Roux-En-Y Gastric Bypass (RYGB) Surgery during High Liquid Sucrose Diet Leads to Gut Microbiota-Related Systematic Alterations.

Roux-en-Y gastric bypass (RYGB) surgery has been proven successful in weight loss and improvement of co-morbidities associated with obesity. Chronic complications such as malabsorption of micronutrients in up to 50% of patients underline the need for additional therapeutic approaches. We investigated systemic RYGB surgery effects in a liquid sucrose diet-induced rat obesity model. After consuming a diet supplemented with high liquid sucrose for eight weeks, rats underwent RYGB or control sham surgery. RYGB, sham pair-fed, and sham ad libitum-fed groups further continued on the diet after recovery. Notable alterations were revealed in microbiota composition, inflammatory markers, feces, liver, and plasma metabolites, as well as in brain neuronal activity post-surgery. Higher fecal 4-aminobutyrate (GABA) correlated with higher Bacteroidota and Enterococcus abundances in RYGB animals, pointing towards the altered enteric nervous system (ENS) and gut signaling. Favorable C-reactive protein (CRP), serine, glycine, and 3-hydroxybutyrate plasma profiles in RYGB rats were suggestive of reverted obesity risk. The impact of liquid sucrose diet and caloric restriction mainly manifested in fatty acid changes in the liver. Our multi-modal approach reveals complex systemic changes after RYGB surgery and points towards potential therapeutic targets in the gut-brain system to mimic the surgery mode of action.

Abatacept in interstitial lung disease associated with rheumatoid arthritis: national multicenter study of 263 patients.

OBJECTIVE: To assess the efficacy of abatacept (ABA) in RA patients with interstitial lung disease (ILD) (RA-ILD). METHODS: This was an observational, multicentre study of RA-ILD patients treated with at least one dose of ABA. ILD was diagnosed by high-resolution CT (HRCT). We analysed the following variables at baseline (ABA initiation), 12 months and at the end of the follow-up: Modified Medical Research Council (MMRC) scale (1-point change), forced vital capacity (FVC) or diffusion lung capacity for carbon monoxide (DLCO) (improvement or worsening ≥10%), HRCT, DAS on 28 joints evaluated using the ESR (DAS28ESR) and CS-sparing effect. RESULTS: We studied 263 RA-ILD patients [150 women/113 men; mean (s.d.) age 64.6 (10) years]. At baseline, they had a median duration of ILD of 1 (interquartile range 0.25-3.44) years, moderate or severe degree of dyspnoea (MMRC grade 2, 3 or 4) (40.3%), FVC (% of the predicted) mean (s.d.) 85.9 (21.8)%, DLCO (% of the predicted) 65.7 (18.3) and DAS28ESR 4.5 (1.5). The ILD patterns were: usual interstitial pneumonia (UIP) (40.3%), non-specific interstitial pneumonia (NSIP) (31.9%) and others (27.8%). ABA was prescribed at standard dose, i.v. (25.5%) or s.c. (74.5%). After a median follow-up of 12 (6-36) months the following variables did not show worsening: dyspnoea (MMRC) (91.9%); FVC (87.7%); DLCO (90.6%); and chest HRCT (76.6%). A significant improvement of DAS28ESR from 4.5 (1.5) to 3.1 (1.3) at the end of follow-up (P < 0.001) and a CS-sparing effect from a median 7.5 (5-10) to 5 (2.5-7.5) mg/day at the end of follow-up (P < 0.001) was also observed. ABA was withdrawn in 62 (23.6%) patients due to adverse events (n = 30), articular inefficacy (n = 27), ILD worsening (n = 3) and other causes (n = 2). CONCLUSION: ABA may be an effective and safe treatment for patients with RA-ILD.

Cellular Origin and Functional Relevance of Collagen I Production in the Kidney.

