Despite the broad spectrum of antirheumatic drugs, RA is still not well controlled in up to 30-50 % of patients. Inhibition of JAK kinases by means of the pan-JAK inhibitor tofacitinib has demonstrated to be effective even in difficult-to-treat patients. Here, we discuss whether the efficacy of JAK inhibition can be improved by simultaneously inhibiting SYK kinase, since both kinases mediate complementary and non-redundant pathways in RA.
Efficacy of dual JAK + SYK inhibition with selective small molecule inhibitors was evaluated in chronic G6PI-induced arthritis, a non-self-remitting and destructive arthritis model in mice. Clinical and histopathological scores, as well as cytokine and anti-G6PI antibody production were assessed in both preventive and curative protocols. Potential immunotoxicity was also evaluated in G6PI-induced arthritis and in a 28-day TDAR model, by analysing the effects of JAK + SYK inhibition on hematological parameters, lymphoid organs, leukocyte subsets and cell function.
Simultaneous JAK + SYK inhibition completely prevented mice from developing arthritis. This therapeutic strategy was also very effective in ameliorating already established arthritis. Dual kinase inhibition immediately resulted in greatly decreased clinical and histopathological scores and led to disease remission in over 70 % of the animals. In contrast, single JAK inhibition and anti-TNF therapy (etanercept) were able to stop disease progression but not to revert it. Dual kinase inhibition decreased Treg and NK cell counts to the same extent as single JAK inhibition but overall cytotoxicity remained intact. Interestingly, treatment discontinuation rapidly reversed such immune cell reduction without compromising clinical efficacy, suggesting long-lasting curative effects. Dual kinase inhibition reduced the Th1/Th17 cytokine cascade and the differentiation and function of joint cells, in particular osteoclasts and fibroblast-like synoviocytes.
Concurrent JAK + SYK inhibition resulted in higher efficacy than single kinase inhibition and TNF blockade in a chronic and severe arthritis model. Thus, blockade of multiple immune signals with dual JAK + SYK inhibition represents a reasonable therapeutic strategy for RA, in particular in patients with inadequate responses to current treatments. Our data supports the multiplicity of events underlying this heterogeneous and complex disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0866-0) contains supplementary material, which is available to authorized users.
Arthritis; JAK; SYK; Small molecule inhibitors; Anti-TNF therapy; Fibroblast-like synoviocytes; Osteoclasts; Memory cells
NF-κB activation depends on the IKK complex consisting of the catalytically active IKK1 and 2 subunits and the scaffold protein NEMO. Hitherto, IKK2 activation has always been associated with IκBα degradation, NF-κB activation, and cytokine production. In contrast, we found that in SCF-stimulated primary bone marrow-derived mast cells (BMMCs), IKK2 is alternatively activated. Mechanistically, activated TAK1 mediates the association between c-Kit and IKK2 and therefore facilitates the Lyn-dependent IKK2 activation which suffices to mediate mitogenic signaling but, surprisingly, does not result in NF-κB activation. Moreover, the c-Kit-mediated and Lyn-dependent IKK2 activation is targeted by MyD88-dependent pathways leading to enhanced IKK2 activation and therefore to potentiated effector functions. In neoplastic cells, expressing constitutively active c-Kit mutants, activated TAK1 and IKKs do also not induce NF-κB activation but mediate uncontrolled proliferation, resistance to apoptosis and enables IL-33 to mediate c-Kit-dependent signaling. Together, we identified the formation of the c-Kit-Lyn-TAK1 signalosome which mediates IKK2 activation. Unexpectedly, this IKK activation is uncoupled from the NF-κB-machinery but is critical to modulate functional cell responses in primary-, and mediates uncontrolled proliferation and survival of tumor-mast cells. Therefore, targeting TAK1 and IKKs might be a novel approach to treat c-Kit-driven diseases.
mast cells; TAK1-IKK2 activation; c-Kit-Lyn-TAK1-IKK2 complex; mitogenic signaling; NF-κB-activation
Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2+-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term “subthreshold IKK activation”.
This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33.
