B-cell activating factor (BAFF) and its receptors' expression in pediatric nephrotic syndrome is associated with worse prognosis.

AIM: Immune pathogenesis of nephrotic syndrome (NS) is not completely understood. We aimed to evaluate the expression of B-cell activating factor (BAFF) and its receptors in renal samples from pediatric NS patients and its relationship with renal function survival. MATERIALS AND METHODS: We conducted an ambispective study on 33 patients with pediatric NS. Immunohistochemistry for BAFF, TACI, BCMA and BR3 was performed. Markers were evaluated on podocytes and interstitial inflammatory infiltrates (III). We performed Kaplan-Meier curves to describe renal function survival according to markers' expression. RESULTS: Thirty-three NS patients were included. Minimal change disease was seen in 21 (63.6%) patients, and focal segmental glomerulosclerosis in 12 (36.4%). BAFF was found in podocytes (18.2% of samples) and III (36.4% of samples), BAFF-R in one sample, TACI in 4 (podocytes and III), and BCMA in 5 samples of podocytes and 7 of III. BAFF on podocytes and III was associated with worst renal function at follow-up; those patients had 25% probability of having GFR >90 mL/min/1.73m2, versus 84.9% when absent (p = 0.0067). Patients with BAFF in III had 42.9% probability of having GFR>90 mL/min/1.73 m2, versus 94.1% when absent (p = 0.0063). CONCLUSION: BAFF expression in renal biopsies could be a prognostic factor for renal function.

Frequency of anti-neutrophil cytoplasmic antibodies in patients with systemic lupus erythematosus / Frecuencia de los anticuerpos anticitoplasma de neutrófilo en pacientes con lupus eritematoso sistémico

ABSTRACT Introduction: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Patients with SLE exhibit multiple serum autoantibodies, including anti-neutrophil cytoplasmic antibodies (ANCAs). There are two main techniques to detect ANCAs: indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA). In this study, an attempt was made to determine the frequency and clinical associations of ANCAs in patients with SLE. Methods: A cross-sectional study was conducted in a tertiary care hospital in Colombia that included 74 patients with SLE. The presence of ANCAs was assessed using IIF with ethanol-fixed slides, and ELISA was used to detect antibody specificities for myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA. Results: Of the 74 patients with SLE evaluated, 60 (81.1%) of them were ANCA-positive by IIF. By contrast, only one patient showed specificity for PR3-ANCA by ELISA. The relevance of ANCA positivity by IIF and clinical and serological features was significant for renal involvement (p = .0174), and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (p = .0308). Conclusion: ANCAs are common in the serum of patients with SLE, as detected by ethanol-fixed slides with IIF staining. However, detection of specificity to PR3 and/or MPO is rare, thus highlighting the importance of detecting these autoantibodies by different techniques.

RESUMEN Introducción: El lupus eritematoso sistémico (LES) es una enfermedad autoinmune sistémica. Los pacientes con LES muestran múltiples autoanticuerpos séricos, incluyendo los anticuerpos anticitoplasma de neutrófilo (ANCA, por sus siglas en inglés). Existen 2 técnicas principales para la detección de ANCA: inmunofluorescencia indirecta (IFI) y ensayo por inmunoadsorción ligado a enzimas (ELISA). En este estudio nuestro objetivo fue determinar la frecuencia y las asociaciones clínicas de los ANCA en pacientes con LES. Métodos: Realizamos un estudio transversal de 74 pacientes con LES en un hospital de alta complejidad de Colombia. La presencia de ANCA se evaluó por IFI, utilizando láminas con fijación de etanol, y con ELISA para determinar las especificidades para mieloperoxidasa (MPO)-ANCA y proteinasa 3 (PR3)-ANCA. Resultados: Fueron evaluados 74 pacientes con LES, 60 (81,1%) de ellos fueron positivos para ANCA. Por el contrario, solo un paciente mostró especificidad para PR3-ANCA por ELISA. La relación entre la positividad para ANCA por IFI y las características clínicas y serológicas fue estadísticamente significativa para compromiso renal (p = 0,0174) y para el índice de actividad de la enfermedad (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]) (p = 0,0308). Conclusiones: Los ANCA detectados mediante fijación con etanol por técnicas de IFI, son comunes en pacientes con LES. Sin embargo, la detección de especificidades para PR3 o MPO es rara; se destaca la importancia de la evaluación de estos autoanticuerpos mediante diferentes técnicas.