Background Interstitial fibrosis is associated with chronic renal failure. In addition to fibroblasts, bone marrow-derived cells and tubular epithelial cells have the capacity to produce collagen. However, the amount of collagen produced by each of these cell types and the relevance of fibrosis to renal function are unclear.Methods We generated conditional cell type-specific collagen I knockout mice and used (reversible) unilateral ureteral obstruction and adenine-induced nephropathy to study renal fibrosis and function.Results In these mouse models, hematopoietic, bone marrow-derived cells contributed to 38%-50% of the overall deposition of collagen I in the kidney. The influence of fibrosis on renal function was dependent on the type of damage. In unilateral ureteral obstruction, collagen production by resident fibroblasts was essential to preserve renal function, whereas in the chronic model of adenine-induced nephropathy, collagen production was detrimental to renal function.Conclusions Our data show that hematopoietic cells are a major source of collagen and that antifibrotic therapies need to be carefully considered depending on the type of disease and the underlying cause of fibrosis.

Abatacept in patients with rheumatoid arthritis and interstitial lung disease: A national multicenter study of 63 patients.

OBJECTIVE: Interstitial lung disease (ILD) is one of the most serious complications of rheumatoid arthritis (RA). In the present study, we aimed to assess the efficacy of abatacept (ABA) in patients with ILD associated to RA. METHODS: National multicenter, non-controlled, open-label registry study of RA patients with ILD treated with ABA. RESULTS: 63 patients (36 women) with RA-associated ILD undergoing ABA therapy were studied. The mean ± standard deviation age at the time of the study was 63.2 ± 9.8 years. The median duration of RA and ILD from diagnosis were 6.8 and 1 year, respectively. RA was seropositive in 55 patients (87.3%). In 15 (23.8%) of 63 patients the development of ILD was closely related to the administration of synthetic or biologic disease modifying anti-rheumatic drugs. After a follow-up of 9.4 ± 3.2 months, two-thirds of patients remained stable whereas one-quarter experienced improvement in the Modified Medical Research Council scale. At that time forced vital capacity remained stable in almost two-thirds of patents and improved in one out of five patients assessed. Also, diffusing capacity of the lung for carbon monoxide remained stable in almost two-thirds and showed improvement in a quarter of the patients assessed. At 12 months, 50% of the 22 patients in whom chest HRCT scan was performed due persistence of respiratory symptoms showed stabilization, 8 (36.4%) improvement and 3 worsening of the HRCT scan pattern. Eleven of 63 patients had to discontinue ABA, mainly due to adverse events. CONCLUSION: ABA appears to be an effective in RA-associated ILD.

A reduced 12-joint ultrasound examination predicts lack of X-ray progression better than clinical remission criteria in patients with rheumatoid arthritis.

To study the predictive value of clinical remission definitions and ultrasound (US) examination on X-ray progression in rheumatoid arthritis (RA). This was an observational prospective multicenter 1-year follow-up cohort of RA patients with moderate disease activity (3.2 < DAS28 ≤ 5.1) who started anti-TNF therapy. DAS28ESR, DAS28CRP, SDAI, CDAI, and ACR/EULAR remission criteria were applied and reduced 12-joint US examination was performed at baseline and at 6 and 12 months. At baseline and month 12, radiographs of hands and feet were obtained in a subset of patients. A blind independent reader scored radiographs. X-ray progression was defined as Sharp van der Heijde change score >1 and no progression was defined as ≤0. 319 of 357 patients completed the study; patients had a mean (SD) age of 53.5 (13.1) years, with a disease duration of 7.5 (7.1) years. Laboratory, clinical, and US values significantly improved at month 6, except CRP, with additional improvement at month 12. Remission and low disease activity rates increased at follow-up. In the subset of 115 patients with radiological studies, clinical remission by any definition was not significantly associated with X-ray progression. Patients without PD signal at baseline and month 6 were a lower risk of X-ray progression than patients with PD signal, OR 0.197 (95% CI 0.046-0.861) and 0.134 (95% CI 0.047-0.378), respectively. Absence of PD signal, but not clinical remission predicts lack of X-ray progression. A feasible 12-joint US examination may add relevant information to RA remission criteria.

Incidence, associated factors and clinical impact of severe infections in a large, multicentric cohort of patients with systemic lupus erythematosus.

