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1.
Neuropathol Appl Neurobiol ; 49(1): e12851, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36181265

RESUMO

AIMS: Axonal injury in multiple sclerosis (MS) and experimental models is most frequently detected in acutely demyelinating lesions. We recently reported a compensatory neuronal response, where mitochondria move to the acutely demyelinated axon and increase the mitochondrial content following lysolecithin-induced demyelination. We termed this homeostatic phenomenon, which is also evident in MS, the axonal response of mitochondria to demyelination (ARMD). The aim of this study is to determine whether ARMD is consistently evident in experimental demyelination and how its perturbation relates to axonal injury. METHODS: In the present study, we assessed axonal mitochondrial content as well as axonal mitochondrial respiratory chain complex IV activity (cytochrome c oxidase or COX) of axons and related these to axonal injury in nine different experimental disease models. We used immunofluorescent histochemistry as well as sequential COX histochemistry followed by immunofluorescent labelling of mitochondria and axons. RESULTS: We found ARMD a consistent and robust phenomenon in all experimental disease models. The increase in mitochondrial content within demyelinated axons, however, was not always accompanied by a proportionate increase in complex IV activity, particularly in highly inflammatory models such as experimental autoimmune encephalomyelitis (EAE). Axonal complex IV activity inversely correlated with the extent of axonal injury in experimental disease models. CONCLUSIONS: Our findings indicate that ARMD is a consistent and prominent feature and emphasise the importance of complex IV activity in the context of ARMD, especially in autoimmune inflammatory demyelination, paving the way for the development of novel neuroprotective therapies.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Esclerose Múltipla/patologia , Axônios/patologia , Encefalomielite Autoimune Experimental/patologia , Neurônios/patologia , Mitocôndrias/patologia
2.
J Immunol ; 201(11): 3229-3243, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30341184

RESUMO

Experimental autoimmune encephalomyelitis (EAE) in common marmosets is a translationally relevant model of the chronic neurologic disease multiple sclerosis. Following the introduction of a new dietary supplement in our purpose-bred marmoset colony, the percentage of marmosets in which clinically evident EAE could be induced by sensitization against recombinant human myelin oligodendrocyte glycoprotein in IFA decreased from 100 to 65%. The reduced EAE susceptibility after the dietary change coincided with reduced Callitrichine herpesvirus 3 expression in the colony, an EBV-related γ1-herpesvirus associated with EAE. We then investigated, in a controlled study in marmoset twins, which disease-relevant parameters were affected by the dietary change. The selected twins had been raised on the new diet for at least 12 mo prior to the study. In twin siblings reverted to the original diet 8 wk prior to EAE induction, 100% disease prevalence (eight out of eight) was restored, whereas in siblings remaining on the new diet the EAE prevalence was 75% (six out of eight). Spinal cord demyelination, a classical hallmark of the disease, was significantly lower in new-diet monkeys than in monkeys reverted to the original diet. In new-diet monkeys, the proinflammatory T cell response to recombinant human myelin oligodendrocyte glycoprotein was significantly reduced, and RNA-sequencing revealed reduced apoptosis and enhanced myelination in the brain. Systematic typing of the marmoset gut microbiota using 16S rRNA sequencing demonstrated a unique, Bifidobacteria-dominated composition, which changed after disease induction. In conclusion, targeted dietary intervention exerts positive effects on EAE-related parameters in multiple compartments of the marmoset's gut-immune-CNS axis.


