ACPA fine-specificity profiles in early rheumatoid arthritis patients do not correlate with clinical features at baseline or with disease progression

Introduction

Autoantibodies against citrullinated peptides/proteins (ACPA) are found in approximately 75% of the sera of patients with rheumatoid arthritis (RA). The RA-specific ACPA are frequently present prior to disease onset and their presence associates with a more erosive disease course. ACPA can therefore be used to aid the diagnosis and prognosis of RA. Recently, it became clear that ACPA are very heterogeneous, both in an individual patient and among different patients. The aim of this study was to investigate whether clinically meaningful ACPA profiles exist in early RA patients.

Methods

Twenty citrullinated peptides and the corresponding non-citrullinated control peptides were immobilized on microarray sensor chips. Sera from 374 early arthritis patients were analyzed by surface plasmon resonance imaging (iSPR) of biomolecular interactions on the sensor chip.

Results

Cluster analysis of the reactivities with the citrullinated peptides, after subtraction of the reactivities with the corresponding control peptides confirmed the heterogeneity of the ACPA response in RA and revealed 12 distinct ACPA profiles. The association of the 5 most frequent profiles with clinical features at diagnosis and during the disease course was examined, showing no statistically significant associations.

Conclusions

Compared to the detection of ACPA in RA sera by CCP-based assays, ACPA profiling in early arthritis patients did not reveal associations with disease activity and progression scores.     

Wild mice provide insights into natural killer cell maturation and memory

The immune system has evolved, and continues to evolve, in response to the selection pressure that infections exert on animals in their natural environments, yet much of our understanding about how the immune system functions comes from studies of model species maintained in the almost complete absence of such environmental selection. The scientific discipline of immunology has among its aims the improvement of human and animal health by the application of immunological knowledge. As research on humans and domesticated animals is highly constrained-ethically, logistically and financially-experimental animal models have become an invaluable tool for dissecting the functioning of the immune system. The house mouse (Mus musculus) is by far the most widely used animal model in immunological research but laboratory-reared mice provide a very narrow view of the immune system-that of a well-fed and comfortably housed animal with minimal exposure to microbial pathogens. Indeed, so much of our immunological knowledge comes from studies of a very few highly inbred mouse strains that-to all intents and purposes-our immunological knowledge is based on enormously detailed studies of very small numbers of individual mice. The limitations of studies in inbred strains of laboratory mice are well-recognized (Pedersen & Babayan 2011), but serious attempts to address these limitations have been few and far between. However, the emerging field of 'ecological immunology' where free-living populations are studied in their natural habitat is beginning to redress this imbalance (Viney et al. 2005; Martin et al. 2006; Owen et al. 2010; Abolins et al. 2011). As demonstrated in the work by Boysen et al. (2011) in this issue of Molecular Ecology, studies in wild animal populations-especially free-living M. musculus-represent a valuable bridge between studies in humans and livestock and studies of captive animals.     

So what if parasites vary?

The British Society for Parasitology Autumn Symposium was held on 14 September 2001 at the Linnean Society of London, UK, only a few yards from the room in which Darwin and Wallace presented their joint papers on organic variation. Fittingly, the symposium--Parasite variation: immunological and ecological significance--considered the consequences of parasite variation.     

Thyroid disease is a favorable prognostic factor in achieving sustained virologic response in chronic hepatitis C undergoing combination therapy: A nested case control study

Background

Interferon-α in combination with ribavirin is the current gold standard for treatment of chronic hepatitis C. It is unknown if the development of autoimmune thyroid disease (TD) during treatment confers an improved chance of achieving sustained virologic response. The aim of this study is to assess the chance of achieving sustained virologic response (SVR) in patients who developed TD during treatment when compared with those who did not.

Methods

We performed a tertiary hospital-based retrospective nested case-control analysis of 19 patients treated for hepatitis C who developed thyroid disease, and 76 controls (matched for age, weight, gender, cirrhosis and aminotransferase levels) who did not develop TD during treatment. Multivariate logistic-regression models were used to compare cases and controls.

Results

The development of TD was associated with a high likelihood of achieving SVR (odds ratio, 6.0; 95% confidence interval, 1.5 to 24.6) for the pooled group containing all genotypes. The likelihood of achieving SVR was increased in individuals with genotype 1 HCV infection who developed TD (odds ratio, 5.2; 95% confidence interval, 1.2 to 22.3), and all genotype 3 patients who developed TD achieved SVR.

