Severe Inflammatory Symptoms Research Articles

Modulatory L-Alliin Effect on Acute Inflammatory Cytokines in Diet-Induced Obesity Mice

Background/Objectives: The inflammatory response has evolved as a protective mechanism against pathogens and tissue damage. However, chronic inflammation can occur, potentially leading to severe disease. Low-grade chronic inflammation is associated with obesity, and the Th1 cytokine profile plays an important role in this proinflammatory environment. Diet-induced obesity (DIO) can lead to persistent dysbiosis and maintain high concentrations of circulating lipopolysaccharides (LPSs) over prolonged periods of time, resulting in metabolic endotoxemia. In this context, the study of natural immunomodulators has recently increased. Objective: The aim of this study is improve scientific evidence for the immunomodulatory role of L-Alliin in obesity and inflammation. Methods: In the present work, we describe the effect of L-Alliin on serum levels of cytokines in DIO mice after an acute inflammatory challenge. L-Alliin is the main organosulfurized molecule of garlic that has been studied for its numerous beneficial physiological effects in health and disease and is beginning to be considered a nutraceutical. Two situations are simulated in this experimental model, health and chronic, low-grade inflammation that occurs in obesity, both of which are confronted with an acute, inflammation-inducing challenge. Results: Based on our findings, L-Alliin seems to somehow stimulate the cellular chemotaxis by eliciting the release of key molecules, including IL-2, IFN-γ, TNF-α, MCP-1, IL-6, IL-9, and G-CSF. However, the molecular mechanism involved remains unknown. This, in turn, mitigates the risk of severe inflammatory symptoms by preventing the release of IL-1β and its downstream molecules such as IL-1α, GM-CSF, and RANTES. Conclusions: Taken together, these results indicate that L-Alliin can boost immunity in healthy organisms and act as an immunomodulator in low-grade inflammation.

Vexas Syndrome: A Newly Discovered Hemato Inflammatory Disease

VEXAS syndrome is a recently described hemato inflammatory disease. It is an acronym from the syndrome’s key characteristics: vacuoles in bone marrow biopsies, low levels of ubiquitin activating enzyme (E1 enzyme), X-linked, autoinflammatory, somatic. It results from a somatically acquired mutation affecting methionine 41 of the E1-ubiquitin ligase UBA1, leading to the expression of a catalytically impaired isoform that drives inflammation. As this gene is located on the X chromosome, only men appear to be affected by this syndrome. Patients have severe inflammatory symptoms that affect multiple organs. Clinical features bridge rheumatological, dermatological, ophthalmological, respiratory, and hematological conditions. There is an association between severe autoinflammatory manifestations and myeloid dysplasia.

Abstract PL02-04: Malignancies in People with HIV: Successes and Challenges at the Intersection of Virology, Immunology, and Oncology

Abstract PL02-04: Malignancies in People with HIV: Successes and Challenges at the Intersection of Virology, Immunology, and Oncology

The Combination of Phages and Faecal Microbiota Transplantation Can Effectively Treat Mouse Colitis Caused by Salmonella enterica Serovar Typhimurium.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is one of the common causes of human colitis. In the present study, two lytic phages vB_SenS-EnJE1 and vB_SenS-EnJE6 were isolated and the therapeutic effect of the combination of phages and faecal microbiota transplantation (FMT) on S. Typhimurium-induced mouse colitis was investigated. The characteristics and genome analysis indicated that they are suitable phages for phage therapy. Results showed that vB_SenS-EnJE1 lysis 41/54 Salmonella strains of serotype O4, and vB_SenS-EnJE6 lysis 46/54 Salmonella strains of serotypes O4 and O9. Severe inflammatory symptoms and disruption of the intestinal barrier were observed in S. Typhimurium -induced colitis. Interestingly, compared with a single phage cocktail (Pc) or single FMT, the combination of Pc and FMT (PcFMT) completely removed S. Typhimurium after 72 h of treatment, and significantly improved pathological damage and restored the intestinal barrier. Furthermore, PcFMT effectively restored the intestinal microbial diversity, especially for Firmicutes/Bacteroidetes [predominantly bacterial phyla responsible for the production of short-chain fatty acids (SCFA)]. Additionally, we found that PcFMT treatment significantly increased the levels of SCFA. All these data indicated that the combination of phages and FMT possesses excellent therapeutic effects on S. Typhimurium -induced intestinal microbiota disorder diseases. Pc and FMT played roles in “eliminating pathogens” and “strengthening vital qi,” respectively. This study provides a new idea for the treatment of intestinal microbiota disorder diseases caused by specific bacterial infections.

