Unravelling autoimmune pathogenesis by screening random peptide libraries with human sera

Fierabracci, Alessandra

doi:10.1016/j.imlet.2009.04.001

Cited by 12 publications

(6 citation statements)

References 111 publications

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“…The disorder develops as a consequence of a combination of genetic predisposition, still unknown environmental factors and stochastic events [2][3][4]. From a pathogenetic point of view, the disease is the result of a breakdown in immune regulation that leads to expansion of autoreactive CD4+ and CD8+ T cells, autoantibodyproducing B lymphocytes and activation of the innate immune system.…”

Section: Introductionmentioning

confidence: 99%

The potential of multimer technologies in type 1 diabetes prediction strategies

Fierabracci

2011

Diabetes Metabolism Res

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Type 1 diabetes is an autoimmune disease which occurs in (human leukocyte antigen) genetically predisposed individuals as a consequence of the organ-specific immune destruction of the insulin-producing β cells in the islets of Langherans within the pancreas. Type 1 diabetes is the result of a breakdown in immune regulation that leads to expansion of autoreactive CD4+ and CD8+ T cells, autoantibody-producing B lymphocytes and activation of the innate immune system. Islet-related autoantibodies revealed themselves to be good predictors of future onset of the disease, although they are not directly pathogenetic; T cells instead play a dominant role in disease initiation and progression. In this review, we first discuss the approaches that several laboratories attempted to measure human islet autoantigen-specific T-cell function in type 1 diabetes. T-cell assays could be used in combination with standardized autoantibody screenings to improve predictive strategies. They could also help to monitor in long-term follow-up the efficacy of tolerogenic immunotherapeutic strategies when established at the onset of the disease, and help to predict the recurrence of disease. Although some recent developments based on enzyme-linked immunosorbent spot and immunoblotting techniques have been able to distinguish with good sensitivity and specificity patients from controls, T-cell results, as revealed by international workshops, were indeed largely inconclusive. Nowadays, novel technologies have been exploited that could contribute to answering the tantalizing question of identifying autoreactive T cells. We particularly focus on and discuss MHC multimer tools and emphasize the advantages they can offer but also their weaknesses when used in combination with other T-cell assays. Copyright © 2011 John Wiley & Sons, Ltd.

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Section: Introductionmentioning

confidence: 99%

The potential of multimer technologies in type 1 diabetes prediction strategies

Fierabracci

2011

Diabetes Metabolism Res

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“…Accumulating evidence thus suggests that stimulation of TLRs, i.e., TLR9, can incite autoimmunity in humans, and infections may play a role in triggering disease relapses [40] . In organ-specific T cell-mediated autoimmune disorders, such as T1D, CD4 + and CD8 + T lymphocytes are the major players in the destruction of pancreatic beta cells [41] . However, the role of B cells in T1D pathogenesis ( vide supra ) in humans remains unclear [41] .…”

Section: Discussionmentioning

confidence: 99%

“…In organ-specific T cell-mediated autoimmune disorders, such as T1D, CD4 + and CD8 + T lymphocytes are the major players in the destruction of pancreatic beta cells [41] . However, the role of B cells in T1D pathogenesis ( vide supra ) in humans remains unclear [41] . Experimental evidence suggests that the NOD strain is highly resistant to T1D when it is rendered deficient in B cells [27] , [32] , [33] , [42] .…”

Section: Discussionmentioning

confidence: 99%

“…NOD B cells, particularly transitional, B1, and marginal-zone B cells are the preferred antigen presenting cells (APC) for the priming and/or expansion of diabetogenic autoreactive CD4 + T cells. Moreover, independent of their pathogenic role, B cells produce islet-related IgG autoantibodies as the earliest manifestation of the diabetogenic process [41] . Antibodies binding to beta cells before the development of insulitis primarily of the IgM isotype, are spontaneously secreted by B1a B cells in the absence of exogenous stimuli or T cell help [43] .…”

