Plasma adiponectin levels are associated with circulating inflammatory cytokines in autoantibody positive first-degree relatives of rheumatoid arthritis patients

Background Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations. Methods We analyzed samples from 144 first-degree relatives (FDRs) of RA probands, of whom 23 were positive for anti-cyclic citrullinated peptide antibody and/or ≥ 2 rheumatoid factor isotypes (IgM, IgG or IgA). We called this phenotype the ‘high risk autoantibody profile (HRP)’ as it has been shown in prior work to be >96% specific for future RA. We measured adiponectin, cytokines, and high-sensitivity C-reactive protein (hsCRP). Using linear mixed effects models, we evaluated interaction between HRP positivity and adiponectin on inflammatory markers, adjusting for age, sex, ethnicity, body mass index, pack-years smoking, and use of cholesterol-lowering medications. Results In everyone, adiponectin concentration was inversely associated with hsCRP and IL-1β in adjusted models, where a 1% higher adiponectin was associated with a 26% lower hsCRP (p = 0.04) and a 26% lower IL-1β (p = 0.04). Significant interactions between HRP and adiponectin for associations with GM-CSF, IL-6, and IL-9 were detected in fully adjusted models (p = 0.0006, p = 0.006, p = 0.01, respectively). In HRP positive FDRs but not HRP negative FDRs, a 1% higher adiponectin was associated with 97% higher GM-CSF, 73% higher IL-6, and 54% higher IL-9 concentrations. Conclusions Adiponectin associates with inflammatory markers, and these associations differ in individuals with a high-risk autoantibody profile compared with those without. The interaction between adiponectin and autoimmunity warrants further investigation into the potential systemic effects of RA-related autoantibodies and adiponectin on inflammation in the absence of clinically apparent RA

Nonparametric Comparison of Exponential Growth Curves

A program to compare exponential growth curves via randomization tests has been developed for the one-way analysis-of variance situation. Exponential growth curves of the form Y = a - b exp( - gt) are first fit to each individual\u27s longitudinal data. The parameters from each individual\u27s curve are then input into the randomization program

B Cell Receptor Signaling-Based Index as a Biomarker for the Loss of Peripheral Immune Tolerance in Autoreactive B Cells in Rheumatoid Arthritis

<div><p>This study examines the loss of peripherally induced B cell immune tolerance in Rheumatoid arthritis (RA) and establishes a novel signaling-based measure of activation in a subset of autoreactive B cells - the <i>Induced tolerance status index</i> (ITSI). Naturally occurring naïve autoreactive B cells can escape the “classical” tolerogenic mechanisms of clonal deletion and receptor editing, but remain peripherally tolerized through B cell receptor (BCR) signaling inhibition (postdevelopmental “receptor tuning” or anergy). ITSI is a statistical index that numerically determines the level of homology between activation patterns of BCR signaling intermediaries in B cells that are either tolerized or activated by auto antigen exposure, and thus quantifies the level of peripheral immune tolerance. The index is based on the logistic regression analysis of phosphorylation levels in a panel of BCR signaling proteins. Our results demonstrate a new approach to identifying autoreactive B cells based on their BCR signaling features.</p></div

BCR signaling pathways associated with the loss of peripheral induced tolerance in autoreactive B_ND cells of RA patients [2]. (A)

<p>Unmanipulated B_ND cells: increased baseline activity Blnk, SHP and Jnk. <b>(B)</b> Response to BCR engagement in B_ND cells: decreased phosphorylation of Blnk, Syk, SHP2, CD19 and increased activation of Erk1/2, Jnk.</p

Normal (tolerance in healthy controls) and pathological (broken tolerance in RA) BCR signaling in autoreactive B cells with induced peripheral immune tolerance.

<p>Normal (tolerance in healthy controls) and pathological (broken tolerance in RA) BCR signaling in autoreactive B cells with induced peripheral immune tolerance.</p

Induced tolerance status index (ITSI) discriminates between autoreactive B_ND cells from healthy controls and RA subjects based on BCR phosphoprotein activation patterns.

<p>Induced tolerance status index (ITSI) discriminates between autoreactive B_ND cells from healthy controls and RA subjects based on BCR phosphoprotein activation patterns.</p

Strategies for BCR phosphoprotein data analysis in autoreactive B_ND cells.

<p>Strategies for BCR phosphoprotein data analysis in autoreactive B_ND cells.</p

Phosphorylation levels of major BCR signal transduction proteins and total tyrosine phosphorylation levels (pTyr) in CD27⁻IgD⁺IgM^low/− B cells of RA patients (red) and healthy control subjects (blue) at baseline and in response to anti-BCR stimulation <i>in vitro</i>.

<p>Phosphorylation levels of major BCR signal transduction proteins and total tyrosine phosphorylation levels (pTyr) in CD27⁻IgD⁺IgM^low/− B cells of RA patients (red) and healthy control subjects (blue) at baseline and in response to anti-BCR stimulation <i>in vitro</i>.</p