Assuntos
Bifidobacterium/genética , Encéfalo/fisiologia , Células/imunologia , Suplementos Nutricionais , Encefalomielite Autoimune Experimental/dietoterapia , Esclerose Múltipla/dietoterapia , Medula Espinal/patologia , Animais , Apoptose , Callithrix , Células Cultivadas , Doenças Desmielinizantes , Dietoterapia , Modelos Animais de Doenças , Microbioma Gastrointestinal/genética , Herpesvirus Humano 3 , Humanos , Glicoproteína Mielina-Oligodendrócito/imunologia , RNA Ribossômico 16S/genética , Análise de Sequência de RNA
3.
Biochemistry ; 58(6): 763-775, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30513201

RESUMO

Multiple sclerosis (MS) is an autoimmune disorder manifested via chronic inflammation, demyelination, and neurodegeneration inside the central nervous system. The progressive phase of MS is characterized by neurodegeneration, but unlike classical neurodegenerative diseases, amyloid-like aggregation of self-proteins has not been documented. There is evidence that citrullination protects an immunodominant peptide of human myelin oligodendrocyte glycoprotein (MOG34-56) against destructive processing in Epstein-Barr virus-infected B-lymphocytes (EBV-BLCs) in marmosets and causes exacerbation of ongoing MS-like encephalopathies in mice. Here we collected evidence that citrullination of MOG can also lead to amyloid-like behavior shifting the disease pathogenesis toward neurodegeneration. We observed that an immunodominant MOG peptide, MOG35-55, displays amyloid-like behavior upon site-specific citrullination at positions 41, 46, and/or 52. These amyloid aggregates are shown to be toxic to the EBV-BLCs and to dendritic cells at concentrations favored for antigen presentation, suggesting a role of amyloid-like aggregation in the pathogenesis of progressive MS.


Assuntos
Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Linfócitos B/metabolismo , Glicoproteína Mielina-Oligodendrócito/metabolismo , Fragmentos de Peptídeos/metabolismo , Sequência de Aminoácidos , Amiloide/imunologia , Amiloide/toxicidade , Proteínas Amiloidogênicas/síntese química , Proteínas Amiloidogênicas/imunologia , Proteínas Amiloidogênicas/toxicidade , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos B/virologia , Benzotiazóis/química , Callithrix , Linhagem Celular , Citrulinação/imunologia , Células Dendríticas/metabolismo , Herpesvirus Humano 4 , Humanos , Camundongos Endogâmicos C57BL , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Crônica Progressiva/metabolismo , Esclerose Múltipla Crônica Progressiva/virologia , Glicoproteína Mielina-Oligodendrócito/síntese química , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Agregação Patológica de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/toxicidade , Linfócitos T/imunologia , Linfócitos T/metabolismo
5.
J Immunol ; 199(2): 435-448, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28592428

RESUMO

The efficacy of B cell depletion therapy in multiple sclerosis indicates their central pathogenic role in disease pathogenesis. The B lymphotropic EBV is a major risk factor in multiple sclerosis, via as yet unclear mechanisms. We reported in a nonhuman primate experimental autoimmune encephalomyelitis model that an EBV-related lymphocryptovirus enables B cells to protect a proteolysis-sensitive immunodominant myelin oligodendrocyte glycoprotein (MOG) epitope (residues 40-48) against destructive processing. This facilitates its cross-presentation to autoaggressive cytotoxic MHC-E-restricted CD8+CD56+ T cells. The present study extends these observations to intact human B cells and identifies a key role of autophagy. EBV infection upregulated APC-related markers on B cells and activated the cross-presentation machinery. Although human MOG protein was degraded less in EBV-infected than in uninfected B cells, induction of cathepsin G activity by EBV led to total degradation of the immunodominant peptides MOG35-55 and MOG1-20 Inhibition of cathepsin G or citrullination of the arginine residue within an LC3-interacting region motif of immunodominant MOG peptides abrogated their degradation. Internalized MOG colocalized with autophagosomes, which can protect from destructive processing. In conclusion, EBV infection switches MOG processing in B cells from destructive to productive and facilitates cross-presentation of disease-relevant epitopes to CD8+ T cells.


