Antigen‐specific B lymphocytes acquire proteoglycan aggrecan from cartilage extracellular matrix resulting in antigen presentation and CD4+ T‐cell activation

The majority of studies examining antigen‐presenting cell (APC) function have focused on the capture and presentation of antigens released from pathogens or damaged cells. However, antigen‐specific B cells are also capable of efficiently extracting antigens that are either tethered to, or integrally part of the plasma membrane of various target cells. In this study we show that B cells are also highly efficient at extracting integral components of the extracellular matrix (ECM) for subsequent presentation. In particular we demonstrate that B cells specific for aggrecan, an integral component of cartilage ECM, acquire this rheumatoid arthritis candidate autoantigen in both a B‐cell‐receptor‐dependent and a contact‐dependent manner. We also demonstrate that the subsequent presentation of aggregan from ECM leads to CD4⁺ T‐cell activation and effector cell formation. Recent studies have identified B‐cell‐mediated antigen presentation as essential for the development of autoimmunity, but a unique role for B cells compared with other APC has yet to be defined. Our findings lead us to propose that the acquisition of ECM‐derived autoantigens represents a mechanism that defines the APC requirement for B cells in the development of autoimmunity.     

Behavioural phenotype of a patient with a de novo 1.2 Mb chromosome 4q25 microdeletion

A female patient, 20 years of age, is reported with a history characterized by developmental and psychomotor delay, and during grammar-school period increasing learning problems, ritualistic behaviours and social withdrawal. Subsequently, challenging and autistic-like behaviours became prominent. The patient showed mild facial dysmorphisms, long thin fingers with bilateral mild short V metacarpals, and hyperlaxity of the joints. Neuropsychiatric examination disclosed obsessive, ritualistic behaviours and vague ideas of reference. Neuropsychological assessment demonstrated mild intellectual disability, mental inflexibility and incongruent affect. MRI-scanning of the brain showed no relevant abnormalities. Genome wide SNP array analysis revealed a 1.2 Mb de novo interstitial microdeletion in 4q25 comprising 11 genes, that was considered to be causative for the developmental delay, perseverative cognitive phenotype and dysmorphisms.To the authors knowledge, this is the first report of a de novo 4q25 microdeletion that presents with a specific behavioural phenotype.     

Antineutrophil Cytoplasmic Autoantibodies: How Are They Detected and What Is Their Use for Diagnosis, Classification and Follow-up?

Antineutrophil cytoplasmic antibodies (ANCA) are traditionally detected by an indirect immunofluorescence technique. According to the international consensus on ANCA testing, ANCA should also be tested by antigen-specific tests for myeloperoxidase-ANCA and proteinase 3-ANCA. The direct noncompetitive enzyme-linked immunosorbent assay (ELISA) used to be the method of choice. Nowadays, these assays are called ??first-generation?? assays. Second-generation tests (capture ELISA) or third-generation tests (anchor ELISA) are more sensitive and specific for ANCA testing. We postulate that ANCA as detected by these newer ANCA tests may replace the need to perform indirect immunofluorescence-based assays. For classification of patients, ANCA serotype seems more important than classifying patients according to their clinical subtype, since genetics, clinical manifestations and response to therapy are more related to ANCA serotype than to clinical subtype. Detection of ANCA to monitor disease activity is still a controversial issue. Treatment based on ANCA levels is at present only experimentally performed in those patients who are treated with B-cell depletion therapy with rituximab. Future studies are needed to establish whether this way of monitoring patients is warranted.     

