Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study

Introduction  

Improvement of rheumatoid arthritis (RA) during pregnancy has been causatively associated with increased galactosylation of immunoglobulin G (IgG) N-glycans. Since previous studies were small, did not include the postpartum flare and did not study sialylation, these issues were addressed in the present study.     

Role of ultrasonography in diagnosing early rheumatoid arthritis and remission of rheumatoid arthritis - a systematic review of the literature

Introduction

Ultrasonography (US) might have an added value to clinical examination in diagnosing early rheumatoid arthritis (RA) and assessing remission of RA. We aimed to clarify the added value of US in RA in these situations performing a systematic review.

Methods

A systematic literature search was performed for RA, US, diagnosis and remission. Methodological quality was assessed; the wide variability in the design of studies prohibited pooling of results.

Results

Six papers on the added value of US diagnosing early RA were found, in which at least bilateral metacarpophalangeal (MCP), wrists and metatarsophalangeal (MTP) joints were scanned. Compared to clinical examination, US was superior with regard to detecting synovitis and predicting progression to persistent arthritis or RA. Eleven papers on assessing remission were identified, in which at least the wrist and the MCP joints of the dominant hand were scanned. Often US detected inflammation in patients clinically in remission, irrespective of the remission criteria used. Power Doppler signs of synovitis predicted X-ray progression and future flare in patients clinically in remission.

Conclusions

US appears to have added value to clinical examination for diagnosing of RA when scanning at least MCP, wrist and MTP joints, and, when evaluating remission of RA, scanning at least wrist and MCP joints of the dominant hand. For both purposes primarily power Doppler US might be used since its results are less equivocal than those of greyscale US.     

