Human Hsp40 proteins, DNAJA1 and DNAJA2, as potential targets of the immune response triggered by bacterial DnaJ in rheumatoid arthritis

Hsp40 proteins of bacterial and human origin are suspected to be involved in the pathogenesis of rheumatoid arthritis (RA). It has been shown that sera of RA patients contain increased levels of antibodies directed to bacterial and human Hsp40s. The aim of this work was to explore immunological similarities between the bacterial (DnaJ) and human (DNAJA1 and DNAJA2) Hsp40 proteins in relation to their possible involvement in the RA. Using polyclonal antibodies directed against a full-length DnaJ or its domains, against DNAJA1 and DNAJA2, as well as monoclonal anti-DnaJ antibodies, we found immunological similarities between the bacterial and human Hsp40s. Both ELISA and Western blotting showed that these similarities were not restricted to the conserved J domains but were also present in the C-terminal variable regions. We also found a positive correlation between the levels of the anti-DnaJ and anti-DNAJA1 antibodies in the sera of RA patients. This finding supports the molecular mimicry hypothesis that human Hsp40 could be the targets of antibodies originally directed against bacterial DnaJ in RA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12192-013-0407-1) contains supplementary material, which is available to authorized users

Correlation between temporomandibular joint dysfunction and Eichner classification

Introduction: The Dental Prosthetics Department's most common patients are elderly who have lost their teeth. Dental deficiencies not only impair the functions of the stomatognathic system but can also be the cause of temporomandibular disorders (TMD). Deficiencies in the lateral sections lead to a decrease in the occlusion height in patients, which negatively affects the aesthetics of the face by shortening the lower floor and overloading the remaining teeth, eventually leading to their pathological wear. Loss of occlusion height changes the spatial arrangement of the lower jaw to the upper jaw, which can lead to changes in the temporomandibular joint. The loss of a tooth or group of teeth is an indication for proper prosthetic treatment. The dentist should be able to take into account, evaluate and, if necessary, cure TMD, but this is not a common skill among dentists. Such treatment requires an appropriate comprehensive approach. There are currently no standards for such treatment. We presented one of the methods as part of our study.Purpose of work:The aim of the study was to check the correlation between the occurrence of temporomandibular disorders and missing teeth and used prosthetic restorations. Material and methods:Medical history records of 58 patients under the care of the Department of Dental Prosthetics at Medical University of Lublin were analyzed. Factors such as age and gender, occlusion height, distribution of missing teeth according to the Eichner classification and symptoms of temporomandibular joint disorders, i.e. crackling, pain, limited and excessive abduction of the jaw were checked. Before starting prosthetic treatment, every patient underwent comprehensive conservative, surgical and periodontics treatment in accordance with existing needs. Results:The study group consisted of 38 women and 20 men. The average age of all patients was 69.6 years; - average for men - 70.45 years, women 68.16 years. The oldest patient was an 88-year-old man, and the youngest was a 43-year-old woman. 31% of patients were toothless. 25.9% of patients had pain within the stomatognathic system, of which 86.7% were women and 13.3% men. Relaxation splint was made in 24.1% of patients.Summary:The study showed that the ailments associated with the stomatognathic system are correlated with a reduction in occlusion height. Larger dental deficits are more common in older people. Pain symptoms are the most common cause of making relaxation splints. Women more often than men complain of pain. The correct treatment scheme for patients with missing teeth and long-term loss of support zones is staggered treatment - two-stage. The first stage of treatment is to restore the correct occlusion height by using the occlusal splint. Then, after the adaptation period, there is a transition to the second stage of treatment - the use of proper prosthetic restoration maintaining the correct height of occlusio

Formation of a WIP-, WASp-, actin-, and myosin IIA–containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling

The tumor natural killer (NK) cell line YTS was used to examine the cytoskeletal rearrangements required for cytolysis. A multiprotein complex weighing ∼1.3 mD and consisting of WASp-interacting protein (WIP), Wiskott-Aldrich syndrome protein (WASp), actin, and myosin IIA that formed during NK cell activation was identified. After induction of an inhibitory signal, the recruitment of actin and myosin IIA to a constitutive WIP–WASp complex was greatly decreased. Both actin and myosin IIA were recruited to WIP in the absence of WASp. This recruitment correlated with increased WIP phosphorylation, which was mediated by PKCθ. Furthermore, the disruption of WIP expression by WIP RNA interference prevented the formation of this protein complex and led to almost complete inhibition of cytotoxic activity. Thus, the multiprotein complex is important for NK cell function, killer cell immunoglobulin-like receptor inhibitory signaling affects proteins involved in cytoskeletal rearrangements, and WIP plays a central role in the formation of the complex and in the regulation of NK cell activity

Asymptomatic CMV infections in long-term renal transplant recipients are associated with the loss of FcRγ from LIR-1+ NK cells

