Progression from suspected to definite systemic sclerosis and the role of anti-topoisomerase I antibodies.

INTRODUCTION: Early diagnosis of systemic sclerosis (SSc) is important to start therapeutic interventions timely. Important risk factors for progression to SSc are the SSc-specific autoantibodies, of whom anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA) are the most frequent. ATA is associated with a severe disease course. A more detailed characterisation of the ATA-response in SSc might increase insights in preclinical disease stages and improve prognostication. To address this we identified all patients with suspected very early ATA-positive SSc, defined as all patients who are ATA-positive not fulfilling American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria, in the Leiden Combined Care in Systemic Sclerosis (CCISS)-cohort and found very low numbers. METHODS: This triggered us to search the literature on the ATA prevalence in patients with suspected very early SSc and contribution of the SSc-specific autoantibodies to progression from suspected very early to definite SSc. To increase insights on the ATA-response in suspected very early SSc, we then evaluated the association between the ATA-response and time between onset of Raynaud's phenomenon (RP) and first non-RP symptom, as a proxy for progressing to definite SSc, in all patients with ATA-positive SSc from the Leiden CCISS-cohort. RESULTS: In short, included studies show that prevalence of ATA is much lower in suspected very early SSc than in populations fulfilling ACR/EULAR 2013 criteria. After 1-15 years of follow-up, only 52% of the patients with suspected very early SSc progress to definite SSc. ATA-IgG levels tend to be higher in patients with ATA-positive SSc with more rapid disease progression. CONCLUSION: Although a role of ATA in disease progression is suggested, more studies on the ATA response in suspected very early SSc are warranted.

Autoreactive B cell responses targeting nuclear antigens in systemic sclerosis: Implications for disease pathogenesis.

A hallmark of disease pathogenesis of systemic sclerosis (SSc) is the presence of autoreactive B cell responses targeting nuclear proteins. Almost all SSc-patients harbour circulating antinuclear autoantibodies of which anti-topoisomerase 1, anti-centromere protein, anti-RNA polymerase III and anti-fibrillarin autoantibodies (ATA, ACA, ARA and AFA, respectively) are the most common and specific for SSc. In clinical practice, autoantibodies serve as diagnostic biomarkers and can aid in the identification of clinical phenotypes of the disease. However, factors driving disease progression in SSc are still poorly understood, and it is difficult to predict disease trajectories in individual patients. Moreover, treatment decisions remain rather empirical, with variable response rates in clinical trials due to patient heterogeneity. Current evidence has indicated that certain patients may benefit from B cell targeting therapies. Hence, it is important to understand the contribution of the antinuclear autoantibodies and their underlying B cell response to the disease pathogenesis of SSc.

Effector mechanisms of influenza-specific antibodies: neutralization and beyond.

INTRODUCTION: Antibodies directed against influenza virus execute their protective function by exploiting a variety of effector mechanisms. Neutralizing antibodies have been thoroughly studied because of their pivotal role in preventing influenza virus infection and their presence in host serum is correlated with protection. Influenza antibodies can also exploit non-neutralizing effector mechanisms, which until recently have been largely overlooked. AREAS COVERED: Here, we discuss the antibody response to influenza virus in its entire breadth. Neutralizing antibodies mostly target variable epitopes on influenza surface proteins and interfere with virus binding, fusion, or egress. Non-neutralizing antibodies instead usually target conserved epitopes which can be located on surface as well as internal proteins. They drive viral clearance via interaction of their Fc region with components of the innate immune system such as immune effector cells (e.g. NK cells, macrophages) or the complement system. EXPERT COMMENTARY: Recent research has unraveled that influenza-specific antibodies target multiple proteins and make use of diverse effector mechanisms. Often these antibodies are cross-reactive among virus strains of the same subtype or even between subtypes. As such they are induced early in life and are boosted by regular encounters with virus or vaccine. Designing strategies to optimally exploit these pre-existing antibodies may represent the key for the development of new broadly protective influenza vaccines.