Starch as a sugar reservoir for nematode-induced syncytia

The plant parasitic nematode Heterodera schachtii invades the roots of Arabidopsis thaliana to induce nematode feeding structures in the central cylinder. During nematode development, the parasites feed exclusively from these structures. Thus, high sugar import and specific sugar processing of the affected plant cells is crucial for nematode development. In the present work, we found starch accumulation in nematode feeding structures and therefore studied the expression genes involved in the starch metabolic pathway. The importance of starch synthesis was further shown using the Atss1 mutant line. As it is rather surprising to find starch accumulation in cells characterised by a high nutrient loss, we speculate that starch serves as long- and short-term carbohydrate storage to compensate the staggering feeding behaviour of the parasites.Key words: Heterodera schachtii, Arabidopsis, nematode, starch metabolism, syncytiaThe obligate plant parasitic nematode Heterodera schachtii is entirely dependent on a system of nutrient supply provided by the plant. Host plants—among those the model plant Arabidopsis thaliana—have to endure invasion of second stage juveniles and the establishment of nematode feeding structures in the plant''s vascular cylinder. For induction of the specific feeding structures, the juveniles pierce one single plant cell with their stylet and inject secretions, thus triggering the formation of a syncytium by local cell walls dissolutions.¹ Further, the central vacuole of the syncytial cells disintegrates, nuclei enlarge and many organelles proliferate.¹ About 24 hours after feeding site induction, the nematode juveniles start feeding in repetitive cycles.² Syncytia have previously been described as strong sinks in the plant''s transport system.³ Thus, in the recent years several studies were carried out to discover solute supply to syncytial cells.^4–7 To our present knowledge, syncytia are symplasmically isolated in the first days of nematode development. During that period, the nematodes depend on transport protein activity in the syncytia plasmamembranes. At later stages plasmodesmata appear to open to the phloem elements, facilitating symplasmic transport.Incoming solutes may either be taken up by the feeding nematode or are synthesised and catalysed by the syncytium''s metabolism. Due to the microscopically observable high density of the cytosol¹ and the increased osmotic pressure,⁸ syncytia appear to accumulate high solute concentrations. In fact, significantly increased sucrose levels have been found in syncytia in comparison to non-infected control roots.⁷ In case of high sugar levels, plant cells generally synthesize starch in order to reduce emerging osmotic stress.⁹ The aim of the work of Hofmann et al.,¹⁰ was to elucidate if starch is utilised as carbohydrate storage in nematode-induced syncytia and to study expression of genes involved in starch metabolism with an emphasis on nematode development.Starch levels of nematode induced syncytia and roots of non-infected plants grown on sand/soil culture were measured by high performance liquid chromatography (HPLC). The results showed a high accumulation of starch in syncytia that was steadily decreasing during nematode development. The accumulation of starch could further be localised within syncytial cells by electron microscopy. Based on these results, we studied the gene expression of the starch metabolic pathway by Affymetrix gene chip analysis. About half of the 56 involved genes were significantly upregulated in syncytia compared to the control and only two genes were significantly downregulated. Thus, the high induction of the gene expression is consistent with the high starch accumulation. Finally, we applied an Arabidopsis mutant line lacking starch synthase I expression that has been described previously.¹¹ Starch synthase I was the second highest upregulated gene in syncytia. It catalyses the linkage of ADP-glucose to the non-reducing end of an a-glucan, forming the linear glucose chains of amylopectin. In a nematode infection assay we were able to prove the significant importance of the gene for nematode development.With the presented results, we can unambiguously prove the accumulation of starch and the induction of the gene expression of the starch metabolic pathway in nematode-induced syncytia. The primary question however is: why do syncytia accumulate soluble sugars and starch although their metabolism is highly induced and nematodes withdraw solutes during continuously repeating feeding cycles?One explanation may be found where least expected—in nematode feeding. It is the feeding activity that induced solute import mechanisms into syncytia resulting in a newly formed sink tissue. However, during moulting events to the third, the fourth juvenile stage and to the adult stage nematodes interrupt feeding for about 20 hours.² During this period sugar supply mechanisms will most probably not be altered thus leading to increasing levels of sugars in the syncytium. Starch may serve as short-term carbohydrate buffering sugar excess. Further, starch may serve as long-term carbohydrate storage during nematode development. In the early stages of juvenile development nematodes withdraw considerably small quantities (about 0,8-times the syncytium volume a day).¹² At later stages, nutrient demand increases so that adult fertilised females require 4-times the syncytium volume per day in order to accomplish egg production.¹² Thus, excessive sugar supply in the first days may be accumulated as starch that gets degraded at later stages when more energy is required from the parasites. Consequently, starch reserve serves as both short-term and long-term carbohydrate storage in nematode-induced syncytia in order to buffer changing feeding pattern of the parasites.? Open in a separate windowFigure 1Arabidopsis wild-type Columbia-0 plants were grown in sand/soil culture. Nematode-induced syncytia and non-infected control roots were harvested at 10, 15 and 20 days after inoculation (dai) and starch content was measured as glucose (Glc) equivalents. Values are means ± SE, n = 3. Different letters indicate significant variations (p < 0.05). © ASPBOpen in a separate windowFigure 2Transmission electron microscope picture of a cross-section of a syncytium associated with female fourth stage juvenile (H. schachtii) induced in roots of Arabidopsis. Bar = 2 µm. S, syncytium; Se, sieve tube; arrow, plastid; asterisk, starch granule. © ASPB     

Modulation of the endocannabinoid system in viable and non-viable first trimester pregnancies by pregnancy-related hormones

Background

In early pregnancy, increased plasma levels of the endocannabinoid anandamide (AEA) are associated with miscarriage through mechanisms that might affect the developing placenta or maternal decidua.

Methods

In this study, we compare AEA levels in failed and viable pregnancies with the levels of the trophoblastic hormones (beta-human chorionic gonadotrophin (beta-hCG), progesterone (P4) and (pregnancy-associated placental protein-A (PAPP-A)) essential for early pregnancy success and relate that to the expression of the cannabinoid receptors and enzymes that modulate AEA levels.

