Stress signaling through Ca2+/calmodulin-dependent protein phosphatase calcineurin mediates salt adaptation in plants

Calcineurin (CaN) is a Ca²⁺- and calmodulin-dependent protein phosphatase (PP2B) that, in yeast, is an integral intermediate of a salt-stress signal transduction pathway that effects NaCl tolerance through the regulation of Na⁺ influx and efflux. A truncated form of the catalytic subunit and the regulatory subunit of yeast CaN were coexpressed in transgenic tobacco plants to reconstitute a constitutively activated phosphatase in vivo. Several different transgenic lines that expressed activated CaN also exhibited substantial NaCl tolerance, and this trait was linked to the genetic inheritance of the CaN transgenes. Enhanced capacity of plants expressing CaN to survive NaCl shock was similar when evaluation was conducted on seedlings in tissue culture raft vessels or plants in hydroponic culture that were transpiring actively. Root growth was less perturbed than shoot growth by NaCl in plants expressing CaN. Also, NaCl stress survival of control shoots was enhanced substantially when grafted onto roots of plants expressing CaN, further implicating a significant function of the phosphatase in the preservation of root integrity during salt shock. Together, these results indicate that in plants, like in yeast, a Ca²⁺- and calmodulin-dependent CaN signal pathway regulates determinants of salt tolerance required for stress adaptation. Furthermore, modulation of this pathway by expression of an activated regulatory intermediate substantially enhanced salt tolerance.     

Is autoimmunology a discipline of its own? A big data-based bibliometric and scientometric analyses

Autoimmunology is a super-specialty of immunology specifically dealing with autoimmune disorders. To assess the extant literature concerning autoimmune disorders, bibliometric and scientometric analyses (namely, research topics/keywords co-occurrence, journal co-citation, citations, and scientific output trends – both crude and normalized, authors network, leading authors, countries, and organizations analysis) were carried out using open-source software, namely, VOSviewer and SciCurve. A corpus of 169,519 articles containing the keyword “autoimmunity” was utilized, selecting PubMed/MEDLINE as bibliographic thesaurus. Journals specifically devoted to autoimmune disorders were six and covered approximately 4.15% of the entire scientific production. Compared with all the corpus (from 1946 on), these specialized journals have been established relatively few decades ago. Top countries were the United States, Japan, Germany, United Kingdom, Italy, China, France, Canada, Australia, and Israel. Trending topics are represented by the role of microRNAs (miRNAs) in the ethiopathogenesis of autoimmune disorders, contributions of genetics and of epigenetic modifications, role of vitamins, management during pregnancy and the impact of gender. New subsets of immune cells have been extensively investigated, with a focus on interleukin production and release and on Th17 cells. Autoimmunology is emerging as a new discipline within immunology, with its own bibliometric properties, an identified scientific community and specifically devoted journals.     

Adjuvant Activity of Naturally Occurring Monophosphoryl Lipopolysaccharide Preparations from Mucosa-Associated Bacteria

Natural heterogeneity in the structure of the lipid A portion of lipopolysaccharide (LPS) produces differential effects on the innate immune response. Gram-negative bacterial species produce LPS structures that differ from the classic endotoxic LPS structures. These differences include hypoacylation and hypophosphorylation of the diglucosamine backbone, both differences known to decrease LPS toxicity. The effect of decreased toxicity on the adjuvant properties of many of these LPS structures has not been fully explored. Here we demonstrate that two naturally produced forms of monophosphorylated LPS, from the mucosa-associated bacteria Bacteroides thetaiotaomicron and Prevotella intermedia, function as immunological adjuvants for antigen-specific immune responses. Each form of mucosal LPS increased vaccination-initiated antigen-specific antibody titers in both quantity and quality when given simultaneously with vaccine antigen preparations. Interestingly, adjuvant effects on initial T cell clonal expansion were selective for CD4 T cells. No significant increase in CD8 T cell expansion was detected. MyD88/Toll-like receptor 4 (TLR4) and TRIF/TLR4 signaling pathways showed equally decreased signaling with the LPS forms studied here as with endotoxic LPS or detoxified monophosphorylated lipid A (MPLA). Natural monophosphorylated LPS from mucosa-associated bacteria functions as a weak but effective adjuvant for specific immune responses, with preferential effects on antibody and CD4 T cell responses over CD8 T cell responses.     

The role of stress in the mosaic of autoimmunity: An overlooked association

Stress is defined as the pscyophysiological reaction in which the steady state is disturbed or threatened. Stress is not always perceived as a negative response. Stress results when environmental demands exceed an individuals' adaptive capacities. Autoimmune diseases are heterogeneous group of chronic diseases which occur secondary to loss of self antigen tolerance. The etiopathogenesis of autoimmune disease is uncertain. Genetic factors as well as environmental factors appear to interplay, leading to a cascade of events resulting in disease onset. Stress has been postulated to play a role in disease onset in the genetically susceptible patients. During the stress response, catecholamines and glucocorticoids are released from locus coeruleus and adrenal gland. These biomolecules exert control over various immune cells in the innate and adaptive arms of the immune system, thereby altering the cytokine profile released. The increase of IL-4 promotes T-helper 2 (T_h2) cell differentiation, while the decrease in IL-12 and the increased IL-10 production reduce the number of T-helper 1 (T_h1) cells. The relationship between stress and autoimmune diseases is intricate. Stress has been shown to be associated with disease onset, and disease exacerbations in rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, Graves' disease as well as other autoimmune conditions. In certain conditions such as psoriasis, stress has been implicated in delaying lesion clearance upon the application of standard treatment regimes. Finally, psychological therapy and cognitive behavioral therapy aimed to reduce stress levels was shown to be effective in influencing better outcomes in many autoimmune diseases. The purpose of this paper is to closer inspect the clinical evidence regarding the role of stress on influencing the various aspects of disease entities.     