Biological Effects of Animal Venoms on the Human Immune System.

Venoms are products of specialized glands and serve many living organisms to immobilize and kill prey, start digestive processes and act as a defense mechanism. Venoms affect different cells, cellular structures and tissues, such as skin, nervous, hematological, digestive, excretory and immune systems, as well as the heart, among other structures. Components of both the innate and adaptive immune systems can be stimulated or suppressed. Studying the effects on the cells and molecules produced by the immune system has been useful in many biomedical fields. The effects of venoms can be the basis for research and development of therapeutic protocols useful in the modulation of the immunological system, including different autoimmune diseases. This review focuses on the understanding of biological effects of diverse venom on the human immune system and how some of their components can be useful for the study and development of immunomodulatory drugs.

Association of Antiribosomal P Antibody with Neurological and Systemic Manifestations in Patients with Systemic Lupus Erythematosus in Southwestern Colombia.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by heterogeneous pathogenesis, various clinical manifestations, and a broad spectrum of autoantibodies which recognize different cellular components. This study examines the clinical significance and serological associations of serum antiribosomal P antibodies (anti-P) derived from SLE patients in a population from southwestern Colombia. METHODS: We performed a cross-sectional study of 66 SLE patients. Serum antiribosomal P0 autoantibodies were detected by line immunoassay using the ANA-LIA MAXX kit and processed on the automated HumaBlot 44FA system (Human Diagnostics, Germany). RESULTS: Of the 66 SLE patients included in the study, 17 patients (25.76%) showed anti-P positivity by line immunoassay (IA), 47 (71.21%) were negative, and results from 2 patients were indeterminate. We did not find an association with neuropsychiatric SLE (NPSLE), renal, or hepatic disorders (P > 0.05). Laboratory findings indicated that anti-P positivity was significantly associated to anti-Smith (P = 0.001), anti-Ro60/SSA (P = 0.046), and anti-dsDNA antibodies (P = 0.034), the latter being true only when performed using indirect immunofluorescence (IIF). CONCLUSION: The anti-P antibodies are not associated with clinical manifestations such as NPSLE, lupus nephritis, or hepatic involvement in the southwest Colombian SLE population. Moreover, we confirmed previously reported association between anti-P antibody, serum anti-dsDNA, and anti-Smith.

Expression of BAFF, APRIL, and cognate receptor genes in lupus nephritis and potential use as urinary biomarkers.

BACKGROUND: B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), and their receptors BAFF-R, BCMA, and TACI are crucial factors for the survival of B lymphocytes. Recent evidence has also demonstrated the importance of BAFF/APRIL signaling in lupus nephritis (LN). This study evaluated the relationships between LN clinical characteristics and the urinary expression levels of BAFF, APRIL, and cognate receptors to assess their potential value as disease biomarkers. METHODS: Expression levels of these genes were assessed in urine samples collected from systemic lupus erythematosus (SLE) patients before renal biopsy using reverse transcription real-time PCR. RESULTS: Thirty-five patients with LN were included. Most of the patients were female (82.86%) with median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) of 15. BAFF mRNA was detectable in 28.57%, APRIL mRNA in 42.85%, BR3 mRNA in 48.57%, and TACI mRNA in 42.85% of urine samples. On the other hand, urinary (u)BCMA mRNA was not found in any sample. Urinary expression of most biomarkers was detected with greater frequency in class III and IV LN compared to class V LN. The expression level of uBR3 mRNA was correlated with SLEDAI-2K and histological activity index. CONCLUSION: Urinary expression of BAFF/APRIL signaling factors, especially TACI, APRIL, and BR3 mRNAs, may be useful biomarkers for LN.

Prevalence of anti-DFS70 autoantibodies in a Latin American cohort of patients with systemic lupus erythematosus and without autoimmune diseases.

