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Contribution of LTi and TH17 cells to B cell aggregate formation in the central nervous system in a mouse model of multiple sclerosis

Schropp, V;Rohde, J;Rovituso, DM;Jabari, S;Bharti, R;Kuerten, S;
Product: Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free)

In a subgroup of patients suffering from progressive multiple sclerosis (MS), which is an inflammation-mediated neurodegenerative disease of the central nervous system (CNS), B cell aggregates were discovered within the meninges. Occurrence of these structures was associated with a more severe disease course and cortical histopathology. We have developed the B cell-dependent MP4-induced experimental autoimmune encephalomyelitis (EAE) as a mouse model to mimic this trait of the human disease. The aim of this study was to determine a potential role of lymphoid tissue inducer (LTi) and TH17 cells in the process of B cell aggregate formation in the MP4 model. We performed flow cytometry of cerebellar and splenic tissue of MP4-immunized mice in the acute and chronic stage of the disease to analyze the presence of CD3-CD5-CD4+RORγt+ LTi and CD3+CD5+CD4+RORγt+ TH17 cells. Myelin oligodendrocyte glycoprotein (MOG):35-55-induced EAE was used as B cell-independent control model. We further determined the gene expression profile of B cell aggregates using laser capture microdissection, followed by RNA sequencing. While we were able to detect LTi cells in the embryonic spleen and adult intestine, which served as positive controls, there was no evidence for the existence of such a population in acute or chronic EAE in neither of the two models. Yet, we detected CD3-CD5-CD4-RORγt+ innate lymphoid cells (ILCs) and TH17 cells in the CNS, the latter especially in the chronic stage of MP4-induced EAE. Moreover, we observed a unique gene signature in CNS B cell aggregates compared to draining lymph nodes of MP4-immunized mice and to cerebellum as well as draining lymph nodes of mice with MOG:35-55-induced EAE. The absence of LTi cells in the cerebellum suggests that other cells might take over the function as an initiator of lymphoid tissue formation in the CNS. Overall, the development of ectopic lymphoid organs is a complex process based on an interplay between several molecules and signals. Here, we propose some potential candidates, which might be involved in the formation of B cell aggregates in the CNS of MP4-immunized mice.

PubMed ID: 31138214
358035802019-06-172019-06-1714:32:1914:32:192019-06-282019-06-2816:06:2916:06:29Schropp, V;Rohde, J;Rovituso, DM;Jabari, S;Bharti, R;Kuerten, S;Schropp, V;Rohde, J;Rovituso, DM;Jabari, S;Bharti, R;Kuerten, S;20192019Contribution of LTi and TH17 cells to B cell aggregate formation in the central nervous system in a mouse model of multiple sclerosisContribution of LTi and TH17 cells to B cell aggregate formation in the central nervous system in a mouse model of multiple sclerosisJournal Of NeuroinflammationJournal Of Neuroinflammation1111111616113113821431138214

In a subgroup of patients suffering from progressive multiple sclerosis (MS), which is an inflammation-mediated neurodegenerative disease of the central nervous system (CNS), B cell aggregates were discovered within the meninges. Occurrence of these structures was associated with a more severe disease course and cortical histopathology. We have developed the B cell-dependent MP4-induced experimental autoimmune encephalomyelitis (EAE) as a mouse model to mimic this trait of the human disease. The aim of this study was to determine a potential role of lymphoid tissue inducer (LTi) and TH17 cells in the process of B cell aggregate formation in the MP4 model. We performed flow cytometry of cerebellar and splenic tissue of MP4-immunized mice in the acute and chronic stage of the disease to analyze the presence of CD3-CD5-CD4+RORγt+ LTi and CD3+CD5+CD4+RORγt+ TH17 cells. Myelin oligodendrocyte glycoprotein (MOG):35-55-induced EAE was used as B cell-independent control model. We further determined the gene expression profile of B cell aggregates using laser capture microdissection, followed by RNA sequencing. While we were able to detect LTi cells in the embryonic spleen and adult intestine, which served as positive controls, there was no evidence for the existence of such a population in acute or chronic EAE in neither of the two models. Yet, we detected CD3-CD5-CD4-RORγt+ innate lymphoid cells (ILCs) and TH17 cells in the CNS, the latter especially in the chronic stage of MP4-induced EAE. Moreover, we observed a unique gene signature in CNS B cell aggregates compared to draining lymph nodes of MP4-immunized mice and to cerebellum as well as draining lymph nodes of mice with MOG:35-55-induced EAE. The absence of LTi cells in the cerebellum suggests that other cells might take over the function as an initiator of lymphoid tissue formation in the CNS. Overall, the development of ectopic lymphoid organs is a complex process based on an interplay between several molecules and signals. Here, we propose some potential candidates, which might be involved in the formation of B cell aggregates in the CNS of MP4-immunized mice.

