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ID PMID Title PublicationDate abstract
30948793 IL-10-producing regulatory B cells restrain the T follicular helper cell response in prima 2019 Dec Increased numbers of T follicular helper (Tfh) cells have been implicated in the development of autoimmune diseases including primary Sjögren's syndrome (pSS), but how the Tfh cell response is regulated during autoimmune pathogenesis remains largely unclear. Here, we first found negative correlations between IL-10(+) regulatory B (Breg) cell numbers and Tfh cell responses and disease activity in patients with pSS and mice with experimental Sjögren's syndrome (ESS). Moreover, we detected high expression of IL-10 receptor on Tfh cells and their precursors in both humans and mice. In culture, IL-10 suppressed human and murine Tfh cell differentiation by promoting STAT5 phosphorylation. By using an adoptive transfer approach and two-photon live imaging, we found significantly increased numbers of Tfh cells with enhanced T cell homing into B cell follicles in the draining cervical lymph nodes of RAG-2-/- mice transferred with IL-10-deficient B cells during ESS development compared with those of RAG-2-/- mice transferred with wild-type B cells. In ESS mice, CD19(+)CD1d(hi)CD5(+) Breg cells with decreased IL-10 production exhibited severely impaired suppressive effects on T cell proliferation. Consistently, CD19(+)CD24(+)CD38(hi) Breg cells from pSS patients showed significantly reduced IL-10 production with defective inhibitory function in the suppression of autologous Tfh cell expansion. Furthermore, the adoptive transfer of IL-10-producing Breg cells markedly suppressed the Tfh cell response and ameliorated ESS progression in ESS mice. Together, these findings demonstrate a critical role for IL-10-producing Breg cells in restraining the effector Tfh cell response during pSS development.
30975774 Breast MALT lymphoma and AL amyloidosis complicating Sjögren's syndrome. 2019 Apr 11 Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) lymphomas of the breast with mammary amyloidosis are exceedingly rare entities. This report describes the case of women with long-standing Sjögren's syndrome presenting with breast MALT lymphoma and amyloïd light-chain (AL) amyloidosis. Breast microcalcification needle biopsy made the positive diagnosis. This unusual finding should be kept in mind. It emphasises the need for careful clinical examination of nodes and extranodal organs supposedly affected in patients with autoimmune disease.
30766889 Association between B Cell Growth Factors and Primary Sjögren's Syndrome-Related Autoanti 2019 Despite the overall success of using R-CHOP for the care for non-Hodgkin's lymphoma patients, it is clear that the disease is quite complex and new insight is needed to further stratify the patient for a better personized treatment. In current study, based on previous studies from animal model, new panels combining well-established cytokine (BAFF) and autoantibodies (anti-SSA/Ro) with newly identified cytokine (IL14) and autoantibodies (TSA) were used to evaluate the association between B cell growth factor and Sjögren's related autoantibodies in NHL patients. The result clearly indicates that there was a unique difference between BAFF and IL14 in association with autoantibodies. While serum BAFF was negatively associated with the presence of both traditional anti-SSA/Ro and novel TSA antibodies in GI lymphoma patient, IL14 was positively associated with the presence of both traditional anti-SSA/Ro and novel TSA antibodies in non-GI lymphoma patient. Long-term follow-ups on these patients and evaluation of their response to the R-CHOP treatment and recurrence rate will be very interesting. Our result provides a solid evidence to support using novel diagnostic panel to better stratify the NHL patients.