OBJECTIVES: To estimate the incidence of severe infection and investigate the associated factors and clinical impact in a large systemic lupus erythematosus (SLE) retrospective cohort. METHODS: All patients in the Spanish Rheumatology Society Lupus Registry (RELESSER) who meet ≥4 ACR-97 SLE criteria were retrospectively investigated for severe infections. Patients with and without infections were compared in terms of SLE severity, damage, comorbidities, and demographic characteristics. A multivariable Cox regression model was built to calculate hazard ratios (HRs) for the first infection. RESULTS: A total of 3658 SLE patients were included: 90% female, median age 32.9 years (DQ 9.7), and mean follow-up (months) 120.2 (±87.6). A total of 705 (19.3%) patients suffered ≥1 severe infection. Total severe infections recorded in these patients numbered 1227. The incidence rate was 29.2 (95% CI: 27.6-30.9) infections per 1000 patient years. Time from first infection to second infection was significantly shorter than time from diagnosis to first infection (p < 0.000). Although respiratory infections were the most common (35.5%), bloodstream infections were the most frequent cause of mortality by infection (42.0%). In the Cox regression analysis, the following were all associated with infection: age at diagnosis (HR = 1.016, 95% CI: 1.009-1.023), Latin-American (Amerindian-Mestizo) ethnicity (HR = 2.151, 95% CI: 1.539-3.005), corticosteroids (≥10mg/day) (HR = 1.271, 95% CI: 1.034-1.561), immunosuppressors (HR = 1.348, 95% CI: 1.079-1.684), hospitalization by SLE (HR = 2.567, 95% CI: 1.905-3.459), Katz severity index (HR = 1.160, 95% CI: 1.105-1.217), SLICC/ACR damage index (HR = 1.069, 95% CI: 1.031-1.108), and smoking (HR = 1.332, 95% CI: 1.121-1.583). Duration of antimalarial use (months) proved protective (HR = 0.998, 95% CI: 0.997-0.999). CONCLUSIONS: Severe infection constitutes a predictor of poor prognosis in SLE patients, is more common in Latin-Americans and is associated with age, previous infection, and smoking. Antimalarials exerted a protective effect.

Comorbidities in Patients With Primary Sjögren's Syndrome and Systemic Lupus Erythematosus: A Comparative Registries-Based Study.

OBJECTIVE: To compare the prevalence of the main comorbidities in 2 large cohorts of patients with primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE), with a focus on cardiovascular (CV) diseases. METHODS: This was a cross-sectional multicenter study where the prevalence of more relevant comorbidities in 2 cohorts was compared. Patients under followup from SJOGRENSER (Spanish Rheumatology Society Registry of Primary SS) and RELESSER (Spanish Rheumatology Society Registry of SLE), and who fulfilled the 2002 American-European Consensus Group and 1997 American College of Rheumatology classification criteria, respectively, were included. A binomial logistic regression analysis was carried out to explore potential differences, making general adjustments for age, sex, and disease duration and specific adjustments for each variable, including CV risk factors and treatments, when appropriate. RESULTS: A total of 437 primary SS patients (95% female) and 2,926 SLE patients (89% female) were included. The mean age was 58.6 years (interquartile range [IQR] 50.0-69.9 years) for primary SS patients and 45.1 years (IQR 36.4-56.3 years) for SLE patients (P < 0.001), and disease duration was 10.4 years (IQR 6.0-16.7 years) and 13.0 years (IQR 7.45-19.76 years), respectively (P < 0.001). Smoking, dyslipidemia, and arterial hypertension were associated less frequently with primary SS (odds ratio [OR] 0.36 [95% confidence interval (95% CI) 0.28-0.48], 0.74 [95% CI 0.58-0.94], and 0.50 [95% CI 0.38-0.66], respectively) as were life-threatening CV events (i.e., stroke or myocardial infarction; OR 0.57 [95% CI 0.35-0.92]). Conversely, lymphoma was associated more frequently with primary SS (OR 4.41 [95% CI 1.35-14.43]). The prevalence of severe infection was lower in primary SS than in SLE (10.1% versus 16.9%; OR 0.54 [95% CI 0.39-0.76]; P < 0.001). CONCLUSION: Primary SS patients have a consistently less serious CV comorbidity burden and a lower prevalence of severe infection than those with SLE. In contrast, their risk of lymphoma is greater.

IL-3 promotes the development of experimental autoimmune encephalitis.