In a subgroup of patients suffering from progressive multiple sclerosis (MS), which is an inflammation-mediated neurodegenerative disease of the central nervous system (CNS), B cell aggregates were discovered within the meninges. Occurrence of these structures was associated with a more severe disease course and cortical histopathology. We have developed the B cell-dependent MP4-induced experimental autoimmune encephalomyelitis (EAE) as a mouse model to mimic this trait of the human disease. The aim of this study was to determine a potential role of lymphoid tissue inducer (LTi) and TH17 cells in the process of B cell aggregate formation in the MP4 model. We performed flow cytometry of cerebellar and splenic tissue of MP4-immunized mice in the acute and chronic stage of the disease to analyze the presence of CD3-CD5-CD4+RORγt+ LTi and CD3+CD5+CD4+RORγt+ TH17 cells. Myelin oligodendrocyte glycoprotein (MOG):35-55-induced EAE was used as B cell-independent control model. We further determined the gene expression profile of B cell aggregates using laser capture microdissection, followed by RNA sequencing. While we were able to detect LTi cells in the embryonic spleen and adult intestine, which served as positive controls, there was no evidence for the existence of such a population in acute or chronic EAE in neither of the two models. Yet, we detected CD3-CD5-CD4-RORγt+ innate lymphoid cells (ILCs) and TH17 cells in the CNS, the latter especially in the chronic stage of MP4-induced EAE. Moreover, we observed a unique gene signature in CNS B cell aggregates compared to draining lymph nodes of MP4-immunized mice and to cerebellum as well as draining lymph nodes of mice with MOG:35-55-induced EAE. The absence of LTi cells in the cerebellum suggests that other cells might take over the function as an initiator of lymphoid tissue formation in the CNS. Overall, the development of ectopic lymphoid organs is a complex process based on an interplay between several molecules and signals. Here, we propose some potential candidates, which might be involved in the formation of B cell aggregates in the CNS of MP4-immunized mice.

5.15.1

EAE induction and clinical assessment:

For immunization, incomplete Freund’s adjuvant (IFA) was prepared by mixing paraffin oil (Sigma-Aldrich, St. Louis, USA; Cat # 18512) and mannide monooleate (Sigma-Aldrich; Cat # M8819) at a 9:1 ratio. Complete Freund’s adjuvant (CFA) was subsequently obtained by adding 5 mg/ml Mycobacterium tuberculosis H37 Ra (Difco Laboratories, Franklin Lakes, NJ, USA; Cat # 231141) to IFA. After emulsifying MP4 (Alexion Pharmaceuticals, Cheshire, CT, USA) in CFA, the mice were immunized subcutaneously into both sides of the flank with a total dose of 200 μg MP4. Additionally, an intraperitoneal injection of 200 ng pertussis toxin (List Biological Laboratories, Hornby, ONT, Canada; Cat # 181) was given at the day of immunization and 48 h later. ...

EAE induction and clinical assessment:

For immunization, incomplete Freund’s adjuvant (IFA) was prepared by mixing paraffin oil (Sigma-Aldrich, St. Louis, USA; Cat # 18512) and mannide monooleate (Sigma-Aldrich; Cat # M8819) at a 9:1 ratio. Complete Freund’s adjuvant (CFA) was subsequently obtained by adding 5 mg/ml Mycobacterium tuberculosis H37 Ra (Difco Laboratories, Franklin Lakes, NJ, USA; Cat # 231141) to IFA. After emulsifying MP4 (Alexion Pharmaceuticals, Cheshire, CT, USA) in CFA, the mice were immunized subcutaneously into both sides of the flank with a total dose of 200 μg MP4. Additionally, an intraperitoneal injection of 200 ng pertussis toxin (List Biological Laboratories, Hornby, ONT, Canada; Cat # 181) was given at the day of immunization and 48 h later. ...

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1500-xhttps://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1500-x2019-05-282019-05-2810.1186/s12974-019-1500-x10.1186/s12974-019-1500-xPertussis Toxin from B. pertussis, Lyophilized (Salt-Free)Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free)stefanie.kuerten@fau.destefanie.kuerten@fau.de181;Acute;Analyze;Autoimmune;B cell;Biological;Cell;Central Nervous System;CNS;Complex;Control;Dependent;Detect;Development;Disease;EAE;Encephalomyelitis;Experimental;Experimental Autoimmune Encephalomyelitis;Expression;Flow Cytometry;Function;Gene;Inflammation;Injection;List;List Biological;Lymph Nodes;Mouse;MS;Pertussis;Positive;Process;Study;Tissue;Toxin;Journal Of Neuroinflammation181;Acute;Analyze;Autoimmune;B cell;Biological;Cell;Central Nervous System;CNS;Complex;Control;Dependent;Detect;Development;Disease;EAE;Encephalomyelitis;Experimental;Experimental Autoimmune Encephalomyelitis;Expression;Flow Cytometry;Function;Gene;Inflammation;Injection;List;List Biological;Lymph Nodes;Mouse;MS;Pertussis;Positive;Process;Study;Tissue;Toxin;Journal Of Neuroinflammation181181contribution-of-lti-and-th17contribution-of-lti-and-th17