At Early Rheumatoid Arthritis Stage, the Infectious Spectrum Is Driven by Non-Familial Factors and Anti-CCP Immunization.

Background/Objectives: Patients with rheumatoid arthritis (RA) are prone to develop infections. Methods: Accordingly, 195 untreated early (e)RA patients and 398 healthy controls were selected from women in Tatarstan's cohort to study infectious history in the anamnesis (four criteria) and in the previous year (16 criteria). Information about annual infections was collected face-to-face from year to year by a qualified rheumatologist/general practitioner and included the active use of information from medical records. Results: In the anamnesis, tuberculosis, and pneumonia, and in the previous year, respiratory tract infections, skin infections, and herpes simplex virus reactivation incidence were reported to be increased in eRA patients, as well as the event number and duration of acute and chronic tonsillitis. Moreover, more bacterial-suspected upper respiratory infections and urinary tract infections were retrieved in sporadic eRA patients as compared to familial eRA patients. An elevated immunization against CCP prevented respiratory tract infection in those with HSV exacerbation. Finally, associations were retrieved between infection (event number/delay) and RA indices: (i) chronic tonsillitis exacerbations with disease activity and health assessment (HAQ) in familial eRA; (ii) bacterial-suspected upper respiratory infections with the number of swollen and tender joints in sporadic eRA; and (iii) HSV exacerbation with inflammation in eRA patients with negative/low response against CCP. Here, we demonstrate the complex nature of the interplay of RA with specific infections. Conclusions: For the first time, differences in the patterns of annual trivial infections and their links with RA indices were found in cohorts of familial and sporadic cases of the disease. Additionally, for the first time, we identified a remarkable relationship between early RA and exacerbations of chronic tonsillitis, as well as tuberculosis in the patient's history. Altogether, this study supports the existence of a complex interplay between infections and RA at onset driven by familial status and the presence of anti-CCP Ab at elevated levels.

Perinatal foodborne titanium dioxide exposure-mediated dysbiosis predisposes mice to develop colitis through life.

BACKGROUND: Perinatal exposure to titanium dioxide (TiO2), as a foodborne particle, may influence the intestinal barrier function and the susceptibility to develop inflammatory bowel disease (IBD) later in life. Here, we investigate the impact of perinatal foodborne TiO2 exposure on the intestinal mucosal function and the susceptibility to develop IBD-associated colitis. Pregnant and lactating mother mice were exposed to TiO2 until pups weaning and the gut microbiota and intestinal barrier function of their offspring was assessed at day 30 post-birth (weaning) and at adult age (50 days). Epigenetic marks was studied by DNA methylation profile measuring the level of 5-methyl-2'-deoxycytosine (5-Me-dC) in DNA from colic epithelial cells. The susceptibility to develop IBD has been monitored using dextran-sulfate sodium (DSS)-induced colitis model. Germ-free mice were used to define whether microbial transfer influence the mucosal homeostasis and subsequent exacerbation of DSS-induced colitis. RESULTS: In pregnant and lactating mice, foodborne TiO2 was able to translocate across the host barriers including gut, placenta and mammary gland to reach embryos and pups, respectively. This passage modified the chemical element composition of foetus, and spleen and liver of mothers and their offspring. We showed that perinatal exposure to TiO2 early in life alters the gut microbiota composition, increases the intestinal epithelial permeability and enhances the colonic cytokines and myosin light chain kinase expression. Moreover, perinatal exposure to TiO2 also modifies the abilities of intestinal stem cells to survive, grow and generate a functional epithelium. Maternal TiO2 exposure increases the susceptibility of offspring mice to develop severe DSS-induced colitis later in life. Finally, transfer of TiO2-induced microbiota dysbiosis to pregnant germ-free mice affects the homeostasis of the intestinal mucosal barrier early in life and confers an increased susceptibility to develop colitis in adult offspring. CONCLUSIONS: Our findings indicate that foodborne TiO2 consumption during the perinatal period has negative long-lasting consequences on the development of the intestinal mucosal barrier toward higher colitis susceptibility. This demonstrates to which extent environmental factors influence the microbial-host interplay and impact the long-term mucosal homeostasis.

Predictive risk factors before the onset of familial rheumatoid arthritis: the Tatarstan cohort study.