We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo.
Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure.
Mast cells; subthreshold IKK activation; mitogenic signaling; NFκB-activation
Transgenic expression of B- and T-cell receptors (BCRs and TCRs, respectively) has been a standard tool to study lymphocyte development and function in vivo. The generation of transgenic mice is time-consuming and, therefore, a faster method to study the biology of defined lymphocyte receptors in vivo would be highly welcome. Using 2A peptide-linked multicistronic retroviral vectors to transduce stem cells, TCRs can be expressed rapidly in mice of any background. We aimed at adopting this retrogenic technology to the in vivo expression of BCRs. Using a well characterised BCR specific for hen egg lysozyme (HEL), we achieved surface expression of the retrogenically encoded BCR in a Rag-deficient pro B-cell line in vitro. In vivo, retrogenic BCRs were detectable only intracellularly but not on the surface of B cells from wild type or Rag2-deficient mice. This data, together with the fact that no BCR retrogenic mouse model has been published in the 7 years since the method was originally published for TCRs, strongly suggests that achieving BCR-expression in vivo with retrogenic technology is highly challenging if not impossible.
Evaluation of disease severity in experimental models of rheumatoid arthritis is inevitably associated with assessment of structural bone damage. A noninvasive imaging technology allowing objective quantification of pathophysiological alterations of bone structure in rodents could substantially extend the methods used to date in preclinical arthritis research for staging of autoimmune disease severity or efficacy of therapeutical intervention. Sodium 18 F-fluoride (18 F-NaF) is a bone-seeking tracer well-suited for molecular imaging. Therefore, we systematically examined the use of 18 F-NaF positron emission tomography/computed tomography (PET/CT) in mice with glucose-6-phosphate isomerase (G6PI)–induced arthritis for quantification of pathological bone metabolism.
F-fluoride was injected into mice before disease onset and at various time points of progressing experimental arthritis. Radioisotope accumulation in joints in the fore- and hindpaws was analyzed by PET measurements. For validation of bone metabolism quantified by 18 F-fluoride PET, bone surface parameters of high-resolution μCT measurements were used.
Before clinical arthritis onset, no distinct accumulation of 18 F-fluoride was detectable in the fore- and hindlimbs of mice immunized with G6PI. In the course of experimental autoimmune disease, 18 F-fluoride bone uptake was increased at sites of enhanced bone metabolism caused by pathophysiological processes of autoimmune disease. Moreover, 18 F-fluoride signaling at different stages of G6PI-induced arthritis was significantly correlated with the degree of bone destruction. CT enabled identification of exact localization of 18 F-fluoride signaling in bone and soft tissue.
The results of this study suggest that small-animal PET/CT using 18 F-fluoride as a tracer is a feasible method for quantitative assessment of pathophysiological bone metabolism in experimental arthritis. Furthermore, the possibility to perform repeated noninvasive measurements in vivo allows longitudinal study of therapeutical intervention monitoring.
Interruption of cytokine signaling, by targeting either the cytokine itself or its cellular receptor, is a mainstay in the therapy for patients with rheumatic diseases. Interleukin (IL)-33, a member of the IL-1 cytokine family, has emerged as an important mediator of inflammatory responses. In a side-by-side examination of IL-33-deficient and IL-33 receptor (IL-33R)-deficient mice in the K/BxN serum transfer model, arthritis was ameliorated in the IL-33R knockout (KO) mice but not in the IL-33 KO mice. These findings complement previous knowledge on IL-33R signaling, demonstrating that the IL-33R cross-activates other signaling pathways in addition to IL-33-mediated signals. The results reported by Martin and colleagues in a previous issue of Arthritis Research & Therapy underline the clinical relevance of IL-33R cross-signaling and further illustrate that targeting a cytokine receptor (IL-33R) can have completely different clinical outcomes than targeting the respective cytokine.