Little is known about the role of IL-3 in multiple sclerosis (MS) in humans and in experimental autoimmune encephalomyelitis (EAE). Using myelin oligodendrocyte glycoprotein (MOG) peptide-induced EAE, we show that CD4+ T cells are the main source of IL-3 and that cerebral IL-3 expression correlates with the influx of T cells into the brain. Blockade of IL-3 with monoclonal antibodies, analysis of IL-3 deficient mice, and adoptive transfer of leukocytes demonstrate that IL-3 plays an important role for development of clinical symptoms of EAE, for migration of leukocytes into the brain, and for cerebral expression of adhesion molecules and chemokines. In contrast, injection of recombinant IL-3 exacerbates EAE symptoms and cerebral inflammation. In patients with relapsing-remitting MS (RRMS), IL-3 expression by T cells is markedly upregulated during episodes of relapse. Our data indicate that IL-3 plays an important role in EAE and may represent a new target for treatment of MS.

Relationship between damage clustering and mortality in systemic lupus erythematosus in early and late stages of the disease: cluster analyses in a large cohort from the Spanish Society of Rheumatology Lupus Registry.

OBJECTIVES: To identify patterns (clusters) of damage manifestations within a large cohort of SLE patients and evaluate the potential association of these clusters with a higher risk of mortality. METHODS: This is a multicentre, descriptive, cross-sectional study of a cohort of 3656 SLE patients from the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics Damage Index. Using cluster analysis, groups of patients with similar patterns of damage manifestations were identified. Then, overall clusters were compared as well as the subgroup of patients within every cluster with disease duration shorter than 5 years. RESULTS: Three damage clusters were identified. Cluster 1 (80.6% of patients) presented a lower amount of individuals with damage (23.2 vs 100% in clusters 2 and 3, P < 0.001). Cluster 2 (11.4% of patients) was characterized by musculoskeletal damage in all patients. Cluster 3 (8.0% of patients) was the only group with cardiovascular damage, and this was present in all patients. The overall mortality rate of patients in clusters 2 and 3 was higher than that in cluster 1 (P < 0.001 for both comparisons) and in patients with disease duration shorter than 5 years as well. CONCLUSION: In a large cohort of SLE patients, cardiovascular and musculoskeletal damage manifestations were the two dominant forms of damage to sort patients into clinically meaningful clusters. Both in early and late stages of the disease, there was a significant association of these clusters with an increased risk of mortality. Physicians should pay special attention to the early prevention of damage in these two systems.

Characterization of Patients With Lupus Nephritis Included in a Large Cohort From the Spanish Society of Rheumatology Registry of Patients With Systemic Lupus Erythematosus (RELESSER).

The aim of the study was to profile those patients included in the RELESSER registry with histologically proven renal involvement in order to better understand the current state of lupus nephritis (LN) in Spain. RELESSER-TRANS is a multicenter cross-sectional registry with an analytical component. Information was collected from the medical records of patients with systemic lupus erythematosus who were followed at participating rheumatology units. A total of 359 variables including demographic data, clinical manifestations, disease activity, severity, comorbidities, LN outcome, treatments, and mortality were recorded. Only patients with a histological confirmation of LN were included. We performed a descriptive analysis, chi-square or Student's t tests according to the type of variable and its relationship with LN. Odds ratio and confidence intervals were calculated by using simple logistic regression. LN was histologically confirmed in 1092/3575 patients (30.5%). Most patients were female (85.7%), Caucasian (90.2%), and the mean age at LN diagnosis was 28.4 ±â€Š12.7 years. The risk for LN development was higher in men (M/F:47.85/30.91%, P < 0.001), in younger individuals (P < 0.001), and in Hispanics (P = 0.03). Complete response to treatment was achieved in 68.3% of patients; 10.35% developed ESRD, which required a kidney transplant in 45% of such cases. The older the patient, the greater was the likelihood of complete response (P < 0.001). Recurrences were associated with persistent lupus activity at the time of the last visit (P < 0.001) and with ESRD (P < 0.001). Thrombotic microangiopathy was a risk factor for ESRD (P = 0.04), as for the necessity of dialysis (P = 0.01) or renal transplantation (P = 0.03). LN itself was a poor prognostic risk factor of mortality (OR 2.4 [1.81-3.22], P < 0.001). Patients receiving antimalarials had a significantly lower risk of developing LN (P < 0.001) and ESRD (P < 0.001), and responded better to specific treatments for LN (P = 0.014). More than two-thirds of the patients with LN from a wide European cohort achieved a complete response to treatment. The presence of positive anti-Sm antibodies was associated with a higher frequency of LN and a decreased rate of complete response to treatment. The use of antimalarials reduced both the risk of developing renal disease and its severity, and contributed to attaining a complete renal response.