Perioperative Management and Long-Term Outcomes in Ocular Cicatricial Pemphigoid Patients Undergoing Cataract Surgery.

Objective To observe the outcomes of cataract surgery in ocular cicatricial pemphigoid (OCP) patients and explore routine perioperative medical treatments. Design Retrospective case series. Methods Fourteen eyes of 8 patients were included in the study. Foster's stage 1-4 OCP patients were given human intravenous immunoglobulin, whereas patients with active inflammation were treated with prednisone tablets and methotrexate. Those who were intolerant to methotrexate and had severe inflammatory symptoms were treated with cyclophosphamide. Cataract surgery was performed for all patients after three months of systemic treatment under stable conditions. The conjunctival biopsy was evaluated by immunofluorescence microscopy. Then, patients were divided into individuals with or without ankyloblepharon. Records were reviewed for OCP stage, type of surgery, best-corrected visual acuity (BCVA), Schirmer I test, corneal fluorescein sodium staining, meibomian gland coloboma range, and ocular surface disease index (OSDI) scores. Follow-up was for the duration of taking topical and systemic medication. Results Nine female (64.29%) and 4 male (35.71%) eyes were diagnosed with OCP by biopsy. The mean follow-up time was 60.64 ± 35.62 months. Thirteen eyes (92.86%) of 7 patients underwent phacoemulsification. One eye underwent phacoemulsification combined with amniotic membrane transplantation. The intracapsular extraction of cataract was applied to one eye. The BCVA improved significantly in all the patients, which remained stable until the last follow-up. The Schirmer I test was higher than that before the surgery. Corneal fluorescein sodium staining after surgery showed a decrease in score compared to the preoperative score. The BCVA of the patients after surgery increased significantly. The OSDI scores of patients with ankyloblepharon were significantly higher than for those without it. Postoperative symblepharon showed no significant difference compared to the preoperative symblepharon. Conclusions In this series, OCP patients with cataracts were able to undergo phacoemulsification surgery, whereas routine use of immunosuppression and closed postoperative follow-up were necessary.

C-Reactive Protein Knockout Attenuates Temporomandibular Joint Inflammation in Rats.

Background C-reactive protein (CRP), a biomarker of inflammation, is highly expressed in osteoarthritis- (OA-) related diseases, but its exact role remains unknown. In this study, we evaluated the biological effect of CRP on temporomandibular joint (TMJ) inflammation. Methods Freund's complete adjuvant (CFA) was used to induce TMJ inflammation in CRP-knockout (CRP-/-) and control rats. Degenerative changes in the TMJ were compared to elucidate the role of CRP in TMJ inflammation. In addition, inflammatory cytokines, macrophage activation, and osteoclast differentiation were evaluated by real-time quantitative polymerase chain reaction, immunohistochemistry, and tartrate-resistant phosphatase staining to explore the potential regulatory mechanism. Results Compared to the control, CFA induced TMJ inflammation, which increased systemic and local CRP expression. Furthermore, CRP-/- rats exhibited less severe inflammatory symptoms. The downregulation of proinflammatory cytokines (interleukin- (IL-) 1β and IL-6) and upregulation of the anti-inflammatory cytokine IL-10 were detected in CRP-/- rats, which also exhibited reduced macrophage activation and osteoclast differentiation. Conclusion These results indicated that controlling the highly elevated levels of CRP during inflammation could modify the cytokine profile, macrophage activation, and osteoclast differentiation, thus, providing beneficial effects for TMJ-OA prevention and treatment.

HMGB1 augments cognitive impairment in sepsis-associated encephalopathy by binding to MD-2 and promoting NLRP3-induced neuroinflammation.

