Publications by year
In Press
Kronenberg-Versteeg D, Eichmann M, Russell MA, de Ru A, Hehn B, Yusuf N, van Veelen PA, Richardson SJ, Morgan NG, Lemburg MK, et al (In Press). Molecular pathways for immune recognition of preproinsulin signal peptide in type 1 diabetes. Diabetes
2022
Sioofy-Khojine A-B, Richardson SJ, Locke JM, Oikarinen S, Nurminen N, Laine A-P, Downes K, Lempainen J, Todd JA, Veijola R, et al (2022). Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage.
Diabetologia,
65(10), 1701-1709.
Abstract:
Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage
Abstract
. Aims/hypothesis
. Enteroviral infection has been implicated consistently as a key environmental factor correlating with the appearance of autoimmunity and/or the presence of overt type 1 diabetes, in which pancreatic insulin-producing beta cells are destroyed by an autoimmune response. Genetic predisposition through variation in the type 1 diabetes risk gene IFIH1 (interferon induced with helicase C domain 1), which encodes the viral pattern-recognition receptor melanoma differentiation-associated protein 5 (MDA5), supports a potential link between enterovirus infection and type 1 diabetes.
.
. Methods
. We used molecular techniques to detect enterovirus RNA in peripheral blood samples (in separated cellular compartments or plasma) from two cohorts comprising 79 children or 72 adults that include individuals with and without type 1 diabetes who had multiple autoantibodies. We also used immunohistochemistry to detect the enteroviral protein VP1 in the pancreatic islets of post-mortem donors (n=43) with type 1 diabetes.
.
. Results
. We observed enhanced detection sensitivity when sampling the cellular compartment compared with the non-cellular compartment of peripheral blood (OR 21.69; 95% CI 3.64, 229.20; p<0.0001). In addition, we show that children with autoimmunity are more likely to test positive for enterovirus RNA than those without autoimmunity (OR 11.60; 95% CI 1.89, 126.90; p=0.0065). Furthermore, we found that individuals carrying the predisposing allele (946Thr) of the common variant in IFIH1 (rs1990760, Thr946Ala) are more likely to test positive for enterovirus in peripheral blood (OR 3.07; 95% CI 1.02, 8.58; p=0.045). In contrast, using immunohistochemistry, there was no correlation between the common variant in IFIH1 and detection of enteroviral VP1 protein in the pancreatic islets of donors with type 1 diabetes.
.
. Conclusions/interpretation
. Our data indicate that, in peripheral blood, antigen-presenting cells are the predominant source of enterovirus infection, and that infection is correlated with disease stage and genetic predisposition, thereby supporting a role for enterovirus infection prior to disease onset.
.
. Graphical abstract
.
.
Abstract.
Jones AG, Eichmann M (2022). T-Cell Autoreactivity in Type 2 Diabetes: Benign or Pathogenic, Smoke or Fire?. Diabetes, 71(6), 1167-1169.
2020
Arif S, Pujol-Autonell I, Eichmann M (2020). Assessing effector T cells in type 1 diabetes.
Current Opinion in Endocrinology, Diabetes and Obesity,
27(4), 240-247.
Abstract:
Assessing effector T cells in type 1 diabetes
Purpose of reviewThe role of T cells specific for islet autoantigens is proven in pathogenesis of type 1 diabetes. Recently, there has been rapid expansion in the number of T-cell subsets identified, this has coincided with an increase in the repertoire of reported islet antigens mainly through the discovery of novel epitopes. A discussion of how these marry together is now warranted and timely.Recent findingsIn this review, we will discuss the autoreactivity against neo-epitopes. We then explore the growing array of T-cell subsets for both CD4+T cells, including follicular and peripheral T helper cells, and CD8+T cells, discussing evolution from naïve to exhausted phenotypes. Finally, we detail how subsets correlate with disease stage and loss of β-cell function and are impacted by immunotherapy.SummaryThe expanding list of T-cell subsets may be potentially encouraging in terms of elucidating disease mechanisms and have a role as biomarkers for disease progression. Furthermore, T-cell subsets can be used in stratifying patients for clinical trials and for monitoring immunotherapy outcomes. However, the definition of subsets needs to be refined in order to ensure that there is a uniform approach in designating T-cell subset attributes that is globally applied.
Abstract.
Yeo L, Pujol-Autonell I, Baptista R, Eichmann M, Kronenberg-Versteeg D, Heck S, Dolton G, Sewell AK, Harkonen T, Mikk M-L, et al (2020). Circulating beta cell-specific CD8(+) T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes.
CLINICAL AND EXPERIMENTAL IMMUNOLOGY,
199(3), 263-277.
Author URL.
Eichmann M, Baptista R, Ellis RJ, Heck S, Peakman M, Beam CA (2020). Costimulation Blockade Disrupts CD4+ T Cell Memory Pathways and Uncouples Their Link to Decline in β-Cell Function in Type 1 Diabetes.
J Immunol,
204(12), 3129-3138.
Abstract:
Costimulation Blockade Disrupts CD4+ T Cell Memory Pathways and Uncouples Their Link to Decline in β-Cell Function in Type 1 Diabetes.