30446998 Activation of Toll-like receptor 7 signaling in labial salivary glands of primary Sjögren 2019 Apr The aim of this study was to determine the expressions of Toll-like receptors (TLRs) 7-9 and type I interferon (IFN) signal in labial salivary glands (LSGs) and cultured salivary gland epithelial cells (SGECs) from primary Sjögren's syndrome (pSS) patients. We performed an immunohistochemistry analysis of LSGs from 11 patients with pSS as defined by American-European Consensus Group classification criteria and five healthy subjects. The pSS patients' SGECs were analyzed by immunofluorescence and western blotting. IFN-α expression was examined by immunosorbent assay and flow cytometry. Mononuclear cells (MNCs) from pSS patients' LSGs showed TLR-7-dominant expression. B cells, plasma cells and plasmacytoid dendritic cells (pDCs) co-expressed with TLR-7. Myeloid differentiation primary response gene 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6) and interferon regulatory factor 7 (IRF7) co-expressed with the pDC marker CD303 in LSGs. Ducts from pSS patients dominantly expressed TLR-7, and TLR-7 in the ducts co-expressed with MyD88, TRAF6 and IRF7. Type I IFNs including IFN-α and IFN-β were detected in MNCs and ducts in pSS patients' LSGs. Increased TRAF6 expression and the nuclear translocation of IRF7 in SGECs were detected by immunofluorescence following loxoribine (a TLR-7 ligand) stimulation despite IFN-β pretreatment. Western blotting showed increased TRAF6 expression in SGECs following IFN-β and loxoribine stimulation. Although no increase in IFN-α was detected in supernatant from stimulated SGECs, the IFN-α in supernatant from stimulated peripheral blood pDCs from pSS patients was significantly increased. Our findings suggest that TLR-7 is dominantly expressed in both MNCs and ducts with downstream signals for type I IFNs, indicating that TLR7-dominant innate immunity is related to the development of sialadenitis in pSS.
30408204 Histopathological diagnosis of persistent pruritic eruptions associated with adult-onset S 2019 Apr AIMS: Persistent pruritic eruptions (PPEs), presenting with dyskeratotic keratinocytes histologically, are characteristic skin rash in patients with adult-onset Still's disease (AOSD). The lesions may be histologically similar to other entities that present with dyskeratosis. In the present study, we compared the histopathological features between PPEs and other entities presenting with dyskeratosis. METHODS AND RESULTS: To investigate whether histopathological findings can be used to discriminate among PPEs and other entities presenting with dyskeratotic keratinocytes, cutaneous histopathological changes of PPEs associated with AOSD (n = 26) were compared with those of systemic lupus erythematosus (SLE) (n = 16), dermatomyositis (n = 19), and drug eruption (n = 16). Dyskeratosis was observed in the upper one-third of the epidermal layer in all 26 PPEs. The rate of dyskeratosis for PPEs was higher than that for SLE (18.8%) and dermatomyositis (15.8%). In drug eruptions, the dyskeratotic cells were distributed in all levels of the epidermis. Variable densities of neutrophils were found in the dermis in all PPEs. CONCLUSIONS: Although this was a retrospective study conducted at a single centre, presentation of dyskeratotic keratinocytes in the upper one-third of the epidermal layer is a distinctive histopathological reactive pattern of PPEs. This pattern may be a useful histopathological marker for early diagnosis of AOSD.
31855154 Intravenous ferric carboxymaltose is effective and safe in patients with inflammatory rheu 2020 May BACKGROUND: The aim of this study was to evaluate the efficacy and safety of ferric carboxymaltose in rheumatic patients with iron deficiency anaemia. MATERIALS AND METHODS: The study retrospectively evaluated a cohort of 34 patients with iron deficiency anaemia affected by inflammatory rheumatic diseases that are refractory or intolerant to oral iron therapy. They were treated with ferric carboxymaltose for a total of 56 cycles of treatment. The primary end point was to evaluate the increase of haemoglobin after ferric carboxymaltose treatment. The secondary end point was safety, including the occurrence of disease flare. RESULTS: Median age of the cohort was 60 years (range 31-91 years), with a male/female ratio of 4/30. Nine (26.5%) were affected by rheumatoid arthritis, 10 (29.4%) by spondyloarthritis, and 15 (44.1%) by other autoimmune connective tissue diseases. Median time from diagnosis was 7 years (IQR 2-12). At time of treatment (T(0)), median haemoglobin was 9.3 g/dL (IQR 8.2-10.3), transferrin saturation 6.2% (IQR 3.8-9.8), and ferritin 8.5 ng/mL (IQR 6.0-12.8). Median ferric carboxymaltose dose was 1,000 mg. At 6 weeks from T(0), median haemoglobin was 12.3 g/dL (IQR 11.6-13.3), with a mean increase of 3.0 g/dL (p<0.01). Twelve (35.3%) patients needed re-treatment with ferric carboxymaltose for recurrence of iron deficiency anaemia. Four (4.3%) patients developed mild grade side effects. One suspected flare reaction has been observed. DISCUSSION: In patients affected by inflammatory rheumatic diseases, ferric carboxymaltose is safe and effective in correcting iron deficiency anaemia.