Vitamin D,autoimmunity and recurrent pregnancy loss: More than an association

Recurrent pregnancy loss (RPL) affects close to 1% of couples; however, the etiology is known in only about 50% of the cases. Recent studies show that autoimmune dysregulation is a probable cause of RPL, which in some cases may be overlooked. In order for a pregnancy to proceed to term, early modulation of immunologic response is required to induce tolerance to the semi‐allogenic fetus. Certain subsets of both the innate and adaptive immune responses play a role in the induction of fetomaternal tolerance. A relatively predominant T‐cell helper (Th) 2 and T regulatory (Treg) cell population seem to favor a better pregnancy outcome, whereas Th1 and Th17 cell populations appear to have an opposite effect. Lately, the role of vitamin D in the modulation of immune response was established. Vitamin D has been shown to promote a more favorable environment for pregnancy through various mechanisms, such as enhancement of the shift toward Th2 cells and regulation of immune cell differentiation and cytokine secretion. Therefore, it seems that vitamin D deficiency sways the balance toward a worse outcome and may play a part in recurrent pregnancy loss. This review sheds light on the immunologic changes, which occur in early pregnancy and the regulatory role vitamin D has in the maintenance of this delicate balance.     

Mechanistic immunological based classification of rheumatoid arthritis

The classical autoimmunity paradigm in rheumatoid arthritis (RA) is strongly supported by immunogenetics suggesting follicular helper T-cell responses driving high titre specific autoantibodies that pre-dates disease onset. Using the immunological disease continuum model of inflammation against self with “pure” adaptive and innate immune disease at opposite boundaries, we propose a novel immune mechanistic classification describing the heterogeneity within RA. Mutations or SNPs in autoinflammatory genes including MEFV and NOD2 are linked to seronegative RA phenotypes including some so called palindromic RA cases. However, just as innate and adaptive immunity are closely functionally integrated, some ACPA+ RA cases have superimposed “autoinflammatory” features including abrupt onset attacks, severe attacks, self-limiting attacks, relevant autoinflammatory mutations or SNPs and therapeutic responses to autoinflammatory pathway therapies including colchicine and IL-1 pathway blockade. An emergent feature from this classification that non-destructive RA phenotypes, both innate and adaptive, have disease epicentres situated in the extracapsular tissues. This mixed innate and adaptive immunopathogenesis may be the key to understanding severe disease flares, resistant disease subsets that are unresponsive to standard therapy and for therapies that target the autoinflammatory component of disease that are not currently considered by expert therapeutic recommendations.     

Tuftsin–phosphorylcholine (TPC) equally effective to methylprednisolone in ameliorating lupus nephritis in a mice model

The role of helminth treatment in autoimmune diseases is growing constantly. Systemic lupus erythematosus (SLE) is a multi‐system autoimmune disease with challenging treatment options. Tuftsin–phosphorylcholine (TPC) is a novel helminth‐based compound that modulates the host immune network. This study was conducted to evaluate the potential value of TPC in ameliorating lupus nephritis in a murine model and specifically to compare the efficacy of TPC to the existing first‐line therapy for SLE: corticosteroids (methylprednisolone). Lupus‐prone NZBxW/F₁mice were treated with TPC (5 µg/mouse), methylprednisolone (MP; 5 mg/body weight) or phosphate‐buffered saline (PBS) (control) three times per week once glomerulonephritis, defined as proteinuria of grade > 100 mg/dl, was established. Levels of anti‐dsDNA autoantibodies were evaluated by enzyme‐linked immunosorbent assay (ELISA), splenic cytokines were measured in vitro and the kidney microscopy was analysed following staining. TPC and MP treatments improved lupus nephritis significantly and prolonged survival in NZBxW/F₁ mice. TPC‐treated mice showed a significantly decreased level of proteinuria (P < 0·001) and anti‐dsDNA antibodies (P < 0·001) compared to PBS‐treated mice. Moreover, TPC and MP inhibited the production of the proinflammatory cytokines interferon IFN‐γ, interleukin IL‐1β and IL‐6 (P < 0·001) and enhanced expression of the anti‐inflammatory cytokine IL‐10 (P < 0·001). Finally, microscopy analysis of the kidneys demonstrated that TPC‐treated mice maintained normal structure equally to MP‐treated mice. These data indicate that the small molecule named TPC hinders lupus development in genetically lupus‐prone mice equally to methylprednisolone in most of the cases. Hence, TCP may be employed as a therapeutic potential for lupus nephritis.     

Chronic hepatitis B viral infection among RA patients—a cross-sectional control study

Clinical Rheumatology - Rheumatoid arthritis (RA) is the most common inflammatory joint disorder presenting also with extra-articular manifestations. As many other autoimmune diseases, it has been...     

The autoimmune/inflammatory syndrome induced by adjuvants (ASIA)/Shoenfeld’s syndrome: descriptive analysis of 300 patients from the international ASIA syndrome registry

Clinical Rheumatology - The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a recently identified condition in which the exposure to an adjuvant leads to an aberrant autoimmune...