Sepsis-associated encephalopathy (SAE) always manifests with severe inflammatory symptoms and cognitive impairment. High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine. In this study we investigated the role of HMGB1 in SAE. An SAE mouse model was established through cecal ligation and puncture surgery and then injected with adenovirus short hairpin RNA (Ad-sh)-HMGB1 or Ad-sh-myeloid differentiation protein (MD-2). The cognitive impairment and pathological injury in mice of different groups were evaluated using the Morris water maze experiment, Y-maze test, tail suspension test, fear conditioning test, and haematoxylin-eosin staining. The expressions of HMGB1 (fully reduced and disulfide (ds)HMGB1), MD-2, and NLRP3 in SAE mice were determined. Then, levels of inflammatory cytokines were measured. The binding relation between HMGB1 and MD-2 was predicted and certified. Additionally, MD-2 was downregulated to verify the role of the binding of HMGB1 and MD-2 in neuroinflammation and cognitive impairment in SAE. Expressions of HMGB1, MD-2, NLRP3, and inflammatory cytokines were enhanced in the SAE mouse model, which were in parallel with impaired cognitive function. HMGB1 silencing resulted in downregulated NLRP3 expression and alleviated neuroinflammation and cognitive impairment in SAE mice. Mechanically, dsHMGB1 bound to MD-2 to activate NLRP3, thereby exacerbating neuroinflammation and cognitive impairment in SAE mice. The limited binding of HMGB1 and MD-2 downregulated NLRP3 expression to alleviate neuroinflammation and cognitive impairment in SAE mice. HMGB1 was overexpressed in SAE, and dsHMGB1 bound to MD-2 to activate NLRP3 inflammasome, inducing neuroinflammation and cognitive impairment in SAE.

Knock-In Mice Expressing a 15-Lipoxygenating Alox5 Mutant Respond Differently to Experimental Inflammation Than Reported Alox5−/− Mice

Arachidonic acid 5-lipoxygenase (ALOX5) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes. We recently created knock-in mice (Alox5-KI) which express an arachidonic acid 15-lipoxygenating Alox5 mutant instead of the 5-lipoxygenating wildtype enzyme. These mice were leukotriene deficient but exhibited an elevated linoleic acid oxygenase activity. Here we characterized the polyenoic fatty acid metabolism of these mice in more detail and tested the animals in three different experimental inflammation models. In experimental autoimmune encephalomyelitis (EAE), Alox5-KI mice displayed an earlier disease onset and a significantly higher cumulative incidence rate than wildtype controls but the clinical score kinetics were not significantly different. In dextran sodium sulfate-induced colitis (DSS) and in the chronic constriction nerve injury model (CCI), Alox5-KI mice performed like wildtype controls with similar genetic background. These results were somewhat surprising since in previous loss-of-function studies targeting leukotriene biosynthesis (Alox5−/− mice, inhibitor studies), more severe inflammatory symptoms were observed in the EAE model but the degree of inflammation in DSS colitis was attenuated. Taken together, our data indicate that these mutant Alox5-KI mice respond differently in two models of experimental inflammation than Alox5−/− animals tested previously in similar experimental setups.

Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases

Kaposi sarcoma (KS)-associated herpesvirus (KSHV)–associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.

Kawasaki Disease and Multisystem Inflammatory Syndrome in Children with COVID-19.

Since December 2019, the world has been exposed to a novel virus from the coronaviruses family, named coronavirus disease 2019 (COVID-19), which has affected the life of millions people around the world. This global pandemic causes a wide spectrum of clinical manifestation in children, adults, and elderly. One side of the spectrum in children is being asymptomatic and the other side is severe inflammatory symptoms. In this article, we describe the clinical manifestations, genetic background, and immune response of children with COVID-19, who are presented with severe multisystem inflammatory syndrome (MIS).

New Functions of Classical Compounds against Orofacial Inflammatory Lesions.