IL-17–producing CD8+ T (Tc17) cells are detectible in multiple sclerosis (MS) lesions; however, their contribution to the disease is unknown. To identify functions of Tc17 cells, we induced EAE, a murine model of MS, in mice lacking IFN regulatory factor 4 (IRF4). IRF4-deficient mice failed to generate Tc17 and Th17 cells and were resistant to EAE. After adoptive transfer of WT CD8+ T cells and subsequent immunization for EAE induction in these mice, the CD8+ T cells developed a Tc17 phenotype in the periphery but could not infiltrate the CNS. Similarly, transfer of small numbers of WT CD4+ T cells alone did not evoke EAE, but when transferred together with CD8+ T cells, IL-17–producing CD4+ (Th17) T cells accumulated in the CNS and mice developed severe disease. Th17 accumulation and development of EAE required IL-17A production by CD8+ T cells, suggesting that Tc17 cells are required to promote CD4+ T cell–mediated induction of EAE. Accordingly, patients with early-stage MS harbored a greater number of Tc17 cells in the cerebrospinal fluid than in peripheral blood. Our results reveal that Tc17 cells contribute to the initiation of CNS autoimmunity in mice and humans by supporting Th17 cell pathogenicity.
Characterization of the response of the host immune system is important in understanding the bidirectional interactions between the host and microbial pathogens. For research on the host site, flow cytometry has become one of the major tools in immunology. Advances in technology and reagents allow now the simultaneous assessment of multiple markers on a single cell level generating multidimensional data sets that require multivariate statistical analysis. We explored the explanatory power of the supervised machine learning method called “induction of decision trees” in flow cytometric data. In order to examine whether the production of a certain cytokine is depended on other cytokines, datasets from intracellular staining for six cytokines with complex patterns of co-expression were analyzed by induction of decision trees. After weighting the data according to their class probabilities, we created a total of 13,392 different decision trees for each given cytokine with different parameter settings. For a more realistic estimation of the decision trees’ quality, we used stratified fivefold cross validation and chose the “best” tree according to a combination of different quality criteria. While some of the decision trees reflected previously known co-expression patterns, we found that the expression of some cytokines was not only dependent on the co-expression of others per se, but was also dependent on the intensity of expression. Thus, for the first time we successfully used induction of decision trees for the analysis of high dimensional flow cytometric data and demonstrated the feasibility of this method to reveal structural patterns in such data sets.
flow cytometry; cytokines; machine learning; induction of decision trees; imbalanced data; multidimensionality
IL-17-producing CD4+ T-helper cells (Th17 cells) have been recognised as important drivers of pathogenesis in a multitude of inflammatory diseases, including arthritis. The cytokines and transcription factors that instruct and execute Th17 lineage differentiation have been identified. This has induced hopes that targeting Th17 cells might yield a magic bullet against autoimmune diseases. A new wave of published reports shows that matters are more complicated: Th cells can coexpress IL-17 with a variety of other cytokines, including IFNγ, IL-4, or IL-10, with different functional consequences. Moreover, IL-17 memory is not stable - Th17 cells can be instructed to express other lineage-defining cytokines and to halt IL-17 expression. Finally, Th17 cells may exert tissue-protective effects, even in the context of some inflammatory diseases. Manipulating Th17 cells or IL-17 effects may be more difficult than initially appreciated. Notwithstanding these facts, IL-17 remains a valuable and even more interesting therapeutic target.
The therapeutic benefit of B cell depletion in patients with rheumatoid arthritis has provided proof of concept that B cells are relevant for the pathogenesis of arthritis. It remains unknown which B cell effector functions contribute to the induction or chronification of arthritis. We studied the clinical and immunological effects of B cell depletion in glucose-6-phosphate isomerase-induced arthritis. We targeted CD22 to deplete B cells. Mice were depleted of B cells before or after immunization with glucose-6-phosphate isomerase (G6PI). The clinical and histological effects were studied. G6PI-specific antibody responses were measured by ELISA. G6PI-specific T helper (Th) cell responses were assayed by polychromatic flow cytometry. B cell depletion prior to G6PI-immunization prevented arthritis. B cell depletion after immunization ameliorated arthritis, whereas B cell depletion in arthritic mice was ineffective. Transfer of antibodies from arthritic mice into B cell depleted recipients did not reconstitute arthritis. B cell depleted mice harbored much fewer G6PI-specific Th cells than control animals. B cell depletion prevents but does not cure G6PI-induced arthritis. Arthritis prevention upon B cell depletion is associated with a drastic reduction in the number of G6PI-specific effector Th cells.