31842396 NF-κB Signaling Regulates Physiological and Pathological Chondrogenesis. 2019 Dec 12 The nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of genes that control cell proliferation and apoptosis, as well as genes that respond to inflammation and immune responses. There are two means of NF-κB activation: the classical pathway, which involves the degradation of the inhibitor of κBα (IκBα), and the alternative pathway, which involves the NF-κB-inducing kinase (NIK, also known as MAP3K14). The mouse growth plate consists of the resting zone, proliferative zone, prehypertrophic zone, and hypertrophic zone. The p65 (RelA), which plays a central role in the classical pathway, is expressed throughout the cartilage layer, from the resting zone to the hypertrophic zone. Inhibiting the classical NF-κB signaling pathway blocks growth hormone (GH) or insulin-like growth factor (IGF-1) signaling, suppresses cell proliferation, and suppresses bone morphogenetic protein 2 (BMP2) expression, thereby promoting apoptosis. Since the production of autoantibodies and inflammatory cytokines, such as tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6, and IL-17, are regulated by the classical pathways and are increased in rheumatoid arthritis (RA), NF-κB inhibitors are used to suppress inflammation and joint destruction in RA models. In osteoarthritis (OA) models, the strength of NF-κB-activation is found to regulate the facilitation or suppression of OA. On the other hand, RelB is involved in the alternative pathway, and is expressed in the periarticular zone during the embryonic period of development. The alternative pathway is involved in the generation of chondrocytes in the proliferative zone during physiological conditions, and in the development of RA and OA during pathological conditions. Thus, NF-κB is an important molecule that controls normal development and the pathological destruction of cartilage.
31819415 The In Vitro Immunomodulatory Effects Of Gold Nanoparticles Synthesized From Hypoxis hemer 2019 BACKGROUND: Macrophages and Natural Killer (NK) cells are an integral part of the innate immune system. These cells produce pro-inflammatory cytokines in response to bacterial infections. However, prolonged inflammation can be a contributing factor in the etiology of several diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis and eczema. Reducing the secretion of pro-inflammatory cytokines is an effective treatment strategy for these conditions. Gold nanoparticles (AuNPs) have been shown to have immunosuppressive effects. Extracts of the Hypoxis hemerocallidea plant have also been shown to have immunomodulatory effects. It has been demonstrated previously that extracts of the H. hemerocallidea can be used to synthesize AuNPs. PURPOSE: This study aimed to investigate whether AuNPs synthesized using H. hemerocallidea extract and its major secondary metabolite, hypoxoside, have any immunomodulatory effects in macrophages and NK cells. METHODOLOGY: AuNPs derived from the H. hemerocallidea extract were synthesized as previously described. Using similar methodologies, this study shows for the first time the synthesis of AuNPs from hypoxoside. The AuNPs were characterized using several optical and spectroscopic techniques. The immunomodulatory effects of the aqueous extract of H. hemerocallidea, hypoxoside, as well as the AuNPs produced from the extract and hypoxoside, were investigated by measuring the cytokine levels in macrophages (IL-1β, IL-6 and TNF-α) and NK cells (IFN-γ) using solid phase sandwich ELISA technique. RESULTS: The results show that spherical AuNPs (average size 26 ± 2 nm) were synthesized from hypoxoside. The results also show that the four treatments (H. hemerocallidea extract, hypoxoside and their respective AuNPs can lower the pro-inflammatory cytokine levels in the macrophages cells, while only AuNPs produced from hypoxoside can reduce cytokine responses in NK cells. CONCLUSION: This study shows that all four treatments investigated here could be further explored for the development of anti-inflammatory therapies.
