ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis

Reactive oxygen species (ROS) have been shown to be toxic but also function as signalling molecules. This biological paradox underlies mechanisms that are important for the integrity and fitness of living organisms and their ageing. The pathways that regulate ROS homeostasis are crucial for mitigating the toxicity of ROS and provide strong evidence about specificity in ROS signalling. By taking advantage of the chemistry of ROS, highly specific mechanisms have evolved that form the basis of oxidant scavenging and ROS signalling systems.     

Altered signalling thresholds in T lymphocytes cause autoimmune arthritis

The development of spontaneous autoimmunity in inbred strains of rodents has allowed us to investigate the molecular basis of chronic inflammatory disease in ways that would not be possible in humans. Recently, two new mouse models of autoimmune inflammatory polyarthritis have been reported that demonstrate how alterations in signalling thresholds sufficient to perturb central T-cell tolerance lead to inflammatory arthritis. These mice provide new insights into the complexities of what may turn out to be a heterogeneous group of diseases that we call rheumatoid arthritis. They will also provide unique tools for dissecting precisely how chronically activated T cells contribute to the effector phase of arthritis through mechanisms that may be less dependent on antigen receptor signalling.     

ROS and redox signalling in the response of plants to abiotic stress

The redox state of the chloroplast and mitochondria, the two main powerhouses of photosynthesizing eukaryotes, is maintained by a delicate balance between energy production and consumption, and affected by the need to avoid increased production of reactive oxygen species (ROS). These demands are especially critical during exposure to extreme environmental conditions, such as high light (HL) intensity, heat, drought or a combination of different environmental stresses. Under these conditions, ROS and redox cues, generated in the chloroplast and mitochondria, are essential for maintaining normal energy and metabolic fluxes, optimizing different cell functions, activating acclimation responses through retrograde signalling, and controlling whole-plant systemic signalling pathways. Regulation of the multiple redox and ROS signals in plants requires a high degree of coordination and balance between signalling and metabolic pathways in different cellular compartments. In this review, we provide an update on ROS and redox signalling in the context of abiotic stress responses, while addressing their role in retrograde regulation, systemic acquired acclimation and cellular coordination in plants.     

T cell receptors in autoimmune disease as targets for immune intervention

The optimal form of treatment for an autoimmune disease should be highly specific, have few side effects, and allow treatment of clinically apparent disease. One target that could fulfill these requirements is the T cell receptor. To answer the question whether treatment of autoimmune disease is possible with anti-T cell receptor antibodies, the heterogeneity of T cell receptor elements utilized in the T cell mediated autoimmune disease experimental allergic encephalomyelitis was analyzed. The limited heterogeneity of these elements allowed prevention and treatment of clinical autoimmune disease with anti-T cell receptor monoclonal antibodies. These results and their potential value for other autoimmune diseases are discussed.     

Regulatory T cells in rheumatoid arthritis

Apart from the deletion of autoreactive T cells in the thymus, various methods exist in the peripheral immune system to control specific human immune responses to self-antigens. One of these mechanisms involves regulatory T cells, of which CD4⁺CD25⁺ T cells are a major subset. Recent evidence suggests that CD4⁺CD25⁺ T cells have a role in controlling the development of autoimmune diseases in animals and in humans. The precise delineation of the function of CD4⁺CD25⁺ T cells in autoimmune inflammation is therefore of great importance for the understanding of the pathogenesis of autoimmune diseases. Moreover, the ability to control such regulatory mechanisms might provide novel therapeutic opportunities in autoimmune disorders such as rheumatoid arthritis. Here we review existing knowledge of CD4⁺CD25⁺ T cells and discuss their role in the pathogenesis of rheumatic diseases.     

Cell signalling in macrophages, the principal innate immune effector cells of rheumatoid arthritis

Rheumatoid arthritis is a multisystemic auto-inflammatory disease affecting up to 1% of the population and leading to the destruction of the joints. Evidence exists for the involvement of the innate as well as the adaptive immune systems in the pathology of the disease. The success of anti-tumour necrosis factor-alpha indicates the importance of pro-inflammatory mediators produced by innate immune cells in rheumatoid arthritis progression. Therefore, considerable efforts have been made in elucidating the signalling pathways leading to the expression of those mediators. This review will concentrate on the role of signalling pathways in innate immune cells in the context of rheumatoid arthritis.     

B-cell targeting in rheumatoid arthritis and other autoimmune diseases

B-cell-targeted therapy for autoimmune disease emerged from theoretical proposition to practical reality between 1997 and 1998, with the availability of the B-cell-depleting monoclonal antibody rituximab. Since then, a score of autoantibody-associated disorders have been treated, with most convincing evidence of efficacy seen in subjects with rheumatoid arthritis. Several classes of B-cell-targeted agent are now under investigation. From the outset, a major goal of B-cell targeting has been the re-establishment of some form of immunological tolerance. In some subjects, the observed improvement of disease for years following therapy fuels hope that this goal might ultimately be achievable.     