Assuntos
Autoimunidade , Autofagia/imunologia , Linfócitos B/imunologia , Linfócitos B/virologia , Esclerose Múltipla/imunologia , Animais , Autofagossomos/imunologia , Autofagossomos/metabolismo , Linfócitos B/metabolismo , Linfócitos T CD8-Positivos/imunologia , Catepsina G/antagonistas & inibidores , Catepsina G/genética , Catepsina G/imunologia , Catepsina G/metabolismo , Células Cultivadas , Apresentação Cruzada/imunologia , Humanos , Epitopos Imunodominantes/química , Epitopos Imunodominantes/imunologia , Camundongos , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/virologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/metabolismo
6.
J Immunol ; 197(4): 1074-88, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27412414

RESUMO

EBV is the major infectious environmental risk factor for multiple sclerosis (MS), but the underlying mechanisms remain obscure. Patient studies do not allow manipulation in vivo. We used the experimental autoimmune encephalomyelitis (EAE) models in the common marmoset and rhesus monkey to model the association of EBV and MS. We report that B cells infected with EBV-related lymphocryptovirus (LCV) are requisite APCs for MHC-E-restricted autoaggressive effector memory CTLs specific for the immunodominant epitope 40-48 of myelin oligodendrocyte glycoprotein (MOG). These T cells drive the EAE pathogenesis to irreversible neurologic deficit. The aim of this study was to determine why LCV infection is important for this pathogenic role of B cells. Transcriptome comparison of LCV-infected B cells and CD20(+) spleen cells from rhesus monkeys shows increased expression of genes encoding elements of the Ag cross-presentation machinery (i.e., of proteasome maturation protein and immunoproteasome subunits) and enhanced expression of MHC-E and of costimulatory molecules (CD70 and CD80, but not CD86). It was also shown that altered expression of endolysosomal proteases (cathepsins) mitigates the fast endolysosomal degradation of the MOG40-48 core epitope. Finally, LCV infection also induced expression of LC3-II(+) cytosolic structures resembling autophagosomes, which seem to form an intracellular compartment where the MOG40-48 epitope is protected against proteolytic degradation by the endolysosomal serine protease cathepsin G. In conclusion, LCV infection induces a variety of changes in B cells that underlies the conversion of destructive processing of the immunodominant MOG40-48 epitope into productive processing and cross-presentation to strongly autoaggressive CTLs.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Encefalomielite Autoimune Experimental/virologia , Infecções por Herpesviridae/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Animais , Apresentação de Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/virologia , Western Blotting , Callithrix , Separação Celular , Encefalomielite Autoimune Experimental/imunologia , Epitopos de Linfócito T/imunologia , Imunofluorescência , Lymphocryptovirus , Ativação Linfocitária/imunologia , Macaca mulatta , Reação em Cadeia da Polimerase , Infecções Tumorais por Vírus/imunologia
7.
J Immunol ; 194(4): 1454-66, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25589073

RESUMO

Costimulatory and coinhibitory receptor-ligand pairs on T cells and APC control the immune response. We have investigated whether selective blockade of CD28-CD80/86 costimulatory interactions, which preserves the coinhibitory CTLA4-CD80/86 interactions and the function of regulatory T (Treg) cells, abrogates the induction of experimental autoimmune encephalomyelitis (EAE) in rhesus monkeys. EAE was induced by intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) in CFA on day 0. FR104 is a monovalent, PEGylated-humanized Fab' Ab fragment against human CD28, cross-reactive with rhesus monkey CD28. FR104 or placebo was administered on days 0, 7, 14, and 21. FR104 levels remained high until the end of the study (day 42). Placebo-treated animals all developed clinical EAE between days 12 and 27. FR104-treated animals did not develop clinical EAE and were sacrificed at the end of the study resulting in a significantly prolonged survival. FR104 treatment diminished T and B cell responses against rhMOG, significantly reduced CNS inflammation and prevented demyelination. The inflammatory profile in the cerebrospinal fluid and brain material was also strongly reduced. Recrudescence of latent virus was investigated in blood, spleen, and brain. No differences between groups were observed for the ß-herpesvirus CMV and the polyomaviruses SV40 and SA12. Cross-sectional measurement of lymphocryptovirus, the rhesus monkey EBV, demonstrated elevated levels in the blood of FR104-treated animals. Blocking rhesus monkey CD28 with FR104 mitigated autoreactive T and B cell activation and prevented CNS pathology in the rhMOG/CFA EAE model in rhesus monkeys.


