Retinoic acids up‐regulate functional eosinophil‐driving receptor CCR3

Eotaxins and their receptor CCR3 have a definitive role for tissue accumulation of eosinophils both under homeostatic and pathologic conditions. However, physiological stimuli that can up‐regulate CCR3 in blood‐derived human eosinophils have not been recognized. As a prior gene microarray study revealed up‐regulation of CCR3 in eosinophils stimulated with retinoic acids (RAs), the expression of functional CCR3 was examined. We found that 9‐cis RA and all‐trans RA (ATRA) significantly induced surface CCR3 expression regardless of the presence of IL‐3 or IL‐5. Pharmacological manipulations with receptor‐specific agonists and antagonists indicated that retinoic acid receptor‐α activation is critical for CCR3 up‐regulation. RA‐induced CCR3 was associated with its functional capacity, in terms of the calcium mobilization and chemotactic response to eotaxin‐1 (CCL11). Our study suggests an important role of vitamin A derivatives in the tissue accumulation of eosinophils.     

Comparisons of neutrophil‐, monocyte‐, eosinophil‐, and basophil‐ lymphocyte ratios among various systemic autoimmune rheumatic diseases

This study was aimed to evaluate levels of neutrophil‐ (NLR), monocyte‐ (MLR), eosinophil‐ (ELR), and basophil‐lymphocyte ratio (BLR) and their association with inflammatory markers in systemic autoimmune rheumatic diseases (SARDs). A total of 1139 SARD patients and 170 healthy individuals were enrolled. Clinical and laboratory data were extracted. NLR and MLR were significantly increased, but BLR decreased in most SARD patients (p < 0.05). ELR were significantly decreased in systemic lupus erythematosus (SLE) patients, but increased in those with other SARDs (p < 0.001). In SLE patients, C‐reactive protein (CRP) showed positive correlation with NLR, MLR, and BLR. IgG negatively correlated with NLR, and did positively with ELR. IgM negatively correlated with NLR and MLR. In those with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and osteoarthritis (OA), NLR and MLR positively correlated with erythrocyte sedimentation rate (ESR) and CRP. In primary Sjögren's syndrome (pSS) patients, ESR showed positive correlation with NLR and MLR. IgA had positive correlation with BLR. In polymyositis/dermatomyositis (PM/DM) patients, ESR and CRP positively correlated with NLR. Additionally, significant correlations were also found between CRP and BLR, IgG and ELR, IgM and ELR. In systemic sclerosis (SSc) patients, clear correlations were only observed between CRP and NLR or MLR. In mixed connective tissue disease (MCTD) patients, NLR positively correlated with ESR and CRP, while NLR and MLR did negatively with IgM. In polymyalgia rheumatic (PMR) patients, MLR positively correlated with CRP, while ELR did negatively with IgG. This study demonstrated increased NLR and MLR and deceased BLR in most SARDs, decreased ELR in SLE and increased ELR in other SARDs. Furthermore, NLR and MLR may be useful tools to reflect inflammatory status of SARDs.     

Immunomodulatory interplay of the microbiome and therapy of rheumatic diseases

Modulation of the immune system by microbes, especially from the gastrointestinal tract, is increasingly considered a key factor in the onset, course and outcome of rheumatic diseases. The interplay of the microbiome, along with genetic predisposition and environmental exposure, is thought to be an important trigger for rheumatic diseases. Improved identification of the relationship of disease-specific genetic alterations and rheumatic diseases has potential diagnostic and therapeutic applications. Treatment of rheumatic disorders is influenced by microbial actions but this interplay can be challenging due to variable and unpredictable responses to therapies. Expanded knowledge of the microbiome now allows clinicians to more precisely select ideal medication regimens and to predict response to and toxicity from drugs. Rheumatic diseases and associated therapies were among the earliest microbiome interactions investigated, yet it is notable that current research is focused on clinical and immunological associations but, in comparison, a limited number of studies regarding the microbiome’s impact on treatment for rheumatic diseases have been published. In the coming years, further knowledge of immunomodulating interactions between the microbiome and the immune system will aid our understanding of autoimmunity and will be increasingly important in selection of therapeutic agents for patients with autoimmune and rheumatic diseases. In this review, recent literature regarding the bidirectional immunomodulatory effects of the microbiome with rheumatic diseases and current understanding and gaps regarding the drug–microbiome interface in the management of these disorders is presented.     