Mechanism of ROS scavenging and antioxidant signalling by redox metallic and fullerene nanomaterials: Potential implications in ROS associated degenerative disorders

BackgroundThe balance between oxidation and anti-oxidation is believed to be critical in maintaining healthy biological systems. However, our endogenous antioxidant defense systems are incomplete without exogenous antioxidants and, therefore, there is a continuous demand for exogenous antioxidants to prevent stress and ageing associated disorders. Nanotechnology has yielded enormous variety of nanomaterials (NMs) of which metallic and carbonic (mainly fullerenes) NMs, with redox property, have been found to be strong scavengers of ROS and antioxidants in preclinical in vitro and in vivo models.Scope of reviewRedox activity of metal based NMs and membrane translocation time of fullerene NMs seem to be the major determinants in ROS scavenging potential exhibited by these NMs. A comprehensive knowledge about the effects of ROS scavenging NMs in cellular antioxidant signalling is largely lacking. This review compiles the mechanisms of ROS scavenging as well as antioxidant signalling of the aforementioned metallic and fullerene NMs.Major conclusionsDirect interaction between NMs and proteins does greatly affect the corona/adsorption formation dynamics but such interaction does not provide the explanation behind diverse biological outcomes induced by NMs. Indirect interaction, however, that could occur via NMs uptake and dissolution, NMs ROS induction and ROS scavenging property, and NMs membrane translocation time seem to work as a central mode of interaction.General significanceThe usage of potential antioxidant NMs in biological systems would greatly impact the field of nanomedicine. ROS scavenging NMs hold great promise in the future treatment of ROS related degenerative disorders.     

Evidence for common autoimmune disease genes controlling onset, severity, and chronicity based on experimental models for multiple sclerosis and rheumatoid arthritis

The pathogenicity of multiple sclerosis is still poorly understood, but identification of susceptibility genes using the animal model experimental allergic encephalomyelitis (EAE) could provide leads. Certain genes may be shared between different autoimmune diseases, and identification of such genes is of obvious importance. To locate gene regions involved in the control of EAE and to compare the findings with the susceptibility loci recently identified in a model for rheumatoid arthritis (pristane-induced arthritis), we made crosses between the encephalomyelitis- and arthritis-susceptible rat strain DA and the resistant E3 strain. Genetic analysis of animals produced in a F2 intercross identified 11 loci associated with specific EAE-associated traits. Interestingly, five of these loci were situated at the same position as major loci controlling pristane-induced arthritis and showed similarities in inheritance pattern and subphenotype associations. Our results show that different phases of EAE are controlled by different sets of genes and that common genes are likely to be involved in different autoimmune diseases.     

B-lymphocyte depletion therapy in rheumatoid arthritis and other autoimmune disorders

B-lymphocyte depletion therapy is being explored in a wide range of autoimmune disorders. In many, there is early evidence for efficacy, and immunosuppression has not been a major problem. The mechanism of action is unclear, but appears to be consistent with the lowering of autoantibody levels, where relevant antibodies are quantifiable. An interesting finding is the persistence of clinical improvement for periods of 1 year or more after B-lymphocyte return, which supports the concept that stochastic generation of rare pathogenic B-lymphocyte subsets may be a rate-limiting step in pathogenesis.     

Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease

Introduction

Genome wide association studies, replicated by numerous well powered validation studies, have revealed a large number of loci likely to play a role in susceptibility to many multifactorial diseases. It is now well established that some of these loci are shared between diseases with similar aetiology. For example, a number of autoimmune diseases have been associated with variants in the PTPN22, TNFAIP3 and CTLA4 genes. Here we have attempted to define overlapping genetic variants between rheumatoid arthritis (RA), type 1 diabetes (T1D) and coeliac disease (CeD).

Methods

We selected eight SNPs previously identified as being associated with CeD and six T1D-associated SNPs for validation in a sample of 3,962 RA patients and 3,531 controls. Genotyping was performed using the Sequenom MassArray platform and comparison of genotype and allele frequencies between cases and controls was undertaken. A trend test P-value < 0.004 was regarded as significant.

Results

We found statistically significant evidence for association of the TAGAP locus with RA (P = 5.0 × 10^-4). A marker at one other locus, C1QTNF6, previously associated with T1D, showed nominal association with RA in the current study but did not remain statistically significant at the corrected threshold.

Conclusions

In exploring the overlap between T1D, CeD and RA, there is strong evidence that variation within the TAGAP gene is associated with all three autoimmune diseases. Interestingly a number of loci appear to be specific to one of the three diseases currently studied suggesting that they may play a role in determining the particular autoimmune phenotype at presentation.     

