How to make complex immunology easy to understand? You don’t. #MSBlog #MSResearch
“This post is going to be difficult so please concentrate. We divide up the immune system into the so called innate and adaptive arms. The innate system is hard-wired by your genes and can’t be changed. In comparison, the adaptive arm learns and has memory. Your genes bestow on B cells and T cells the complex programmes that allow them to be intelligent and learn and remember. Unfortunately, this acquired immunological memory resides in the individual and dies with the individual at the end of their life; in other words is not passed onto the next generation as a heritable factor. An example of this type of immunity is what happens when you have an infection or receive a vaccination. When you have never seen a virus your immune system has to recognise that the infecting virus, or vaccine, is foreign and then mount a specific immune response to the agent. When you see the virus or vaccine for the first time it takes quite a long time to make a specific, or adaptive, immune response; this is called the primary response. However, if you get infected with the same virus, or have a booster vaccine, your immune response kicks in very quickly because you have memory cells that become activated; this is called the secondary response. What keeps you alive whilst the primary adaptive response is developing is your innate immunity. Interestingly, it is the innate immunity that tells your adaptive immunity that the infection, or vaccine, is foreign and that you need to respond to it. What this tells is that the two arms of the immune system work in concert and co-evolved with each other. I hope this is making sense to you.”
“The adaptive or memory response has two main arms; the so called B cell arm that makes antibodies, which function as heat seeking missiles and attack the enemy at a distance, and the T cell arm that are like the infantry and attack the enemy at close range. Antibodies are proteins that stick to antigens on the invading organism and destroy it using different mechanisms. The T cell arm of the adaptive system can be further divided into many cell types but the main ones in terms of memory are the so called CD8 and CD4 positive cells. Are you still with me?”
“In MS we know B cells, and the antibodies they produce, are important because we find so called oligoclonal antibody bands (OCBs) in the spinal fluid of MSers. At present we don’t know what these OCBs bind to. Instead of focusing on OCBs the study below concentrates on T cells and uses new DNA technology techniques to detect oligoclonal T cells. The researchers sequence the so called T cell receptors and note that like OCBs they are enriched in the spinal fluid. Finding oligoclonal T cell receptors (OTCRs) in the spinal fluid of MSers is in itself not a new finding; several other groups have shown this using other techniques. What is new is that they compare these OTCRs with TCRs from T cells from other people that have been shown to react to EBV infected cells in the past. And lo and behold these EBV-reactive CD8+ OTCRs are enriched in the spinal fluid of MSers. Interestingly, the CD4+ OTCRs were also found in controls. The knee jerk response is that these T cells are responding to EBV. I wish it was as simple as that. The thing about T cells is that they are such a large family of cells we have no idea if these OTCRs belong to so called effector cells, memory cells or regulatory T cells. In addition, the fact these OTCRs appear to on paper to be EBV specific they may actually be responsive to another antigen that resembles EBV antigens. In immunology we call this molecular mimicry. What really needs to happen is that these investigators need to design experiments to select these specific T cells from the spinal fluid of MSers and to look at the functionality of these cells in more detail. Are you still with me?”
“I you haven’t followed me I can simply say that in the study below investigator have detected the equivalent of OCBs for T cells in the spinal fluid of MSers. These oligoclonal T cells have been analysed and on paper appear to be enriched for cells that react against EBV, or a similar antigen. Whether or not this is relevant for MS needs more work.”
“This and other papers add to the literature supporting a role for EBV in the pathogenesis of MS.”
Lossius et al. High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells. Eur J Immunol. 2014 Aug 7. doi: 10.1002/eji.201444662
Background: Epstein-Barr virus (EBV) has long been suggested as a pathogen in multiple sclerosis (MS).
Methods: Here, we used high-throughput sequencing to determine the diversity, compartmentalization, persistence and EBV-reactivity of the T-cell receptor repertoires in MS. T-cell receptor (TCR)β genes were sequenced in paired samples of cerebrospinal fluid (CSF) and blood from patients with MS and controls with other inflammatory neurological diseases.
Results: The TCR repertoires were highly diverse in both compartments and patient groups. Expanded T-cell clones, represented by TCRβ sequences >0.1%, were of different identity in CSF and blood of MS patients, and persisted for more than a year. Reference TCRβ libraries generated from peripheral blood T cells reactive against autologous EBV-transformed B cells were highly enriched for public EBV-specific sequences and were used to quantify EBV-reactive TCRβ sequences in CSF. TCRβ sequences of EBV-reactive CD8+ T cells, including several public EBV-specific sequences, were intrathecally enriched in MS patients only, whereas those of EBV-reactive CD4+ T cells were also enriched in CSF of controls.
Conclusions: These data provide evidence for a clonally diverse, yet compartmentalized and persistent, intrathecal T-cell response in MS. The presented strategy links TCR sequence to intrathecal T-cell specificity, demonstrating enrichment of EBV-reactive CD8+ T cells in MS.