Anti-inflammatory agents have been widely used to ameliorate severe inflammatory symptoms of a number of diseases, and such therapeutics are particularly useful for diseases with intolerable pain without significant mortality. A typical example of this is a disease known as stomatitis; although stomatitis itself is not a life-threatening disease, it severely impairs the individual’s quality of life, and thus a standard therapeutic strategy for it has already been established. The topical application of a bioactive agent is quite easy, and a strong anti-inflammatory agent can be used without significant adverse effects. In contrast, natural products with relatively mild bioactivity are used for systemic intervention. However, new aspects of classical drugs used in these established therapeutic methods have recently been discovered, which is expanding the utility of these compounds to other oral diseases such as osteoarthritis of temporomandibular joints (TMJ-OA). In this review article, after summarizing the general concept and pathobiology of stomatitis, its established therapeutics are explained. Thereafter, recent advances in the research into related compounds, which is uncovering new biological functions of the agents used therein, are introduced. Indeed, regenerative therapeutics for TMJ-OA may be developed with the classical compounds currently being used.

TNFAIP3-DEPTOR complex regulates inflammasome secretion through autophagy in ankylosing spondylitis monocytes

ABSTRACTAnkylosing spondylitis (AS) is a chronic autoimmune inflammatory disease with severe inflammatory symptoms in the axial skeleton. The cause of ankylosing spondylitis is unknown. TNFAIP3, also named A20, uses ubiquitin-related functions to regulate immune activation, deficiency of which is highly related to autoimmune disease. However, the role of TNFAIP3 in human AS has not been reported. Our objective was to study the role and mechanism of TNFAIP3 in ankylosing spondylitis. TNFAIP3 expression on different types of immunocytes from AS peripheral blood was measured by flow cytometry. In vitro, monocytes were transfected with a TNFAIP3 shRNA lentivirus, and IL6 and IL1B activation was tested using real-time PCR and ELISA. The novel interaction complex TNFAIP3-DEPTOR was determined through GST pull-down, yeast two-hybrid system, confocal microscopy, and co-immunoprecipitation. Transmission electron microscopy, the RFP-GFP-LC3 adenovirus, and LC3 expression were used for autophagy detection. Here, we show that TNFAIP3 expression in AS peripheral blood non-classical monocytes was decreased. In normal monocytes, TNFAIP3 induced autophagy, which restricted inflammasome activation to the early stage of LPS stimulation. Zinc-finger domains of TNFAIP3 were able to interact and stabilize DEPTOR. TNFAIP3 and DEPTOR together rapidly promoted autophagy after LPS treatment to prevent NLRP3 inflammasome formation. Finally, TNFAIP3 and DEPTOR deficiency in AS non-classical monocytes facilitated inflammasome activation. Our study indicates that TNFAIP3-DEPTOR complex-induced early-onset autophagy is vital for immune inhibition in autoimmune disease.

Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interleukin-6 by X-Box Binding Protein 1.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and a subset of multicentric Castleman disease (MCD). The KSHV life cycle has two principal gene repertoires, latent and lytic. KSHV viral interleukin-6 (vIL-6), an analog of human IL-6, is usually lytic; production of vIL-6 by involved plasmablasts is a central feature of KSHV-MCD. vIL-6 also plays a role in PEL and KS. We show that a number of plasmablasts from lymph nodes of patients with KSHV-MCD express vIL-6 but not ORF45, a KSHV lytic gene. We further show that vIL-6 is directly induced by the spliced (active) X-box binding protein-1 (XBP-1s), a transcription factor activated by endoplasmic reticulum (ER) stress and differentiation of B cells in lymph nodes. The promoter region of vIL-6 contains several potential XBP-response elements (XREs), and two of these elements in particular mediate the effect of XBP-1s. Mutation of these elements abrogates the response to XBP-1s but not to the KSHV replication and transcription activator (RTA). Also, XBP-1s binds to the vIL-6 promoter in the region of these XREs. Exposure of PEL cells to a chemical inducer of XBP-1s can induce vIL-6. Patient-derived PEL tumor cells that produce vIL-6 frequently coexpress XBP-1, and immunofluorescence staining of involved KSHV-MCD lymph nodes reveals that most plasmablasts expressing vIL-6 also coexpress XBP-1. These results provide evidence that XBP-1s is a direct activator of KSHV vIL-6 and that this is an important step in the pathogenesis of KSHV-MCD and PEL. Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (KSHV-MCD) is characterized by severe inflammatory symptoms caused by an excess of cytokines, particularly KSHV-encoded viral interleukin-6 (vIL-6) produced by lymph node plasmablasts. vIL-6 is usually a lytic gene. We show that a number of KSHV-MCD lymph node plasmablasts express vIL-6 but do not have full lytic KSHV replication. Differentiating lymph node B cells express spliced (active) X-box binding protein-1 (XBP-1s). We show that XBP-1s binds to the promoter of vIL-6 and can directly induce production of vIL-6 through X-box protein response elements on the vIL-6 promoter region. We further show that chemical inducers of XBP-1s can upregulate production of vIL-6. Finally, we show that most vIL-6-producing plasmablasts from lymph nodes of KSHV-MCD patients coexpress XBP-1s. These results demonstrate that XBP-1s can directly induce vIL-6 and provide evidence that this is a key step in the pathogenesis of KSHV-MCD and other KSHV-induced diseases.