Respiration phase‐locks to fast stimulus presentations: Implications for the interpretation of posterior midline “deactivations”

The posterior midline region (PMR)—considered a core of the default mode network—is deactivated during successful performance in different cognitive tasks. The extent of PMR‐deactivations is correlated with task‐demands and associated with successful performance in various cognitive domains. In the domain of episodic memory, functional MRI (fMRI) studies found that PMR‐deactivations reliably predict learning (successful encoding). Yet it is unclear what explains this relation. One intriguing possibility is that PMR‐deactivations are partially mediated by respiratory artifacts. There is evidence that the fMRI signal in PMR is particularly prone to respiratory artifacts, because of its large surrounding blood vessels. As respiratory fluctuations have been shown to track changes in attention, it is critical for the general interpretation of fMRI results to clarify the relation between respiratory fluctuations, cognitive performance, and fMRI signal. Here, we investigated this issue by measuring respiration during word encoding, together with a breath‐holding condition during fMRI‐scanning. Stimulus‐locked respiratory analyses showed that respiratory fluctuations predicted successful encoding via a respiratory phase‐locking mechanism. At the same time, the fMRI analyses showed that PMR‐deactivations associated with learning were reduced during breath‐holding and correlated with individual differences in the respiratory phase‐locking effect during normal breathing. A left frontal region—used as a control region—did not show these effects. These findings indicate that respiration is a critical factor in explaining the link between PMR‐deactivation and successful cognitive performance. Further research is necessary to demonstrate whether our findings are restricted to episodic memory encoding, or also extend to other cognitive domains. Hum Brain Mapp 35:4932–4943, 2014. © 2014     

Searching for the Cartilage-associated Mimicry Epitope in Adjuvant Arthritis

Adjuvant arthritis (AA) is a T cell mediated disease which can be induced in genetically susceptible rats by immunization with heat-killed Mycobacterium tuberculosis ( Mt ) suspended in incomplete Freund's adjuvant. The critical mycobacterial T cell epitope for the induction of AA was previously identified as residues 178-186 of the mycobacterial 65 kDa heat shock protein ( Mt. hsp65 178-186 ). It was suggested that the development of AA was due to molecular mimicry between a mycobacterial epitope and a cartilage-associated self-antigen. However, until now such cartilage-associated mimicry epitope has not been identified. In this study we designed a computer search profile to predict mimicry self-epitopes, and investigated whether one or more of these self-epitopes could serve as mimicry epitopes in AA. Although several of these self-epitopes were recognized by arthritogenic T cells, no cross-reactivity was found between T cells specific for these self-epitopes and Mt. hsp65 178-186 specific T cells.     

Outcome assessment for Brachial Plexus birth injury. Results from the iPluto world‐wide consensus survey

There is no consensus regarding strategies to optimally treat children with a brachial plexus birth injury (BPBI). Comparison of outcome data presented by different centers is impossible due to the use of (1) many different outcome measures to evaluate results; (2) different follow‐up periods after interventions; and (3) different patient ages at the time of assessment. The goal of iPluto (international PLexus oUtcome sTudy grOup) was to define a standardized dataset which should be minimally collected to evaluate upper limb function in children with BPBI. This dataset must enable comparison of the treatment results of different centers if prospectively used. Three rounds of internet surveys were used to reach consensus on the dataset. A Delphi‐derived technique was applied using a nine point Likert scale. Consensus was defined as having attained a rating of 7/8/9 by > = 75% of the participants. A total of 59 participants from five continents participated in the Second and Third Rounds of the survey. Consensus was reached regarding four elements: (1) evaluation should take place at the age of 1/3/5/7 years; range of motion in degrees should be measured for (2) passive joint movement; (3) active range of motion; and (4) the Mallet score should be determined. Consensus on how to asses and report outcome for BPBI was only reached on motor items from the “Body Function and Structure” domain. Consensus regarding additional ICF domains to obtain a more elaborate set of outcome items, should be addressed in future research. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:2533–2541, 2018.     

Alkaline phosphatase: An old enzyme newly discovered as a medicine

Alkaline phosphatase (AP), a non-toxic natural compound (enzyme) has a great potential to replace or avoid the use of various drugs, in particular anti-inflammatory drugs (e.g. used during surgery and to reduce arthritis) and antibiotics applied to farm animals, which both have serious negative effects on the environment. Promising studies are being performed to demonstrate the possibility to avoid complications after major surgery (thereby eliminating the need to use harmful drugs for many years) and the reduction of antibiotics use in piglets.