Central nervous system infiltrates are characterized by features of ongoing B cell-related immune activity in MP4-induced experimental autoimmune encephalomyelitis

Batoulis, Helena; Wunsch, Marie; Birkenheier, Johannes; Rottlaender, Andrea; Gorboulev, Valentin; Küerten, Stefanie

doi:10.1016/j.clim.2015.03.009

Cited by 16 publications

(18 citation statements)

References 66 publications

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“…Our results show for the first time the coexpression with p75NTR through which the proliferation, differentiation, and production of antibodies can be regulated [74][75][76]. Also, there is the implication of the GC-like structures in the CNS (or B cell follicles) where B cells accumulate, whereas the existence and the role of these structures, both in MS and EAE, are controversial [77,78]. It is believed that they preserve and renew the inflammatory conditions by activating T cells and producing auto-antibodies locally inside the CNS, avoiding the time-consuming peripheral trigger and also participating to the CNS neurodegeneration [79,80].…”

Section: Discussionmentioning

confidence: 81%

Spatio-temporal expression profile of NGF and the two-receptor system, TrkA and p75NTR, in experimental autoimmune encephalomyelitis

Delivanoglou

Boziki

Theotokis

et al. 2020

J Neuroinflammation

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Background: Nerve growth factor (NGF) and its receptors, tropomyosin receptor kinase A (TrkA) and panneurotrophin receptor p75 (p75NTR), are known to play bidirectional roles between the immune and nervous system. There are only few studies with inconclusive results concerning the expression pattern and role of NGF, TrkA, and p75NTR (NGF system) under the neuroinflammatory conditions in multiple sclerosis (MS) and its mouse model, the experimental autoimmune encephalomyelitis (EAE). The aim of this study is to investigate the temporal expression in different cell types of NGF system in the central nervous system (CNS) during the EAE course. Methods: EAE was induced in C57BL/6 mice 6-8 weeks old. CNS tissue samples were collected on specific time points: day 10 (D10), days 20-22 (acute phase), and day 50 (chronic phase), compared to controls. Real-time PCR, Western Blot, histochemistry, and immunofluorescence were performed throughout the disease course for the detection of the spatio-temporal expression of the NGF system. Results: Our findings suggest that both NGF and its receptors, TrkA and p75NTR, are upregulated during acute and chronic phase of the EAE model in the inflammatory lesions in the spinal cord. NGF and its receptors were colocalized with NeuN + cells, GAP-43 + axons, GFAP + cells, Arginase1 + cells, and Mac3 + cells. Furthermore, TrkA and p75NTR were sparsely detected on CNPase + cells within the inflammatory lesion. Of high importance is our observation that despite EAE being a T-mediated disease, only NGF and p75NTR were shown to be expressed by B lymphocytes (B220 + cells) and no expression on T lymphocytes was noticed. Conclusion: Our results indicate that the components of the NGF system are subjected to differential regulation during the EAE disease course. The expression pattern of NGF, TrkA, and p75NTR is described in detail, suggesting possible functional roles in neuroprotection, neuroregeneration, and remyelination by direct and indirect effects on the components of the immune system.

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Section: Discussionmentioning

confidence: 81%

Spatio-temporal expression profile of NGF and the two-receptor system, TrkA and p75NTR, in experimental autoimmune encephalomyelitis

Delivanoglou

Boziki

Theotokis

et al. 2020

J Neuroinflammation

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“…Not in extenso discussed in this review article are EAE models in which myelin damage is augmented with antibodies directed to CNS components, nor was the relevance of B-cells discussed (9). Although MS is still dominated by concepts of myelin reactive autoaggressive T-cells, analogy to murine EAE models, and a belief that CNS immunoglobulins, including oligoclonal bands, represent meaningless, nonsense antibodies, the effectiveness of Bcell depletion therapy (such as rituximab) clearly points toward an important function of antibodies and/or B-cells in MS pathogenesis (56).…”