Background: A familial history of rheumatoid arthritis (RA) predisposes an individual to develop RA. This study aimed at investigating factors associated with this conversion from the Tatarstan cohort. Methods: A total of 144 individuals, referred to as pre-RA and at risk for familial RA, were selected 2 years (range: 2-21 years) before conversion to RA and compared to non-converted 328 first-degree relatives (FDR) from RA as assessed after ≥2 years follow-up, and 355 healthy controls were also selected (HC). Preclinical parameters and socio-demographic/individual/HLA genetic factors were analyzed when data were available at the time of enrollment. Results: As compared to FDR and HC groups, pre-RA individuals were characterized before conversion to RA by the presence of arthralgia, severe morning symptoms, a lower educational level, and rural location. An association with the HLA-DRB1 SE risk factor was also retrieved with symmetrical arthralgia and passive smoking. On the contrary, alcohol consumption and childlessness in women were protective and associated with the HLA-DRB1*07:01 locus. Conclusion: Before RA onset, a combination of individual and genetic factors characterized those who are at risk of progressing to RA among those with familial RA relatives.

Intestinal involvement in lupus: From pathophysiology to therapeutic perspectives.

Lupus erythematosus is a complex autoimmune disease characterized by skin and/or systemic involvement. Among systemic disorders, half of the patients will experience non-specific digestive symptoms, usually due to drug medication or transitory infections. In rare cases, lupus enteritis can be observed, and its diagnosis may precede the disease and/or be associated with an inflammatory bowel disease (IBD). Among the underlying mechanisms explaining the digestive damages observed in systemic lupus erythematosus (SLE) and the intestinal barrier function (IBF), increased intestinal permeability, microbiota dysbiosis, and intestinal immune system dysregulations are described in numerous murine and human studies. New therapeutic approaches in addition to conventional treatments are evoked in order to better control the IBF disruption and maybe prevent the onset or worsening of the disease. Thus, the aims of this review are to present the alterations of the digestive tract in SLE patients and the link between SLE and IBD as well as how the different elements of the IBF could participate in SLE pathogenesis.

Characteristics of the (Auto)Reactive T Cells in Rheumatoid Arthritis According to the Immune Epitope Database.

T cells are known to be involved in the pathogenesis of rheumatoid arthritis (RA). Accordingly, and to better understand T cells' contribution to RA, a comprehensive review based on an analysis of the Immune Epitope Database (IEDB) was conducted. An immune CD8+ T cell senescence response is reported in RA and inflammatory diseases, which is driven by active viral antigens from latent viruses and cryptic self-apoptotic peptides. RA-associated pro-inflammatory CD4+ T cells are selected by MHC class II and immunodominant peptides, which are derived from molecular chaperones, host extra-cellular and cellular peptides that could be post-translationally modified (PTM), and bacterial cross-reactive peptides. A large panel of techniques have been used to characterize (auto)reactive T cells and RA-associated peptides with regards to their interaction with the MHC and TCR, capacity to enter the docking site of the shared epitope (DRB1-SE), capacity to induce T cell proliferation, capacity to select T cell subsets (Th1/Th17, Treg), and clinical contribution. Among docking DRB1-SE peptides, those with PTM expand autoreactive and high-affinity CD4+ memory T cells in RA patients with an active disease. Considering original therapeutic options in RA, mutated, or altered peptide ligands (APL) have been developed and are tested in clinical trials.

Impact of imlifidase treatment on immunoglobulins in an HLA-hypersensitized lupus nephritis patient with anti-SSA/SSB antibodies after kidney transplantation: A case report.

Bacterial recombinant cysteine protease Ides (imlifidase, Idefirix®, Hansa Biopharma) is used to prevent humoral transplant rejection in highly HLA-sensitized recipients, and to control IgG-mediated autoimmune diseases. We report the case of a 51 years old woman suffering from lupus nephritis with end stage kidney disease, grafted for the second time and pre-treated with imlifidase. The patient was HLA-hypersensitized (calculated Panel Reactive Antibodies [Abs], cPRA>99 %) and has three preformed Donor Specific Antibodies (DSA). Circulating immunoglobulins were monitored at initiation (0, 6, 36, 72 and 96 h), and at Ab recovery one and two months following imlifidase injection. From baseline, the higher depletion was reported after 36h for total IgG (-75 %) and IgG subclasses (-87 % for IgG1, IgG2 and IgG3, -78 % for IgG4), while no significant impact on IgA and IgM was observed. Anti-SSA 60 kDa and anti-SSB auto-Abs quickly decreased after imlifidase injection (-96 % for both after 36 h) as well as post-vaccinal specific IgG (-95 % for tetanus toxoid, -97 % for pneumococcus and -91 % for Haemophilus influenzae Abs after 36 h). At the Ab recovery phase, total IgG and anti-SSA60/SSB Abs reached their initial level at two months. Regarding alloreactive Abs, anti-HLA Abs including the three DSA showed a dramatic decrease after injection with 100 % depletion from baseline after 36 h as assessed by multiplex single bead antigen assay, leading to negative crossmatches using both lymphocytotoxicity (LCT) and flow cell techniques. DSA rebound at recovery was absent and remained under the positivity threshold (MFI = 1000) after 6 months. The findings from this case report are that imlifidase exerts an early depleting effect on all circulating IgG, while IgG recovery may depend in part from imlifidase's capacity to target memory B cells.