Conclusions

Development of TD during treatment for hepatitis C infection is associated with a significantly increased chance of achieving SVR. The pathophysiogical mechanisms for this observation remain to be determined.

Trial Registration

The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRB12610000830099     

Evaluation of stability and size distribution of sunflower oil-coated micro bubbles for localized drug delivery

Background

In recent years magnesium alloys have been intensively investigated as potential resorbable materials with appropriate mechanical and corrosion properties. Particularly in orthopedic research magnesium is interesting because of its mechanical properties close to those of natural bone, the prevention of both stress shielding and removal of the implant after surgery.

Methods

ZEK100 plates were examined in this in vitro study with Hank's Balanced Salt Solution under physiological conditions with a constant laminar flow rate. After 14, 28 and 42 days of immersion the ZEK100 plates were mechanically tested via four point bending test. The surfaces of the immersed specimens were characterized by SEM, EDX and XRD.

Results

The four point bending test displayed an increased bending strength after 6 weeks immersion compared to the 2 week group and 4 week group. The characterization of the surface revealed the presence of high amounts of O, P and Ca on the surface and small Mg content. This indicates the precipitation of calcium phosphates with low solubility on the surface of the ZEK100 plates.

Conclusions

The results of the present in vitro study indicate that ZEK100 is a potential candidate for degradable orthopedic implants. Further investigations are needed to examine the degradation behavior.     

Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity

Introduction

B-cell depletion has become a common treatment strategy in anti-TNF-refractory rheumatoid arthritis (RA). Although the exact mechanism of how B-cell depletion leads to clinical amelioration in RA remains to be elucidated, repetitive treatment with B-cell-depleting agents leading to long-term B-cell depletion has been reported to be beneficial. The latter has led to the hypothesis that the beneficial effects of B-cell depletion might act through their influence on pathogenic autoreactive plasma cells.

Methods

In this study, we investigated the effects of a fixed retreatment regimen with anti-CD20 mAbs on the humoral (auto)immune system in a cohort of therapy-refractory RA patients.

Results

Fixed retreatment led to long-term B-cell depletion in peripheral blood, bone marrow and, to a lesser extent, synovium. Also, pathologic autoantibody secretion (that is, anticitrullinated peptide antibodies (ACPAs)) was more profoundly affected by long-term depletion than by physiological protective antibody secretion (that is, against measles, mumps and rubella). This was further illustrated by a significantly shorter estimated life span of ACPA-IgG secretion compared to total IgG secretion as well as protective antibody secretion.

Conclusion

By studying plasma cell function during an extensive 2-year period of B-cell depletion, autoantibody secretion was significantly shorter-lived than physiologically protective antibody secretion. This suggests that the longevity of autoreactive plasma cells is different from protective long-lived plasma cells and might indicate a therapeutic window for therapies that target plasma cells.     

Receptive Field Vectors of Genetically-Identified Retinal Ganglion Cells Reveal Cell-Type-Dependent Visual Functions

Sensory stimuli are encoded by diverse kinds of neurons but the identities of the recorded neurons that are studied are often unknown. We explored in detail the firing patterns of eight previously defined genetically-identified retinal ganglion cell (RGC) types from a single transgenic mouse line. We first introduce a new technique of deriving receptive field vectors (RFVs) which utilises a modified form of mutual information (“Quadratic Mutual Information”). We analysed the firing patterns of RGCs during presentation of short duration (~10 second) complex visual scenes (natural movies). We probed the high dimensional space formed by the visual input for a much smaller dimensional subspace of RFVs that give the most information about the response of each cell. The new technique is very efficient and fast and the derivation of novel types of RFVs formed by the natural scene visual input was possible even with limited numbers of spikes per cell. This approach enabled us to estimate the ''visual memory'' of each cell type and the corresponding receptive field area by calculating Mutual Information as a function of the number of frames and radius. Finally, we made predictions of biologically relevant functions based on the RFVs of each cell type. RGC class analysis was complemented with results for the cells’ response to simple visual input in the form of black and white spot stimulation, and their classification on several key physiological metrics. Thus RFVs lead to predictions of biological roles based on limited data and facilitate analysis of sensory-evoked spiking data from defined cell types.