31762210 Peripheral neuropathies in rheumatic diseases: More diverse and frequent than expected. A 2020 Feb BACKGROUND/OBJECTIVE: Peripheral neuropathies (PN) are heterogeneous nerve disorders; frequently rheumatic patients have neuropathic symptoms. In some rheumatic diseases (RD) PN are secondary to nerve compression while others are related to metabolic abnormalities, inflammation or vasculitis. Our aim was to explore the frequency of neuropathic symptoms with three neuropathy questionnaires (NQ) and nerve conduction studies (NCS) in RD. METHODS: This is a cross-sectional study in patients with any RD attending for the first time to a rheumatology outpatient clinic. We included all patients who accepted to participate and who answered three NQ and received a physical evaluation. Twenty patients were randomly selected to perform NCS and 10 healthy subjects were included as controls. The topographic diagnoses were: mononeuropathy, multiplex mononeuropathy, and/or polyneuropathy. STATISTICAL ANALYSIS: descriptive statistics (mean, median, standard deviation, interquartile range and frequency, odds ratios and Pearson correlation test). RESULTS: One hundred patients and 10 healthy subjects were included. Sixty-nine were female, mean age 40.6 ± 15.7 years. Rheumatic diagnoses were: systemic lupus erythematosus (26%), rheumatoid arthritis (16%), gout (14%), and osteoarthritis (11%). Fifty-two patients had neuropathic signs during physical examination and 67% had positive questionnaires with variable scores among several RD. Abnormal NCS was reported in 14 patients (70%): 6 (42.8%) median nerve mononeuropathies, 4 (28.5%) multiplex mononeuropathies and 4 (28.5%) polyneuropathies. None of the healthy subjects had neuropathy (NQ, physical evaluation, or NCS). Risk of being NCS positive is higher when the patients were NQ positive. CONCLUSION: PN has variable distribution and high frequency in patients with RD; NQ+ increases the risk of presenting NCS+ for PN.
31755098 CD28 and CD57 define four populations with distinct phenotypic properties within human CD8 2020 Mar After repeated antigen exposure, both memory and terminally differentiated cells can be generated within CD8(+) T cells. Although, during their differentiation, activated CD8(+) T cells may first lose CD28, and CD28(-) cells may eventually express CD57 as a subsequent step, a population of CD28(+) CD57(+) (DP) CD8(+) T cells can be identified in the peripheral blood. How this population is distinct from CD28(-) CD57(-) (DN) CD8(+) T cells, and from the better characterized non-activated/early-activated CD28(+) CD57(-) and senescent-like CD28(-) CD57(+) CD8(+) T cell subsets is currently unknown. Here, RNA expression of the four CD8(+) T cell subsets isolated from human PBMCs was analyzed using microarrays. DN cells were more similar to "early" highly differentiated cells, with decreased TNF and IFN-γ production, impaired DNA damage response and apoptosis. Conversely, increased apoptosis and expression of cytokines, co-inhibitory, and chemokine receptors were found in DP cells. Higher levels of DP CD8(+) T cells were observed 7 days after Hepatitis B vaccination, and decreased levels of DP cells were found in rheumatoid arthritis patients. More DP and DN CD8(+) T cells were present in the bone marrow, in comparison with PBMCs. In summary, our results indicate that DP and DN cells are distinct CD8(+) T cell subsets displaying defined properties.
31718644 Debridement, antibiotics, and implant retention for periprosthetic knee infections: a pool 2019 Nov 12 BACKGROUND: The debridement, antibiotics, and implant retention (DAIR) procedure is an established therapeutic option for periprosthetic knee infections (PKI). However, the efficacy and the indication for this procedure are still controversial. METHODS: All the relevant literatures were systematically reviewed and analyzed. The present study aimed to assess the success rate of DAIR in the management of PKI, identify the factors associated with prognosis of DAIR, and establish a simple algorithm for predicting a high success rate of DAIR. RESULTS: Totally, 33 studies with 1266 cases were included. The overall success rate following DAIR in the management of PKI was 57.11%. In the subgroup analyses, the factors of "the time from symptoms to debridement was < 3 weeks" and "the bacterial species other than methicillin-resistant Staphylococcus aureus" significantly improved the success rate of DAIR and thus were defined as the major criteria. The statistically insignificant factors of "the open debridement and liner exchange" and "the comorbidity of rheumatoid arthritis" were set as the minor criteria. The success rate of DAIR for PKI meeting all the major criteria and no less than one minor criterion was 80.98%, which was significantly higher than the overall success rate of DAIR (p < 0.05). CONCLUSION: PKI cases meeting two major criteria and no less than one minor criterion may confer a high success rate of DAIR. This simple algorithm may contribute to identifying the appropriate PKI patient for DAIR treatment and predicting the prognosis of DAIR.