Fibromyalgia prevalence and related factors in a large registry of patients with systemic lupus erythematosus.

OBJECTIVES: The objective of this study is to determine the prevalence of fibromyalgia (FM) in systemic lupus erythematosus (SLE) patients and to study its relationship to depression and other SLE-related factors. METHODS: A cross-sectional data analysis from the RELESSER-Transversal Spanish Registry, which includes SLE patients in a national multicentre retrospective charts review, was performed. INCLUSION CRITERIA: patients who fulfilled ≥4 ACR 1997 SLE criteria. Main variables were disease duration, depression, sociodemographics, comorbidities, SLE activity symptoms, serological findings, therapies and different disease status indices. Statistical analyses included a descriptive, associative and logistic regression analyses. A literature review was performed. RESULTS: 3,591 SLE patients were included, 90.1% women, 34.6 years of age at diagnosis (SD 14.6 years) and 93.1% Caucasians. FM prevalence was 6.2%. SLE patients with disease duration >5 years showed more FM than those with duration <5 years: 6.9% vs. 4.0%, respectively (p<0.05). SLE-FM patients showed higher prevalence of depression compared to non-FM-SLE patients: 53.1% vs. 14.6%, respectively (p<0.001). After adjusting by risk factors, the OR (CI) of suffering depression in FM-SLE patients was 6.779 (4.770-9.636), p<0.001. The OR of having secondary Sjögren's 2.447 (1.662-3.604), p<0.001, photosensitivity 2.184 (1.431-3.334), p<0.001, and oral ulcers 1.436 (1.005-2.051), p=0.047. CONCLUSIONS: Prevalence of FM in Caucasian SLE patients was high compared to the general population, and was significantly higher in those in later stages of disease. SLE patients with depression showed a strong risk of developing FM. Photosensitivity, oral ulcers and secondary Sjögren's were the only SLE-related factors associated with FM.

IL-3 contributes to development of lupus nephritis in MRL/lpr mice.

MRL/lpr mice develop a spontaneous autoimmune disease that closely resembles human systemic lupus erythematosus (SLE) with DNA autoantibodies, hypergammaglobulinemia, immune complex glomerulonephritis, and systemic vasculitis. Little is known about the role of IL-3 in SLE. In order to study this we analyzed the expression of IL-3 in murine lupus and determined whether blockade of IL-3 with a monoclonal antibody or injection of recombinant IL-3 affects lupus nephritis in MRL/lpr mice. During disease progression IL-3 levels were increased in the plasma and in the supernatant of cultured splenocytes from MRL/lpr mice. Administration of IL-3 aggravated the disease with significantly higher renal activity scores, more renal fibrosis, and more glomerular leukocyte infiltration and IgG deposition. Blockade of IL-3 significantly improved acute and chronic kidney damage, reduced the glomerular infiltration of leukocytes and the glomerular deposition of IgG, and decreased the development of renal fibrosis. Furthermore, DNA autoantibody production, proteinuria, and serum creatinine levels were significantly lower in the anti-IL-3 group. Thus, IL-3 plays an important role in the pathogenesis of SLE and the progression of lupus nephritis. Hence, blockade of IL-3 may represent a new strategy for treatment of lupus nephritis.

Patterns of use and dosing of tocilizumab in the treatment of patients with rheumatoid arthritis in routine clinical practice: the ACT-LIFE study.

