Sunday, 31 August 2014

Peripheral and central B cells involved in MS

Why does targeting systemic B cells in MS work? #MSResearch #MSBlog

"The B cell remains top of the MS pop chart. It is the cell that is responsible for producing antibodies and providing memory for future antibody production in the case of infection. B cells can also act as so called professional antigen presenting cells that takes up antigens and display the antigens on their surface to stimulate the T cell arm the immune system. There is also a subset of B cells that are regulatory and dampen down and help control inflammation. This short list tells you that B cells have many potential roles in MS."

"We know that B cells are critical player in MS as they are found in the central nervous system and produce oligoclonal bands (OCBs) that are an invariable finding in MS. The B cells that produce OCBs are highly selected and have undergone controlled mutagenesis to improve their binding capability to antigens. At present we still have not identified a specific antigen that these OCBs recognise; if we did we would be closer to the cause of MS."

"The studies below using new DNA sequencing technologies tell us that there is a link between the B cells that are found in the brain and those found in the peripheral blood of MSers. In other words the populations of cells in these compartments are linked to each other. I am not surprised by these results as there must be an exchange of cells between the two compartments. Interestingly the second study showed that so called founding members of the B cell clonal population, those with earlier or founder mutations, were found in the lymph nodes of the neck suggesting that this is the site where they get activated. The authors suggest that this may be the site where the so called B cell depleting therapies work, rather than in the CNS."

"This information is important and helps frame the role of B cells in MS as been a systemic (whole body) rather than purely local with the CNS. These studies may explain why system anti-B cell therapies that deplete or stop B cell trafficking work in MS. What is not explored in these studies is the role of EBV in B cell biology. I think the latter is critical if we want to understand how EBV triggers and maintains abnormal B cell function in MS."

This figure tries to explain the complex biology of B cell maturation. With each step selection of different immunoglobulin genes and mutation in the antigen binding regions allows one to track the development of clonal selection of B cells. This can be done in cells from the spinal fluid, brain, cervical or neck lymph nodes, and peripheral blood of MSers. This then allows one to pinpoint where the original clonal members come from. Some the techniques used in  these studies are cutting edge and require quite complex data analysis to track the families of B cells. What is important is that there is an overlap between B cells in the CNS and peripheral blood of MSers, providing a peripheral treatment target for anti-B-cell therapies.


Background: In MS, lymphocyte-in particular B cell-transit between the central nervous system (CNS) and periphery may contribute to the maintenance of active disease. Clonally related B cells exist in the cerebrospinal fluid (CSF) and peripheral blood (PB) of MSers; however, it remains unclear which subpopulations of the highly diverse peripheral B cell compartment share antigen specificity with intrathecal B cell repertoires and whether their antigen stimulation occurs on both sides of the blood-brain barrier. 


Methods: To address these questions, we combined flow cytometric sorting of PB B cell subsets with deep immune repertoire sequencing of CSF and PB B cells. Immunoglobulin (IgM and IgG) heavy chain variable (VH) region repertoires of five PB B cell subsets from MSers were compared with their CSF Ig-VH transcriptomes. 

Results: In six of eight patients, we identified peripheral CD27(+)IgD(-) memory B cells, CD27(hi)CD38(hi) plasma cells/plasmablasts, or CD27(-)IgD(-) B cells that had an immune connection to the CNS compartment. 

Conclusion: Pinpointing Ig class-switched B cells as key component of the immune axis thought to contribute to ongoing MS disease activity strengthens the rationale of current B cell-targeting therapeutic strategies and may lead to more targeted approaches

Stern et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med. 2014 Aug 6;6(248):248ra107.

Background: MS is an inflammatory disease of the central nervous system (CNS) characterized by autoimmune-mediated demyelination and neurodegeneration. The CNS of MSers harbors expanded clones of antigen-experienced B cells that reside in distinct compartments including the meninges, cerebrospinal fluid (CSF), and parenchyma. It is not understood whether this immune infiltrate initiates its development in the CNS or in peripheral tissues. B cells in the CSF can exchange with those in peripheral blood, implying that CNS B cells may have access to lymphoid tissue that may be the specific compartment(s) in which CNS-resident B cells encounter antigen and experience affinity maturation. 

Methods: Paired tissues were used to determine whether the B cells that populate the CNS mature in the draining cervical lymph nodes (CLNs). 

Results: High-throughput sequencing of the antibody repertoire demonstrated that clonally expanded B cells were present in both compartments. Founding members of clones were more often found in the draining CLNs. More mature clonal members derived from these founders were observed in the draining CLNs and also in the CNS, including lesions. 

Conclusion: These data provide new evidence that B cells traffic freely across the tissue barrier, with the majority of B cell maturation occurring outside of the CNS in the secondary lymphoid tissue. Our study may aid in further defining the mechanisms of immunomodulatory therapies that either deplete circulating B cells or affect the intrathecal B cell compartment by inhibiting lymphocyte transmigration into the CNS.

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