31712773 Pancreatic nerve electrostimulation inhibits recent-onset autoimmune diabetes. 2019 Dec Vagus nerve stimulation can ameliorate autoimmune diseases such as rheumatoid arthritis by modulation of the immune system. Its efficacy for the treatment of type 1 diabetes has not been explored, in part because the nerves projecting to the pancreatic lymph nodes (pLNs) in mice are unmapped. Here, we map the nerve projecting to the pancreas and pLNs in mice and use a minimally invasive surgical procedure to implant micro-cuff electrodes onto the nerve. Pancreatic nerve electrical stimulation (PNES) resulted in β-adrenergic receptor-mediated-accumulation of B and T cells in pLNs and reduced production of pro-inflammatory cytokines following lipopolysaccharide stimulation. Autoreactive T cells showed reduced proliferation in pLNs of mice receiving PNES as compared to sham controls. In a spontaneous mouse model of autoimmune diabetes, PNES inhibited disease progression in diabetic mice.
31474340 [Takayasu's arteritis and atherosclerosis]. 2019 Sep INTRODUCTION: Chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), are accompanied by high cardiovascular morbidity and mortality secondary to accelerated and premature atherosclerosis. Atherosclerosis is correlated with chronic systemic inflammation independently of the factors for cardiovascular risk. Vasculitis of large arteries such as Takayasu's disease, are characterized both by chronic systemic inflammation and local parietal vascular inflammation. METHODS: We prospectively analyzed in a case-control study, a group of 64 carriers of Takayasu's arteritis patients with a mean age of 41 years [±11.94], a group of 50 RA female patients aged 45 years [±10.27], and a control group with an average age of 44 years [±12.63]. We recorded classic cardiovascular risk factors and used the Framingham equation to calculate the risk. We measured the intima-media thickness (IMT) in the carotids and noted the presence of carotid, aortic and femoral atheroma. RESULTS: The mean calculated cardiovascular risk was 3.5 % in the Takayasu's group. It was 4.4 % in the RA group, and 4.5 % in controls with no significant difference between the three groups (P=0.153). Subclinical atherosclerosis defined by IMT> 0.70mm and/or the presence of atheroma plaque was found in 87 % of Takayasu's patients versus 76 % of RA patients, (P=0.088) and 48 % of controls (P<0.001). Most atherosclerotic plaques were found in the Takayasu group. Compared to the control group the carotid intima-media thickness was significantly higher in the Takayasu group. The average IMT in the Takayasu group was 0.91mm [±0.368], 0.76mm [±0.151] for the PR group, and 0.71mm [±0.141] for controls. DISCUSSION: Atherosclerosis observed in Takayasu's disease was accelerated and premature, occurring in young patients with a low overall cardiovascular risk. Recent data support the central role of inflammation in all stages of atherogenesis from endothelial dysfunction to plaque rupture. Systemic inflammation associated with local parietal inflammation observed in Takayasu's arteritis, appears to be responsible for accelerated and premature atherosclerosis. The results of our study and the literature review favor an active strategy for cardiovascular prevention in Takayasu's disease.
31294625 Anticytokine Immune Therapy and Atherothrombotic Cardiovascular Risk. 2019 Aug Accumulating observations in humans and animals indicate that inflammation plays a key role in atherosclerosis development and subsequent complications. Moreover, the use of loss- or gain-of-function genetically modified, atherosclerosis-prone mice has provided strong experimental evidence for a causal role of innate and adaptive immunity in atherosclerosis and has revealed the pathogenic activity of proinflammatory cytokines, including TNF (tumor necrosis factor)-α, IL (interleukin)-1β, IL-6, and IL-18, and the atheroprotective effect of anti-inflammatory cytokines, including IL-10 and TGF-β. For the past 15 years, treatments using monoclonal antibodies specifically targeting cytokines, commonly referred as biological therapies, have transformed the treatment of chronic inflammatory diseases, such as rheumatoid arthritis or psoriasis, both conditions associated with increased cardiovascular risk. Analyzing the impact of anticytokine therapies on the cardiovascular outcomes of patients with chronic inflammatory diseases provides insight into the clinical relevance of experimental data on the role of inflammation in atherothrombotic cardiovascular diseases. CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) provided the first evidence that targeting inflammation in humans with atherosclerosis could improve clinical outcomes. Treatment with the anti-IL-1β antibody canakinumab significantly reduced recurrent cardiovascular events in individuals with stable coronary artery disease well-treated with standard-of-care measures. Other clinical studies support the protective effects of treatment with anti-TNF-α and anti-IL-6 receptor monoclonal antibodies on cardiovascular risk. Blockade of the IL-23/IL-17 axis, however, warrants caution as a cardiovascular intervention. Targeting this pathway has improved psoriasis but may augment cardiovascular risk in certain patients. Thus, careful consideration of the cardiovascular risk profile may influence the choice of the most appropriate treatment for patients with chronic inflammatory diseases.Visual Overview: An online visual overview is available for this article.
