Multifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis.

Molecular markers of autoimmunity, such as antibodies to citrullinated protein antigens (ACPA), are detectable prior to inflammatory arthritis (IA) in rheumatoid arthritis (RA) and may define a state that is 'at-risk' for future RA. Here we present a cross-sectional comparative analysis among three groups that include ACPA positive individuals without IA (At-Risk), ACPA negative individuals and individuals with early, ACPA positive clinical RA (Early RA). Differential methylation analysis among the groups identifies non-specific dysregulation in peripheral B, memory and naïve T cells in At-Risk participants, with more specific immunological pathway abnormalities in Early RA.

Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis.

Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15HLADR and CD48S100A2 monocytes, recently identified in inflamed RA synovia and blood of those with RA flares.

Affinity Maturation of the Anti-Citrullinated Protein Antibody Paratope Drives Epitope Spreading and Polyreactivity in Rheumatoid Arthritis.

Objective: Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA). While epitope spreading of the serum ACPA response is believed to contribute to RA pathogenesis, little is understood regarding how this phenomenon occurs. This study was undertaken to analyze the antibody repertoires of individuals with RA to gain insight into the mechanisms leading to epitope spreading of the serum ACPA response in RA.

Robust B Cell Responses Predict Rapid Resolution of Lyme Disease.

Lyme disease ( infection) is increasingly recognized as a significant source of morbidity worldwide. Here, we show that blood plasmablasts and CD27 memory B cells are elevated in untreated Lyme disease, with higher plasmablast levels associated with more rapid resolution of clinical symptoms. Stronger serum reactivity to surface proteins and peptides from was also associated with faster resolution of clinical symptoms.

Affinity Maturation Drives Epitope Spreading and Generation of Proinflammatory Anti-Citrullinated Protein Antibodies in Rheumatoid Arthritis.

Objective: Rheumatoid arthritis (RA) is characterized by the presence of anti-citrullinated protein antibodies (ACPAs); nevertheless, the origin, specificity, and functional properties of ACPAs remain poorly understood. The aim of this study was to characterize the evolution of ACPAs by sequencing the plasmablast antibody repertoire at serial time points in patients with established RA.

Methods: Blood samples were obtained at up to 4 serial time points from 8 individuals with established RA who were positive for ACPAs by the anti-cyclic citrullinated peptide test.

Transglutaminase is a Critical Link Between Inflammation and Hypertension.

Background: The pathogenesis of essential hypertension is multifactorial with different underlying mechanisms contributing to disease. We have recently shown that TNF superfamily member 14 LIGHT (an acronym for homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes, also known as TNFSF14) induces hypertension when injected into mice. Research reported here was undertaken to examine the role of transglutaminase (TGase) in LIGHT-induced hypertension.

A pre-eclampsia-associated Epstein-Barr virus antibody cross-reacts with placental GPR50.

To characterize antibody specificities associated with pre-eclampsia (PE), bacterial displayed peptide library screening and evolution was applied to identify peptide epitopes recognized by plasma antibodies present in women with PE near the time of delivery. Pre-eclamptic women exhibited elevated IgG1 titers towards a peptide epitope KRPSCIGCK within the Epstein-Barr virus nuclear antigen 1 (EBNA-1). EBNA-1 epitope antibodies cross-reacted with a similar epitope within the extracellular N-terminus of the human G protein-coupled receptor, GPR50, expressed in human placental tissue and immortalized placental trophoblast cells.

Elevated Transglutaminase Activity Triggers Angiotensin Receptor Activating Autoantibody Production and Pathophysiology of Preeclampsia.

Background: Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy associated with autoantibodies, termed AT1-AA, that activate the AT1 angiotensin receptor. Although the pathogenic nature of these autoantibodies has been extensively studied, little is known about the molecular cause of their generation.

Methods And Results: Here we show that tissue transglutaminase (TG2), an enzyme that conducts posttranslational modification of target proteins, directly modified the 7-amino acid (7-aa) epitope peptide that localizes to the second extracellular loop of the AT1 receptor.

Characterization of antibody specificities associated with preeclampsia.

The presence of maternal autoantibodies has been previously associated with preeclampsia, although the composition of the antibody repertoire in preeclampsia has not been well characterized. Given this, we applied a bacterial display peptide library to identify peptides that preferentially react with plasma antibodies from patients with preeclampsia (n=15) versus healthy-outcome pregnancies (n=18). Screening using fluorescence-activated cell sorting identified 38 peptides that preferentially bind to antibodies from individuals with preeclampsia.