Cellular Mechanisms of Central Nervous System Repair by Natural Autoreactive Monoclonal Antibodies

The focus of multiple sclerosis research has recently turned to the relatively rare and clearly more challenging condition of primary progressive multiple sclerosis (PPMS). Many risk factors such as genetic susceptibility, age, and Epstein–Barr virus (EBV) infection may interdepend on various levels, causing a complex pathophysiological cascade. Variable pathological mechanisms drive disease progression, including inflammation-associated axonal loss, continuous activation of central nervous system resident cells, such as astrocytes and microglia as well as mitochondrial dysfunction and iron accumulation. Histological studies revealed diffuse infiltration of the gray and white matter as well as of the meninges with inflammatory cells such as B-, T-, natural killer, and plasma cells. While numerous anti-inflammatory agents effective in relapsing remitting multiple sclerosis basically failed in treatment of PPMS, the B-cell-depleting monoclonal antibody ocrelizumab recently broke the dogma that PPMS cannot be treated by an anti-inflammatory approach by demonstrating efficacy in a phase 3 PPMS trial. Other treatments aiming at enhancing remyelination (MD1003) as well as EBV-directed treatment strategies may be promising agents on the horizon. In this article, we aim to summarize new advances in the understanding of risk factors, pathophysiology, and treatment of PPMS. Moreover, we introduce a novel concept to understand the nature of the disease and possible treatment strategies in the near future.

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“…Moreover, the secreted antibodies may play a role in regulating the immune system and inducing remyelination (39). …”

Section: Pathological Changesmentioning

confidence: 99%

Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

2017

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“…We have shown that HIgM22 recognizes the surface antigen(s) on mature oligodendrocytes. Studies in cerebroside sulfotransferase (CST) knockout mice suggest that HIgM22 binds to a sulfated molecule(s), synthesized by CST enzyme activity, which catalyzes the 3′-sulfation of galactose residues in several glycolipids [84]. The major product of CST in the mammalian nervous system is sulfatide, an essential component of myelin [85].…”

Section: Neural Reactive Natural Igms and The Nature Of Neural Surface mentioning

confidence: 99%

Human-derived natural antibodies: biomarkers and potential therapeutics

Hassouna

et al. 2015

Future Neurol.

Self Cite

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The immune system generates antibodies and antigen-specific T-cells as basic elements of the immune networks that differentiate self from non-self in a finely tuned manner. The antigen-specific nature of immune responses ensures that normal immune activation contains non-self when tolerating self. Here we review the B-1 subset of lymphocytes which produce self-reactive antibodies. By analyzing the IgM class of natural antibodies that recognize antigens from the nervous system, we emphasize that natural antibodies are biomarkers of how the immune system monitors the host. The immune response activated against self can be detrimental when triggered in an autoimmune genetic background. In contrast, tuning immune activity with natural antibodies is a potential therapeutic strategy.

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“…Natural autoantibodies have been implicated as effectors of pathology after ischemia/reperfusion injury in muscle and gut47. However, they also might help coordinate neuroprotective functions in microglia and macrophages, including the induction of recycling endocytosis and TNF-α release, ligation of anti-inflammatory FcRs and induction of remyelination via stimulation of oligodendrocyte progenitor cells48,49. The induction of these protective mechanisms during an immune response might explain the therapeutic benefit of intravenous immunoglobulin (IVIG) therapy for CNS and non-CNS diseases49,50.…”

Section: Functional Implications Of B Cell Responses After Spinal Cormentioning

confidence: 99%

B cells and autoantibodies: complex roles in CNS injury

Ankeny

Popovich

2010

Trends in Immunology

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Emerging data indicate that traumatic injury to the brain or spinal cord activates B lymphocytes, culminating in the production of antibodies specific for antigens found within and outside the central nervous system (CNS). In this article, we summarize what is known about the effects of CNS injury on B cells. We outline the potential mechanisms for CNS trauma-induced B cell activation and discuss the potential consequences of these injury-induced B cell responses. Based on recent data, we hypothesize that a subset of autoimmune B cell responses initiated by CNS injury are pathogenic and that targeted inhibition of B cells could improve recovery in brain and spinal cord injured patients.

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Cellular Mechanisms of Central Nervous System Repair by Natural Autoreactive Monoclonal Antibodies

Cited by 51 publications

References 19 publications

Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

Primary Progressive Multiple Sclerosis: Putting Together the Puzzle

Human-derived natural antibodies: biomarkers and potential therapeutics

B cells and autoantibodies: complex roles in CNS injury

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