IL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes differed between distinct Ab clones, because the characterization of such Abs (i.e., depletion, agonistic or blocking Abs) was unclear in some cases.
To elucidate the precise role of IL-33, we newly generated neutralizing monoclonal Abs for IL-33. Exogenous IL-33 potentiated LPS-mediated cytokine production by macrophages. That LPS-mediated cytokine production by macrophages was suppressed by inhibition of endogenous IL-33 by the anti-IL-33 neutralizing mAbs.
Our findings suggest that LPS-mediated macrophage activation is accelerated by macrophage-derived paracrine IL-33 stimulation.
T-helper (Th) lymphocytes contribute to arthritis pathogenesis by helping B cells to produce antibodies, by producing cytokines that activate effector cells involved in the destruction of cartilage and bone, and by contributing to osteoclast differentiation. There are murine models of arthritis, most notably collagen- and proteoglycan-induced arthritis, in which arthritis depends on T-cell recognition of antigens that are expressed in the joints. In spite of this, we still do not know the antigens recognised by arthritogenic Th cells in humans. Moreover, current evidence for Th cells exerting arthritogenic effector functions within the joints is only indirect.
The purpose of this work was to establish and validate combined small animal positron emission tomography - computed tomography (PET/CT) as a new in vivo imaging method for visualisation and quantification of joint inflammation.
Signalling of radioisotope 18F labelled Fluorodeoxyglucose (18F-FDG) injected in mice with glucose-6-phosphate isomerase (G6PI)-induced arthritis was analysed by PET/CT. Accumulation of 18F-FDG in tissue was quantified by PET measurement, whereas high definition CT delivered anatomical information. The fusion of both images revealed in detail spatial and temporal distribution and metabolism of 18F-FDG.
A distinct 18F-FDG signal could be measured by PET in carpal and tarsal joints, from mice with early or established arthritis. In contrast, no accumulation of 18F-FDG was detectable before arthritis onset. Comparison of 18F-FDG joint uptake with histopathological evaluation revealed a significant correlation of both methods.
Small animal PET/CT using 18F-FDG is a feasible method for monitoring and, more importantly, quantitative assessment of inflammation in G6PI-arthritis. Since it is possible to perform repeated non-invasive measurements in vivo, not only numbers of animals in preclinical studies can markedly be reduced by this method, but also longitudinal studies come into reach, e. g. for individual flare-up reactions or monitoring therapy response in progressive arthritis.
Peroral infection with Toxoplasma gondii leads to the development of small intestinal inflammation dependent on Th1 cytokines. The role of Th17 cells in ileitis is unknown. We report interleukin (IL)-23–mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii–induced immunopathology. Moreover, IL-23–dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down-regulated and dispensable. CD4+ T cells were the main source of IL-22 in the small intestinal lamina propria. Thus, IL-23 regulates small intestinal inflammation via IL-22 but independent of IL-17. Gelatinases may be useful targets for treatment of intestinal inflammation.
T-helper (Th) lymphocytes are critically required for the pathogenesis of glucose-6-phosphate isomerase (G6PI)-induced arthritis, but neither the G6PI epitopes recognized by arthritogenic T cells nor their pathogenic effector functions have been fully elucidated to date. We aimed at identifying arthritogenic G6PI peptides.
We used a library of overlapping peptides spanning the entire G6PI sequence to identify the epitopes recognized by G6PI-specific Th cells. Immunodominant peptides were then used to immunize mice. Arthritis development was evaluated clinically and histologically. The humoral and cellular immune responses upon peptide immunization were analyzed by ELISA and multiparameter flow cytometry, respectively.