The aim of the study was to identify and describe the patterns of use of tocilizumab in clinical practice to ensure safety and optimal management of rheumatoid arthritis (RA). This is a 12-month prospective observational study in patients with moderate or severe RA of ≥6 months' duration who have started tocilizumab after failure of at least one previous disease-modifying antirheumatic drug (DMARD) including TNF inhibitors. For some analyses, patients were categorized by the use of tocilizumab as monotherapy or in combination, and by previous use of biological therapy. Overall, 379 were evaluable (84.4 % received tocilizumab after prior biologics and 78.4 % in combination with classic DMARDs). Tocilizumab was discontinued in 68/379 (17.9 %) patients after a median of 6.7 (3.7-10.4) months, mainly due to a lack of efficacy (24/379, 6.3 %) and adverse events (23/379, 6.1 %). Of 131 temporary interruptions of tocilizumab required in 101/379 (26.6 %) patients, 81/131 (61.8 %) were related to adverse events, and in 120/131 (91.6 %) cases, tocilizumab was reintroduced at 8 mg/kg. Thirty-six tocilizumab dose reductions occurred in 34/379 (9 %) patients due to abnormal laboratory values in 20/34 (55.6 %) cases. DAS28-ESR scores decreased from baseline (5.6 ± 1.0) to week 24 (3.0 ± 1.4) and week 52 (2.7 ± 1.3). DAS28 response differed between biologics-naive and biologics-experienced patients, both at weeks 24 and 52. In clinical practice, tocilizumab is effective in RA while retaining the expected safety and tolerability profile. Tocilizumab seems to be more effective for biologics-naive patients than for biologics-experienced patients, while it proves to be similarly effective when used in combination or monotherapy.

Comprehensive description of clinical characteristics of a large systemic lupus erythematosus cohort from the Spanish Rheumatology Society Lupus Registry (RELESSER) with emphasis on complete versus incomplete lupus differences.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement and pronounced racial and ethnic heterogeneity. The aims of the present work were (1) to describe the cumulative clinical characteristics of those patients included in the Spanish Rheumatology Society SLE Registry (RELESSER), focusing on the differences between patients who fulfilled the 1997 ACR-SLE criteria versus those with less than 4 criteria (hereafter designated as incomplete SLE (iSLE)) and (2) to compare SLE patient characteristics with those documented in other multicentric SLE registries.RELESSER is a multicenter hospital-based registry, with a collection of data from a large, representative sample of adult patients with SLE (1997 ACR criteria) seen at Spanish rheumatology departments. The registry includes demographic data, comprehensive descriptions of clinical manifestations, as well as information about disease activity and severity, cumulative damage, comorbidities, treatments and mortality, using variables with highly standardized definitions.A total of 4.024 SLE patients (91% with ≥4 ACR criteria) were included. Ninety percent were women with a mean age at diagnosis of 35.4 years and a median duration of disease of 11.0 years. As expected, most SLE manifestations were more frequent in SLE patients than in iSLE ones and every one of the ACR criteria was also associated with SLE condition; this was particularly true of malar rash, oral ulcers and renal disorder. The analysis-adjusted by gender, age at diagnosis, and disease duration-revealed that higher disease activity, damage and SLE severity index are associated with SLE [OR: 1.14; 95% CI: 1.08-1.20 (P < 0.001); 1.29; 95% CI: 1.15-1.44 (P < 0.001); and 2.10; 95% CI: 1.83-2.42 (P < 0.001), respectively]. These results support the hypothesis that iSLE behaves as a relative stable and mild disease. SLE patients from the RELESSER register do not appear to differ substantially from other Caucasian populations and although activity [median SELENA-SLEDA: 2 (IQ: 0-4)], damage [median SLICC/ACR/DI: 1 (IQ: 0-2)], and severity [median KATZ index: 2 (IQ: 1-3)] scores were low, 1 of every 4 deaths was due to SLE activity.RELESSER represents the largest European SLE registry established to date, providing comprehensive, reliable and updated information on SLE in the southern European population.

B-cell inhibition by cross-linking CD79b is superior to B-cell depletion with anti-CD20 antibodies in treating murine collagen-induced arthritis.