While it is established that cytomegalovirus (CMV) disease affects NK-cell profiles, the functional consequences of asymptomatic CMV replication are unclear. Here, we characterize NK cells in clinically stable renal transplant recipients (RTRs; n = 48) >2 years after transplantation. RTRs and age-matched controls (n = 32) were stratified by their CMV serostatus and the presence of measurable CMV DNA. CMV antibody or CMV DNA influenced expression of NKG2C, LIR-1, NKp30, NKp46, and FcRγ, a signaling adaptor molecule, on CD56dim NK cells. Phenotypic changes ascribed to CMV were clearer in RTRs than in control subjects and affected NK-cell function as assessed by TNF-α and CD107a expression. The most active NK cells were FcRγ–LIR-1+NKG2C– and displayed high antibody-dependent cell cytotoxicity responses in the presence of immobilized CMV glycoprotein B reactive antibody. However, perforin levels in supernatants from RTRs with active CMV replication were low. Overall we demonstrate that CMV can be reactivated in symptom-free renal transplant recipients, affecting the phenotypic, and functional profiles of NK cells. Continuous exposure to CMV may maintain and expand NK cells that lack FcRγ but express LIR-1

Inhibitory signaling blocks activating receptor clustering and induces cytoskeletal retraction in natural killer cells

Signaling from immunotyrosine-based inhibitory motifs (ITIMs) neutralizes activating signals by inducing a retraction of NK cells from the surface of stimulatory cells

Natural Killer Cell Signal Integration Balances Synapse Symmetry and Migration

Imaging immune surveillance by natural killer (NK) cells has revealed that integration of activating and inhibitory signals determines whether or not NK cells stop to kill the target cell or retain a migratory configuration

An expression module of WIPF1-coexpressed genes identifies patients with favorable prognosis in three tumor types

Wiskott–Aldrich syndrome (WAS) predisposes patients to leukemia and lymphoma. WAS is caused by mutations in the protein WASP which impair its interaction with the WIPF1 protein. Here, we aim to identify a module of WIPF1-coexpressed genes and to assess its use as a prognostic signature for colorectal cancer, glioma, and breast cancer patients. Two public colorectal cancer microarray data sets were used for discovery and validation of the WIPF1 co-expression module. Based on expression of the WIPF1 signature, we classified more than 400 additional tumors with microarray data from our own experiments or from publicly available data sets according to their WIPF1 signature expression. This allowed us to separate patient populations for colorectal cancers, breast cancers, and gliomas for which clinical characteristics like survival times and times to relapse were analyzed. Groups of colorectal cancer, breast cancer, and glioma patients with low expression of the WIPF1 co-expression module generally had a favorable prognosis. In addition, the majority of WIPF1 signature genes are individually correlated with disease outcome in different studies. Literature gene network analysis revealed that among WIPF1 co-expressed genes known direct transcriptional targets of c-myc, ESR1 and p53 are enriched. The mean expression profile of WIPF1 signature genes is correlated with the profile of a proliferation signature. The WIPF1 signature is the first microarray-based prognostic expression signature primarily developed for colorectal cancer that is instrumental in other tumor types: low expression of the WIPF1 module is associated with better prognosis

The Human Herpesvirus-7 (HHV-7) U21 Immunoevasin Subverts NK-Mediated Cytoxicity through Modulation of MICA and MICB

Herpesviruses have evolved numerous immune evasion strategies to facilitate establishment of lifelong persistent infections. Many herpesviruses encode gene products devoted to preventing viral antigen presentation as a means of escaping detection by cytotoxic T lymphocytes. The human herpesvirus-7 (HHV-7) U21 gene product, for example, is an immunoevasin that binds to class I major histocompatibility complex molecules and redirects them to the lysosomal compartment. Virus infection can also induce the upregulation of surface ligands that activate NK cells. Accordingly, the herpesviruses have evolved a diverse array of mechanisms to prevent NK cell engagement of NK-activating ligands on virus-infected cells. Here we demonstrate that the HHV-7 U21 gene product interferes with NK recognition. U21 can bind to the NK activating ligand ULBP1 and reroute it to the lysosomal compartment. In addition, U21 downregulates the surface expression of the NK activating ligands MICA and MICB, resulting in a reduction in NK-mediated cytotoxicity. These results suggest that this single viral protein may interfere both with CTL-mediated recognition through the downregulation of class I MHC molecules as well as NK-mediated recognition through downregulation of NK activating ligands

Remodelling of Cortical Actin Where Lytic Granules Dock at Natural Killer Cell Immune Synapses Revealed by Super-Resolution Microscopy

Super-resolution 3D imaging reveals remodeling of the cortical actin meshwork at the natural killer cell immune synapse, which is likely to be important for secretion of lytic granules

Signals controlling lytic granule polarization at the cytotoxic immune synapse

Cytotoxic immunity relies on specialized effector T cells, the cytotoxic T cells, which are endowed with specialized cytolytic machinery that permits them to induce death of their targets. Upon recognition of a target cell, cytotoxic T cells form a lytic immune synapse and by docking the microtubule-organizing center at the synaptic membrane get prepared to deliver a lethal hit of enzymes contained in lytic granules. New insights suggest that the directionality of lytic granule trafficking along the microtubules represents a fine means to tune the functional outcome of the encounter between a T cell and its target. Thus, mechanisms regulating the directionality of granule transport may have a major impact in settings characterized by evasion from the cytotoxic response, such as chronic infection and cancer. Here, we review our current knowledge on the signaling pathways implicated in the polarized trafficking at the immune synapse of cytotoxic T cells, complementing it with information on the regulation of this process in natural killer cells. Furthermore, we highlight some of the parameters which we consider critical in studying the polarized trafficking of lytic granules, including the use of freshly isolated cytotoxic T cells, and discuss some of the major open questions