| 1. |
- Raposo, Bruno, et al.
(författare)
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T cells specific for post-translational modifications escape intrathymic tolerance induction
- 2018
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Establishing effective central tolerance requires the promiscuous expression of tissue-restricted antigens by medullary thymic epithelial cells. However, whether central tolerance also extends to post-translationally modified proteins is not clear. Here we show a mouse model of autoimmunity in which disease development is dependent on post-translational modification (PTM) of the tissue-restricted self-antigen collagen type II. T cells specific for the non-modified antigen undergo efficient central tolerance. By contrast, PTM-reactive T cells escape thymic selection, though the PTM variant constitutes the dominant form in the periphery. This finding implies that the PTM protein is absent in the thymus, or present at concentrations insufficient to induce negative selection of developing thymocytes and explains the lower level of tolerance induction against the PTM antigen. As the majority of self-antigens are post-translationally modified, these data raise the possibility that T cells specific for other self-antigens naturally subjected to PTM may escape central tolerance induction by a similar mechanism.
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| 2. |
- Krzywicka, Katarzyna, et al.
(författare)
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Decompressive surgery in cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia.
- 2023
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Ingår i: European journal of neurology. - : Wiley. - 1468-1331 .- 1351-5101. ; 30:5, s. 1335-1345
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is an adverse drug reaction occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. CVST-VITT patients often present with large intracerebral haemorrhages and a high proportion undergoes decompressive surgery. Clinical characteristics, therapeutic management and outcomes of CVST-VITT patients who underwent decompressive surgery are described and predictors of in-hospital mortality in these patients are explored.Data from an ongoing international registry of patients who developed CVST within 28days of SARS-CoV-2 vaccination, reported between 29 March 2021 and 10 May 2022, were used. Definite, probable and possible VITT cases, as defined by Pavord et al. (N Engl J Med 2021; 385: 1680-1689), were included.Decompressive surgery was performed in 34/128 (27%) patients with CVST-VITT. In-hospital mortality was 22/34 (65%) in the surgical and 27/94 (29%) in the non-surgical group (p<0.001). In all surgical cases, the cause of death was brain herniation. The highest mortality rates were found amongst patients with preoperative coma (17/18, 94% vs. 4/14, 29% in the non-comatose; p<0.001) and bilaterally absent pupillary reflexes (7/7, 100% vs. 6/9, 67% with unilaterally reactive pupil, and 4/11, 36% with bilaterally reactive pupils; p=0.023). Postoperative imaging revealed worsening of index haemorrhagic lesion in 19 (70%) patients and new haemorrhagic lesions in 16 (59%) patients. At a median follow-up of 6months, 8/10 of surgical CVST-VITT who survived admission were functionally independent.Almost two-thirds of surgical CVST-VITT patients died during hospital admission. Preoperative coma and bilateral absence of pupillary responses were associated with higher mortality rates. Survivors often achieved functional independence.
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| 3. |
- Madsen, Rasmus Kirkegaard, 1979-, et al.
(författare)
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Physiological metabolic differences between Ncf1 mutant and wild type mice
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The Ncf1 gene is a major determinant of disease severity in experimental animal models of Rheumatoid Arthritis. The Ncf1 codes a protein that is important for regulating the activity of the NADPH oxidase (NOX2) complex. This complex produces reactive oxygen species (ROS) important both for killing off pathogens but also for regulating the immune response.Using metabolic profiling techniques we have found that mutation of the Ncf1 gene leads to alteration of the metabolic profile even without induction of inflammation, thus demonstrating a physiological role for the gene. Transgenic expression of Ncf1 in macrophages restored the metabolic profile so it was very similar to that seen in wild type animals. This indicates that macrophages have an immune regulatory role even outside inflammation.The metabolic differences between genotypes were subtle so the experiments were repeated to ensure validity of the results. The most stable metabolic effect across studies was an increase in free fatty acids in animals with functional NOX2 oxidation. This is likely due to production of immune regulatory compounds in the pathways initiated by phospholipase A2.
