Ameliorated course of glucose-6-phosphate isomerase (G6PI)-induced arthritis in IFN-γ receptor knockout mice exposes an arthritis-promoting role of IFN-γ

Frey, Oliver; Mitera, Tania; Kelchtermans, Hilde; Schurgers, Evelien; Kamradt, Thomas; Matthys, Patrick

doi:10.1016/j.jaut.2010.12.006

Cited by 15 publications

(15 citation statements)

References 44 publications

(47 reference statements)

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“…In the spleen and draining lymph nodes of all mice, CD4 T cells specific for the whole mCOL7c-GST fusion protein were detected at frequencies of about 1–2% (Figure 3a/b). The percentage of these cells is comparable to CD4 T cell frequencies specific for the immunizing antigens found after immunization with other antigens [32], [33]. Lymph nodes were massively expanded, but cell numbers within one lymph node did not exceed about 50% of cell numbers in spleen.…”

Section: Resultssupporting

confidence: 66%

“…To better understand this phenomenon, we performed a complementary analysis of the mCOL7c- and GST-specific T cells. After immunization with mCOL7c-GST, CD4 T cells specific for mCOL7c were nearly undetectable while T cells specific for GST were found in much higher numbers, but comparable to those described after immunization with other protein antigens [33]. These data suggest that the mCOL7c-specific plasma cell response is driven by T cells specific for GST.…”

Section: Discussionsupporting

confidence: 71%

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Persistent Autoantibody-Production by Intermediates between Short-and Long-Lived Plasma Cells in Inflamed Lymph Nodes of Experimental Epidermolysis Bullosa Acquisita

et al. 2013

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Autoantibodies are believed to be maintained by either the continuous generation of short-lived plasma cells in secondary lymphoid tissues or by long-lived plasma cells localized in bone marrow and spleen. Here, we show in a mouse model for the autoimmune blistering skin disease epidermolysis bullosa acquisita (EBA) that chronic autoantibody production can also be maintained in inflamed lymph nodes, by plasma cells exhibiting intermediate lifetimes. After EBA induction by immunization with a mCOL7c-GST-fusion protein, antigen-specific plasma cells and CD4 T cells were analyzed. Plasma cells were maintained for months in stable numbers in the draining lymph nodes, but not in spleen and bone marrow. In contrast, localization of mCOL7c-GST -specific CD4 T cells was not restricted to lymph nodes, indicating that availability of T cell help does not limit plasma cell localization to this site. BrdU-incorporation studies indicated that pathogenic mCOL7c- and non-pathogenic GST-specific plasma cells resemble intermediates between short-and long-lived plasma cells with half-lives of about 7 weeks. Immunization with mCOL7c-GST also yielded considerable numbers of plasma cells neither specific for mCOL7c- nor GST. These bystander-activated plasma cells exhibited much shorter half-lives and higher population turnover, suggesting that plasma cell lifetimes were only partly determined by the lymph node environment but also by the mode of activation. These results indicate that inflamed lymph nodes can harbor pathogenic plasma cells exhibiting distinct properties and hence may resemble a so far neglected site for chronic autoantibody production.

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Section: Resultssupporting

confidence: 66%

Section: Discussionsupporting

confidence: 71%

Persistent Autoantibody-Production by Intermediates between Short-and Long-Lived Plasma Cells in Inflamed Lymph Nodes of Experimental Epidermolysis Bullosa Acquisita

et al. 2013

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“…We used a data set from intracellular cytokine staining of activated Th cells (Frey et al, 2011b). The cells were stained and analyzed for the expression of six cytokines as described in the following.…”

Section: Methodsmentioning

confidence: 99%

“…The cells were stained and analyzed for the expression of six cytokines as described in the following. DBA/1 mice in the age of 6–12 weeks were subcutaneously immunized at the base of the tail with recombinant glucose-6-phosphate isomerase (G6PI) in an emulsion containing also Freunds complete adjuvant as described (Bruns et al, 2009; Frey et al, 2010a,b, 2011a,b). At day 21 after immunization, the draining lymph nodes (inguinal, axillary, paraaortic) were aseptically removed and prepared to a single cell suspension.…”

