Friday, 10 February 2017

A T cell to Help the CNS B cell?

The problem in MS could be the B cell follicles, sometimes found in CNS. These were described years earlier in rheumatoid arthritis, so it is intersting that recently it has been reported that there is a T cell subset that helps the B cells to do their thang.
If you look in a B cell follicle of a lymph gland you find CD4 T cells. These have got the name of Follicular B helper T cells (also known as just follicular helper T cells or TFH), are antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs such as lymph nodes, spleens and Peyer's patches, and are identified by their constitutive expression of the B cell follicle homing receptor CXCR5. Upon cellular interaction and cross-signaling with their cognate follicular (Fo B) B cells, TFH cells trigger the formation and maintenance of germinal centers through the expression of CD40 ligand (CD40L) and the secretion of IL-21 and IL-4.TFH cells also migrate into these seeded germinal centers, predominantly composed of rapidly dividing and mutating B cells. Within germinal centers, TFH cells play a critical role in mediating the selection and survival of B cells that go on to differentiate either into plasma cells capable of producing high affinity antibodies against foreign antigen, and memory B cells capable of quick immune re-activation in the future if ever the same antigen is re-encountered.

TFH cells are also thought to facilitate negative selection of potentially autoimmune-causing mutated B cells in the germinal center. The TFH have distinct gene expression profiles, supporting the theory that TFH are a subset of CD4+ T cells distinct from Th-1, Th-2, Th-17 or Tregs. These include SLAM, PDCD1 = PD-1.

However you are not going to want B cells that help B cell follicles in CNS/Joint to home in the same way as B cell help for follicles in lympg glands so they may not express attractant molecules like CCCXR5. So it is interesting if we look in arthritis

Rao DA et al.Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.Nature. 2017;542(7639):110-114

CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1hiCXCR5-CD4+ T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1hiCXCR5-'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.

So the race is now on to find them in MS

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