Friday, 28 September 2012

Research: Co-stimulation molecule changes in MS

Epub: Jiang etc. Enhancement of Membrane B7-H3 Costimulatory Molecule but Reduction of Its Soluble Form in Multiple Sclerosis. J Clin Immunol. 2012 Sep 21.

PURPOSE: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system mediated by T cells. B7-H3 plays a diverse role in regulating T cell responses. However, its expression and clinical significance in MS are not well known. This study analyzed the expression of membrane B7-H3 (mB7-H3) and levels of soluble B7-H3 (sB7-H3) in MS patients to determine its clinical significance.

METHODS: Peripheral blood (PB) or cerebrospinal fluid (CSF) samples from healthy controls, other noninflammatory neurological disorders, viral encephalitis, and MS patients were collected. Expression of mB7-H3 on immune cells was detected by flow cytometry. Levels of sB7-H3 in serum or CSF samples were measured by ELISA.

RESULTS: mB7-H3 expression was up-regulated in CSF from MS patients compared to PB (p < 0.001). However, serum or CSF levels of sB7-H3 in MS patients were significantly lower than those in controls (p < 0.05). Relapsing-MS patients had higher CSF mB7-H3 expression than the remitting subgroup. Relapsing-MS patients had decreased serum and CSF sB7-H3 levels compared with the remitting subgroup. Neurological deficits showed negative correlations with serum or CSF sB7-H3 levels, but a positive correlation with CSF mB7-H3 expression. Methylprednisolone therapy significantly elevated sB7-H3 levels and reduced mB7-H3 expression compared with pre-therapy levels. sB7-H3 levels did not correlate with mB7-H3 expression.

CONCLUSIONS: We demonstrated enhanced mB7-H3 expression and reduced sB7-H3 levels in MS patients which correlated with the clinical characteristics of MS patients. These results suggest that B7-H3 may be a promising biomarker and associated with the pathogenesis of MS.


B7-H3 (CD276) is a molecule with co-stimulatory function. This means that it is not part of the direct contact between a T cell and its target which involves interaction of the T cell receptor and the target presented by a macrophage (the activation-the stimulatory step),  which is required to stimulate the T cell, but an addition interaction (co-stimulation) between the T cell and the macrophage that is required to make the activations step cause multiplication of the T cell. Without it they are switched off. The firs of these  co-stimulatory molecules was B7-1 (CD80) and B7-2 (CD86) which interacts with CD28 and CD152. The B7-H3 is anchored into the cell membrane but it can also be cleaved and shed into the fluid outside cells and get into the blood and this is called soluble B7-H3. This can inhibit some immune functions and so it is consistent with the observation that with lower sB7-H3 there was more disease activity such that it was lower in Msers than health controls and within MSers it was lower during attacks than in remission. Is this cause or consequnce? 

Is this going to be a biomarker, if is the results show significance of only p<0.05 then this is not very likely as there will be too much overlap between groups.

This reminds of a story, we wanted some fresh MSer CSF and also some healthy controls, so whilst we were asking MSers to do this we thought that we should be willing to do this also so Prof G, MouseDoctor II and Myself all volunteered to have this done. However it was not considered ethical, because of doing an unnecessary procedure with risks if it went wrong and so we never got the samples. This is another example what is OK in one country or with one committee, may not be OK in another.

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