Anti-Citrullinated Peptide Antibodies Control Oral Porphyromonas and Aggregatibacter species in Patients with Rheumatoid Arthritis.

Oral microbiome changes take place at the initiation of rheumatoid arthritis (RA); however, questions remain regarding the oral microbiome at pre-RA stages in individuals with clinically suspect arthralgia (CSA). Two cross-sectional cohorts were selected including 84 Tatarstan women (15 early-RA as compared to individuals with CSA ranging from CSA = 0 [n = 22], CSA = 1 [n = 19], CSA = 2 [n = 11], and CSA ≥ 3 [n = 17]) and 42 women with established RA (median: 5 years from diagnosis [IQ: 2-11]). Amplicon sequence variants (ASVs) obtained from oral samples (16S rRNA) were analyzed for alpha and beta diversity along with the abundance at the genus level. A decrease in oral Porphyromonas sp. is observed in ACPA-positive individuals, and this predominates in early-RA patients as compared to non-RA individuals irrespective of their CSA score. In the RA-established cohort, Porphyromonas sp. and Aggregatibacter sp. reductions were associated with elevated ACPA levels. In contrast, no associations were reported when considering individual, genetic and clinical RA-associated factors. Oral microbiome changes related to the genera implicated in post-translational citrullination (Porphyromonas sp. and Aggregatibacter sp.) characterized RA patients with elevated ACPA levels, which supports that the role of ACPA in controlling the oral microbiome needs further evaluation.

Lupus band test can be used in combination with anti-chromatin antibodies and complement analysis to predict transition from cutaneous to systemic lupus.

The lupus band test (LBT) is frequently performed for patients with lupus erythematosus (LE) but its capacity to discriminate cutaneous (C)LE from systemic (S)LE is debated, as well as its association with serum antinuclear antibodies (ANA) and complement reduction. Among 158 patients, 56 received retrospectively a diagnosis of CLE, 37 have SLE and 65 other skin disorders. Considering 29 clinical, histopathologic, LBT, and serological parameters: 5 parameters were effective in distinguishing LE from other skin disorders (e.g. skin photosensitivity, LBT positivity, basal vacuolar changes, thickening of the basement membrane, and anti-SSA-60 kDa); and 8 parameters were able to separate SLE from CLE (e.g. arthritis, lupus nephritis, hematological manifestations, Raynaud/sicca manifestations, anti-chromatin, anti-dsDNA, and low levels of C3/4). A positive LBT was further determined to be associated with systemic manifestations when associated with anti-chromatin response and complement reduction in the profile of patients evolving to a systemic form of lupus.

Untargeted Lipidomic Profiling of Dry Blood Spots Using SFC-HRMS.

Lipids are essential cellular constituents that have many critical roles in physiological functions. They are notably involved in energy storage and cell signaling as second messengers, and they are major constituents of cell membranes, including lipid rafts. As a consequence, they are implicated in a large number of heterogeneous diseases, such as cancer, diabetes, neurological disorders, and inherited metabolic diseases. Due to the high structural diversity and complexity of lipid species, the presence of isomeric and isobaric lipid species, and their occurrence at a large concentration scale, a complete lipidomic profiling of biological matrices remains challenging, especially in clinical contexts. Using supercritical fluid chromatography coupled with high-resolution mass spectrometry, we have developed and validated an untargeted lipidomic approach to the profiling of plasma and blood. Moreover, we have tested the technique using the Dry Blood Spot (DBS) method and found that it allows for the easy collection of blood for analysis. To develop the method, we performed the optimization of the separation and detection of lipid species on pure standards, reference human plasma (SRM1950), whole blood, and DBS. These analyses allowed an in-house lipid data bank to be built. Using the MS-Dial software, we developed an automatic process for the relative quantification of around 500 lipids species belonging to the 6 main classes of lipids (including phospholipids, sphingolipids, free fatty acids, sterols, and fatty acyl-carnitines). Then, we compared the method using the published data for SRM 1950 and a mouse blood sample, along with another sample of the same blood collected using the DBS method. In this study, we provided a method for blood lipidomic profiling that can be used for the easy sampling of dry blood spots.