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| 4. |
- Raposo, Bruno
(författare)
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Genetic regulation of autoantibodies in arthritis : lessons from mouse models
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autoimmune diseases such as rheumatoid arthritis (RA) or multiple sclerosis (MS) are commonly regarded as complex or multifactorial diseases. This complexity regards to effector mechanisms involved in pathologic manifestations, and also to the diversity of genetic and environmental factors that predispose individuals to such diseases. Identification of genetic traits becomes relevant to better understand the progression of these diseases, enabling the development of new therapies. Autoantibody formation against cartilage structures (e.g. collagen type II, CII), anticitrullinated proteins (ACPA) and anti-Fc domains of other antibodies (rheumatoid factors, RF) are pathogenic and typically observed in RA patients. It is thus important to investigate their role in the disease development. In study I we evaluated the usefulness of a particular outbred stock of mice, the Northport heterogeneous stock (HS), in the study of genetic associations of different animal models. We observed that HS mice were suitable for studying disease models of MS, while being limited to study certain RA models, due to the absence of particular major histocompatibility complex (MHC) alleles. By introducing an arthritis permissive MHC H-2q allele, in study II we made use of the best characterized animal model of RA in mice (collagen-induced arthritis, CIA), and evaluated the genetic associations of autoantibody production during the course of the disease. The genetic associations with RF and ACPA production were evident and clearly distinct from anti- CII antibody responses. Amongst several identified quantitative trait loci (QTLs), we distinguished the Fc gamma receptor (FcγR) and immunoglobulin heavy chain (IgH) loci as the most central QTL regulating autoantibody formation. The Cia9 congenic fragment confirmed our FcγR association, while the involvement of the IgH locus on specific antigen recognition was thoroughly investigated in study III. Here we identified different germ-line polymorphisms controlling the antibody production and recognition of a specific CII epitope, named J1. Finally, in study IV, Cia37 congenic mice were used to investigate the role of vitamin D receptor (VDR) polymorphisms in arthritis susceptibility. The influence of vitamin D on cytokine secretion and the VDR gene expression profile observed, strongly implicate the VDR and vitamin D as regulators of autoimmunity in mice. In summary, several genetic associations as well as mechanistic hypothesis involving autoantibody formation are described in this thesis. We hope these findings can be of use for better understanding the pathology of RA, as well as for the development of new therapeutics to treat RA patients.
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| 5. |
- Raposo, Bruno, et al.
(författare)
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System A amino acid transporters regulate glutamine uptake and attenuate antibody-mediated arthritis
- 2015
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Ingår i: Immunology. - Chichester : Wiley-Blackwell Publishing Inc.. - 0019-2805 .- 1365-2567. ; 146:4, s. 607-617
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Tidskriftsartikel (refereegranskat)abstract
- Proliferation of rapidly dividing bone marrow-derived cells is strongly dependent on the availability of free glutamine, whose uptake is mediated through different amino acid transporters. The sodium-coupled neutral amino acid transporter (SNAT) family was previously reported to be associated with the development of collagen-induced arthritis in mice. Here, we tested the hypothesis whether impairment of SNAT proteins influences immune cell function and in turn alters arthritis development. The 2-(methylamino)isobutyric acid (MeAIB), a SNAT-specific substrate, was used to modulate the function of SNAT proteins. We demonstrate that glutamine uptake by murine naive lymphocytes, and consequent cell proliferation, is strongly associated with system A transporters. Physiological impairment of SNAT proteins reduced the antibody-initiated effector phase of arthritis, mainly by affecting the levels of circulating monocytes and neutrophils. MeAIB was also shown to affect the proliferation of immortalized cells, through trans-inhibition of SNAT proteins. Based on our observations, we conclude that SNAT proteins regulate the initial stages of lymphocyte activation by regulating glutamine uptake, and that the effector phase of arthritis can be affected by non-metabolized SNAT substrates. Most probably, metabolically active cells within both the adaptive and the innate immune systems are regulated by SNAT proteins and play a role in modifying arthritis development. © 2015 John Wiley & Sons Ltd.