Depletion of B cells with the anti-CD20 antibody rituximab is an established therapy for rheumatoid arthritis. However, rituximab has only moderate efficacy, most likely due to insufficient depletion of B cells in lymphoid organs and expansion of pathogenic B cells. We found that an antibody against mouse CD79b profoundly blocks B-cell proliferation induced via the B-cell receptor, CD40, CD180, and chondroitin sulfate, but not via TLR4 or TLR9. Treatment with anti-CD79b also induces death in resting and activated B cells. B-cell inhibition is mediated by cross-linkage of CD79b, but independent of Fc-receptor engagement. In the model of collagen-induced arthritis, an antibody against mouse CD20 depletes B cells very efficiently but fails to suppress the humoral immune response against collagen and the development of arthritis. In contrast, the antibody against CD79b, and a deglycosylated variant of this antibody, almost completely inhibits the increase in anti-collagen antibodies and the development of arthritis. In mice with established arthritis only the fully glycosylated antibody against CD79b is effective. Our data show that targeting B cells via CD79b is much more effective than B-cell depletion with anti-CD20 antibodies for therapy of arthritis. These findings may have important implications for treatment of B-cell-mediated autoimmune diseases.

Basophils inhibit proliferation of CD4⁺ T cells in autologous and allogeneic mixed lymphocyte reactions and limit disease activity in a murine model of graft versus host disease.

Basophils are known to modulate the phenotype of CD4(+) T cells and to enhance T helper type 2 responses in vitro and in vivo. In this study, we demonstrate that murine basophils inhibit proliferation of CD4(+) T cells in autologous and allogeneic mixed lymphocyte reactions. The inhibition is independent of Fas and MHC class II, but dependent on activation of basophils with subsequent release of interleukin-4 (IL-4) and IL-6. The inhibitory effect of basophils on T-cell proliferation can be blocked with antibodies against IL-4 and IL-6 and is absent in IL-4/IL-6 double-deficient mice. In addition, we show that basophils and IL-4 have beneficial effects on disease activity in a murine model of acute graft-versus-host disease (GvHD). When basophils were depleted with the antibody MAR-1 before induction of GvHD, weight loss, GvHD score, mortality and plasma tumour necrosis factor levels were increased while injection of IL-4 improved GvHD. Basophil-depleted mice with GvHD also have increased numbers of CD4(+) T cells in the mesenteric lymph nodes. Our data show for the first time that basophils suppress autologous and allogeneic CD4(+) T-cell proliferation in an IL-4-dependent manner.

Chondroitin sulfate activates B cells in vitro, expands CD138+ cells in vivo, and interferes with established humoral immune responses.

Glycosaminoglycans have anti-inflammatory properties and interact with a variety of soluble and membrane-bound molecules. Little is known about their effects on B cells and humoral immune responses. We show that CS but not dextran or other glycosaminoglycans induces a pronounced proliferation of B cells in vitro compared with TLR4 or TLR9 ligands. With the use of inhibitors and KO mice, we demonstrate that this proliferation is mediated by the tyrosine kinases BTK and Syk but independent of CD44. Antibodies against Ig-α or Ig-ß completely block CS-induced B cell proliferation. Injection of CS in mice for 4-5 days expands B cells in the spleen and results in a marked increase of CD138(+) cells in the spleen that is dependent on BTK but independent of CD4(+) T cells. Long-term treatment with CS for 14 days also increases CD138(+) cells in the bone marrow. When mice were immunized with APC or collagen and treated with CS for up to 14 days during primary or after secondary immune responses, antigen-specific humoral immune responses and antigen-specific CD138(+) plasma cells in the bone marrow were reduced significantly. These data show that CD138(+) cells, induced by treatment with CS, migrate into the bone marrow and may displace other antigen-specific plasma cells. Overall, CS is able to interfere markedly with primary and fully established humoral immune responses in mice.

El software educativo en el proceso de enseñanza-aprendizaje de la disciplina Historia de Cuba / The educative software in the teaching-learning process of the History of Cuba discipline

En el estudio diagnóstico realizado por los profesores de la disciplina Historia en la Facultad de Tecnología de la Salud en Villa Clara, se detectaron las necesidades de literatura docente, bibliografía y materiales para facilitar la comprensión de los contenidos que se imparten en la asignaturaHistoria de Cuba, lo que afecta la calidad del proceso de enseñanza-aprendizaje. Se utilizaron en la investigación métodos de nivel teórico como el tránsito de lo concreto a lo abstracto, histórico-lógico, sistémico_estructural, inductivo_deductivo, analítico_sintético y la modelación; y del nivel empírico: análisis de documentos, observación, entrevista, encuesta. A partir de sus resultados se elabora un software multimedia educativo, Cubanahis, que sirve como medio de enseñanza para la clase, el estudio independiente y de soporte bibliográfico de la asignatura, además propicia la asequibilidad y comprensión en la asimilación de contenidos con cierto nivel de complejidad, lo que garantiza un aprendizaje desarrollador.