Expression of Blimp-1 in dendritic cells modulates the innate inflammatory response in dextran sodium sulfate-induced colitis.

A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease. Here, we demonstrate that Blimp-1 in CD103(+) dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp-1(cko) mice with a deletion of Blimp-1 in CD103(+) DCs and CD11c(hi) macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103(+) DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages from Blimp-1(cko) mice expressed increased levels of matrix metalloproteinase 8, 9 and 12 mRNA. WT macrophages cocultured with colonic DCs but not bone marrow-derived DCs from Blimp-1(cko) produced increased matrix metalloproteinases in an interleukin (IL)-1β- and IL-6-dependent manner. Treatment of Blimp-1(cko) mice with anti-IL-1β and anti-IL-6 abrogated the exaggerated clinical response. Overall, these data demonstrate that Blimp-1 expression in DCs can alter an innate inflammatory response by modulating the activation of myeloid cells. This is a novel mechanism of contribution of Blimp-1 for the pathogenesis of inflammatory bowel diseases, implicating another therapeutic target for the development of inflammatory bowel disease.

Anti-inflammatory effect of lactobacilli bacteria on HepG2 cells is through cross-regulation of TLR4 and NOD2 signalling

Pathogen peptidoglycans are detected via host’s innate immune system. This course of action is executed by nucleotide-binding oligomerization domain (NOD) proteins, which have been identified inducing inflammation through nuclear factor-kappa B (NF-κB). Excessive stimulation of liver cells by endotoxin leds to severe inflammatory symptoms. In this research, seven strains of lactobacilli bacteria were prior processed into crude cell wall extracts, followed by testing if crude cell wall extracts could lessen pro-inflammatory processes launched by lipopolysaccharides. The results showed lactobacilli bacteria activated NOD2 expression in mild degrees, and did not lead to serious inflammation. Prior exposure of HepG2 cells to lactobacilli bacteria rendered them desensitized to subsequent LPS challenge. The mechanism by which lactobacilli bacteria attenuated inflammation might be because of the fact that lactobacilli bacteria induced interleukin-10, suppressor of cytokine signalling 1/3 and peroxisome proliferator-activated receptors alpha via NOD2-NF-κB pathway, and then cross-regulated Toll-like receptor 4 (TLR4) downstream signal transduction.

Monogenic Autoinflammatory Syndromes: State of the Art on Genetic, Clinical, and Therapeutic Issues

Monogenic autoinflammatory syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin, serous membranes, eyes, joints, gastrointestinal tract, and nervous system, predominantly with a childhood onset. To date, there are twelve known MAISs: familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, familial cold urticaria syndrome, Muckle-Wells syndrome, CINCA syndrome, mevalonate kinase deficiency, NLRP12-associated autoinflammatory disorder, Blau syndrome, early-onset sarcoidosis, PAPA syndrome, Majeed syndrome, and deficiency of the interleukin-1 receptor antagonist. Each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency, associated with findings of increased inflammatory parameters in laboratory investigation. The purpose of this paper is to describe the main genetic, clinical, and therapeutic aspects of MAISs and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists.

