Search

As a lymphoid organ, the spleen hosts a wide range of immune cell populations, which not only remove blood-borne antigens, but also generate and regulate antigen-specific immune responses. In particular, the splenic microenvironment has been demonstrated to play a prominent role in adaptive immune responses to enveloped viral infections and alloantigens. During both types of immunizations, antigen-specific immunoglobulins G (IgGs) have been characterized by the reduced amount of fucose present on N-linked glycans of the fragment crystallizable (Fc) region. These glycans are essential for mediating the induction of immune effector functions. Therefore, we hypothesized that a spleen may modulate humoral responses and serve as a preferential site for afucosylated IgG responses, which potentially play a role in immune thrombocytopenia (ITP) pathogenesis. To determine the role of the spleen in IgG-Fc glycosylation, we performed IgG subclass-specific liquid chromatography–mass spectrometry (LC–MS) analysis of Fc glycosylation in a large cohort of individuals splenectomized due to trauma, due to ITP, or spherocytosis. IgG-Fc fucosylation was consistently increased after splenectomy, while no effects for IgG-Fc galactosylation and sialylation were observed. An increase in IgG1- and IgG2/3-Fc fucosylation level upon splenectomy has been reported here for the first time, suggesting that immune responses occurring in the spleen may be particularly prone to generate afucosylated IgG responses. Surprisingly, the level of total IgG-Fc fucosylation was decreased in ITP patients compared to healthy controls. Overall, our results suggest a yet unrecognized role of the spleen in either the induction or maintenance of afucosylated IgG responses by B cells.

Background Involvement of metals or silica in the pathogenesis of sarcoidosis has been suggested by several case reports and specific epidemiological studies. However, the combination of occupational exposure and an immunological reaction has not been studied before in a group of sarcoidosis patients and non-sarcoidosis controls. Methods In 256 sarcoidosis patients and 73 control patients with obstructive sleep apnea, exposure to metal and silica was assessed using a questionnaire consisting of a complete occupational history subsequently linked to job-exposure matrices. Next, immunoreactivity to aluminium, beryllium, zirconium and silica was determined in 33 sarcoidosis and 19 control patients using a lymphocyte proliferation test. Results In sarcoidosis, 83 out 256 patients (32.4%) had occupational exposure to metals or silica, compared to 24.7% in the control group (p = 0.21). A significantly higher percentage of the sarcoidosis patients tested showed immunoreactivity to metals or silica compared to the control group (21.2 and 0% respectively, p = 0.039). Conclusions Immunoreactivity to silica and metals was only found in sarcoidosis patients, supporting the hypothesis that these antigens may be involved in the pathogenesis of a distinct subgroup of sarcoidosis patients. This indicates that when searching for causative agents in sarcoidosis patients, besides beryllium, also zirconium, aluminium and silica deserve clinical investigation.

Antineutrofiele cytoplasmatische antistoffen (ANCA) vormen een belangrijke bijdrage aan de diagnostiek van kleinevatenvasculitis. De betreffende vasculitiden worden samengevat als ANCA-geassocieerde vasculitis. Sinds 1999 bestaat een internationale consensus over de meest geschikte methode voor de detectie van ANCA in het laboratorium. Het uitgangspunt hierbij is screening met een indirecte immunofluorescentietest op een substraat van neutrofiele granulocyten, indien positief gevolgd door immunoassays specifiek voor antistoffen tegen myeloperoxidase en proteïnase 3. Gedurende de laatste twee decennia zijn de antigeen-specifieke immunoassays sterk verbeterd en is de positie van de indirecte immunofluorescentietest in het algoritme ter discussie komen te staan. Op basis van de resultaten van een multicentrische studie is in 2017 een nieuwe internationale consensus gepubliceerd. In dit artikel worden allereerst de opzet en de resultaten van de multicentrische studie beschreven. Vervolgens worden de nieuwe aanbevelingen weergegeven met onderbouwing uit de studie. Tenslotte wordt implementatie van de nieuwe consensus in Nederlandse laboratoria bediscussieerd.

Recently, legislative mandates worldwide are requiring systematic consideration of much larger numbers of chemicals. This necessitates more efficient and effective toxicity testing, as a basis to be more predictive in a risk assessment context. This in turn requires much more emphasis early in the design of test strategies on both potential exposure and mechanism or modes of toxicity and a resulting shift based on the latter, from hazard identification to hazard characterization in order to group substances and additionally inform development of predictive computational tools. It also requires a much better common understanding in the regulatory risk assessment community of the nature of appropriate information to inform consideration of mode of action and resulting implications for dose-response and ultimately, risk characterization. This requires a shift in focus from the previously principally qualitative considerations of toxicological science to the necessarily more predictive and quantitative focus of risk assessment and has implications for appropriate communication and training of risk assessors. Human relevance of mode of action frameworks continue to play a critical role in hypothesis generation and the systematic consideration of the weight of evidence supporting the use of mechanistic data in regulatory risk assessment. Framework analyses increase the transparency of delineation of the relative degrees of uncertainty associated with various options for consideration in dose-response and risk characterization for impacted populations. Framework analyses are also instrumental in acquiring transparency on critical data gaps that will further reduce uncertainty. As such, they force distinction of choices made on the basis of science policy versus those that are science judgment related, including reliance on default, based on erroneous premise that it is always health protective. The potential of these frameworks to increase consistency and transparency in decision making contributes to increase common understanding among communities and jurisdictions. They are an important tool for coordination and communication between the research and regulatory risk assessment communities. They are also an essential “bridge” in the evolution of toxicity testing to be more predictive, relevant and risk-based, through relation of early perturbations to apical endpoints in a context relevant to current application in regulatory risk assessment. As we move forward to develop more integrative test strategies to meet evolving and demanding regulatory mandates to deal efficiently with significantly larger numbers of chemicals including groups and combined exposures, early assimilation of the information in a mode of action context as envisaged by application of these frameworks is essential.