Thyroid‐associated orbitopathy is linked to gastrointestinal autoimmunity

Common autoimmune disorders tend to co‐exist in the same subjects and cluster in families. The objective of this study was to determine the prevalence of autoimmune co‐morbidity in patients with autoimmune thyroid disease (AITD) with and without thyroid‐associated orbitopathy (TAO). This was a cross‐sectional study conducted at an academic tertiary referral centre. Of 1310 patients with AITD [n = 777 or 59% with Graves' disease (GD) and n = 533, 41% with Hashimoto's thyroiditis (HT)] followed at a specialized joint thyroid–eye out‐patient clinic, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome, 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) type A autoimmune gastritis, 57 (4·4%) vitiligo and 25 (1·9%) Addison's disease. Coeliac disease and autoimmune gastritis were associated positively with GD [odds ratio (OR) = 2·18; P = 0·002 and OR = 6·52; P < 0·001], whereas type 1 diabetes, Addison's disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis and Sjögren's syndrome were ‘protective’ for GD and thus linked to HT, OR = 0·49 (P < 0·001), 0·06 (P < 0·001), 0·25 (P < 0·001), 0·50 (P = 0·090) and 0·32 (P = 0·003), respectively. Of 610 (46·6%) AITD patients with TAO, 584 (95·7%) and 26 (4·3%) had GD and HT, respectively (P < 0·001). TAO was most prevalent in GD patients with coeliac disease (94%, OR = 1·87, P < 0·001). Multivariate analysis showed high OR for coeliac disease and autoimmune gastritis (3·4 and 4·03, both P < 0·001) pertaining to the association with TAO while type 1 diabetes, Addison's disease and alopecia areata were protective for TAO. In patients with TAO, coeliac disease is the most prevalent co‐morbid autoimmune condition and rates are increased compared to GD patients without TAO.     

The genetically determined production of the alarmin eosinophil‐derived neurotoxin is reduced in visceral leishmaniasis

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis. Recent findings indicate that dendritic cells have a key role in the defense against the Leishmania parasite and that the activity of this cell may be modified by the eosinophil secretory protein eosinophil‐derived neurotoxin (EDN). We hypothesized that the interactions between dendritic cells and EDN might be of importance in the disease development. Cellular content of EDN was analyzed by ELISA. The single‐nucleotide polymorphisms at positions 405, 416, and 1122 in the EDN gene were analyzed by real‐time PCR with TaqMan^® reagents. The study cohorts comprised 239 Sudanese subjects (65 healthy controls and 174 with VL) and 300 healthy Swedish controls. The eosinophil content of EDN was lower in VL as compared with controls (p < 0.0001). The EDN405 (G>C) genotype distribution was similar among Swedish and Sudanese controls, whereas VL subjects had a higher prevalence of the EDN405‐GG genotype (p < 0.0001). The content of EDN in the eosinophils was closely linked to the EDN405 polymorphism (p = 0.0002). Our findings suggest that the predisposition to acquire VL is related to the genetic polymorphism of the EDN gene and the reduced production by the eosinophil of this gene product.     

The tRNA‐associated dysregulation in immune responses and immune diseases

Transfer RNA (tRNA), often considered as a housekeeping molecule, mainly participates in protein translation by transporting amino acids to the ribosome. Nevertheless, accumulating evidence has shown that tRNAs are closely related to various physiological and pathological processes. The proper functioning of the immune system is the key to human health. The aim of this review is to investigate the relationships between tRNAs and the immune system. We detail the biogenesis and structure of tRNAs and summarize the pathogen tRNA‐mediated infection and host responses. In addition, we address recent advances in different aspects of tRNA‐associated dysregulation in immune responses and immune diseases, such as tRNA molecules, tRNA modifications, tRNA derivatives and tRNA aminoacylation. Therefore, tRNAs play an important role in immune regulation. Although our knowledge of tRNAs in the context of immunity remains, for the most part, unknown, this field deserves in‐depth research to provide new ideas for the treatment of immune diseases.     

Translational Mini‐Review Series on B Cell‐Directed Therapies: The pathogenic role of B cells in autoantibody‐associated autoimmune diseases – lessons from B cell‐depletion therapy

B cell depletion therapy with rituximab (BCDT) is a licensed treatment for rheumatoid arthritis and has shown promising results in the treatment of severe, refractory patients with other autoantibody‐associated autoimmune diseases (AAID). The exact role that B cells play in the pathogenesis of AAID and consequently the mechanisms by which BCDT is effective are not known. The two more widely discussed hypotheses are that BCDT is effective because it removes the precursors of plasma cells producing pathogenic autoantibody species, or because it depletes a critical mass of autoreactive B cell clones that present antigen to pathogenic autoreactive T cells. This review will focus on the effects of BCDT and whether the response of patients with AAID to BCDT could be due ultimately to its effects on autoantibodies. A better knowledge of the main role that B cells play in the pathogenesis of the different diseases and a better understanding of the most likely mechanism of relapse following an earlier response to BCDT would help to guide further developments of B cell targeting therapies and potentially increase the chance of designing a protocol that could induce a long‐term remission.     