Assuntos
Antígenos CD28/antagonistas & inibidores , Encefalomielite Autoimune Experimental/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Animais , Linfócitos B , Encefalomielite Autoimune Experimental/virologia , Humanos , Macaca mulatta , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/imunologia , Viroses/complicações , Latência Viral
8.
Mult Scler ; 22(4): 559-63, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26540733

RESUMO

BACKGROUND: Multiple sclerosis (MS) develops exclusively in humans. Non-human primates are resistant against MS, although they are highly susceptible to the MS animal model, experimental autoimmune encephalomyelitis (EAE). Unravelling of the cause(s) underlying this discrepancy is highly relevant as insights might be gained into the elusive event(s) that trigger(s) MS. A well-established difference between the human primate (Homo sapiens) and non-human primates is that humans are unable to synthesize the sialic acid N-glycolylneuraminic acid (Neu5Gc). VIEWPOINT: We propose the concept that long-term ingestion by human primates of the foreign Neu5Gc, via red meat consumption, is an ignored environmental risk factor for MS. Conceptually, incorporation of dietary Neu5Gc into vital regions of the central nervous system, such as the blood-brain barrier (BBB) and the axon-myelin unit, creates targets for binding of de novo synthesized heterophilic anti-NeuGc antibodies. Binding of the antibodies can cause BBB leakage and destabilization of the axon-myelin coupling. The ensuing cytodegeneration and release of self-antigens could be a start of the characteristic pathological features of MS.


Assuntos
Dieta/efeitos adversos , Esclerose Múltipla/etiologia , Ácidos Neuramínicos/efeitos adversos , Carne Vermelha/efeitos adversos , Animais , Anticorpos/imunologia , Axônios/imunologia , Axônios/patologia , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Suscetibilidade a Doenças , Humanos , Modelos Animais , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/patologia , Ácidos Neuramínicos/imunologia , Fatores de Risco , Especificidade da Espécie
9.
J Immunol ; 192(9): 4242-53, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24696233

RESUMO

Depleting mAbs against the pan B cell marker CD20 are remarkably effective in the treatment of autoimmune-mediated inflammatory disorders, but the underlying mechanisms are poorly defined. The primary objective of this study was to find a mechanistic explanation for the remarkable clinical effect of the anti-CD20 mAbs in a representative nonhuman primate autoimmune-mediated inflammatory disorder model, experimental autoimmune encephalomyelitis (EAE) in common marmosets, allowing detailed analysis of secondary lymphoid organs (SLO). We observed that the depletion of CD20(+) B cells creates a less immunostimulatory environment in the SLO reflected by reduced expression of MHC class II, CD40, CD83, and CD80/CD86. APCs isolated from SLO of B cell-depleted EAE monkeys were also less responsive to mitogenic stimulation. The depleted B cell areas were replenished by T cells, of which the majority expressed CD127 (IL-7R) and CCR7. Such effects were not detected in EAE marmosets treated with mAb against BLyS or APRIL, where B cell depletion via withdrawal of essential survival cytokines was not associated with a marked clinical effect. We propose that at least part of the efficacy of anti-CD20 mAb therapy is attributable to the sustained CCR7 expression on T cells within SLO, limiting their release into the circulation.


