Disturbed Complement Receptor Expression Pattern of B Cells Is Enhanced by Toll-like Receptor CD180 Ligation in Diffuse Cutaneous Systemic Sclerosis.

Autoantibody production is a hallmark of systemic sclerosis (SSc) and the most extensively studied role of B cells in the pathogenesis of the disease. However, the potential involvement of innate immune molecules in B-cell dysfunction in SSc is less understood. B-cell activation is an early event in the pathogenesis of SSc and is influenced by complement receptors (CRs) and Toll-like receptors (TLRs), shaping antibody responses. CR2 and CR1 modulate B-cell activation, and the roles of CR3 and CR4 are associated with autoimmune conditions. We investigated the expression of CRs in B cells from patients with the more severe form of the disease, diffuse cutaneous SSc (dcSSc), and the effect of TLR CD180 ligation on their expression. We found no significant difference in the basal expression of CD21 and CD11c in B cells between dcSSc and healthy controls (HCs). However, reduced basal CD11b expression in B cells in dcSSc compared to HCs, accompanied by a decrease in CD35 and an increase in CD11c expression following CD180 ligation may promote plasma cell formation and autoantibody production. Additionally, we searched for correlations between dcSSc-associated anti-DNA topoisomerase I (Scl-70) autoantibody, anti-citrate synthase (CS) natural autoantibody and complement component 3 (C3) levels and found a negative correlation between C3 and anti-CS autoantibody in dcSSc but not in HCs, supporting the hypothesis that natural autoantibodies could activate the complement system contributing to tissue injury in SSc.

Raising Epidemiological Awareness: Assessment of Measles/MMR Susceptibility in Highly Vaccinated Clusters within the Hungarian and Croatian Population-A Sero-Surveillance Analysis.

Perceptions of the complete eradication of vaccine-preventable diseases such as measles, mumps, and rubella (MMR) may foster complacency and compromise vaccination efforts. Decreased measles vaccination rates during the COVID-19 pandemic have heightened the risk of outbreaks, even in adequately vaccinated populations. To address this, we have aligned with ECDC recommendations, leveraging previous cross-border sero-epidemiological assessments between Pécs, Hungary, and Osijek, Croatia, to identify latent risk groups and uncover potential parallels between our nations. Testing 2680 Hungarian and 1764 Croatian serum samples for anti-MMR IgG via ELISAs revealed anti-measles seropositivity ratios below expectations in Croatian cohorts aged ~20-30 (75.7%), ~30-40 (77.5%) and ~40-50 years (73.3%). Similarly, Hungarian samples also showed suboptimal seropositivity ratios in the ~30-40 (80.9%) and ~40-50 (87.3%) age groups. Considering mumps- and rubella-associated seropositivity trends, in both examined populations, individuals aged ~30-50 years exhibited the highest vulnerability. Additionally, we noted congruent seropositivity trends across both countries, despite distinct immunization and epidemiological contexts. Therefore, we propose expanding research to encompass the intricate dynamics of vaccination, including waning long-term immunity. This understanding could facilitate targeted interventions and bolster public awareness. Our findings underscore persistent challenges in attaining robust immunity against measles despite vaccination endeavors.

Following Natural Autoantibodies: Further Immunoserological Evidence Regarding Their Silent Plasticity and Engagement in Immune Activation.

Contradictory reports are available on vaccine-associated hyperstimulation of the immune system, provoking the formation of pathological autoantibodies. Despite being interconnected within the same network, the role of the quieter, yet important non-pathological and natural autoantibodies (nAAbs) is less defined. We hypothesize that upon a prompt immunological trigger, physiological nAAbs also exhibit a moderate plasticity. We investigated their inducibility through aged and recent antigenic triggers. Anti-viral antibodies (anti-MMR n = 1739 and anti-SARS-CoV-2 IgG n = 330) and nAAbs (anti-citrate synthase IgG, IgM n = 1739) were measured by in-house and commercial ELISAs using Croatian (Osijek) anonymous samples with documented vaccination backgrounds. The results were subsequently compared for statistical evaluation. Interestingly, the IgM isotype nAAb showed a statistically significant connection with anti-MMR IgG seropositivity (p < 0.001 in all cases), while IgG isotype nAAb levels were elevated in association with anti-SARS CoV-2 specific seropositivity (p = 0.019) and in heterogeneous vaccine regimen recipients (unvaccinated controls vector/mRNA vaccines p = 0.002). Increasing evidence supports the interplay between immune activation and the dynamic expansion of nAAbs. Consequently, further questions may emerge regarding the ability of nAAbs silently shaping the effectiveness of immunization. We suggest re-evaluating the impact of nAAbs on the complex functioning of the immunological network.

Ligation of TLR Homologue CD180 of B Cells Activates the PI3K/Akt/mTOR Pathway in Systemic Sclerosis and Induces a Pathological Shift in the Expression of BAFF Receptors.

The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) pathways are known to play a key role in B-cell activation and fibrosis in systemic sclerosis (SSc). Receptors of B-cell activator factor (BAFF) utilize these pathways, which can be influenced by Toll-like receptors (TLRs), as TLRs can alter the expression of BAFF-binding receptors. Our results show that B-cell stimulation via TLR homologue CD180 phosphorylates Akt in diffuse cutaneous SSc (dcSSc) to a lower extent than in healthy controls (HCs). We found basal downregulated BAFF receptor (BAFF-R) and enhanced transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) expression in dcSSc B cells, which might enhance the formation of autoantibody-secreting plasma cells. Moreover, this pathological shift was observed in naive B cells, emphasizing the importance of their increase in SSc. Additionally, we measured higher serum levels of autoantibodies to BAFF in dcSSc patients, suggesting that an imbalance in the complex system of BAFF/anti-BAFF autoantibodies/BAFF-binding receptors may contribute to the development of SSc. Anti-CD180 antibody treatment had opposite effects on the expression of BAFF-R and TACI in HC B cells, resulting in similar levels as observed in SSc B cells without stimulation, which argues against the usefulness of such therapy in SSc.