Toll‐like receptor‐mediated eosinophil–basophil differentiation: autocrine signalling by granulocyte–macrophage colony‐stimulating factor in cord blood haematopoietic progenitors

Eosinophils are multi‐functional leucocytes that play a role in inflammatory processes including allergy and infection. Although bone marrow (BM) inflammatory cells are the main source of eosinophil‐basophil (Eo/B) differentiation‐inducing cytokines, a recent role has been demonstrated for cytokine induction through Toll‐like receptor (TLR)‐mediated signalling in BM progenitors. Having previously demonstrated that cord blood (CB) progenitors induce Eo/B colony‐forming units (CFU) after lipopolysaccharide (LPS) stimulation, we sought to investigate the intracellular mechanisms by which LPS induces Eo/B differentiation. Freshly isolated CD34‐enriched human CB cells were stimulated with LPS (and/or pharmacological inhibitors) and assessed for alterations in haematopoietic cytokine receptor expression and signalling pathways by flow cytometry, Eo/B CFU in methylcellulose cultures, and cytokine secretion using Luminex assays. The LPS stimulation resulted in a significant increase in granulocyte–macrophage colony‐stimulating factor (GM‐CSF)‐responsive, as opposed to interleukin‐5‐responsive, Eo/B CFU, which also correlated with significant increases in CD34⁺ cell GM‐CSFRα expression. Functionally, CB CD34⁺ cells secrete abundant amounts of GM‐CSF following LPS stimulation, via a p38 mitogen‐activated protein kinase (MAPK)‐dependent mechanism; this secretion was responsible for Eo/B CFU formation ex vivo, as shown by antibody blockade. We show for the first time that LPS stimulation of CB progenitor cells results in autocrine activation of p38 MAPK‐dependent GM‐CSF secretion facilitating Eo/B differentiation ex vivo. This work provides evidence that early life exposure to products of bacterial agents can modulate Eo/B differentiation, representing a novel mechanism by which progenitor cells can respond to microbial stimuli and so affect immune and inflammatory responses.     

The role of mucosal‐associated invariant T cells in infectious diseases

Mucosal‐associated invariant T (MAIT) cells are donor‐unrestricted lymphocytes that are surprisingly abundant in humans, representing 1–10% of circulating T cells and further enriched in mucosal tissues. MAIT cells recognize and are activated by small molecule ligands produced by microbes and presented by MR1, a highly conserved MHC‐related antigen‐presenting protein that is ubiquitously expressed in human cells. Increasing evidence suggests that MAIT cells play a protective role in anti‐bacterial immunity at mucosal interfaces. Some fungi are known to produce MAIT‐activating ligands, but the role of MAIT cells in fungal infections has not yet been investigated. In viral infections, specifically HIV, which has received the most study, MAIT cell biology is clearly altered, but the mechanisms explaining these alterations and their clinical significance are not yet understood. Many questions remain unanswered about the potential of MAIT cells for protection or pathogenesis in infectious diseases. Because they interact with the universal, donor‐unrestricted ligand‐presenting MR1 molecule, MAIT cells may be attractive immunotherapy or vaccine targets. New tools, including the development of MR1‐ligand tetramers and next‐generation T‐cell receptor sequencing, have the potential to accelerate MAIT cell research and lead to new insights into the role of this unique set of lymphocytes in infectious diseases.     

Immunomodulatory role of chitosan‐based nanoparticles and oligosaccharides in cyclophosphamide‐treated mice

Chitosan, the deacetylated form of chitin, a natural polysaccharide, is known for its various biomedical applications. The present study aimed at exploring the immunomodulatory properties of chitosan (CSNP) and gallic acid‐grafted chitosan (cGANP) nanoparticles in mice model of cyclophosphamide (CPA)‐induced immunosuppression. In addition, chitooligosaccharides, the hydrolysed form of chitin and chitosan, were also evaluated for its potential against immunosuppression in mice. CPA (80 mg/kg/ip) induced significant immunosuppression, which was reversed with cGANP treatment as indicated by a significant increase in the thymus and spleen indices compared to the CPA‐treated group. The CSNP and chitooligosaccharides (chitin and chitosan) failed to reverse CPA‐induced changes. ELISA revealed an elevation in the levels of IL‐6 and a reduction in IFN‐γ levels with CPA treatment. All the test compounds reduced the IL‐6 levels, whereas only the nanoparticle formulations (CSNP and cGANP) exhibited a significant augmentation in the IFN‐γ levels. Both the cytokines, IL‐6 and IFN‐γ, are secreted separately by two different types of T helper cells (Th cells), which mediate cellular and humoral immune responses in a coordinated manner. Th‐1 cells release IFN‐γ, facilitating cell‐mediated immunity, whereas IL‐6 is released by Th‐2 cells, expediting humoral immune response. The nanoparticles (CSNP and cGANP) seemed to be better immune enhancers than the chitooligosaccharides owing to their ability to reverse the cytokine changes induced by CPA. Overall, it was evident that the nanoparticles, most likely, boosted the cell‐mediated immunity through the induction of the Th‐1 branch of the immune response.     