Assuntos
Anticorpos Monoclonais/farmacologia , Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD20/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Callithrix , Quimiotaxia de Leucócito/efeitos dos fármacos , Citometria de Fluxo , Imuno-Histoquímica , Depleção Linfocítica/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
J Neuroinflammation ; 12: 169, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26377397

RESUMO

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) in the common marmoset monkey (Callithrix jacchus) is a relevant preclinical model for translational research into immunopathogenic mechanisms operating in multiple sclerosis (MS). Prior studies showed a core pathogenic role of T and B cells specific for myelin oligodendrocyte glycoprotein (MOG). However, in those studies, the quality of the response against MOG epitopes was strongly biased by bacterial antigens in the complete Freund's adjuvant (CFA), in which the immunizing recombinant human (rh) MOG protein had been formulated. In response to the need of a more refined EAE model, we have tested whether disease could also be induced with rhMOG in incomplete Freund's adjuvant (IFA). METHOD: Marmosets were immunized with rhMOG emulsified in IFA in the dorsal skin. Monkeys that did not develop neurological deficit were given booster immunizations at 28-day interval with the same antigen preparation. In a second experiment, three marmoset twin pairs were sensitized against MOG peptides in IFA to study a possibility for suppressive activity towards pathogenic T cells directed against the encephalitogenic epitope MOG40-48. RESULTS: Despite the absence of strong danger signals in the rhMOG/IFA inoculum, all monkeys developed clinically evident EAE symptoms. Moreover, in all monkeys, demyelinated lesions were present in the white matter and in two cases also in the cortical grey matter. Immune profiling at height of the disease showed a dominant T cell response against the overlapping peptides 14-36 and 24-46, but reactivity against the pathogenically most relevant peptide 34-56 was conspicuously absent. In the second experiment, there was an indication for a possible suppressive mechanism. CONCLUSIONS: Immunization of marmoset monkeys with rhMOG in IFA elicits clinical EAE in all animals. Moreover, rhMOG contains pathogenic and regulatory epitopes, but the pathogenic hierarchy of rhMOG epitopes is strongly influenced by the adjuvant in which the protein is formulated.


Assuntos
Callithrix , Encefalomielite Autoimune Experimental/imunologia , Adjuvante de Freund/imunologia , Lipídeos/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Animais , Anticorpos/sangue , Encéfalo/metabolismo , Encéfalo/patologia , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Adjuvante de Freund/efeitos adversos , Humanos , Imunização/efeitos adversos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Lipídeos/efeitos adversos , Ativação Linfocitária/imunologia , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Glicoproteína Mielina-Oligodendrócito/efeitos adversos , Peptídeos/efeitos adversos , Peptídeos/imunologia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/imunologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Linfócitos T/imunologia
11.
J Immunol ; 190(5): 1961-73, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23365083

RESUMO

The immune system is characterized by the preferential migration of lymphocytes through specific tissues (i.e., tissue tropism). Tissue tropism is mediated, in part, by the α(4) integrins expressed by T lymphocytes. The α(4)ß(1) integrin mediates migration of memory T lymphocytes into the CNS, whereas the α(4)ß(7) integrin mediates migration preferentially into gastrointestinal tissue. This paradigm was established primarily from investigations in rodents; thus, the objective of this investigation was to determine if blocking the α(4)ß(7) integrin exclusively would affect migration of T lymphocytes into the CNS of primates. The effects of the dual α(4)ß(1) and α(4)ß(7) antagonist natalizumab were compared with those of the α(4)ß(7) antagonist vedolizumab on experimental autoimmune encephalomyelitis in the rhesus monkey. Animals received an initial i.v. bolus of placebo, natalizumab (30 mg/kg), or vedolizumab (30 mg/kg) before intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein and then Ab once weekly thereafter. Natalizumab prevented CNS inflammation and demyelination significantly (p < 0.05), compared with time-matched placebo control animals, whereas vedolizumab did not inhibit these effects, despite saturating the α(4)ß(7) integrin in each animal for the duration of the investigation. These results demonstrate that blocking α(4)ß(7) exclusively does not inhibit immune surveillance of the CNS in primates.


