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

Abstract

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.

Does gene expression analysis inform us in rheumatoid arthritis?

“…van der Pouw Kraan et al 40 also reported on a RA subgroup that presented with an interferon type I signature in PBMC, a signature that was previously reported to be a typical molecular characteristic in SLE 41 42. They also described a pathogen-response programme in PBMC reminiscent of that of a poxvirus infection in macaques 43. These observations suggest that different molecular mechanisms may be involved in RA, which may explain other reports and observations, most strikingly the differences in treatment response.…”

Gene Expression Profiling in Rheumatoid Arthritis

“…Since a quarter of the early arthritis genes overlapped with an influenza-induced gene set it was suggested that the early arthritis signature may partly reflect the response to an unknown infectious agent (Olsen et al, 2004). Accordingly, van der Pouw Kraan and colleagues observed similarity with a common virus response signature in a subset of RA patients (van der Pouw Kraan et al, 2008). Not surprisingly, the majority of these patients had an activated IFN-response program.…”

“…Moreover, the immune defense gene program that was activated in the subgroup of RA patients was reminiscent to that of virus-infected macaques (van der Pouw Kraan et al, 2008). Comparative analysis between paired tissue and peripheral blood profile revealed that there exists no concordance in the presence of IFN-response activity between the two compartments (van Baarsen et al, 2010a)…”

“…Initial analyses of synovial tissue gene expression profiles prior to the start of infliximab therapy suggested that patients with features of an activated immune status in their tissue compartment are more likely to benefit from anti-TNF treatment based on ΔDAS28 response criteria ( Van der Pouw Kraan et al, 2008;Lindberg et al, 2006). Similar findings were reported for baseline serum markers associated with responsiveness (Hueber et al, 2009).…”

Upcoming value of gene expression analysis in rheumatology

“…При этом больные РА с более высокими уровнями синовиального воспаления и экспрессии TNFa в синовии [18], а также при увеличении экспрессии генов бета-рецептора IL2, SH2 домена 2А и GOS2 в периферической крови более чувствительны к блокаде TNFa [19]. Более того, высокая базальная экспрессия TNFa у больных, у которых концентрация С-реактивного белка (СРБ) в крови после терапии уменьшалась до уровня, наблюдаемого у здоровых лиц, оказалась маркером эффективности терапии ингибитором TNFa, инфликсимабом [20].…”