INTRODUCTION/OBJECTIVES: Anti-dense fine speckled 70 (DFS70) autoantibodies were reported to be more prevalent in healthy individuals than those with autoimmune diseases such as systemic lupus erythematosus (SLE). We determined anti-DFS70 autoantibody prevalence in a Latin American cohort of patients with SLE and healthy individuals. METHODS: This study included 127 individuals with anti-nuclear antibodies (ANAs; > 1:160) suggesting the presence of anti-DFS70, including 64 patients with SLE and 63 healthy controls. The anti-DFS70 autoantibodies were determined by immunoadsorption using NOVA Lite® HEp-2 Select kit with DAPI. Negative fluorescence after adsorption with the DFS70 antigen indicated anti-DFS70 autoantibody positivity. RESULTS: The presence of anti-DFS70 autoantibodies was confirmed by indirect immunofluorescence in 21 (33.3%) healthy controls and 8 (12.5%) patients with SLE (p = 0.005). Among the anti-DFS70-positive patients with SLE, the most frequent compromise was renal involvement in six cases (75%), 4 patients (37.5%) were positive for anti-Sm, which was the most frequently associated antibody, and one patient (12.5%) was positive for anti-DNA. CONCLUSIONS: Anti-DFS70 autoantibodies might be considered a biomarker to differentiate patients with SLE from ANA-positive individuals without autoimmune diseases. KEY POINTS: • In a Latin American cohort, the anti-DFS70 was higher in individuals without autoimmune diseases compared with that in patients with SLE.• The anti-DFS70 might have utility as a biomarker of exclusion in patients with non-specific clinical signs of AARDs.

CRISPR/Cas: from adaptive immune system in prokaryotes to therapeutic weapon against immune-related diseases.

CRISPR/Cas evolved as an adaptive immune system in bacteria and archaea to inactivate foreign viral and plasmid DNA. However, the capacities of various CRISPR/Cas systems for precise genome editing based on sequence homology also allow their use as tools for genomic and epigenomic modification in eukaryotes. Indeed, these genetic characteristics have proven useful for disease modeling and testing the specific functions of target genes under pathological conditions. Moreover, recent studies provide compelling evidence that CRISPR/Cas systems could be useful therapeutic tools against human diseases, including cancer, monogenic disorders, and autoimmune disorders.HighlightsCRISPR/Cas evolved as an adaptive immune system in bacteria and archaea.CRISPR/Cas systems are nowadays used as tools for genomic modification.CRISPR/Cas systems could be useful therapeutic tools against human disease, including autoimmune conditions.

Mechanisms of action and historical facts on the use of intravenous immunoglobulins in systemic lupus erythematosus.

The current existing therapies for severe cases of systemic lupus erythematosus (SLE) patients are still limited. Intravenous immunoglobulin (IVIGs), which are purified from the plasma of thousands of healthy human donors, have been profiled as efficacious and life-saving options for SLE patients refractory to conventional therapy. The specific mechanism of action by which IVIGs generate immunomodulation in SLE is not currently understood. In this manuscript, we reviewed some of the hypothesis that have been postulated to explain the IVIG effects, including those on T and B cell intracellular signalling and activation, as well as the interferon signalling pathways involved in the detection of nucleic acids and the defective removal of immune complexes and debris.

Complicaciones agudas de la Diabetes mellitus, visión práctica para el médico en urgencias: Revisión de tema / Acute complications of diabetes mellitus, practical vision for the emergency physician: Review

La Diabetes Mellitus (DM) representa una de las Enfermedades Crónicas No Transmisibles (ECNT) más prevalentes del mundo, cuyas complicaciones agudas o emergencias hiperglucémicas más importantes, en el escenario de la medicina de urgencias, son la Cetoacidosis Diabética (CAD), el Estado Hiperglucémico Hiperosmolar (EHH) y la Hipoglucemia, todas ellas asociadas a un control inadecuado o insuficiente de la enfermedad. Con el objetivo de mejorar eficazmente la condición clínica de los pacientes que presentan algún tipo de emergencia hiperglucémica, los médicos del servicio de urgencias deben tener claridad en diversos aspectos clave relacionados con la fisiopatología y el abordaje apropiado para cada situación. En este artículo se reúne la información más actualizada respecto a la definición, epidemiología, etiopatogenia, manifestaciones clínicas, diagnóstico, tratamiento y prevención, de las tres complicaciones agudas de la DM, a fin de ofrecer al clínico una guía práctica para el abordaje y manejo adecuado de los pacientes diabéticos en el contexto de las emergencias hiperglucémicas.

Diabetes Mellitus (DM) represents one of the most prevalent Chronic Noncommunicable Diseases (NCDs) in the world, which acute complications or major hyperglycemic emergencies, in the scenario of emergency medicine, are Diabetic Ketoacidosis (DKA), the State Hyperosmolar hyperglycemic (EHH) and Hypoglycaemia, all associated with inadequate or insufficient control of the disease. In order to effectively improve the clinical condition of patients presenting with some type of hyperglycaemic emergency, emergency department physicians should be clear about various key aspects related to the pathophysiology and the appropriate approach for each situation. This article gathers the most up-to-date information regarding the definition, epidemiology, etiopathogenesis, clinical manifestations, diagnosis, treatment and prevention of the three acute complications of DM mentioned above, in order to offer the clinician a practical guide for the approach and proper management of diabetic patients in the context of hyperglycemic emergencies.

Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility.

The mechanisms of Leishmania resistance to antimonials have been primarily determined in experimentally derived Leishmania strains. However, their participation in the susceptibility phenotype in field isolates has not been conclusively established. Being an intracellular parasite, the activity of antileishmanials is dependent on internalization of drugs into host cells and effective delivery to the intracellular compartments inhabited by the parasite. In this study we quantified and comparatively analyzed the gene expression of nine molecules involved in mechanisms of xenobiotic detoxification and Leishmania resistance to antimonial drugs in resistant and susceptible laboratory derived and clinical L.(Viannia) panamensis strains(n=19). In addition, we explored the impact of Leishmania susceptibility to antimonials on the expression of macrophage gene products having putative functions in transport, accumulation and metabolism of antimonials. As previously shown for other Leishmania species, a trend of increased abcc3 and lower aqp-1 expression was observed in the laboratory derived Sb-resistant L.(V.) panamensis line. However, this was not found in clinical strains, in which the expression of abca2 was significantly higher in resistant strains as both, promastigotes and intracellular amastigotes. The effect of drug susceptibility on host cell gene expression was evaluated on primary human macrophages from patients with cutaneous leishmaniasis (n=17) infected ex-vivo with the matched L.(V.) panamensis strains isolated at diagnosis, and in THP-1 cells infected with clinical strains (n=6) and laboratory adapted L.(V.) panamensis lines. Four molecules, abcb1 (p-gp), abcb6, aqp-9 and mt2a were differentially modulated by drug resistant and susceptible parasites, and among these, a consistent and significantly increased expression of the xenobiotic scavenging molecule mt2a was observed in macrophages infected with Sb-susceptible L. (V.) panamensis. Our results substantiate that different mechanisms of drug resistance operate in laboratory adapted and clinical Leishmania strains, and provide evidence that parasite-mediated modulation of host cell gene expression of molecules involved in drug transport and metabolism could contribute to the mechanisms of drug resistance and susceptibility in Leishmania.

Treatment failure and miltefosine susceptibility in dermal leishmaniasis caused by Leishmania subgenus Viannia species.

Treatment failure and parasite drug susceptibility in dermal leishmaniasis caused by Leishmania (Viannia) species are poorly understood. Prospective evaluation of drug susceptibility of strains isolated from individual patients before drug exposure and at clinical failure allows intrinsic and acquired differences in susceptibility to be discerned and analyzed. To determine whether intrinsic susceptibility or loss of susceptibility to miltefosine contributed to treatment failure, we evaluated the miltefosine susceptibility of intracellular amastigotes and promastigotes of six Leishmania (Viannia) braziliensis and six Leishmania (Viannia) panamensis strains isolated sequentially, at diagnosis and treatment failure, from two children and four adults ≥55 years old with concurrent conditions. Four patients presented only cutaneous lesions, one had mucosal disease, and one had disseminated mucocutaneous disease. Expression of the Leishmania drug transporter genes abca2, abca3, abcc2, abcc3, abcg4, abcg6, and LbMT was evaluated by quantitative reverse transcription-PCR (qRT-PCR). Intracellular amastigotes (median 50% effective concentration [EC50], 10.7 µmol/liter) were more susceptible to miltefosine than promastigotes (median EC50, 55.3 µmol/liter) (P < 0.0001). Loss of susceptibility at failure, demonstrated by a miltefosine EC50 of >32 µmol/liter (the upper limit of intracellular amastigote assay), occurred in L. panamensis infection in a child and in L. braziliensis infection in an adult and was accompanied by decreased expression of the miltefosine transporter LbMT (LbMT/ß-tubulin, 0.42- to 0.26-fold [P = 0.039] and 0.70- to 0.57-fold [P = 0.009], respectively). LbMT gene polymorphisms were not associated with susceptibility phenotype. Leishmania ABCA3 transporter expression was inversely correlated with miltefosine susceptibility (r = -0.605; P = 0.037). Loss of susceptibility is one of multiple factors involved in failure of miltefosine treatment in dermal leishmaniasis.