Assuntos
Autoimunidade/efeitos dos fármacos , Inibição de Migração Celular/imunologia , Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/imunologia , Integrina alfa4beta1/antagonistas & inibidores , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Humanos , Vigilância Imunológica/efeitos dos fármacos , Injeções Intravenosas , Integrina alfa4beta1/imunologia , Macaca mulatta , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Natalizumab , Especificidade de Órgãos , Placebos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia
12.
Am J Primatol ; 76(9): 801-27, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24723482

RESUMO

Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and scientific advances of the past century. NHPs are used because of their similarity to humans in physiology, neuroanatomy, reproduction, development, cognition, and social complexity-yet it is these very similarities that make the use of NHPs in biomedical research a considered decision. As primate researchers, we feel an obligation and responsibility to present the facts concerning why primates are used in various areas of biomedical research. Recent decisions in the United States, including the phasing out of chimpanzees in research by the National Institutes of Health and the pending closure of the New England Primate Research Center, illustrate to us the critical importance of conveying why continued research with primates is needed. Here, we review key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical and biological research.


Assuntos
Modelos Animais de Doenças , Primatas , Experimentação Animal/ética , Animais , Humanos , Estados Unidos
13.
Ann Clin Transl Neurol ; 11(4): 973-988, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38425098

RESUMO

OBJECTIVE: Multiple sclerosis (MS) is a chronic central nervous system disease whose white matter lesion origin remains debated. Recently, we reported subtle changes in the MS normal appearing white matter (NAWM), presenting with an increase in myelin blisters and myelin protein citrullination, which may recapitulate some of the prodromal degenerative processes involved in MS pathogenesis. Here, to clarify the relevance of these changes for subsequent MS myelin degeneration we explored their prevalence in WM regions characterized by subtly reduced myelination (dubbed as micro-diffusely abnormal white matter, mDAWM). METHODS: We used an in-depth (immuno)histochemistry approach in 27 MS donors with histological presence of mDAWM and 5 controls. An antibody panel against degenerative markers was combined and the presence of myelin/axonal aberrations was analyzed and compared with the NAWM from the same cases/slices/regions. RESULTS: mDAWM-defined areas exhibit ill-defined borders, no signs of Wallerian degeneration, and they associate with visible veins. Remarkably, such areas present with augmented myelin blister frequency, enhanced prevalence of polar myelin phospholipids, citrullination, and degradation of myelin basic protein (MBP) when compared with the NAWM. Furthermore, enhanced reactivity of microglia/macrophages against citrullinated MBP was also observed in this tissue. INTERPRETATION: We report a new histologically defined early phase in MS lesion formation, namely mDAWM, which lacks signs of Wallerian pathology. These results support the prelesional nature of the mDAWM. We conceptualize that evolution to pathologically evident lesions comprises the previously documented imbalance of axo-myelinic units (myelin blistering) leading to their degeneration and immune system activation by released myelin components.


Assuntos
Esclerose Múltipla , Substância Branca , Humanos , Bainha de Mielina/patologia , Esclerose Múltipla/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Vesícula/patologia , Imageamento por Ressonância Magnética/métodos , Doença Crônica
16.
J Immunol ; 185(7): 3990-4003, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20739677

