Autoantibodies against Neurologic Antigens in Nonneurologic Autoimmunity

Stathopoulos, Panos; Chastre, Anne; Waters, Patrick; Irani, Sarosh R.; Fichtner, Miriam L.; Benotti, Erik S.; Guthridge, Joel M.; Seifert, Jennifer; Nowak, Richard J.; Buckner, Jane H.; Holers, V. Michael; James, Judith A.; Hafler, David A.; O’Connor, Kevin

doi:10.4049/jimmunol.1801295

Cited by 24 publications

(19 citation statements)

References 64 publications

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“…These autoantibodies were shown to disrupt the Agrin-LRP4 signaling and to be mainly of the complement activating IgG1 subclass (6). In contrast to findings, which show that that AChR and MuSK autoantibodies are specific for MG (129), LRP4 antibodies appear to cross disease boundaries. For example, LRP4 autoantibodies have been detected in some patients with amyotrophic lateral sclerosis (ALS) who presented with myasthenic symptoms (130,131).…”

Section: Lrp4 and Seronegative Myasthenia Gravismentioning

confidence: 64%

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology

et al. 2020

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Myasthenia gravis (MG) is a prototypical autoantibody mediated disease. The autoantibodies in MG target structures within the neuromuscular junction (NMJ), thus affecting neuromuscular transmission. The major disease subtypes of autoimmune MG are defined by their antigenic target. The most common target of pathogenic autoantibodies in MG is the nicotinic acetylcholine receptor (AChR), followed by muscle-specific kinase (MuSK) and lipoprotein receptor-related protein 4 (LRP4). MG patients present with similar symptoms independent of the underlying subtype of disease, while the immunopathology is remarkably distinct. Here we highlight these distinct immune mechanisms that describe both the B cell-and autoantibody-mediated pathogenesis by comparing AChR and MuSK MG subtypes. In our discussion of the AChR subtype, we focus on the role of long-lived plasma cells in the production of pathogenic autoantibodies, the IgG1 subclass mediated pathology, and contributions of complement. The similarities underlying the immunopathology of AChR MG and neuromyelitis optica (NMO) are highlighted. In contrast, MuSK MG is caused by autoantibody production by short-lived plasmablasts. MuSK MG autoantibodies are mainly of the IgG4 subclass which can undergo Fab-arm exchange (FAE), a process unique to this subclass. In FAE IgG4, molecules can dissociate into two halves and recombine with other half IgG4 molecules resulting in bispecific antibodies. Similarities between MuSK MG and other IgG4-mediated autoimmune diseases, including pemphigus vulgaris (PV) and chronic inflammatory demyelinating polyneuropathy (CIDP), are highlighted. Finally, the immunological distinctions are emphasized through presentation of biological therapeutics that provide clinical benefit depending on the MG disease subtype.

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Section: Lrp4 and Seronegative Myasthenia Gravismentioning

confidence: 64%

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology

et al. 2020

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“…The pathological roles of anti-MOG IgG1 antibodies are not fully understood, and some MOG antibody disease (MOGAD) patients exhibit high titers of autoantibodies with pathogenic properties, while other patients-along with healthy and disease controls-exhibit lower titers (275,276). Of note and in contrast to AQP4 NMOSD, clinical response of MOGAD patients to rituximab is modest, with up to a third of patients relapsing despite full depletion of peripheral B cells (236,(277)(278)(279).…”

