Research: Lymphoid aggregates

    Kuerten S, Schickel A, Kerkloh C, Recks MS, Addicks K, Ruddle NH, Lehmann PV. Tertiary lymphoid organ development coincides with determinant spreading of the myelin-specific T cell response. Acta Neuropathol. 2012 . [Epub ahead of print]

    While the role of T cells has been studied extensively in multiple sclerosis (MS), the pathogenic contribution of B cells has only recently attracted major attention, when it was shown that B cell aggregates can develop in the meninges of a subset of MS patients and were suggested to be correlates of late-stage and more aggressive disease in this patient population. However, whether these aggregates actually exist has subsequently been questioned and their functional significance has remained unclear. Here, we studied myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), which is one of the few animal models for MS that is dependent on B cells. We provide evidence that B cell aggregation is reflective of lymphoid neogenesis in the central nervous system (CNS) in MBP-PLP-elicited EAE. B cell aggregation was present already few days after disease onset. With disease progression CNS B cell aggregates increasingly displayed the phenotype of tertiary lymphoid organs (TLOs). Our results further imply that these TLOs were not merely epiphenomena of the disease, but functionally active, supporting intrathecal determinant spreading of the myelin-specific T cell response. Our data suggest that the CNS is not a passive "immune-privileged" target organ, but rather a compartment, in which highly active immune responses can perpetuate and amplify the autoimmune pathology and thereby autonomously contribute to disease progression.
    We have talked about B cell follicles before. There it was reported that Th17 ( a subset of white blood cell that produces interleukin 17 that is thought to drive autoimmunity) cells specifically induced ectopic (In this context not in the lymphoid organs) lymphoid follicles in the central nervous system (CNS). Development of ectopic lymphoid follicles was partly dependent on the cytokine interleukin 17 (IL-17) and on the cell surface molecule Podoplanin , which was expressed on Th17 cells, but not on other effector T cell subsets. These B cell aggregates appear to be a feature of MS.
    In this study they have looked at a particular model where it has been reported that disease does not develop properly in B cell deficieicent mice so it is B cell dependent for antigen presenting cell function. They have developed a term of tertiary (three) lymphoid organs because they are not primary (first, Bone marrrow, thymus) or secondary (Spleen peyers patch, tonsil, lymph glands). This is wrong as they are aggregates in a tissue. These are not organs!. They suggest that these B cell aggregates are where naive T cell responses are developed such that new target immune responses are generated. 
    This study implies that these aggreates is why some the diversity of the repertoire of T cells that are autoimmune expands with time. This is known as determinant spreading (epitope spreading). Some people, with their head in the sand (I say this because they ignore the expanding literature that shows that this is not the case, which is how dogma perpetuates itself), maintain that determinant spread causes the next episode of disease and have peddled this for years. 
    Although there is no question that determinant spread does occur with time, in my opinion it is not necessary for relapsing disease to occur. This can and does occur because of reactivation of the cellular response that occurred. Just think that there can be hundred of lesions comming and going during the course of MS are these all due to immune attack against a different wouldn't make sense. I am not sure I have seen these B cell agggregates where I know that determinant spread is occurring maybe we should look harder.
    This study would suggest that if you inhibit B cell activity that it would stop relapsing disease...This is what rituximab does. This would then not suggest they are involved in progression unless B cells are driving this aspect. Trial results so far would argue against this but in MS these follicles are more associated with progressive MS rather than RRMS. Is this a disease duration thing?

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