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| 6. |
- Sharma, Ravi Kumar, et al.
(författare)
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Identification of proteinase 3 autoreactive CD4+T cells and their T-cell receptor repertoires in antineutrophil cytoplasmic antibody-associated vasculitis
- 2023
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Ingår i: Kidney International. - : ELSEVIER SCIENCE INC. - 0085-2538 .- 1523-1755. ; 103:5, s. 973-985
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Tidskriftsartikel (refereegranskat)abstract
- Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease involving autoreactivity to proteinase 3 (PR3) as demonstrated by presence of ANCAs. While autoantibodies are screened for diagnosis, autoreactive T cells and their features are less well-studied. Here, we investigated PR3-specific CD4+T cell responses and features of autoreactive T cells in patients with PR3-AAV, using a cohort of 72 patients with either active or inactive disease. Autoreactive PR3-specific CD4+T cells producing interferon g in response to protein stimulation were found to express the G-protein coupled receptor 56 (GPR56), a cell surface marker that distinguishes T cells with cytotoxic capacity. GPR56+CD4+T cells were significantly more prominent in the blood of patients with inactive as compared to active disease, suggesting that these cells were affected by immunosuppression and/or that they migrated from the circulation to sites of organ involvement. Indeed, GPR56+CD4+T cells were identified in T-cell infiltrates of affected kidneys and an association with immunosuppressive therapy was found. Moreover, distinct TCR gene segment usage and shared (public) T cell clones were found for the PR3-reactive TCRs. Shared T cell clones were found in different patients with AAV carrying the disease-associated HLA- DP allele, demonstrating convergence of the autoreactive T cell repertoire. Thus, we identified a CD4+T cell signature in blood and in affected kidneys that display PR3 autoreactivity and associates with T cell cytotoxicity. Our data provide a basis for novel rationales for both immune monitoring and future therapeutic intervention in PR3-AAV.
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| 7. |
- Vaartjes, Daniëlle, et al.
(författare)
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Increased salt exposure affects both lymphoid and myeloid effector functions, influencing innate-associated disease but not T-cell-associated autoimmunity.
- 2018
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 154:4, s. 683-694
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Tidskriftsartikel (refereegranskat)abstract
- High salt consumption has since long been associated with elevated blood pressure and cardiovascular disease. Recently, mouse studies suggested that a high dietary salt intake exacerbates the clinical manifestations of autoimmunity. Using naïve cells ex vivo after pre-exposure of mice to high salt intake, we showed that increased salt exposure affects the viability and effector functions of immune cells. CD4+ T-cells evidenced a pro-inflammatory phenotype characterized by increased secretion of IFNγ and IL-17A, when exposed to high salt concentrations in vitro. Interestingly, this phenotype was associated with osmotic pressure, as replacing salt for d-mannitol resulted in similar observations. However, high salt intake did not alter the development of T-cell-dependent autoimmunity. Instead, recruitment of peritoneal macrophages was increased in mice pre-exposed to high salt concentrations. These cells had an increased production of both TNFα and IL-10, suggesting that salt stimulates expansion and differentiation of different subsets of macrophages. Moreover, mice pre-exposed to high salt intake developed exacerbated symptoms of colitis, when induced by dextran sulphate sodium. The aggravated colitis in salt-exposed animals was associated with a higher frequency of CD4+ T-cells and CD11b+ CD64+ macrophages producing TNFα. These phenotypes correlated with elevated titres of faecal IgA and higher lymphocytic cellularity in the colon, mesenteric lymph nodes and spleen. In conclusion, we report here that high salt intake affects both lymphoid and myeloid cells ex vivo. However, the effects of high salt intake in vivo seem less pronounced in terms of CD4+ T-cell responses, whereas macrophage-dependent pathologies are significantly influenced.
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