Distinct Human and Viral Interleukin-6 Profiles and Other Viral and Immunologic Abnormalities In KSHV-Associated Multicentric Castleman Disease: Relationship with Disease Activity and Individual Disease Manifestations

Abstract 1573 Background:Multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder characterized by flares of severe inflammatory symptoms, including fever and cachexia, with cytopenias and biochemical abnormalities. In the idiopathic form, its pathogenesis is linked to overproduction of interleukin (IL)-6. A distinct form of MCD is caused by Kaposi sarcoma-associated herpesvirus (KSHV, also called human herpesvirus [HHV]-8). KSHV encodes a viral homolog of IL-6, vIL-6, and this has been hypothesized to be central to KSHV-MCD pathogenesis. However, viral and human cytokines have not been examined together in KSHV-MCD, and their contribution to disease activity and symptoms is not known. Methods:Patients with pathologically-proven KSHV-MCD were enrolled on a prospective natural history study incorporating pilot evaluation of novel therapies (NCT00099073). Factors potentially important in pathogenesis were assayed at flare and complete clinical and laboratory remission: KSHV viral load (VL) in peripheral blood mononuclear cells, vIL-6, IL-1β, IL-5, human IL-6 (hIL-6), IL-8, IL-10, IL-12p70, IFN-γ and TNF-α. Paired analyses were performed for each patient comparing initial flare and remission. Associations between cytokines and individual disease manifestations were explored across all flares. Results:21 patients had at least one flare for analysis (19 [90%] male; med age 44 [range 29–52]). 34 flares were observed (range 1–3 per patient) and followed to remission (20 patients) or death (1). All were HIV infected: CD4 med 252cells/μL (range 24–1319), HIV VL med <48 copies/mL (<48–64,100), 94% receiving antiretrovirals. Clinical symptoms included fever (present in 62%, med 38°C [range 36.1–40.5]); fatigue (91%, med CTC grade 2 [0–3]), gastrointestinal (GI) symptoms (68%, med grade 1 [0–3]) and respiratory symptoms (61%, med grade 1 [0–2]). Laboratory findings included anemia (97%, 9.9g/L [6.8–14.4]), thrombocytopenia (68%, 100×103cells/μL [6–567]), hypoalbuminemia (97%, 2.7g/L [1.2–3.9]) hyponatremia (68%, 133mEg/L [127–143]) and C-reactive protein (CRP) elevation (100%, 87.3g/L [6.3–339.5]).Factors elevated during initial flares were: KSHV VL (med 14,700/106 PBMCs [range 0–3,913,000] P <0.0001 compared with remission); vIL-6 (detected in 48%, <1560pg/mL [<1560-20,500] P= 0.0039); hIL-6 (15.9pg/mL [1.4-171.5] P= 0.0006); IL-10 (449pg/mL [2.8-85,900] P= 0.0007); TNF-α (29.0 pg/ml [7.9–90.8] P= 0.0083) and IL-1β (1.2 pg/ml [0.1–5.7] P= 0.0027). IL-5 was decreased compared with remission (0.6 [0.1–15.4] P= 0.016). Differences were most marked for vIL-6 (undetectable in all remissions), hIL-6 (med increase from remission 520%) and IL-10 (med increase from remission 5000%). KSHV VL was correlated with hIL-6 (R = 0.68, P= 0.001) and IL-10 (R=0.82, P= 0.001) across all flares and remissions; other correlations were weaker. There was also a strong association between KSHV VL and vIL-6 (P= 0.001 by Jonckheere-Terpstra). For hIL-6 and vIL-6 only, we observed distinct profiles across flares: vIL-6 elevation only (2 flares, 6%), hIL-6 only (17 flares, 50%), and hIL-6 with vIL-6 (13 flares, 38%). In 2 flares (6%), neither vIL-6 nor hIL-6 were detected at onset, but in both hIL-6 alone soon became elevated. In contrast, KSHV VL, IL-10, TNF-α and IL-1β were consistently elevated during flares. Compared with hIL-6-only flares, hIL-6 with vIL-6 flares exhibited significantly higher CRP (P =0.0009); worse hyponatremia (P =0.02); higher KSHV VL (P =0.016) and IL-10 (P= 0.012); and lower IL-5 (P= 0.009). In linear/logistic regression models of disease manifestations with cytokines, best predictors were: GI symptoms, respiratory symptoms, temperature, platelet count: hIL-6 alone; hemoglobin: hIL-6 and vIL-6; sodium: hIL-6, vIL-6 and IL-10; albumin: IL-1β and vIL-6. Conclusions:This prospective analysis shows for the first time that vIL-6 and hIL-6 can independently or together lead to flares of KSHV-MCD. It shows novel associations of KSHV-MCD flares with IL-1β and TNF-α elevation and IL-5 depression while confirming associations with KSHV VL and IL-10. It further suggests that vIL-6 and hIL-6 may jointly contribute to the severity of some symptoms during flares. As vIL-6 can signal independently of the ligand-binding IL-6 receptor-a, these findings have implications for the development of novel KSHV-MCD therapies targeting IL-6 and its downstream signaling. Disclosures:No relevant conflicts of interest to declare.