31279231 Intractable axonal neuropathy with multifocal peripheral nerve swelling in neuromyelitis o 2019 Oct We report a patient with neuromyelitis optica spectrum disorders (NMOSD) with anti-aquaporin 4 (AQP4) antibodies, who developed intractable axonal neuropathy presenting with multifocal peripheral nerve swelling by magnetic resonance (MR) neurography. A 52-year-old woman with a 12-year history of polymyositis and rheumatoid arthritis had been treated with prednisolone, tacrolimus, and abatacept (CTLA-4-Ig). She developed progressive numbness and tingling sensations in the distal parts of all limbs at the age of 50 years, followed by weakness of both upper limbs 6 months later. Neurological examination revealed severe muscle weakness and atrophy of the right upper limb with proximal dominance, diffuse moderate weakness of the left upper limb, severe sensory impairment of all modalities of four limbs in glove and stocking distribution, wide-based gait with positive Romberg's sign, and absence of all tendon reflexes. She was diagnosed with NMOSD due to positive serum anti-AQP4 antibodies and a longitudinally extensive cervical spinal cord lesion on MR images. Intravenous methylprednisolone pulse therapy, plasma exchange and intravenous immunoglobulin administration were performed, which improved the spinal cord lesion on MRI, but did not ameliorate her symptoms. Notably, she also had axonal neuropathy characterized by asymmetrical, multifocal swelling of peripheral nerves by MR neurography. Histopathological examination of the biopsied sural nerve revealed axonal degeneration and endoneurial edema but no inflammatory cell infiltration. Although she was treated with intravenous methylprednisolone, intravenous immunoglobulin, oral prednisolone, tacrolimus and tocilizumab, her symptoms gradually progressed. Neurologists should be aware of co-existing intractable axonal neuropathy in NMOSD cases presenting as immunotherapy-resistant sensorimotor disturbances.
31238924 Case report: Anaerobiospirillum prosthetic joint infection in a heart transplant recipient 2019 Jun 26 BACKGROUND: We report a case of prosthetic hip joint infection in a heart transplant recipient due to Anaerobiospirillum succiniciproducens, a genus of spiral-shaped curved anaerobic gram-negative rod which colonizes the gastrointestinal tract of cats and dogs. Invasive infections in humans are rare and typically occur in immunocompromised hosts. CASE PRESENTATION: A 65-year-old male dog breeder with a history of rheumatoid arthritis, bilateral hip arthroplasties, and non-ischemic cardiomyopathy with a heart transplant 10 years ago presented with a three month history of progressive left hip pain and frank purulence on hip aspiration. He underwent irrigation and debridement of the left hip and one-stage revision with hardware exchange. Although gram stain and culture from synovial fluid and intraoperative cultures were initially negative, anaerobic cultures from tissue specimens later grew a spiral-shaped gram-negative rod, identified as Anaerobiospirillum spp. by 16S rRNA gene sequencing. The patient was treated with ceftriaxone 2 g daily for 6 weeks with a good response to treatment. A similar organism was unable to be isolated from culture of 2 of the patient's dogs, however, they were thought to be the most likely source of his infection. CONCLUSION: Anaerobiospirillum spp. should be considered in immunocompromised patients with exposure to dogs or cats who present with bacteremia, gastrointestinal infection, pyomyositis, or prosthetic joint infections, especially in cases of culture-negative or with anaerobic culture growth.
31082193 PF-06651600, a Dual JAK3/TEC Family Kinase Inhibitor. 2019 Jun 21 PF-06651600 was developed as an irreversible inhibitor of JAK3 with selectivity over the other three JAK isoforms. A high level of selectivity toward JAK3 is achieved by the covalent interaction of PF-06651600 with a unique cysteine residue (Cys-909) in the catalytic domain of JAK3, which is replaced by a serine residue in the other JAK isoforms. Importantly, 10 other kinases in the kinome have a cysteine at the equivalent position of Cys-909 in JAK3. Five of those kinases belong to the TEC kinase family including BTK, BMX, ITK, RLK, and TEC and are also inhibited by PF-06651600. Preclinical data demonstrate that inhibition of the cytolytic function of CD8(+) T cells and NK cells by PF-06651600 is driven by the inhibition of TEC kinases. On the basis of the underlying pathophysiology of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, alopecia areata, and vitiligo, the dual activity of PF-06651600 toward JAK3 and the TEC kinase family may provide a beneficial inhibitory profile for therapeutic intervention.