We previously reported that costimulation blockade by abatacept limits the decline of β-cell function and the frequency of circulating CD4+ central memory T cells (TCM) (CD45RO+CD62L+) in new-onset type 1 diabetes. In human subjects receiving placebo, we found a significant association between an increase in CD4+ TCM cells and the decline of β-cell function. To extend and refine these findings, we examined changes in human CD4+ and CD8+ naive and memory T cell subsets at greater resolution using polychromatic flow and mass cytometry. In the placebo group, we successfully reproduced the original finding of a significant association between TCM and β-cell function and extended this to other T cell subsets. Furthermore, we show that abatacept treatment significantly alters the frequencies of a majority of CD4+ conventional and regulatory T cell subsets; in general, Ag-naive subsets increase and Ag-experienced subsets decrease, whereas CD8+ T cell subsets are relatively resistant to drug effects, indicating a lesser reliance on CD28-mediated costimulation. Importantly, abatacept uncouples the relationship between changes in T cell subsets and β-cell function that is a component of the natural history of the disease. Although these data suggest immunological markers for predicting change in β-cell function in type 1 diabetes, the finding that abatacept blunts this relationship renders the biomarkers nonpredictive for this type of therapy. In sum, our findings point to a novel mechanism of action for this successful immunotherapy that may guide other disease-modifying approaches for type 1 diabetes.
Abstract.
Author URL.
Edner NM, Heuts F, Thomas N, Wang CJ, Petersone L, Kenefeck R, Kogimtzis A, Ovcinnikovs V, Ross EM, Ntavli E, et al (2020). Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes.
Nat Immunol,
21(10), 1244-1255.
Abstract:
Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes.
Follicular helper T (TFH) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether TFH cells were decreased by costimulation blockade using the CTLA-4-immunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS)+ TFH cells and other ICOS+ populations, including peripheral helper T cells, were highly sensitive to costimulation blockade. We used pretreatment TFH profiles to derive a model that could predict clinical response to abatacept in individuals with T1D. Using two independent approaches, we demonstrated that higher frequencies of ICOS+ TFH cells at baseline were associated with a poor clinical response following abatacept administration. Therefore, TFH analysis may represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade.
Abstract.
Author URL.
2018
Yeo L, Woodwyk A, Sood S, Lorenc A, Eichmann M, Pujol-Autonell I, Melchiotti R, Skowera A, Fidanis E, Dolton GM, et al (2018). Autoreactive T effector memory differentiation mirrors beta cell function in type 1 diabetes.
JOURNAL OF CLINICAL INVESTIGATION,
128(8), 3460-3474.
Author URL.
2017
Ali MA, Liu Y-F, Arif S, Tatovic D, Shariff H, Gibson VB, Yusuf N, Baptista R, Eichmann M, Petrov N, et al (2017). Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes.
SCIENCE TRANSLATIONAL MEDICINE,
9(402).
Author URL.
Harbige J, Eichmann M, Peakman M (2017). New insights into non-conventional epitopes as T cell targets: the missing link for breaking immune tolerance in autoimmune disease?.
JOURNAL OF AUTOIMMUNITY,
84, 12-20.
Author URL.
2016
Gomez-Tourino I, Arif S, Eichmann M, Peakman M (2016). T cells in type 1 diabetes: Instructors, regulators and effectors: a comprehensive review.
JOURNAL OF AUTOIMMUNITY,
66, 7-16.
Author URL.
2015
Knight RR, Dolton G, Kronenberg-Versteeg D, Eichmann M, Zhao M, Huang GC, Beck K, Cole DK, Sewell AK, Skowera A, et al (2015). A distinct immunogenic region of glutamic acid decarboxylase 65 is naturally processed and presented by human islet cells to cytotoxic CD8 T cells.
CLINICAL AND EXPERIMENTAL IMMUNOLOGY,
179(1), 100-107.
Author URL.
Collison JL, Carlin LM, Eichmann M, Geissmann F, Peakman M (2015). Heterogeneity in the Locomotory Behavior of Human Monocyte Subsets over Human Vascular Endothelium in Vitro.
JOURNAL OF IMMUNOLOGY,
195(3), 1162-1170.
Author URL.
Skowera A, Ladell K, McLaren JE, Dolton G, Matthews KK, Gostick E, Kronenberg-Versteeg D, Eichmann M, Knight RR, Heck S, et al (2015). beta-Cell-Specific CD8 T Cell Phenotype in Type 1 Diabetes Reflects Chronic Autoantigen Exposure.
DIABETES,
64(3), 916-925.
Author URL.
2014
Eichmann M, de Ru A, van Veelen PA, Peakman M, Kronenberg-Versteeg D (2014). Identification and characterisation of peptide binding motifs of six autoimmune disease-associated human leukocyte antigen-class I molecules including HLA-B*39:06.
TISSUE ANTIGENS,
84(4), 378-388.
Author URL.
2013
Knight RR, Kronenberg D, Zhao M, Huang GC, Eichmann M, Bulek A, Wooldridge L, Cole DK, Sewell AK, Peakman M, et al (2013). Human beta-Cell Killing by Autoreactive Preproinsulin-Specific CD8 T Cells is Predominantly Granule-Mediated with the Potency Dependent Upon T-Cell Receptor Avidity.
DIABETES,
62(1), 205-213.
Author URL.
Eichmann M, Peakman M (2013). The role of T lymphocytes in the pathogenesis of autoimmune type 1 diabetes: Implications for potential virus-mediated pathways. In (Ed)
Diabetes and Viruses, 271-286.
Abstract:
The role of T lymphocytes in the pathogenesis of autoimmune type 1 diabetes: Implications for potential virus-mediated pathways
Abstract.
2012
Kronenberg D, Knight RR, Estorninho M, Ellis RJ, Kester MG, de Ru A, Eichmann M, Huang GC, Powrie J, Dayan CM, et al (2012). Circulating Preproinsulin Signal Peptide-Specific CD8 T Cells Restricted by the Susceptibility Molecule HLA-A24 Are Expanded at Onset of Type 1 Diabetes and Kill beta-Cells.
DIABETES,
61(7), 1752-1759.
Author URL.
2011
Luber B, Deplazes J, Keller G, Walch A, Rauser S, Eichmann M, Langer R, Hoefler H, Hegewisch-Becker S, Folprecht G, et al (2011). Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
BMC CANCER,
11 Author URL.