Plasma levels of mannan‐binding lectin (MBL)‐associated serine proteases (MASPs) and MBL‐associated protein in cardio‐ and cerebrovascular diseases

Growing evidence suggests a prominent role of the complement system in the pathogenesis of cardio‐ and cerebrovascular diseases (CVD). Mannan‐binding lectin‐associated serine proteases (MASPs) MASP‐1 and MASP‐2 of the complement lectin pathway contribute to clot formation and may represent an important link between inflammation and thrombosis. MBL‐associated protein MAp44 has shown cardioprotective effects in murine models. However, MAp44 has never been measured in patients with CVD and data on MASP levels in CVD are scarce. Our aim was to investigate for the first time plasma levels of MAp44 and MASP‐1, ‐2, ‐3 concomitantly in patients with CVD. We performed a pilot study in 50 healthy volunteers, in stable coronary artery disease (CAD) patients with one‐vessel (n = 51) or three‐vessel disease (n = 53) and age‐matched controls with normal coronary arteries (n = 53), 49 patients after myocardial infarction (MI) and 66 patients with acute ischaemic stroke. We measured MAp44 and MASP‐1 levels by in‐house time‐resolved immunofluorometric assays. MASP‐2 and MASP‐3 levels were measured using commercial enzyme‐linked immunosorbent assay kits. MASP‐1 levels were highest in subacute MI patients and lowest in acute stroke patients. MASP‐2 levels were lower in MI and stroke patients compared with controls and CAD patients. MASP‐3 and MAp44 levels did not differ between groups. MASP or MAp44 levels were not associated with severity of disease. MASP and MAp44 levels were associated with cardiovascular risk factors including dyslipidaemia, obesity and hypertension. Our results suggest that MASP levels may be altered in vascular diseases. Larger studies are needed to confirm our results and elucidate the underlying mechanisms.     

Antiviral therapy of symptomatic HCV‐associated mixed cryoglobulinemia: Meta‐analysis of clinical studies

Hepatitis C virus (HCV) infection may be associated with extra‐hepatic illness including mixed cryoglobulinemia. Evidence on HCV‐related mixed cryoglobulinemia in the non‐transplantation setting exists even if its appropriate management remains unclear. The cornerstone of treatment for symptomatic HCV‐associated mixed cryoglobulinemia is antiviral therapy but little is known about its activity. A systematic review of the literature with a meta‐analysis of clinical studies was performed in order to assess efficacy and safety of combination antiviral therapy for symptomatic HCV‐associated mixed cryoglobulinemia in non‐immunosuppressed individuals. The random effects model of DerSimonian and Laird was used, with heterogeneity and sensitivity analyses. The primary outcome was sustained virological response (as a measure of efficacy), and the secondary outcome was the rate of patients stopping (or dose reducing) antiviral agents (as a measure of tolerability). Ten clinical studies (300 unique patients) were identified; the rate of baseline kidney involvement ranged between 4% and 39%. The summary estimate of frequency of sustained viral response was 0.42 with a 95% confidence interval (CI) of 0.31; 0.54 (random effects model). Significant heterogeneity occurred (P = 0.00001; I² = 77.6%). Stratified analysis showed higher efficacy in those studies using combination therapy with pegylated—than conventional IFN; the summary estimate of sustained viral response being 0.52 (95% CI, 0.40; 0.63) and 0.32 (95% CI, 0.15; 0.49), respectively. There was good association between viral and clinical response, weighted K 0.634 (95% CI, 0.455; 0.814), by a meta‐analysis at individual level on a subset of reports (n = 3; 74 unique patients). The summary estimate of frequency of patients stopping (or dose reducing) antiviral agents was 0.15 (95% CI, 0.08; 0.21); no heterogeneity occurred (P = 0.05; I² = 51%). In summary, combination antiviral therapy (pegylated IFN plus ribavirin) gives satisfactory response in more than the half of patients with symptomatic mixed cryoglobulinemia associated with HCV. HCV‐related mixed cryoglobulinemia is uncommon in developed countries and this clearly hampers randomized controlled clinical trials aimed to evaluate efficacy and safety of antiviral therapy in non‐immunosuppressed individuals. J. Med. Virol. 85: 1019–1027, 2013. © 2013 Wiley Periodicals, Inc.