31069134 T cell repertoire to citrullinated self-peptides in healthy humans is not confined to the 2019 Post-translational modifications are induced in stressed cells which cause them to be recognised by the system. One such modification is citrullination where the positive charged arginine is modified to a neutral citrulline. We demonstrate most healthy donors show an oligoclonal CD4 response in vitro to at least one citrullinated vimentin or enolase peptide. Unlike rheumatoid arthritis patients, these T cell responses were not restricted by HLA-DRB1 shared epitope (SE) alleles, suggesting they could be presented by other MHC class II alleles. As HLA-DP is less polymorphic than HLA-DR, we investigated whether the common allele, HLA-DP4 could present citrullinated epitopes. The modification of arginine to citrulline enhanced binding of the peptides to HLA-DP4 and induced high-frequency CD4 responses in HLA-DP4 transgenic mouse models. Our previous studies have shown that tumours present citrullinated peptides restricted through HLA-DR4 which are good targets for anti-tumour immunity. In this study, we show that citrullinated vimentin and enolase peptides also induced strong anti-tumour immunity (100% survival, p < 0.0001) against established B16 tumours and against the LLC/2 lung cancer model (p = 0.034) both expressing HLA-DP4. Since most tumours do not constitutively express MHC class II molecules, models were engineered that expressed MHC class II under the control of an IFNγ inducible promoter. Immunisation with citrullinated peptides resulted in 90% survival (p < 0.001) against established B16 HHD tumour expressing IFNγ inducible DP4. These studies show that citrullinated peptides can be presented by a range of MHC class II molecules, including for the first time HLA-DP4, and are strong targets for anti-tumour immunity.
30990720 Mapping Citrullinated Sites in Multiple Organs of Mice Using Hypercitrullinated Library. 2019 May 3 Protein citrullination (or deimination), an irreversible post-translational modification, has been implicated in several physiological and pathological processes, including gene expression regulation, apoptosis, rheumatoid arthritis, and Alzheimer's disease. Several research studies have been carried out on citrullination under many conditions. However, until now, challenges in sample preparation and data analysis have made it difficult to confidently identify a citrullinated protein and assign the citrullinated site. To overcome these limitations, we generated a mouse hyper-citrullinated spectral library and set up coordinates to confidently identify and validate citrullinated sites. Using this workflow, we detect a four-fold increase in citrullinated proteome coverage across six mouse organs compared with the current state-of-the art techniques. Our data reveal that the subcellular distribution of citrullinated proteins is tissue-type-dependent and that citrullinated targets are involved in fundamental physiological processes, including the metabolic process. These data represent the first report of a hyper-citrullinated library for the mouse and serve as a central resource for exploring the role of citrullination in this organism.
30498997 The inflammatory function of human IgA. 2019 Mar The prevailing concept regarding the immunological function of immunoglobulin A (IgA) is that it binds to and neutralizes pathogens to prevent infection at mucosal sites of the body. However, recently, it has become clear that in humans IgA is also able to actively contribute to the initiation of inflammation, both at mucosal and non-mucosal sites. This additional function of IgA is initiated by the formation of immune complexes, which trigger Fc alpha Receptor I (FcαRI) to synergize with various other receptors to amplify inflammatory responses. Recent findings have demonstrated that co-stimulation of FcαRI strongly affects pro-inflammatory cytokine production by various myeloid cells, including different dendritic cell subsets, macrophages, monocytes, and Kupffer cells. FcαRI-induced inflammation plays a crucial role in orchestrating human host defense against pathogens, as well as the generation of tissue-specific immunity. In addition, FcαRI-induced inflammation is suggested to be involved in the pathogenesis of various chronic inflammatory disorders, including inflammatory bowel disease, celiac disease, and rheumatoid arthritis. Combined, IgA-induced inflammation may be used to either promote inflammatory responses, e.g. in the context of cancer therapy, but may also provide new therapeutic targets to counteract chronic inflammation in the context of various chronic inflammatory disorders.