We identified six immunodominant T-cell epitopes in DBA/1 mice, of which three are arthritogenic. One of these peptides (G6PI469–483) is identical in man and mice. Immunization with this peptide induces arthritis, which is less severe and of shorter duration than arthritis induced by immunization with full-length G6PI. Upon immunization with either G6PI or peptide, the antigen-specific Th cells produce IL-17, RANKL, IFNγ and TNFα.
We identified immunodominant and arthritogenic epitopes of G6PI. Not all immunodominant peptides are arthritogenic. This is the first description of arthritis induced by immunization with a self-peptide in mice.
EBV is a candidate trigger of rheumatoid arthritis (RA). We determined both EBV-specific T cell and B cell responses and cell-associated EBV DNA copies in patients with RA and demographically matched healthy virus carriers. Patients with RA showed increased and broadened IgG responses to lytic and latent EBV-encoded Ags and 7-fold higher levels of EBV copy numbers in circulating blood cells. Additionally, patients with RA exhibited substantial expansions of CD8+ T cells specific for pooled EBV Ags expressed during both B cell transformation and productive viral replication and the frequency of CD8+ T cells specific for these Ags correlated with cellular EBV copy numbers. In contrast, CD4+ T cell responses to EBV and T cell responses to human CMV Ags were unchanged, altogether arguing against a defective control of latent EBV infection in RA. Our data show that the regulation of EBV infection is perturbed in RA and suggest that increased EBV-specific effector T cell and Ab responses are driven by an elevated EBV load in RA.
The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor κB (NF-κB)–dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-κB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-γ, IL-2, and tumor necrosis factor-α, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.
Antibodies specific for glucose-6-phosphate isomerase (G6PI) from T-cell receptor transgenic K/BxN mice are known to induce arthritis in mice, and immunization of DBA/1 mice with G6PI led to acute arthritis without permanent deformation of their joints. Because rheumatoid arthritis is a chronic disease, we set out to identify the capacity of G6PI to induce chronic arthritis in mice. Immunization with recombinant human G6PI induced a chronically active arthritis in mice with a C3H genomic background, whereas the DBA/1 background allowed only acute arthritis and the C57BL/10 background permitted no or very mild arthritis. The disease was associated with the major histocompatibility region sharing an allelic association similar to that of collagen-induced arthritis (i.e. q > p > r). All strains developed a strong antibody response to G6PI that correlated only in the C3H.NB strain with arthritis severity. Similarly, a weak response to type II collagen in a few mice was observed, which was associated with arthritis in C3H.NB mice. Mice on the C3H background also developed ankylosing spondylitis in the vertebrae of the tail. Both C3H.Q and B10.Q mice deficient for B cells were resistant to arthritis. We conclude that G6PI has the ability to induce a chronic arthritis, which is MHC associated and B-cell dependent. Thus, there are striking similarities between this and the collagen-induced arthritis model.
The antigens that trigger the pathogenic immune response in rheumatoid arthritis (RA) remain unknown. Until recently it was assumed that either viral or microbial antigens, or joint-specific antigens were the target of arthritogenic T and B lymphocytes in RA. Consequently, murine models of arthritis are induced by immunization with either joint-specific antigens such as type II collagen or microbial products such as streptococcal cell wall. In the K/B×N T-cell receptor transgenic mouse model arthritis is caused by a systemic autoimmune response to the ubiquitously expressed glycolytic enzyme glucose-6-phosphate isomerase (G6PI). The autoreactive transgenic T cells recognize G6PI and provide help for the production of arthritogenic IgG antibodies against G6PI. More recently it was shown that G6PI immunization induces severe symmetrical peripheral polyarthritis in genetically unaltered DBA/I mice. In that model CD4+ T cells are necessary not only for the induction but also for the effector phase of arthritis. Here we review the pathomechanisms that lead from systemic autoreactivity to arthritis in these models, consider the relevance of anti-G6PI immune reactivity for RA, and discuss the insights into the pathogenesis of RA and possibly other autoimmune conditions that can be gained from these models.
