Compromised central tolerance of ICA69 induces multiple organ autoimmunity

Fan, Yong; Gualtierotti, Giulio; Tajima, Asako; Grupillo, Maria; Coppola, Antonina; He, Jing; Bertera, Suzanne; Owens, Gregory P.; Pietropaolo, Massimo; Rudert, William A.; Trucco, Massimo

doi:10.1016/j.jaut.2014.07.001

Cited by 18 publications

(22 citation statements)

References 63 publications

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“…Interestingly, analysis of our patient cohort revealed that RRMS patients display an enhanced TCR repertoire diversity as illustrated by increased numbers of unique clones and an increased sample overlap. Our findings support pilot data from de Paula Alves Sousa and coworkers (43) in a small cohort of five RRMS patients and together suggest that in MS there is a perturbation of clonal elimination, potentially caused by an impaired deletion of autoreactive clones (44)(45)(46)(47). It would be of interest to obtain more information about the TCR repertoire in the target organ, i.e.…”

Section: Discussionsupporting

confidence: 90%

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Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

et al. 2019

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Interference with immune cell proliferation represents a successful treatment strategy in T cell–mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells. Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment. Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity.

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Section: Discussionsupporting

confidence: 90%

“…PBMCs were loaded with a pool of peptides each 10 µg/ml (MBP 85-99 , MOG 222-241 , PLP [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] , PLP 129-148 , MOG 97-serum. IL-2 (20 U/ml) was added on days 4, 7, and 10.…”

Section: Determination Of Myelin-specific Frequencies Of Human T Cellsmentioning

confidence: 99%

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

et al. 2019

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“…To investigate ICA69 autoimmunity (Bonner et al, 2012; Pietropaolo et al, 1993), in an elegant recent study two genetically modified mouse lines were generated to modulate thymic ICA69 expression: the heterozygous ICA69del/wt line and the thymic medullary epithelial cell-specific deletion Aire-ΔICA69 line (Fan et al, 2014). Suboptimal central negative selection of ICA69-reactive T-cells was observed in both lines.…”

Section: Genetic Susceptibilitymentioning

confidence: 99%

Immunogenetics of type 1 diabetes mellitus

Morran

Vonberg

Khadra

et al. 2015

Molecular Aspects of Medicine

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116

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Type 1 diabetes mellitus (T1DM) is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors. Similar to the majority of autoimmune diseases, T1DM usually has a relapsing remitting disease course with autoantibody and T cellular responses to islet autoantigens, which precede the clinical onset of the disease process. The immunological diagnosis of autoimmune diseases relies primarily on the detection of autoantibodies in the serum of T1DM patients. Although their pathogenic significance remains uncertain, they have the practical advantage of serving as surrogate biomarkers for predicting the clinical onset of T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects, (i.e. HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. In addition, HLA alleles such as DQB1*0602 are associated with dominant protection from T1DM in multiple populations.A discordance rate of greater than 50% between monozygotic twins indicates a potential involvement of environmental factors on disease development. Viral infections may play a role in the chain of events leading to disease, albeit conclusive evidence linking infections with T1DM remains to be firmly established. Two syndromes have been described in which an immunemediated form of diabetes occurs as the result of a single gene defect. These syndromes are termed autoimmune polyglandular syndrome type I (APS-I) or autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED), and X-linked poyendocrinopathy, immune dysfunction and diarrhea (XPID). These two syndromes are unique models to understand the mechanisms involved in the loss of tolerance to self-antigens in autoimmune diabetes and its associated organ-specific autoimmune disorders. A growing number of animal models of these diseases have greatly helped elucidate the immunologic mechanisms leading to autoimmune diabetes.

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“…To examine the function of the TEC/EAK aggregates in vivo , collect the TEC/EAK hydrogel after O/N culture and transplant under the kidney capsule of an athymic nude mouse, using previously described procedure 11,14 .…”

Section: Protocolmentioning

confidence: 99%

Promoting 3-D Aggregation of FACS Purified Thymic Epithelial Cells with EAK 16-II/EAKIIH6 Self-assembling Hydrogel

Tajima

Liu

Pradhan

et al. 2016

JoVE

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Thymus involution, associated with aging or pathological insults, results in diminished output of mature T-cells. Restoring the function of a failing thymus is crucial to maintain effective T cell-mediated acquired immune response against invading pathogens. However, thymus regeneration and revitalization proved to be challenging, largely due to the difficulties of reproducing the unique 3D microenvironment of the thymic stroma that is critical for the survival and function of thymic epithelial cells (TECs). We developed a novel hydrogel system to promote the formation of TEC aggregates, based on the self-assembling property of the amphiphilic EAK16-II oligopeptides and its histidinylated analogue EAKIIH6. TECs were enriched from isolated thymic cells with density-gradient, sorted with fluorescence-activated cell sorting (FACS), and labeled with anti-epithelial cell adhesion molecule (EpCAM) antibodies that were anchored, together with anti-His IgGs, on the protein A/G adaptor complexes. Formation of cell aggregates was promoted by incubating TECs with EAKIIH6 and EAK16-II oligopeptides, and then by increasing the ionic concentration of the medium to initiate gelation. TEC aggregates embedded in EAK hydrogel can effectively promote the development of functional T cells in vivo when transplanted into the athymic nude mice.

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Compromised central tolerance of ICA69 induces multiple organ autoimmunity

Cited by 18 publications

References 63 publications

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

Immunogenetics of type 1 diabetes mellitus

Promoting 3-D Aggregation of FACS Purified Thymic Epithelial Cells with EAK 16-II/EAKIIH6 Self-assembling Hydrogel

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