MS is a B-cell mediated disease. Can we find the cause? #MSBlog #MSResearch
“More on B cells. For those of you who are not immunologists the following paper will be seem confusing. B cells are the types of lymphocyte that mature to make antibodies. When they are naive, i.e. have not participated in a specific immune reaction, the carry on them a primitive, or early, IgM antibody; we refer to these primitive antibodies as been germline antibodies as they are hardwired in our genomes. When the B cells are involved in an immune response they change the type of antibody on their surface by mutating it to recognise a specific antigen or protein (somatic hypermutation) or changing it from an IgM to IgG (isotype switching). The new DNA sequences generated by this process are not in our genomes, but only exist in the B-cells of that specific clone. Both somatic hypermutation and isotype switching leave behind molecular fingerprints that can be detected using modern DNA technology and compared to the germline sequences. I hope this is not to confusing?”
“What the paper below is showing is that B-cells expressing IgM in the spinal fluid of MSers are not naive B-cells (germline IgM) but express IgM antibody molecules on their surface that have undergone hypermutation (antigen selected); in other words these antibodies have been selected to react with a specific antigen. This indicates that something is driving the maturation of IgM expressing B cells within the central nervous system of MSers, similar to what happens with IgG. What is the antigen or antigens responsible for this? This is the million dollar question. If we could only find the antigen(s) driving these B cells response we will be much closer to knowing the cause of MS. Why do I say this? In infectious diseases in which we know the infecting organism we find that the vast majority of the IgM and IgG molecules that have undergone hypermutation react with antigens from the infecting organism.”
“This paper supports the hypothesis that B-cells play a central role in the pathogenesis of MS and B cells hold the clue to the cause of the disease. We already know that all highly-effective DMTs have some activity against B-cell biology within the central nervous system, which also supports the B-cell hypothesis of MS.”
Epub: Beltrán et al. Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation. Brain. 2014 Jul 23. pii: awu205.
Background: Intrathecal oligoclonal bands of the cerebrospinal fluid are considered the most important immunological biomarkers of MS. They typically consist of clonally expanded IgG antibodies that underwent affinity maturation during sustained stimulation by largely unknown antigens. In addition, ∼40% of MSers have oligoclonal bands that consist of expanded IgM antibodies.
Objectives & Methods: We investigated the molecular composition of IgM- and IgG-chains from cerebrospinal fluid of 12 MSers, seven patients with other neurological diseases, and eight healthy control subjects by high-throughput deep-sequencing and single-cell PCR. Further, we studied the expression of activation-induced cytidine deaminase, the key enzyme for affinity maturation of antibodies, in cerebrospinal fluid samples of 16 patients.
Results: From the cerebrospinal fluid of two MSers we isolated single B cells and investigated the co-expression of antibody chains with activation-induced cytidine deaminase. In striking contrast to IgM-chains from peripheral blood, IgM-chains from cerebrospinal fluid of MSers or neuroborreliosis showed a high degree of somatic hypermutation. We found a high content of mutations that caused amino acid exchanges as compared to silent mutations. In addition, more mutations were found in the complementarity determining regions of the IgM-chains, which interact with yet unknown antigens, as compared to framework regions. Both observations provide evidence for antigen-driven affinity maturation. Furthermore, single B cells from the cerebrospinal fluid of MSers co-expressed somatically hypermutated IgM-chains and activation-induced cytidine deaminase, an enzyme that is crucial for somatic hypermutation and class switch recombination of antibodies and is normally expressed during activation of B cells in germinal centres. Clonal tracking of particular IgM+ B cells allowed us to relate unmutated ancestor clones in blood to hypermutated offspring clones in CSF. Unexpectedly, however, we found no evidence for intrathecal isotype switching from IgM to IgG.
Conclusions: Our data suggest that the intrathecal milieu sustains a germinal centre-like reaction with clonal expansion and extensive accumulation of somatic hypermutation in IgM-producing B cells.