RESUMO

Depletion of CD20(+) B cells has been related to reduced clinical activity in relapsing-remitting multiple sclerosis. The underlying mechanism is not understood, because serum IgG levels were unaltered by the treatment. We report the effect of late B cell depletion on cellular and humoral immune mechanisms in a preclinical multiple sclerosis model (i.e., experimental autoimmune encephalomyelitis [EAE] in the common marmoset). We used a novel human anti-human CD20 IgG1κ mAb (HuMab 7D8) that cross-reacts with marmoset CD20. EAE was induced in 14 marmosets by immunization with recombinant human myelin oligodendrocyte glycoprotein (MOG) in CFA. After 21 d, B cells were depleted in seven monkeys by HuMab 7D8, and seven control monkeys received PBS. The Ab induced profound and long-lasting B cell depletion from PBMCs and lymphoid organs throughout the observation period of 106 d. Whereas all of the control monkeys developed clinically evident EAE, overt neurologic deficits were reduced substantially in three HuMab 7D8-treated monkeys, and four HuMab 7D8-treated monkeys remained completely asymptomatic. The effect of HuMab 7D8 was confirmed on magnetic resonance images, detecting only small lesions in HuMab 7D8-treated monkeys. The infusion of HuMab 7D8 arrested the progressive increase of anti-MOG IgG Abs. Although CD3(+) T cell numbers in lymphoid organs were increased, their proliferation and cytokine production were impaired significantly. Most notable were the substantially reduced mRNA levels of IL-7 and proinflammatory cytokines (IL-6, IL-17A, IFN-γ, and TNF-α). In conclusion, B cell depletion prevents the development of clinical and pathological signs of EAE, which is associated with impaired activation of MOG-reactive T cells in lymphoid organs.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Depleção Linfocítica/métodos , Animais , Anticorpos Monoclonais/imunologia , Antígenos CD20/imunologia , Linfócitos B/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Callithrix , Separação Celular , Citocinas/biossíntese , Citocinas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Citometria de Fluxo , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/uso terapêutico , Cadeias kappa de Imunoglobulina/imunologia , Cadeias kappa de Imunoglobulina/uso terapêutico , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Reação em Cadeia da Polimerase
17.
Biomedicines ; 10(3)2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35327408

RESUMO

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS), traditionally considered a chronic autoimmune attack against the insulating myelin sheaths around axons. However, the exact etiology has not been identified and is likely multi-factorial. Recently, evidence has been accumulating that implies that autoimmune processes underlying MS may, in fact, be triggered by pathological processes initiated within the CNS. This review focuses on a relatively unexplored immune cell-the "innate-like" B1 lymphocyte. The B1 cell is a primary-natural-antibody- and anti-inflammatory-cytokine-producing cell present in the healthy brain. It has been recently shown that its frequency and function may differ between MS patients and healthy controls, but its exact involvement in the MS pathogenic process remains obscure. In this review, we propose that this enigmatic cell may play a more prominent role in MS pathology than ever imagined. We aim to shed light on the human B1 cell in health and disease, and how dysregulation in its delicate homeostatic role could impact MS. Furthermore, novel therapeutic avenues to restore B1 cells' beneficial functions will be proposed.

18.
J Immunol ; 183(5): 2984-94, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19648269

RESUMO

Tolerogenic dendritic cells (TDC) offer a promising therapeutic potential to ameliorate autoimmune diseases. Reported to inhibit adaptive immune responses, little is known about their innate immunity receptor repertoire. In this study, we compared three types of human TDC (IL-10-DC, dexamethasone (DX)-DC, and 1,25(OH)(2)D(3)-DC) by their TLR expression and response to a set of TLR ligands. TDC are endowed with the same TLR set as standard monocyte-derived dendritic cells but respond differentially to the TLR stimuli Pam3CSK4, polyinosinic-polycytidylic acid, LPS, and flagellin. TDC expressed low or no IL-12-related cytokines and remarkably elevated IL-10 levels. Interestingly, only TDC up-regulated the expression of TLR2 upon stimulation. This boosted the tolerogenic potential of these cells, because IL-10 production was up-regulated in TLR2-stimulated, LPS-primed DX-DC, whereas IL-12 and TNF-alpha secretion remained low. When comparing the TDC subsets, DX-DC and 1,25(OH)(2)D(3)-DC up-regulated TLR2 irrespective of the TLR triggered, whereas in IL-10-DC this effect was only mediated by LPS. Likewise, DX-DC and 1,25(OH)(2)D(3)-DC exhibited impaired ability to mature, reduced allostimulatory properties, and hampered capacity to induce Th1 differentiation. Therefore, both DX-DC and 1,25(OH)(2)D(3)-DC display the strongest tolerogenic and anti-inflammatory features and might be most suitable tools for the treatment of autoimmune diseases.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Tolerância Imunológica , Mediadores da Inflamação/antagonistas & inibidores , Receptor 2 Toll-Like/biossíntese , Receptor 2 Toll-Like/sangue , Regulação para Cima/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Células Dendríticas/classificação , Regulação para Baixo/imunologia , Retroalimentação Fisiológica/imunologia , Flagelina/antagonistas & inibidores , Flagelina/metabolismo , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/fisiologia , Ligantes , Lipopeptídeos/antagonistas & inibidores , Lipopeptídeos/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/metabolismo , Monócitos/citologia , Monócitos/imunologia , Monócitos/metabolismo , Poli I-C/antagonistas & inibidores , Poli I-C/metabolismo , Receptor 2 Toll-Like/agonistas
19.
J Mol Med (Berl) ; 99(8): 1033-1042, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33948692