Section: Methodsmentioning

confidence: 99%

“…At day 21 after immunization, the draining lymph nodes (inguinal, axillary, paraaortic) were aseptically removed and prepared to a single cell suspension. In addition, beside the wild type DBA/1 mice (WT) also interferon-gamma (IFN-γ) receptor knock-out DBA/1 mice (KO) were analyzed (Frey et al, 2011b) and we performed the analyses also for other time points (day 9 and day 21 after immunization). Altogether, we studied four conditions: WT-day 21 (standard condition) as well as the additional conditions WT-day 9, KO-day 21, and KO-day 9.…”

Section: Methodsmentioning

confidence: 99%

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Multivariate Analysis of Flow Cytometric Data Using Decision Trees

Simon¹,

Guthke²,

Kamradt³

et al. 2012

Front. Microbio.

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Characterization of the response of the host immune system is important in understanding the bidirectional interactions between the host and microbial pathogens. For research on the host site, flow cytometry has become one of the major tools in immunology. Advances in technology and reagents allow now the simultaneous assessment of multiple markers on a single cell level generating multidimensional data sets that require multivariate statistical analysis. We explored the explanatory power of the supervised machine learning method called “induction of decision trees” in flow cytometric data. In order to examine whether the production of a certain cytokine is depended on other cytokines, datasets from intracellular staining for six cytokines with complex patterns of co-expression were analyzed by induction of decision trees. After weighting the data according to their class probabilities, we created a total of 13,392 different decision trees for each given cytokine with different parameter settings. For a more realistic estimation of the decision trees’ quality, we used stratified fivefold cross validation and chose the “best” tree according to a combination of different quality criteria. While some of the decision trees reflected previously known co-expression patterns, we found that the expression of some cytokines was not only dependent on the co-expression of others per se, but was also dependent on the intensity of expression. Thus, for the first time we successfully used induction of decision trees for the analysis of high dimensional flow cytometric data and demonstrated the feasibility of this method to reveal structural patterns in such data sets.

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MHC class II alleles associated with Th1 rather than Th17 type immunity drive the onset of early arthritis in a rat model of rheumatoid arthritis

2017

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Polymorphisms in the MHC class II (MHCII) genes are strongly associated with rheumatoid arthritis, supporting the importance of autoreactive T helper (Th) cells for the development of this disease. Here, we used pristane-induced arthritis (PIA), induced by the non-antigenic hydrocarbon pristane, to study the impact of different MHCII alleles on T-cell activation and differentiation. In MHCII-congenic rats with disease-promoting MHCII alleles, pristane primarily induced activation of Th1 cells, whereas activated T cells were Th17 biased in rats with protective MHCII alleles. Neutralization of IFN-γ during T-cell activation abrogated the development of disease, suggesting that Th1 immunity is important for disease induction. Neutralization of IL-17, by contrast, suppressed arthritis only when performed in rats with established disease. Adoptive T-cell transfers showed that T cells acquired arthritogenic capacity earlier in strains with a prevailing Th1 response. Moreover, upon pristane injection, these strains exhibited more Ag-primed OX40+ and proliferating T cells of polyclonal origin. These data show that T cells are polarized upon the first encounter with peptide-MHCII complexes in an allele-dependent fashion. In PIA, the polyclonal expansion of autoreactive Th1 cells was necessary for the onset of arthritis, while IL-17 mediated immunity contributed to the progression to chronic disease.

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Ameliorated course of glucose-6-phosphate isomerase (G6PI)-induced arthritis in IFN-γ receptor knockout mice exposes an arthritis-promoting role of IFN-γ

Cited by 15 publications

References 44 publications

Persistent Autoantibody-Production by Intermediates between Short-and Long-Lived Plasma Cells in Inflamed Lymph Nodes of Experimental Epidermolysis Bullosa Acquisita

Persistent Autoantibody-Production by Intermediates between Short-and Long-Lived Plasma Cells in Inflamed Lymph Nodes of Experimental Epidermolysis Bullosa Acquisita

Multivariate Analysis of Flow Cytometric Data Using Decision Trees

MHC class II alleles associated with Th1 rather than Th17 type immunity drive the onset of early arthritis in a rat model of rheumatoid arthritis

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