Killer cell activating receptors function as costimulatory molecules on CD4+CD28null T cells clonally expanded in rheumatoid arthritis

Expansion of CD4+CD28null T cells is a characteristic finding in patients with rheumatoid arthritis. Despite lacking CD28 molecules, these unusual CD4 T cells undergo clonal proliferation and form large and long-lived clonal populations. They produce high levels of IFN-gamma, exhibit autoreactivity, and have cytolytic function. The mechanisms facilitating the expansion and longevity of CD4+CD28null T cell clones in vivo are unknown. Here, we report that CD4+CD28null, but not CD4+CD28+, T cells express MHC class I-recognizing receptors normally found on NK cells. CD4+CD28null T cells preferentially expressed killer cell activating receptors (KAR), often in the absence of killer cell inhibitory receptors. Cross-linking of KAR molecules enhanced the proliferative response to TCR-mediated stimulation, but not the cytolytic function of CD4+CD28null T cells, suggesting different signaling pathways in CD4 T cells and NK cells. Triggering of KAR signaling led to the phosphorylation of several cellular targets, although the pattern of phosphorylation differed from that induced by the TCR. Aberrant expression of KAR molecules in the absence of inhibitory receptors and in the appropriate HLA setting may lead to the clonal outgrowth of autoreactive CD4+CD28null T cells commonly seen in rheumatoid arthritis.     

Genetic interrelationship between insulin-dependent diabetes mellitus, the autoimmune thyroid diseases, and rheumatoid arthritis.

To investigate the possible coinheritance of autoimmune diseases that are associated with the same HLA antigen, we studied 70 families in which at least two siblings had either type I diabetes mellitus (IDDM), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), or a combination of these diseases. HLA-A, B, and C typing was performed on all affected sibs in one generation or more. First, we estimated by sib-pair analysis the disease allele frequency (pD) and the mode of inheritance for each disease. According to the method of ascertainment entered into the analysis, the pD for ATD ranged from .120 to .180, for an additive (dominant) mode of inheritance. For RA, the pD ranged from .254 to .341, also for additive inheritance, although recessive inheritance could not be excluded. For IDDM, the pD ranged from .336 to .337 for recessive inheritance; additive inheritance was rejected. Second, we examined the distribution of shared parental haplotypes in pairs of siblings that were discordant for their autoimmune diseases. The results suggested that the same haplotype may predispose to both IDDM and ATD, or IDDM and RA, but not to both RA and ATD. Analysis of pedigrees supported this hypothesis. In 16 families typed for HLA-DR also, the haplotype predisposing to both IDDM and ATD was assigned from pedigree information to DR3 (44%), DR4 (39%), or DR5, DR6, or DR7 (5.5% each). In some families, these haplotypes segregated over several generations with ATD only (either clinical or subclinical), suggesting that in such families, ATD was a marker for a susceptibility to IDDM. In several families, an IDDM haplotype segregated with RA but not with ATD. This suggests that ATD- and RA-associated susceptibilities to IDDM may be biologically different and thus independently increase the risk of IDDM.     

Humanized mice as a model for rheumatoid arthritis

Genetic susceptibility to rheumatoid arthritis (RA), a common autoimmune disease, is associated with certain HLA-DR4 alleles. Treatments are rarely curative and are often tied to major side effects. We describe the development of a humanized mouse model wherein new, less toxic, vaccine-like treatments for RA might be pretested. This model includes four separate transgenes: HLA-DR*0401 and human CD4 molecules, a RA-related human autoantigenic protein (HCgp-39), and a T-cell receptor (TCRalphabeta) transgene specific for an important HCgp-39 epitope, eliciting strong Th1 responses in the context of HLA-DR*0401.     

Cells of the synovium in rheumatoid arthritis. T lymphocytes

Recent findings have substantiated the importance of T lymphocytes to the pathogenesis of rheumatoid arthritis (RA). Here, we review emerging data regarding genetic predisposition, spontaneous animal models of arthritis, and cell-cell interactions that implicate T cells as driving synovial inflammation and joint destruction. Information regarding the proinflammatory role of interleukin-17-producing T cells and the functional state of regulatory T cells both in animal models and in patients with RA is also discussed. In light of the overwhelming evidence that disrupted T-cell homeostasis greatly contributes to joint pathology in RA, the therapeutic potential of targeting activators of pro-inflammatory T cells or their products is compelling.     

Activated T cells complicate the identification of regulatory T cells in rheumatoid arthritis

Most cell surface markers for CD4⁺CD25⁺ regulatory T cells (Tregs) are also expressed by activated non-regulatory T cells. Recently, CD127 down-regulation was found to identify functional Tregs in healthy individuals, but there are no data from patients with inflammatory conditions. We examined peripheral blood mononuclear cells (PBMC) from rheumatoid arthritis patients with active inflammation and from healthy controls, and found that CD4⁺ T cells contained an equal proportion of CD25⁺CD127⁻/low cells in both groups. In patients, not all these cells expressed intracellular FOXP3. Upon activation by anti-CD3/anti-CD28, PBMC rapidly down-regulated CD127, while FOXP3 up-regulation was transitory and occurred in fewer cells. The activated cells were not anergic to restimulation and had no suppressive effects. The distinct kinetics indicate that the FOXP3⁻CD127⁻/low cells in rheumatoid arthritis patients most likely represent activated non-regulatory T cells. This complicates the use of CD127 for identification of Tregs in inflammatory diseases.