arthritis; CD4+ T lymphocytes; DBA/I mice; FCγ receptors; glucose-6-phosphate-isomerase
The lung is an important entry site for respiratory pathogens such as influenza A virus. In order to combat such invading infectious agents, effector/memory T cells home to the lung and other peripheral tissues as well as lymphoid organs. In this process, chemokines and their receptors fulfill important roles in the guidance of T cells into such organs and specialized microenvironments within tissues. In this study, we determined if CD4+ T cells residing in different lung compartments and draining lymph nodes of influenza A virus-infected and naïve mice express receptors allowing their recirculation into secondary lymphoid tissues. We found high levels of l-selectin and CC chemokine receptor 7 (CCR7) expression in lung-derived CD4+ T cells, similar to that detected on T cells in secondary lymphoid organs. Upon influenza A virus infection, the bulk of gamma interferon-positive (IFN-γ+) and IFN-γ− CD4+ T cells recovered from lung parenchyma retained functional CCR7, whereas virus-specific IFN-γ-producing T cells were CCR7−. In contrast, a majority of virus-specific IFN-γ+ T cells in the lung draining lymph node were CCR7+. Independent of infection, CD4+ T cells obtained from the lung airways exhibited the lowest expression level of l-selectin and CCR7, indicating that T cells at this anatomical site represent the most differentiated effector cell type, lacking the ability to recirculate. Our results suggest that effector/memory T cells that enter inflammatory sites retain functional CCR7 expression, which is lost only upon response to viral antigen and after localization to the final effector site.
CD4+ T cell help is important for the generation of CD8+ T cell responses. We used depleting anti-CD4 mAb to analyze the role of CD4+ T cells for memory CD8+ T cell responses after secondary infection of mice with the intracellular bacterium Listeria monocytogenes, or after boost immunization by specific peptide or DNA vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8+ T cell responses markedly enlarged the population size of antigen-specific CD8+ T cells. After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8+ T cell populations were enlarged at least 10-fold. In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells. In depletion and transfer experiments, the suppressive function could be ascribed to CD4+CD25+ T cells. Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions. Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response. Down-modulation of CD8+ T cell responses during infection could prevent harmful consequences after eradication of the pathogen.
T lymphocytes; memory; bacterial infection; regulation; vaccination
Lyme disease is a tick-borne multisystem disease that affects primarily the skin, nervous system, heart and joints. At least three species of Borrelia burgdorferi sensu lato, namely Borrelia burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii, can cause the disease. This review will focus mainly on the pathophysiology of Lyme arthritis, the long-term outcome of Lyme disease, and the recently licensed vaccine against Lyme disease.
arthritis; autoimmunity; infection; Lyme disease; T lymphocytes
T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.
inflammation; eosinophil; asthma; cytokines; immunoglobulin superfamily
Clinical evidence suggests that neurological lesions can protect from arthritis. Acute cerebral ischaemia induces severe immunosuppression, resulting in enhanced susceptibility to infections. We aimed to determine if stroke-induced immunosuppression can ameliorate arthritis and to delineate the immunological mechanisms involved.
Unilateral cerebral ischaemia was induced in mice by occlusion of one middle cerebral artery (MCAO) at different time points after induction of G6PI-induced arthritis in mice. Clinical and histological signs of arthritis were assessed. Regulatory T cells were specifically depleted by injection of diphtheria toxin into transgenic DEREG mice. Immunological correlates of MCAO were determined by flow cytometry and serological methods.
MCAO reduced the clinical and histological signs of arthritis significantly. To be effective, stroke had to be induced during the induction phase or the early clinical stage of arthritis. MCAO induced a global loss of leucocytes. Despite the reduced absolute number of lymphocytes, the functional differentiation of T helper cells into Th1/17 cells and the production of autoantibodies were unimpaired. Depletion experiments showed that regulatory T cells were dispensable for the protective effect of MCAO.
MCAO ameliorates arthritis. The correlate of protection from arthritis is not the reduction of a particular pathogenic leucocyte subset or the preferential expansion or emergence of a protective cell population but the global reduction of leucocytes during arthritis.
Arthritis; Inflammation; T Cells