Results

The median plasma AEA level in non-viable pregnancies (1.48 nM; n = 20) was higher than in viable pregnancies (1.21 nM; n = 25; P = 0.013), as were progesterone and beta-hCG levels (41.0 vs 51.5 ng/mL; P = 0.052 for P4 and 28,650 vs 6,560 mIU/L; P = 0.144 for beta-hCG, respectively, but were not statistically significant). Serum PAPP-A levels in the viable group were approximately 6.8 times lower than those in the non-viable group (1.82 vs 12.25 mg/L; P = 0.071), but again these differences were statistically insignificant. In the spontaneous miscarriage group, significant correlations between P4 and beta-hCG, P4 and PAPP-A and AEA and PAPP-A levels were observed. Simultaneously, immunohistochemical distributions of the two main cannabinoid receptors and the AEA-modifying enzymes, fatty acid amide hydrolase (FAAH) and N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD), changed within both the decidua and trophoblast.

Conclusions

The association of higher AEA levels with early pregnancy failure and with beta-hCG and PAPP-A, but not with progesterone concentrations suggest that plasma AEA levels and pregnancy failure are linked via a mechanism that may involve trophoblastic beta-hCG, and PAPP-A, but not, progesterone production. Although the trophoblast, decidua and embryo contain receptors for AEA, the main AEA target in early pregnancy failure remains unknown.     

T-helper 17 cell cytokines and interferon type I: partners in crime in systemic lupus erythematosus?

Introduction

A hallmark of systemic autoimmune diseases like systemic lupus erythematosus (SLE) is the increased expression of interferon (IFN) type I inducible genes, so-called IFN type I signature. Recently, T-helper 17 subset (Th17 cells), which produces IL-17A, IL-17F, IL-21, and IL-22, has been implicated in SLE. As CCR6 enriches for Th17 cells, we used this approach to investigate whether CCR6⁺ memory T-helper cells producing IL-17A, IL-17F, IL-21, and/or IL-22 are increased in SLE patients and whether this increase is related to the presence of IFN type I signature.

Methods

In total, 25 SLE patients and 15 healthy controls (HCs) were included. SLE patients were divided into IFN type I signature-positive (IFN⁺) (n = 16) and negative (IFN^-) (n = 9) patients, as assessed by mRNA expression of IFN-inducible genes (IFIGs) in monocytes. Expression of IL-17A, IL-17F, IL-21, and IL-22 by CD4⁺CD45RO⁺CCR6⁺ T cells (CCR6⁺ cells) was measured with flow cytometry and compared between IFN⁺, IFN^- patients and HCs.

Results

Increased percentages of IL-17A and IL-17A/IL-17F double-producing CCR6⁺ cells were observed in IFN⁺ patients compared with IFN^- patients and HCs. IL-17A and IL-17F expression within CCR6⁺ cells correlated significantly with IFIG expression. In addition, we found significant correlation between B-cell activating factor of the tumor necrosis family (BAFF)–a factor strongly correlating with IFN type I - and IL-21 producing CCR6⁺ cells.

Conclusions

We show for the first time higher percentages of IL-17A and IL-17A/IL-17F double-producing CCR6⁺ memory T-helper cells in IFN⁺ SLE patients, supporting the hypothesis that IFN type I co-acts with Th17 cytokines in SLE pathogenesis.     

Mannose-binding lectin does not explain the course and outcome of pregnancy in rheumatoid arthritis

Introduction  

Rheumatoid arthritis (RA) improves during pregnancy and flares after delivery. It has been hypothesized that high levels of the complement factor mannose-binding lectin (MBL) are associated with a favourable disease course of RA by facilitating the clearance of pathogenic immunoglobulin G (IgG) lacking galactose sugar moieties. During pregnancy, increased galactosylation of IgG and simultaneously increased MBL levels can be observed, with the latter being strictly related to maternal MBL genotypes. Therefore, increased MBL levels in concert with increased IgG galactosylation may be associated with pregnancy-induced improvement of RA. The objective of this study was to investigate whether MBL genotypes are associated with changes in RA disease activity and with changes in IgG galactosylation during pregnancy and in the postpartum period. We also studied the association between MBL genotypes and pregnancy outcomes in RA.