Identification of pathogenic autoantibody responses in multiple sclerosis

R Medicine (General);RB Pathology

Elliott, Christina ; Linington, Christopher

University:University of Glasgow

Department:Institute of Infection Immunity and Inflammation

关键词: Multiple sclerosis, autoimmunity, demyelination, autoantibodies;   

Others  :  http://theses.gla.ac.uk/2870/1/2011Elliott_PhD.pdf

来源: University of Glasgow

【 摘 要 】

Multiple sclerosis (MS) is a chronic disease of the human central nervous system (CNS) in which repeated episodes of inflammatory demyelination result in formation of persistently demyelinated plaques of gliotic scar tissue associated with varying degrees of axonal loss. MS is now considered a “complex trait” that is triggered in genetically susceptible individuals by environmental factors.The disease is also considered to contain an autoimmune component where both the adaptive and innate immune systems have been implicated in disease pathogenesis.There has been a steady accumulation of circumstantial evidence from both clinical and experimental studies that implicate a role for autoantibody dependent mechanisms.However this issue remains controversial in the absence of formal evidence that patients actually develop a pathogenic autoantibody response.The aim of this thesis was to resolve this question.To do this we developed an in vitro bioassay based on a dissociated myelinating culture system from embryonic rat spinal cord.We demonstrated that this in vitro system could reproduce many features of in vivo myelinated axons.To validate this model as a viable screening assay characterised complement mediated autoantibody responses using a series of monoclonal antibodies and anti-sera.Due to their significance in the literature we focussed in particular on the MOG specific and Nfasc specific responses and comprehensively demonstrated that our bioassay offered a robust screening strategy in which to detect pathogenic antibody responses in the presence and absence of exogenous complement.To determine whether we could use our model to detect pathogenic autoantibody responses in MS patients, we purified the IgG fraction from a cohort of MS patients (n=20), OND (n=10) and healthy controls (n=13).Using this patient purified IgG we demonstrated a MS specific demyelinating activity, which was present in ~50% of samples screened.However in 10% of patients demyelination occurred secondary to pronounced axonal injury.These effects were dependent on exogenous complement and were unique to the MS cohort.Pathogenic antibody responses tended to be most prevalent in those patients with an aggressive disease course.In addition to complement mediated CNS injury we also demonstrated that this pathogenic MS IgG could disrupt myelin formation in developing myelinating cultures.Attempts to define the specificity revealed that this was heterogeneous, however in one MS patient we discovered that Nfasc155 provided a dominant antigen for pathogenic autoantibody responses. Together these data provide formal demonstration that MS is associated with pathogenic autoantibody responses.This has significant long term consequences for the clinical management of the disease