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

Hindawi Publishing Corporation Multiple Sclerosis International Volume 2015, Article ID 296184, 15 pages http://dx.doi.org/10.1155/2015/296184 Review Article Intrathecal IgG Synthesis: A Resistant and Valuable Target for Future Multiple Sclerosis Treatments Mickael Bonnan Service de Neurologie, Hôpital F. Mitterrand, 4 boulevard Hauterive, 64046 Pau, France Correspondence should be addressed to Mickael Bonnan; mickael Received 28 September 2014; Revised 15 December 2014; Accepted 16 December 2014 Academic Editor: Bianca Weinstock-Guttman Copyright © 2015 Mickael Bonnan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 1. Introduction Intrathecal IgG synthesis is a key biological feature of multiple sclerosis (MS). A growing body of evidence suggests that intrathecal IgG secreting cells may be pathogenic either by a direct action of toxic IgG or by locally secreting bystander toxic products of B-cells (review in [1]). We first provide a brief introduction to the synthesis pathway of intrathecal IgG in the context of CNS lymphoid organs. As intrathecal IgGs are end-products of these lymphoid infiltrates, intrathecal IgG synthesis may be considered as a specific marker of the persistence of these inflammatory lesions. Here we review the consequences on intrathecal IgG synthesis of all drugs given in the past in MS. We make special mention of rituximab and natalizumab owing to their paradoxical action on intrathecal IgG synthesis. 2. Pathway of Intrathecal IgG Synthesis Multiple sclerosis (MS) is characterized by intrathecal IgG synthesis that occurs as a very early event and is the most robust diagnostic biological criterion of the disease. Either an elevated IgG index or oligoclonal bands (OCB) are found positive in more than 95% MS patients [2, 3]. In the few patients (<0–5%) lacking intrathecal synthesis, a repeated cerebrospinal fluid (CSF) exam is often positive [4–7] and intrathecal secretion is demonstrated by many other techniques such as MRZ reaction, high CSF IgA synthesis [8, 9], oligoclonal free 𝜅 light-chains [10], or clonal 𝑉𝐻 and CDR rearrangements [11, 12], suggesting that OCB and IgG index tests are insufficiently sensitive. Once acquired, intrathecal synthesis persists mostly unchanged over time [13–17] and never disappears. Moreover, the intimate affinity maturation of IgG and the peptidic targets of OCB IgG persist over time [2, 18, 19]. As a consequence, each patient has a unique pattern “OCB fingerprint” of CSF immunoglobulins [20, 21]. This biological signature may be scored according to the typical positions of mutational replacements (hotspots) on IgG and can be used as a composite signature Z-score, which is highly predictive of the conversion of clinically isolated syndromes (CIS) to clinically defined MS [22, 23]. These hotspot codons reside in the complementary determining 2 region (CDR) where they are predicted to have contact with the (unknown) antigen(s). A growing set of evidences points to a central role of compartmentalized lymphoid tissue (tertiary lymphoid organs, TLO) in the formation and maintenance of intrathecal IgG synthesis ([24, 25], review in [26–28]). The main somatic hypermutations found in IgG are to be found in the CDR [12], which is targeted by the enzyme activation-induced cytidine deaminase (AICD) that is specifically expressed by B-cells in the context of lymphoid organs. The complex process of IgG affinity maturation also requires dendritic cells as professional antigen-presenting cells; cognate maturation of B-cells in collaboration with T-cells; clonal proliferation and selection in local germinal centers, provided by the TLO structure. Moreover, indirect evidence of intrathecal lymphoid structures is provided by deep analysis of the clonal lineage of IgG and B-cells inside and outside the CNS. CSF IgG, plasmablasts, and plasma cells are expanded from a few single ancestors and are clonally related. Although present on both sides of the blood-brain-barrier (BBB), clonal Bcell and T-cell lineages are mostly confined to the CNS, sometimes “private” to brain regions, indicating a mainly local continuous affinity maturation inside the CNS [29–33]. In animal models, the TLO correlates with epitope spreading in T-cells [34]. Furthermore, both intrathecally synthesized IgG and the underlying lymphoid organs are potentially involved in the pathophysiology of cortical lesions (review in [1, 35]). Although no specific target has yet emerged, converging evidence indicates that IgG may directly target CNS structures [36–40]. Inflammatory cells may also be toxic owing to IgG-independent mechanisms [41–44]—TNF𝛼, lymphotoxin, and IFN𝛾 being good candidates [45] and B-cells their potential source [46]. Finally, the meningeal lymphoid tissue observed in MS patients is spatially correlated to type III cortical lesions [25, 47, 48]. These cortical lesions represent half of the cortical lesions, cover up to 40–60% of the cortical ribbon in progressive MS, and are associated with a major neuronal loss [49–51]. Lastly, both cortical lesions and TLO strongly correlate with clinical impairment [25, 35, 47, 52]. In conclusion, intrathecal synthesis is an early-occurring event in the course of MS, which, once acquired, persists essentially unchanged throughout life and may be involved in the pathogenesis of progressive MS. Since cortical subpial lesions, TLO, intrathecal IgG synthesis, and impairment are intimately linked, it might be valuable to target B-cells situated in the TLO and to evaluate the effect in terms of t (...truncated)