Comparative Kinetics ofEscherichia coli- andStaphylococcus aureus-Specific Activation of Key Immune Pathways in Mammary Epithelial Cells Demonstrates ThatS. aureusElicits a Delayed Response Dominated by Interleukin-6 (IL-6) but Not by IL-1A or Tumor Necrosis Factor Alpha

Infections of the udder by Escherichia coli very often elicit acute inflammation, while Staphylococcus aureus infections tend to cause mild, subclinical inflammation and persistent infections. The molecular causes underlying the different disease patterns are poorly understood. We therefore profiled the kinetics and extents of global changes in the transcriptome of primary bovine mammary epithelial cells (MEC) after challenging them with heat-inactivated preparations of E. coli or S. aureus pathogens. E. coli swiftly and strongly induced an expression of cytokines and bactericidal factors. S. aureus elicited a retarded response and failed to quickly induce an expression of bactericidal factors. Both pathogens induced similar patterns of chemokines for cell recruitment into the udder, but E. coli stimulated their synthesis much faster and stronger. The genes that are exclusively and most strongly upregulated by E. coli may be clustered into a regulatory network with tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) in a central position. In contrast, the expression of these master cytokines is barely regulated by S. aureus. Both pathogens quickly trigger an enhanced expression of IL-6. This is still possible after completely abrogating MyD88-dependent Toll-like receptor (TLR) signaling in MEC. The E. coli-specific strong induction of TNF-α and IL-1 expression may be causative for the severe inflammatory symptoms of animals suffering from E. coli mastitis, while the avoidance to quickly induce the synthesis of bactericidal factors may support the persistent survival of S. aureus within the udder. We suggest that S. aureus subverts the MyD88-dependent activation of immune gene expression in MEC.

Acute respiratory distress syndrome associated with rapid aggravation of rheumatoid arthritis

A 76-year-old woman with seropositive rheumatoid arthritis (RA) developed acute respiratory distress syndrome (ARDS) following an appearance of severe inflammatory symptoms in multiple synovial joints. High-dose pulse therapy with methylprednisolone induced a marked improvement in pulmonary conditions. To the best of our knowledge, this is the first case in the literature to show a causal relationship between ARDS and RA. We should be alert to the possibility that ARDS can occur as an acute-type pulmonary complication of RA, particularly when patients show rapid aggravation of rheumatic activity.

Anaplastic large‐cell lymphoma which showed severe inflammatory status and myelodysplasia with increased VEGF and IL‐6 serum levels after long‐term immunosuppressive therapy

We report a patient with anaplastic large-cell lymphoma (ALCL) who has been given immunosuppressive therapy for Evans syndrome for 10 years. He was admitted with spike fever, intra-abdominal lymphadenopathy, and multiple liver masses. Examination of biopsy specimens obtained by para-aortic lymph nodes and liver masses resulted in a diagnosis of ALCL. Immunohistochemically, these cells were reactive to anti-CD30 antibody but were not of B- or T-lineage. Bone marrow aspiration demonstrated the invasion of giant neoplastic cells and trilineage myelodysplasia. Because the patient showed severe inflammatory symptoms, we examined serum levels of various cytokines. Pretreatment levels of IL-6 and VEGF in this patient were significantly elevated compared to those of normal controls. He was treated with combination chemotherapy (ABVD regimen), achieving complete remmesion. Myelodysplasia and serum IL-6 and VEGF also normalized after treatment. We assumed that ALCL resulted from long-term immunosuppressive therapy and that the up-regulation of IL-6 and VEGF played a role in pathogenesis of this type of lymphoma. Am. J. Hematol. 66:49–52, 2001. © 2001 Wiley-Liss, Inc.