RESUMO

Reassessment of published observations in patients with multiple sclerosis (MS) suggests a microglial malfunction due to inappropriate (over)activity of the mitogen-activated protein kinase pathway ERK (MAPKERK). These observations regard biochemistry as well as epigenetics, and all indicate involvement of this pathway. Recent preclinical research on neurodegeneration already pointed towards a role of MAPK pathways, in particular MAPKERK. This is important as microglia with overactive MAPK have been identified to disturb local oligodendrocytes which can lead to locoregional demyelination, hallmark of MS. This constitutes a new concept on pathophysiology of MS, besides the prevailing view, i.e., autoimmunity. Acknowledged risk factors for MS, such as EBV infection, hypovitaminosis D, and smoking, all downregulate MAPKERK negative feedback phosphatases that normally regulate MAPKERK activity. Consequently, these factors may contribute to inappropriate MAPKERK overactivity, and thereby to neurodegeneration. Also, MAPKERK overactivity in microglia, as a factor in the pathophysiology of MS, could explain ongoing neurodegeneration in MS patients despite optimized immunosuppressive or immunomodulatory treatment. Currently, for these patients with progressive disease, no effective treatment exists. In such refractory MS, targeting the cause of overactive MAPKERK in microglia merits further investigation as this phenomenon may imply a novel treatment approach.


Assuntos
Sistema de Sinalização das MAP Quinases , Microglia/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Alelos , Animais , Doenças Desmielinizantes , Modelos Animais de Doenças , Suscetibilidade a Doenças , Predisposição Genética para Doença , Humanos , Microglia/imunologia , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/terapia , Mutação , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fenótipo , Fatores de Risco
20.
EBioMedicine ; 68: 103392, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34044219

RESUMO

Multiple sclerosis (MS) is after trauma the most important neurological disease in young adults, affecting 1 per 1000 individuals. With currently available medications, most of these targeting the immune system, satisfactory results have been obtained in patients with relapsing MS, but these can have serious adverse effects. Moreover, despite some promising developments, such as with B cell targeting therapies or sphingosine-1-phosphate modulating drugs, there still is a high unmet need of safe drugs with broad efficacy in patients with progressive MS. Despite substantial investments and intensive preclinical research, the proportion of promising lead compounds that reaches the approved drug status remains disappointingly low. One cause lies in the poor predictive validity of MS animal models used in the translation of pathogenic mechanisms into safe and effective treatments for the patient. This disturbing situation has raised criticism against the relevance of animal models used in preclinical research and calls for improvement of these models. This publication presents a potentially useful strategy to enhance the predictive validity of MS animal models, namely, to analyze the causes of failure in forward translation (lab to clinic) via reverse translation (clinic to lab). Through this strategy new insights can be gained that can help generate more valid MS models.


Assuntos
Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Animais , Modelos Animais de Doenças , Descoberta de Drogas , Humanos , Imunossupressores/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/imunologia
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