Section: Discussionmentioning

confidence: 99%

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Altered B Cell Homeostasis and Toll-Like Receptor 9-Driven Response in Type 1 Diabetes Carriers of the C1858T PTPN22 Allelic Variant: Implications in the Disease Pathogenesis

et al. 2014

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Type 1 diabetes is an autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of T cells but also of B cells in innate and adaptive immunity. The Lyp variant was shown to diminish interferon production and responses upon Toll-like receptor stimulation in macrophages and dendritic cells, possibly leading to uncontrolled infections as triggers of the diabetogenic process. The aim of this study was to unravel the yet uncharacterized effects that the variant could exert on the immune and autoimmune responses, particularly regarding the B cell phenotype, in the peripheral blood lymphocytes of diabetic patients and healthy controls in basal conditions and after unmethylated bacterial DNA CpG stimulation. The presence of the Lyp variant resulted in a significant increase in the percentage of transitional B cells in C/T carriers patients and controls compared to C/C patients and controls, in C/T carrier patients compared to C/C controls and in C/T carrier patients compared to C/C patients. A significant reduction in the memory B cells was also observed in the presence of the risk variant. After four days of CpG stimulation, there was a significant increase in the abundance of IgM+ memory B cells in C/T carrier diabetics than in C/C subjects and in the groups of C/T carrier individuals than in C/C individuals. IgM− memory B cells tended to differentiate more precociously into plasma cells than IgM+ memory B cells in heterozygous C/T subjects compared to the C/C subjects. The increased Toll-like receptor response that led to expanded T cell-independent IgM+ memory B cells should be further investigated to determine the putative contribution of innate immune responses in the disease pathogenesis.

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“…Previous methods to discover peptides binding to disease antibodies, including antibody profiling and signature analysis using peptide libraries (7,24), have demonstrated the existence of unique antibody specificities in a broad range of diseases (25). And although the peptides identified have demonstrated diagnostic potential, alone or in panel format (8,25), their translation to the clinic has been hindered by inadequate diagnostic sensitivity and specificity values. By applying concepts from in vitro directed evolution to human patient samples, we were able to screen large libraries in an iterative fashion for molecular properties (affinity, cross-reactivity, and molecular specificity) that favor diagnostic sensitivity and specificity.…”

Section: Discussionmentioning

confidence: 99%

Antibody biomarker discovery through in vitro directed evolution of consensus recognition epitopes

Ballew

Murray

Collin

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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To enable discovery of serum antibodies indicative of disease and simultaneously develop reagents suitable for diagnosis, in vitro directed evolution was applied to identify consensus peptides recognized by patients' serum antibodies. Bacterial cell-displayed peptide libraries were quantitatively screened for binders to serum antibodies from patients with celiac disease (CD), using cellsorting instrumentation to identify two distinct consensus epitope families specific to CD patients (PEQ and/ F Q consensus epitope identified a celiac-specific epitope, distinct from the two CD hallmark antigens tissue transglutaminase-2 and deamidated gliadin, exhibiting 71% sensitivity and 99% specificity (n = 231). Expansion of the first-generation PEQ consensus epitope via in vitro evolution yielded octapeptides QPEQAFPE and PFPEQxFP that identified ω-and γ-gliadins, and their deamidated forms, as immunodominant B-cell epitopes in wheat and related cereal proteins. The evolved octapeptides, but not first-generation peptides, discriminated one-way blinded CD and non-CD sera (n = 78) with exceptional accuracy, yielding 100% sensitivity and 98% specificity. Because this method, termed antibody diagnostics via evolution of peptides, does not require prior knowledge of pathobiology, it may be broadly useful for de novo discovery of antibody biomarkers and reagents for their detection.

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Unravelling autoimmune pathogenesis by screening random peptide libraries with human sera

Cited by 12 publications

References 111 publications

The potential of multimer technologies in type 1 diabetes prediction strategies

The potential of multimer technologies in type 1 diabetes prediction strategies

Altered B Cell Homeostasis and Toll-Like Receptor 9-Driven Response in Type 1 Diabetes Carriers of the C1858T PTPN22 Allelic Variant: Implications in the Disease Pathogenesis

Antibody biomarker discovery through in vitro directed evolution of consensus recognition epitopes

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