Rituximab abrogates aquaporin-4–specific germinal center activity in patients with neuromyelitis optica spectrum disorders

Damato, Valentina; Theorell, Jakob; Al-Diwani, Adam; Kienzler, Anne‐Kathrin; Makuch, Mateusz; Sun, Bo; Handel, Adam E.; Akdeniz, Deniz; Berretta, Antonio; Ramanathan, Sudarshini; Fower, Andrew; Whittam, Daniel; Gibbons, Emily; McGlashan, Nicholas; Green, Edward D.; Huda, Saif; Woodhall, Mark; Palace, Jacqueline; Sheerin, Fintan; Waters, Patrick; Leite, Maria Isabel; Jacob, Anu; Irani, Sarosh R.

doi:10.1073/pnas.2121804119

Cited by 27 publications

(33 citation statements)

References 52 publications

(69 reference statements)

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“…Hereby, rituximab effectively eliminated the intranodal synthesis of aquaporin-4 Abs and aquaporin-4-reactive B cells, which might explain how rituximab can be clinically effective without concomitant reduction of serum autoantibody levels. 26 In NMDAR encephalitis, tertiary lymphoid architectures in ovarian teratomas were suggested, and a production of NMDAR autoantibodies was detected from cultured teratoma explants and dissociated intratumoral B cells and from 3/7 cultures of cervical lymph nodes. 27 Our data point to a relevance of germinal center reactions also in GAD65-Ab SD.…”

Section: Discussionmentioning

confidence: 99%

Antibodies Against Glutamic Acid Decarboxylase 65 Are Locally Produced in the CSF and Arise During Affinity Maturation

Biljecki

Eisenhut

Beltrán

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesAntibodies (Abs) against the cytoplasmic protein glutamic acid decarboxylase 65 (GAD65) are detected in patients with neurologic syndromes together referred to as GAD65-Ab spectrum disorders. The response of some of these patients to plasma exchange or immunoglobulins indicates that GAD65-Abs could contribute to disease pathogenesis at least at some stages of disease. However, the involvement of GAD65-reactive B cells in the CNS is incompletely understood.MethodsWe studied 7 patients with high levels of GAD65-Abs and generated monoclonal Abs (mAbs) derived from single cells in the CSF. Sequence characteristics, reactivity to GAD65, and the role of somatic hypermutations of the mAbs were analyzed.ResultsTwelve CSF-derived mAbs were generated originating from 3 patients with short disease duration, and 7/12 of these mAbs (58%) were GAD65 reactive in at least 1 detection assay. Four of 12 (33%) were definitely positive in all 3 detection assays. The intrathecal anti-GAD65 response was polyclonal. GAD65-Abs were mostly of the IgG1 subtype and had undergone affinity maturation. Reversion of 2 GAD65-reactive mAbs to their corresponding germline-encoded unmutated common ancestors abolished GAD65 reactivity.DiscussionGAD65-specific B cells are present in the CNS and represent a sizable fraction of CSF B cells early in the disease course. The anti-GAD65 response in the CSF is polyclonal and shows evidence of antigen-driven affinity maturation required for GAD65 recognition. Our data support the hypothesis that the accumulation of GAD65-specific B cells and plasma cells in the CSF is an important feature of early disease stages.

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Section: Discussionmentioning

confidence: 99%

Antibodies Against Glutamic Acid Decarboxylase 65 Are Locally Produced in the CSF and Arise During Affinity Maturation

Biljecki

Eisenhut

Beltrán

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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“…In fact, B-cell depletion by monoclonal anti-CD20 antibodies is recommended to be administered without a window after TPE in NMOSD patients [ 16 ]. Paradoxically, anti-CD20 therapies were proven very effective in NMOSD starting from the first infusion, even though they apparently do not affect plasma cells nor circulating AQP-4 antibodies [ 17 ]. The exact mechanism of action that underlies both anti-CD20 therapy and TPE in NMOSD, whereby the former leads to lasting depletion of B cells while having no immediate impact on pre-existing immunoglobulins and humoral immunity [ 18 , 19 , 20 ], and the latter effectively clears antibodies but spares lymphocyte counts, remains uncertain.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory Aspects of Therapeutic Plasma Exchange in Neurological Disorders—A Pilot Study

Foettinger

Pilz

Wipfler

et al. 2023

IJMS

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Therapeutic plasma exchange (TPE) is used for drug-resistant neuroimmunological disorders, but its mechanism of action remains poorly understood. We therefore prospectively explored changes in soluble, humoral, and cellular immune components associated with TPE. We included ten patients with neurological autoimmune disorders that underwent TPE and assessed a panel of clinically relevant pathogen-specific antibodies, total serum immunoglobulin (Ig) levels, interleukin-6 (IL-6, pg/mL), C-reactive protein (CRP, mg/dL), procalcitonin (PCT, µg/L) and major lymphocyte subpopulations (cells/µL). Blood was collected prior to TPE (pre-TPE, baseline), immediately after TPE (post-TPE), as well as five weeks (follow-up1) and 130 days (follow-up2) following TPE. Pathogen-specific antibody levels were reduced by −86% (p < 0.05) post-TPE and recovered to 55% (follow-up1) and 101% (follow-up2). Ig subclasses were reduced by −70–89% (p < 0.0001) post-TPE with subsequent complete (IgM/IgA) and incomplete (IgG) recovery throughout the follow-ups. Mean IL-6 and CRP concentrations increased by a factor of 3–4 at post-TPE (p > 0.05) while PCT remained unaffected. We found no alterations in B- and T-cell populations. No adverse events related to TPE occurred. TPE induced a profound but transient reduction in circulating antibodies, while the investigated soluble immune components were not washed out. Future studies should explore the effects of TPE on particular cytokines and assess inflammatory lymphocyte lineages to illuminate the mode of action of TPE beyond autoantibody removal.

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“…However, it is not yet proven that LLPCs mediate pathogenic antibody production in AE. Rather, serial serum autoantibody IgM measurements and cervical lymph node sampling suggest that continual germinal centre (GC) activity may account for ongoing autoantibody production in NMDAR antibody encephalitis [10,11] and in the closely related astrocytopathic antibody-mediated illness, neuromyelitis optica spectrum disorder [12]. Hence, rather than LLPCs, GC-based mechanisms, including short-lived plasma cells or other immune or neuronal cell types that express CD38 or contain active proteosomes, may represent an alternative therapeutic target in at least some forms of AE.…”

Section: E D I T O R I a Lmentioning

confidence: 99%

Autoimmune encephalitis: Should we consider third‐line immunotherapies earlier?

Kelly

Irani

2023

Euro J of Neurology

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Rituximab abrogates aquaporin-4–specific germinal center activity in patients with neuromyelitis optica spectrum disorders

Cited by 27 publications

References 52 publications

Antibodies Against Glutamic Acid Decarboxylase 65 Are Locally Produced in the CSF and Arise During Affinity Maturation

Antibodies Against Glutamic Acid Decarboxylase 65 Are Locally Produced in the CSF and Arise During Affinity Maturation

Immunomodulatory Aspects of Therapeutic Plasma Exchange in Neurological Disorders—A Pilot Study

Autoimmune encephalitis: Should we consider third‐line immunotherapies earlier?

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