Antigen microarray profiling of autoantibodies in rheumatoid arthritis

Hueber, Wolfgang; Kidd, Brian; Tomooka, Beren; Lee, Byung J.; Bruce, Bonnie; Fries, James F.; Sønderstrup, Grete; Monach, Paul A.; Drijfhout, Jan W.; Venrooij, Walther J. van; Utz, Paul J.; Genovese, Mark C.; Robinson, William H.

doi:10.1002/art.21269

Cited by 251 publications

(215 citation statements)

References 85 publications

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“…1,2 The heterogeneous character of RA is further illustrated by the differential responsiveness to treatment [3][4][5] and the presence of distinct autoantibody specificities, like rheumatoid factor and anti-citrullinated peptide antibodies (ACPA) in the serum. 6,7 The existence of such molecular heterogeneity in RA synovium fits a model proposed by Firestein and Zvaifler, 8 who suggested two independent processes, an immune-mediated and a stromal cell-driven form, which might drive destruction of bone and cartilage.…”

Section: Introductionsupporting

confidence: 68%

Expression of a pathogen-response program in peripheral blood cells defines a subgroup of Rheumatoid Arthritis patients

et al. 2007

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Rheumatoid arthritis (RA) is a heterogeneous disease with unknown etiology. Here we aimed to distinguish RA subtypes based on peripheral blood (PB) gene expression profiles in comparison with a pathogen-response transcriptional program. PB was obtained from 35 RA patients and 15 healthy individuals. For expression profiling we used DNA microarrays. A combined cluster analysis of RA and control samples together with samples from a viral infection model revealed that the gene expression profile of a subgroup of RA patients (RA A ) was reminiscent to that of poxvirus-infected macaques. Statistical analysis, followed by Gene Ontology analysis of the RA A patients confirmed that these patients form a distinct group, with activation of several host defense mechanisms that resemble a common host-pathogen response. Analysis of the promoter region of genes that were overexpressed in the RA A patients, revealed an enrichment of transcription factor binding sites for NFkB and interferon-activated transcription factors. Moreover, this subgroup of RA patients expressed significantly increased titers of anti-cyclic citrullinated peptide antibodies. We conclude that activation of a host-pathogen response defines a subgroup of RA patients characterized by increased autoreactivity against citrullinated proteins.

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Section: Introductionsupporting

confidence: 68%

Expression of a pathogen-response program in peripheral blood cells defines a subgroup of Rheumatoid Arthritis patients

et al. 2007

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“…The following linear citrullinated peptides and their native counterparts were used for fine specificity studies: C2 (vim) (STCit SVS SSS YCitCit MFG G) (22) and C3 (vim) (VYA TCitS SAV CitLCit SSV P) (23) derived from human vimentin, C4 (fib) (NEE GFF SACit GHR PLD KK) (23) and C5 (fib) (FLA EGG GVCit GPR VVE RH) (unpublished data) derived from human fibrinogen, and C6 (enolase) (KIH ACitE IFD SCitG NPT V) (24) derived from human non-neuronal enolase. All synthetic peptides were coated on streptavidin-coated plates (Fisher, Winnepeg, Manitoba, Canada) via a C-terminal long-chain biotin.…”

Section: Methodsmentioning

confidence: 99%

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

Ioan‐Facsinay¹,

Willemze²,

Robinson³

et al. 2008

Arthritis & Rheumatism

166

144

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Objective. Anti-citrullinated protein antibodies (ACPAs) display high association with rheumatoid arthritis (RA) and are implicated in its pathogenesis. The presence of ACPAs is known to precede the onset of RA. In order to identify the features that could confer its pathogenicity, we extensively characterized this antibody response in a unique North American native population of patients with RA and their unaffected relatives.Methods. The levels of IgA, IgM, and IgG ACPAs, as well as IgM and IgA rheumatoid factor (RF), were measured in serum samples obtained from 81 patients with RA and 195 of their unaffected relatives. The isotype distribution, the fine specificity of the ACPA response, and its association with RF were compared in health and disease.Results. ACPA positivity was observed in 19% of the healthy relatives and ϳ91% of the patients with RA. ACPA isotype usage was strikingly lower in unaffected relatives than in patients with RA (1-2 versus 5-6 isotypes). Fine specificity studies showed that reactivity to citrullinated fibrinogen and vimentin was present in sera from patients with RA, while it was virtually absent in their unaffected relatives. Finally, the ACPA and RF responses were associated in patients with RA but were discordant in their healthy relatives. Extended analyses revealed that the presence of ACPAs was associated with RA irrespective of RF status, while the association of RF with disease relied on its interaction with ACPAs.Conclusion. The fine specificity and isotype usage of the ACPA response are qualitatively different in health and disease. Epitope spreading and expansion of the isotype repertoire might be necessary for development of RA, and this could be facilitated by the presence of RF antibodies.Autoantibodies are characteristic of a large number of autoimmune diseases. Determining the pathogenicity of autoantibodies by showing their capacity to transfer disease, however, is complicated by ethical and practical difficulties. Therefore, only a small minority of autoantibodies, such as antiplatelet antibodies in idiopathic thrombocytopenia purpura or the antidesmoglein antibodies in pemphigus vulgaris, were convincingly shown to mediate a pathogenetic effect through placental transfer (1) or transfer into experimental animals (2), respectively.

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“…Their group demonstrated specific autoantibody binding that was linear over a 3-log range and was four to eight times more sensitive than ELISAs. Hueber et al [5] designed a synovial proteome microarray containing 650 candidate autoantigens, which reliably stratified patients with early rheumatoid arthritis into clinically relevant disease subsets. Huang et al [6] developed a cytokine array with increased sensitivity and a broader detection range compared with standard ELISAs.…”

Section: Introductionmentioning

confidence: 99%

Customising an antibody leukocyte capture microarray for systemic lupus erythematosus: Beyond biomarker discovery

Lin

Adelstein

et al. 2010

Proteomics Clinical Apps

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease that has heterogeneous clinical manifestation with diverse patterns of organ involvement, autoantibody profiles and varying degrees of severity of disease. Research and clinical experience indicate that different subtypes of SLE patients will likely benefit from more tailored treatment regimes, but we currently lack a fast and objective test with high enough sensitivity to enable us to perform such sub‐grouping for clinical use. In this article, we review how proteomic technologies could be used as such an objective test. In particular, we extensively review many leukocyte surface markers that are known to have an association with the pathogenesis of SLE, and we discuss how these markers can be used in the further development of a novel SLE‐specific antibody leukocyte capture microarray. In addition, we review some bioinformatics challenges and current methods for using the data generated by these cell‐capture microarrays in clinical use. In a broader context, we hope our experience in developing a disease specific cell‐capture microarray for clinical application can be a guide to other proteomic practitioners who intend to extend their technologies to develop clinical diagnostic and prognostic tests for complex diseases.

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Antigen microarray profiling of autoantibodies in rheumatoid arthritis

Cited by 251 publications

References 85 publications

Expression of a pathogen-response program in peripheral blood cells defines a subgroup of Rheumatoid Arthritis patients

Expression of a pathogen-response program in peripheral blood cells defines a subgroup of Rheumatoid Arthritis patients

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

Customising an antibody leukocyte capture microarray for systemic lupus erythematosus: Beyond biomarker discovery

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