Increased immune reactivity to central nervous system–derived naturally presented peptides in patients with active multiple sclerosis

Riedhammer, Christine; Halbritter, Dagmar; Weissert, Robert

doi:10.1016/j.jaci.2016.08.015

Cited by 3 publications

(8 citation statements)

References 16 publications

(16 reference statements)

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“…Myelin basic protein (MBP) is thought to be the major autoantigen which is involved (71, 72). Many researchers have addressed this topic and found additional myelin proteins that can be the target of the autoimmune response (1).…”

Section: Specific Diseasesmentioning

confidence: 99%

“…Moreover, proteins expressed on neurons and axons have also been discussed to be targets of the immune response in patients with MS based on work in EAE (76). Recently, in patients with MS, we have shown that peptides can be eluted from MHC molecules from CNS tissue that are recognized by T cells secreting IFN-γ (Th1) (72, 77). Importantly, the increased immune reactivity against such peptides is observed in patients with active MS, i.e., in patients with MS who have an acute bout- or/and contrast-enhancing lesions in the CNS indicating active inflammation.…”

Section: Specific Diseasesmentioning

confidence: 99%

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Adaptive Immunity Is the Key to the Understanding of Autoimmune and Paraneoplastic Inflammatory Central Nervous System Disorders

Weissert

2017

Front. Immunol.

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There are common aspects and mechanisms between different types of autoimmune diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSDs), and autoimmune encephalitis (AE) as well as paraneoplastic inflammatory disorders of the central nervous system. To our present knowledge, depending on the disease, T and B cells as well as antibodies contribute to various aspects of the pathogenesis. Possibly the events leading to the breaking of tolerance between the different diseases are of great similarity and so far, only partially understood. Beside endogenous factors (genetics, genomics, epigenetics, malignancy) also exogenous factors (vitamin D, sun light exposure, smoking, gut microbiome, viral infections) contribute to susceptibility in such diseases. What differs between these disorders are the target molecules of the immune attack. For T cells, these target molecules are presented on major histocompatibility complex (MHC) molecules as MHC-bound ligands. B cells have an important role by amplifying the immune response of T cells by capturing antigen with their surface immunoglobulin and presenting it to T cells. Antibodies secreted by plasma cells that have differentiated from B cells are highly structure specific and can have important effector functions leading to functional impairment or/and lesion evolvement. In MS, the target molecules are mainly myelin- and neuron/axon-derived proteins; in NMOSD, mainly aquaporin-4 expressed on astrocytes; and in AE, various proteins that are expressed by neurons and axons.

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Section: Specific Diseasesmentioning

confidence: 99%

Section: Specific Diseasesmentioning

confidence: 99%

Adaptive Immunity Is the Key to the Understanding of Autoimmune and Paraneoplastic Inflammatory Central Nervous System Disorders

Weissert

2017

Front. Immunol.

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“…Two additional peptides were sequences of tetanus toxoid ( 14 ) and JC virus ( 15 ) ( Table 2 ). The eluted ligands had been shown to induce elevated Th1 T cell responses in patients with active MS ( 10 ). All measurements were performed according to the manufacturer´s instructions (Mabtech, Nacka Strand, Sweden).…”

Section: Methodsmentioning

confidence: 99%

“…Specifically, we assessed the influence of treatment of alemtuzumab on auto-antigen-specific Th1 T cells. Potentially, these are the disease drivers in patients with active MS ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of Alemtuzumab on (Auto)antigen-Specific Immune Responses

et al. 2020

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Alemtuzumab (anti-CD52 mAb) leads to a long-lasting disease activity suppression in patients with relapsing forms of multiple sclerosis (MS). In this study, we examined the change of the immune cell repertoire and the cellular reactivity after treatment with alemtuzumab. We analyzed the number of IFN-γ–secreting cells in presence of several peptides which had been eluted from the central nervous system (CNS) of MS patients and are possible targets of autoreactive T cells in MS. The patients showed a stabilized disease activity measured in clinical parameters and lesion formation after the treatment. We detected a reduction of the number of IFN-γ–secreting cells in the presence of every tested self-antigen. The number of IFN-γ–secreting cells was also reduced in the presence of non-self-antigens. We also found a clear change in the immune cell repertoire. After an almost complete depletion of all lymphocytes, the cell specificities showed different reconstitution patterns, resulting in different cell fractions. The percentage of CD4+ T cells was clearly reduced after therapy, whereas the fractions of B and NK cells were elevated. When we evaluated the number of IFN-γ–secreting cells in relation to the number of present CD4+ T cells, we still found a significant reduction. We conclude that the reduction of IFN-γ–secreting cells by alemtuzumab is not only due to a reduction of the CD4+ T cell fraction within the peripheral blood mononuclear cell (PBMC) compartment but might also be caused by functional changes or a shift in the distribution of different subtypes in the CD4+ T cell pool.

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“…Indeed, all evidence, as mentioned by both sides of the current debate, is equally consistent with an "outside-in" versus "inside-out" pathogenesis. 1 As a result, and given the large body of work done on understanding the immunobiology of MS and the immunotherapeutics that sprang from these insights, Garber and Barnett's argument in favor of shifting gears toward improved therapies targeting degeneration and repair has merit.…”

Section: Declaration Of Conflicting Interestsmentioning

confidence: 99%

We should focus more on finding therapeutic targets for the non-inflammatory damage in MS – No

Hart

Weissert

2018

Mult Scler

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Increased immune reactivity to central nervous system–derived naturally presented peptides in patients with active multiple sclerosis

Abstract: Disclosure of potential conflict of interest: R. Weissert serves on the board for Roche, Genzyme, Merck Serono, Biogen, and Novartis and receives grant support from Novartis and Sanofi Aventis. The rest of the authors declare that they have no relevant conflicts of interest.

Cited by 3 publications

References 16 publications

Adaptive Immunity Is the Key to the Understanding of Autoimmune and Paraneoplastic Inflammatory Central Nervous System Disorders

Adaptive Immunity Is the Key to the Understanding of Autoimmune and Paraneoplastic Inflammatory Central Nervous System Disorders

Effects of Alemtuzumab on (Auto)antigen-Specific Immune Responses

We should focus more on finding therapeutic targets for the non-inflammatory damage in MS – No

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