we are studying disease directly in humans. Also, we are doing so not only from an observational standpoint (which are actually very useful in providing information), but we also want to dissect the molecular and cellular mechanisms underpinning disease. This work  unveiled a pathway by which joint damage might occur. Identifying such pathways is the first step in the development of more specific and targeted drug design. The more disease, and in this case tissue, -specific a drug is the more likely it is to be more efficient and to cause less side effects.

Can you use an analogy to help us understand your work?

Yes, it is like TLR4 on T cells functions as a GPS that “informs” the T cells about where in the body they are and if they reached their final destination, which in this case are the joints. Probably a better analogy would be a GPS on a futuristic car, as TLR4 in addition of “informing” the T cells where they are, once arrived at destination “tells” them what to do next, in this case putting the foot on gas the pedal. Helena Soares

 What questions remain to be asked?

In this paper we provided a mechanism where TLR4 T cells can produce more pro-inflammatory cytokines at the joint that will indirectly trigger cartilage and bone erosion connected to rheumatoid arthritis. However, we think that these cells can actually have a more prominent role in the disease. So, we are addressing if TLR4 T cells can directly exert bone erosion and their underlying mechanism. Deciphering these pathways could have a huge impact in the way that the patients are treated, as we would be able to identify patients that are more prone to joint destruction before the damage is already advanced, only detectable by X-Rays, and treat them selectively. Daniela Silva