The diagnostic study carried out by the professors of the History of Cuba discipline in the Health Technology Faculty in Villa Clara detected the necessity of teaching literature, bibliography and material aids to facilitate the comprehension of contents present in the History of Cuba subject which affect the teaching-learning process. Theoretical and empirical methods were used, for instance, from the abstract level to the concrete one, historical logical, systemic_structural, inductive_deductive, analytical_synthetically and modeling; analysis of documents, observation, interview and surveys. According to their results it was elaborated a multi-media educative software "Cubanahis" which serves as a class teaching aid, the independent study and bibliographic support of the subject, besides, it facilitates the assimilation and comprehension of difficult contents and the grasping of a meaningful learning.

Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model.

Collagen-producing bone marrow-derived cells (fibrocytes) have been detected in animal models and patients with fibrotic diseases. In vitro data suggest that they develop from monocytes with the help of accessory cells and profibrotic soluble factors. Using a mouse model of renal fibrosis, unilateral ureteral obstruction, we found the number of circulating fibrocytes was not reduced when monocytes were depleted with a monoclonal antibody against CCR2 or when CCR2-/- mice with very low numbers of circulating or splenic monocytes were analyzed. The absence of CCR2, however, interfered with migration of fibrocytes into the kidney. The phenotype of splenic and renal fibrocytes was very similar and distinct from classical monocytes as fibrocytes expressed no CD115, medium levels of CCR2, and high levels of CD11b and Ly-6G. Using a depleting monoclonal antibody against Ly-6G or bone marrow chimeric mice expressing the diphtheria toxin receptor under the control of CD11b, we could efficiently deplete fibrocytes from the kidney. Depletion of fibrocytes or reduced migration of fibrocytes into the kidney resulted in lower renal expression of collagen-I. Thus, fibrocytes develop outside the kidney independent of infiltrating monocytes and rely on CCR2 for migration into target organs.

El software educativo en el proceso de enseñanza-aprendizaje de la disciplina Historia de Cuba / The educative software in the teaching-learning process of the History of Cuba discipline

En el estudio diagnóstico realizado por los profesores de la disciplina Historia en la Facultad de Tecnología de la Salud en Villa Clara, se detectaron las necesidades de literatura docente, bibliografía y materiales para facilitar la comprensión de los contenidos que se imparten en la asignatura Historia de Cuba, lo que afecta la calidad del proceso de enseñanza-aprendizaje. Se utilizaron en la investigación métodos de nivel teórico como el tránsito de lo concreto a lo abstracto, histórico-lógico, sistémico_estructural, inductivo_deductivo, analítico_sintético y la modelación; y del nivel empírico: análisis de documentos, observación, entrevista, encuesta. A partir de sus resultados se elabora un software multimedia educativo, Cubanahis, que sirve como medio de enseñanza para la clase, el estudio independiente y de soporte bibliográfico de la asignatura, además propicia la asequibilidad y comprensión en la asimilación de contenidos con cierto nivel de complejidad, lo que garantiza un aprendizaje desarrollador.

The diagnostic study carried out by the professors of the History of Cuba discipline in the Health Technology Faculty in Villa Clara detected the necessity of teaching literature, bibliography and material aids to facilitate the comprehension of contents present in the History of Cuba subject which affect the teaching-learning process. Theoretical and empirical methods were used, for instance, from the abstract level to the concrete one, historical logical, systemic-structural, inductive-deductive, analytical-synthetically and modeling; analysis of documents, observation, interview and surveys. According to their results it was elaborated a multi-media educative software "Cubanahis" which serves as a class teaching aid, the independent study and bibliographic support of the subject, besides, it facilitates the assimilation and comprehension of difficult contents and the grasping of a meaningful learning.