Intrathecal IgG Synthesis: A Resistant and Valuable Target for Future Multiple Sclerosis Treatments

Abstract

Intrathecal IgG synthesis is a key biological feature of multiple sclerosis (MS). When acquired early, it persists over time. A growing body of evidence suggests that intrathecal Ig-secreting cells may be pathogenic either by a direct action of toxic IgG or by locally secreting bystander toxic products. Intrathecal IgG synthesis depends on the presence of CNS lymphoid organs, which are strongly linked at anatomical level to cortical subpial lesions and at clinical level to the impairment slope in progressive MS. As a consequence, targeting CNS lymphoid lesions could be a valuable new target in MS, especially during the progressive phase. As intrathecal IgGs are end-products of these lymphoid lesions, intrathecal IgG synthesis may be considered as a specific marker of the persistence of these inflammatory lesions. Here we review the effect upon intrathecal IgG synthesis of all drugs ever used in MS. Except for steroids, all these therapeutic strategies, including rituximab, failed to decrease intrathecal IgG synthesis, with the exception of a questionable incomplete action of natalizumab. Thus, IgG synthesis is a robust marker of persistent intrathecal inflammation and its complete normalization should be one of the goals in future therapeutic strategies.

Reduced cerebrospinal fluid levels of interleukin-10 in children with febrile seizures

“…In this study, the upper limit of the [CSF albumin/ serum albumin] ratio was accepted as 1/230 [10]. In the IgG index, values less than 0.7 were considered normal [11].…”

Immunopathology of Japanese macaque encephalomyelitis is similar to multiple sclerosis

“…Importantly, the detection of intrathecally synthesized oligoclonal IgG bands (OCBs) in the CSF is a commonly used paraclinical measure to diagnose MS when used in conjunction with MRI and clinical history (Petzold, 2013, Bonnan, 2015). Further substantiating the role of B cells in MS are clinical trials with the anti-CD20 monoclonal antibodies, rituximab and ocrelizumab, a treatment that resulted in reduced inflammatory brain lesions as detected by MRI and decreased clinical relapses in subjects with relapsing MS (Hauser et al, 2008).…”

Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis

“…4 Furthermore, the longevity of plasma cells and their resistance to therapeutic interventions underlie the static nature of these traditional CSF biomarkers. 4–7 Conversely, CSF pleocytosis, although a dynamic biomarker responsive to therapeutic interventions, 8 provides unsatisfactory sensitivity and specificity ratios (Fig 1). 6 As a consequence, most difficult-to-diagnose patients end up with a brain biopsy or blind trial of immunomodulatory agents.…”