Section: Myelin-oligodendrocyte Glycoprotein Antibody Diseasementioning

confidence: 99%

Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders

2021

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As B cells differentiate into antibody-secreting cells (ASCs), short-lived plasmablasts (SLPBs) are produced by a primary extrafollicular response, followed by the generation of memory B cells and long-lived plasma cells (LLPCs) in germinal centers (GCs). Generation of IgG4 antibodies is T helper type 2 (Th2) and IL-4, -13, and -10-driven and can occur parallel to IgE, in response to chronic stimulation by allergens and helminths. Although IgG4 antibodies are non-crosslinking and have limited ability to mobilize complement and cellular cytotoxicity, when self-tolerance is lost, they can disrupt ligand-receptor binding and cause a wide range of autoimmune disorders including neurological autoimmunity. In myasthenia gravis with predominantly IgG4 autoantibodies against muscle-specific kinase (MuSK), it has been observed that one-time CD20+ B cell depletion with rituximab commonly leads to long-term remission and a marked reduction in autoantibody titer, pointing to a short-lived nature of autoantibody-secreting cells. This is also observed in other predominantly IgG4 autoantibody-mediated neurological disorders, such as chronic inflammatory demyelinating polyneuropathy and autoimmune encephalitis with autoantibodies against the Ranvier paranode and juxtaparanode, respectively, and extends beyond neurological autoimmunity as well. Although IgG1 autoantibody-mediated neurological disorders can also respond well to rituximab induction therapy in combination with an autoantibody titer drop, remission tends to be less long-lasting and cases where titers are refractory tend to occur more often than in IgG4 autoimmunity. Moreover, presence of GC-like structures in the thymus of myasthenic patients with predominantly IgG1 autoantibodies against the acetylcholine receptor and in ovarian teratomas of autoimmune encephalitis patients with predominantly IgG1 autoantibodies against the N‐methyl‐d‐aspartate receptor (NMDAR) confers increased the ability to generate LLPCs. Here, we review available information on the short-and long-lived nature of ASCs in IgG1 and IgG4 autoantibody-mediated neurological disorders and highlight common mechanisms as well as differences, all of which can inform therapeutic strategies and personalized medical approaches.

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“…Mature naïve-derived recombinant antibodies were also tested on a flow cytometric AQP4 live cell-based assay as described previously (Stathopoulos et al, 2019). Briefly, human embryonic kidney (HEK) 293T cells were transiently transfected with plasmid vectors encoding human AQP4-GFP.…”

Section: Anti-aqp4 Autoantibody Cell-based Assaymentioning

confidence: 99%

Early B cell tolerance defects in neuromyelitis optica favour anti-AQP4 autoantibody production

Cotzomi

Stathopoulos

Lee

et al. 2019

Brain

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Neuromyelitis optica spectrum disorders (NMOSD) constitute rare autoimmune disorders of the CNS that are primarily characterized by severe inflammation of the spinal cord and optic nerve. Approximately 75% of NMOSD patients harbour circulating pathogenic autoantibodies targeting the aquaporin-4 water channel (AQP4). The source of these autoantibodies remains unclear, but parallels between NMOSD and other autoantibody-mediated diseases posit compromised B cell tolerance checkpoints as common underlying and contributing factors. Using a well established assay, we assessed tolerance fidelity by creating recombinant antibodies from B cell populations directly downstream of each checkpoint and testing them for polyreactivity and autoreactivity. We examined a total of 863 recombinant antibodies. Those derived from three anti-AQP4-IgG seropositive NMOSD patients (n = 130) were compared to 733 antibodies from 15 healthy donors. We found significantly higher frequencies of poly-and autoreactive new emigrant/transitional and mature naïve B cells in NMOSD patients compared to healthy donors (Pvalues 5 0.003), thereby identifying defects in both central and peripheral B cell tolerance checkpoints in these patients. We next explored whether pathogenic NMOSD anti-AQP4 autoantibodies can originate from the pool of poly-and autoreactive clones that populate the naïve B cell compartment of NMOSD patients. Six human anti-AQP4 autoantibodies that acquired somatic mutations were reverted back to their unmutated germline precursors, which were tested for both binding to AQP4 and poly-or autoreactivity. While the affinity of mature autoantibodies against AQP4 ranged from modest to strong (K d 15.2-559 nM), none of the germline revertants displayed any detectable binding to AQP4, revealing that somatic hypermutation is required for the generation of anti-AQP4 autoantibodies. However, two (33.3%) germline autoantibody revertants were polyreactive and four (66.7%) were autoreactive, suggesting that pathogenic anti-AQP4 autoantibodies can originate from the pool of autoreactive naïve B cells, which develops as a consequence of impaired early B cell tolerance checkpoints in NMOSD patients.

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Autoantibodies against Neurologic Antigens in Nonneurologic Autoimmunity

Cited by 24 publications

References 64 publications

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology

Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders

Early B cell tolerance defects in neuromyelitis optica favour anti-AQP4 autoantibody production

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