Section: Discussionmentioning

confidence: 94%

Multiple sclerosis animal models: a clinical and histopathological perspective

et al. 2017

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There is a broad consensus that multiple sclerosis (MS) represents more than an inflammatory disease: it harbors several characteristic aspects of a classical neurodegenerative disorder, that is, damage to axons, synapses and nerve cell bodies. While we are equipped with appropriate therapeutic options to prevent immune-cell driven relapses, effective therapeutic options to prevent the progressing neurodegeneration are still missing. In this review article, we will discuss to what extent pathology of the progressive disease stage can be modeled in MS animal models. While acute and relapsing-remitting forms of experimental autoimmune encephalomyelitis (EAE), which are T cell dependent, are aptly suited to model relapsing-remitting phases of MS, other EAE models, especially the secondary progressive EAE stage in Biozzi ABH mice is better representing the secondary progressive phase of MS, which is refractory to many immune therapies. Besides EAE, the cuprizone model is rapidly gaining popularity to study the formation and progression of demyelinating CNS lesions without T cell involvement. Here, we discuss these two non-popular MS models. It is our aim to point out the pathological hallmarks of MS, and discuss which pathological aspects of the disease can be best studied in the various animal models available.

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“…Accordingly, some but not all CNS B cells also expressed GC markers including GL7, PNA, and Bcl6, some had undergone class switch recombination to IgG, and a few PCs were detectable in the CNS of Th17 recipients (75). Proliferating B cells were also found in the SJL and MP4-immunization model (70–72), and some B cells in the MP4-immunization model also expressed GC markers and AICD, the enzyme required for CSR and somatic hypermutation (72, 94). Consistent with this finding a germline transcript analysis indicated that B cells switched to IgG2b and IgG3 in the CNS, and sequencing of Ig transcripts revealed some CNS B cell clones that could not be detected in the spleen (94).…”

Section: Occurrence and Significance In Eaementioning

confidence: 99%

“…Proliferating B cells were also found in the SJL and MP4-immunization model (70–72), and some B cells in the MP4-immunization model also expressed GC markers and AICD, the enzyme required for CSR and somatic hypermutation (72, 94). Consistent with this finding a germline transcript analysis indicated that B cells switched to IgG2b and IgG3 in the CNS, and sequencing of Ig transcripts revealed some CNS B cell clones that could not be detected in the spleen (94). Although these data support the hypothesis that GC reactions may happen in CNS TLOs, one has to keep in mind that it is extremely difficult to exclude that lymphocytes acquired the observed phenotype in the periphery and then migrated to the CNS.…”

Section: Occurrence and Significance In Eaementioning

confidence: 99%

Tertiary Lymphoid Organs in Central Nervous System Autoimmunity

Mitsdoerffer

Peters

2016

Front. Immunol.

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Multiple sclerosis (MS) is an autoimmune disease characterized by chronic inflammation in the central nervous system (CNS), which results in permanent neuronal damage and substantial disability in patients. Autoreactive T cells are important drivers of the disease; however, the efficacy of B cell depleting therapies uncovered an essential role for B cells in disease pathogenesis. They can contribute to inflammatory processes via presentation of autoantigen, secretion of pro-inflammatory cytokines, and production of pathogenic antibodies. Recently, B cell aggregates reminiscent of tertiary lymphoid organs (TLOs) were discovered in the meninges of MS patients, leading to the hypothesis that differentiation and maturation of autopathogenic B and T cells may partly occur inside the CNS. Since these structures were associated with a more severe disease course, it is extremely important to gain insight into the mechanism of induction, their precise function, and clinical significance. Mechanistic studies in patients are limited. However, a few studies in the MS animal model experimental autoimmune encephalomyelitis (EAE) recapitulate TLO formation in the CNS and provide new insight into CNS TLO features, formation, and function. This review summarizes what we know so far about CNS TLOs in MS and what we have learned about them from EAE models. It also highlights the areas that are in need of further experimental work, as we are just beginning to understand and evaluate the phenomenon of CNS TLOs.

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Central nervous system infiltrates are characterized by features of ongoing B cell-related immune activity in MP4-induced experimental autoimmune encephalomyelitis

Cited by 16 publications

References 66 publications

Spatio-temporal expression profile of NGF and the two-receptor system, TrkA and p75NTR, in experimental autoimmune encephalomyelitis

Spatio-temporal expression profile of NGF and the two-receptor system, TrkA and p75NTR, in experimental autoimmune encephalomyelitis

Multiple sclerosis animal models: a clinical and histopathological perspective

Tertiary Lymphoid Organs in Central Nervous System Autoimmunity

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