Special Issue:
Challenges and Opportunities in Systemic Lupus Erythematosus
Ammouri W
Internal Medicine department, Unité d’Hématologie clinique, Ibn Sina Hospital, University Mohamed V of Medicine, Rabat, Morocco
Harmouche H
Internal Medicine department, Unité d’Hématologie clinique, Ibn Sina Hospital, Mohamed V University of Medicine, Rabat, Morocco
Khibri Hajar
Internal Medicine department, Unité d’Hématologie clinique, Ibn Sina Hospital, University Mohamed V of Medicine, Rabat, Morocco
Maamar Mouna
Internal Medicine department, Unité d’Hématologie clinique, Ibn Sina Hospital, University Mohamed V of Medicine, Rabat, Morocco
Mezalek Tazi Zoubida
Internal Medicine department, Unité d’Hématologie clinique, Ibn Sina Hospital, University Mohamed V of Medicine, Rabat, Morocco
Adnaoui Mohamed
Internal Medicine department, Unité d’Hématologie clinique, Ibn Sina Hospital, University Mohamed V of Medicine, Rabat, Morocco.
Abstract
Macrophage activation syndrome can be primary with a genetic etiology, or secondary, associated with malignancies, infections or systemic diseases. Its a severe and potentially life-threatening complication of autoimmune diseases. The incidence of MAS among patients with systemic lupus erythematosus is not well known, as most of the previous studies were limited to a small number of case series or case reports. In recent years it has been suggested that macrophage activation syndrome in systemic lupus erythemaosus may be underrecognized because it can mimic the clinical features of the underlying disease or be confused with an infectious complication. The diagnosis of macrophage activation sydrome in adults is supported by hyperferritinemia (higher than 2000 ng/ml), and/or splenomegaly, pronounced cytopenias, hypofibrinogenemia, characteristic cytokine profile and hypertriglyceridemia. In the case of systemic lupus erythematosus flare, hyerferritinemia is the strongest indicator to differentiate them from MAS. So far, no validated and universally embraced diagnostic criteria for macrophage activation syndrome in adult secondary to systemic lupus erythematosus are available. It is important to know the parameters that can guide the clinician towards the diagnosis of macrophage activation syndrome in adult with systemic lupus. Early diagnosis and intensive therapy are essential in improving clinical outcomes. Hence, we decided to write this mini- review to focus on the demographic data, on the pathophysiological mechanisms, clinical and laboratory manifestations, treatments, and outcomes of patients with systemic lupus erythematosus associated macrophage activation syndrome.
Marta E. Alarcón-Riquelme
Center for Genomics and Oncological Research (GENyO). Pfizer/University of Granada/Andalusian Government; Institute for Environmental Medicine, Karolinska InstituWtet, Stockholm, Sweden
Ruth D. Rodríguez
Center for Genomics and Oncological Research (GENyO). Pfizer/University of Granada/Andalusian Government
Abstract
The clinical and genotypic characterization of autoimmune diseases, including systemic lupus erythematosus (SLE), has made great strides recently as a result of tremendous advancements in gene sequencing technologies. Systemic lupus erythematosus is a complex multisystem disease characterized by high clinical variability due to abnormalities in both the innate and adaptive immune systems. Several genetic variants as well as environmental and hormonal factors have been identified, but the etiology of lupus is not fully understood yet. The ability of genome-wide association studies to scan thousands of individuals has enabled researchers to associate thousands of common variants to lupus. Common polymorphisms may jointly predispose to lupus, but their individual impact on the disease is minimal. It’s becoming progressively more evident that rare mutations have a far higher influence. The role of rare variation in lupus has been the subject of intense research. Several approaches including genotyped-based follow-up of the variants in families, hierarchical screening, and imputation, have been applied to elucidate their functional involvement. Nevertheless, due to their rarity and the absence of standardized methodology, rare variants are still challenging to study.
Most lupus patients present a polygenic form of the disease, which is defined by the complex interplay between genetic and environmental factors. Still, certain lupus patients and patients with lupus-like phenotypes might be affected by monogenic lupus, a group of disorders largely caused by individual gene mutation abnormalities. Although monogenic lupus is rare, it has been associated with a sizable number of genes in a range of pathways, mostly resulting in early-onset phenotypes. The study of rare variants causing monogenic lupus has resulted in incredibly useful breakthroughs in our understanding of the f
Teresa V. Gouveia
Department of Internal Medicine, Centro Hospitalar Lisboa-Norte, Lisboa, Portugal.
Lucía B. Molinero
Department of Internal Medicine, Hospital Provincial del Centenario, Rosario, Argentina.
David A. Isenberg
Centre for Rheumatology, Department of Medicine, University College London, London, United Kingdom
Abstract
Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease, which involves the production of class-switched autoantibodies against intracellular antigens, particularly nuclear antigens, leading to tissue damage and immune complex deposition in multiple organs. Strategies for B cell modulation include direct depletion using monoclonal antibodies, such as rituximab, or indirect impairment of survival via targeting B cell activating factors, notably belimumab. While the pursuit of autoreactive B cell modulation has yielded progress, challenges persist, including modest therapeutic responses, allergic reactions and infections. Thus, to overcome these challenges and focus on achieving a more effective B cell depletion, new strategies may involve fully humanized monoclonal antibodies, such as obinutuzumab, which demonstrated promising results in the NOBILITY study, involving patients with lupus nephritis, Another approach is the use of chimeric antigen receptor T cells therapy, a strategy that has been approved for the treatment of patients with relapsed or refractory B-cell malignancies and has been shown in lupus patients to lead to a rapid and sustained breakdown of the B cell-mediated autoimmune response, reported to lead to drug-free remission of refractory SLE. In addition, combinations of existing therapies and innovative cellular approaches, such rituximab plus belimumab, have been studied. There have now been four studies describing the use of a rituximab plus belimumab in lupus nephritis and non-renal lupus. In the BEAT-LUPUS, the primary endpoint (reduction in anti-double strand DNA) was achieved, however, in BLISS-BELIEVE study the primary endpoint (Systemic Lupus Erythematosus Disease Activity Index 2000) was not met. The CALIBRATE trial was a safety study. The SynBioSe 1 study demonstrated clinical improvement, as indicated by the Systemic Lupus Erythematosus Disease Activity Index and Lupus Low Disease Activity State indices.
This review will provide a brief review of the established conventional approaches to B cell depletion and then discuss the trends towards innovative concepts aimed at achieving this goal.
Niclas Stefan Rasmussen
Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Copenhagen Research Center for Autoimmune Connective Tissue Diseases – COPEACT, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Søren Jacobsen
Copenhagen Research Center for Autoimmune Connective Tissue Diseases – COPEACT, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Claus Henrik Nielsen
Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Christoffer Tandrup Nielsen
Copenhagen Research Center for Autoimmune Connective Tissue Diseases – COPEACT, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Abstract
Background: Generation of galectin-3 binding protein (G3BP)-expressing microvesicles can be induced in-vitro by Toll-like receptor 9 ligation in mononuclear cells. Microvesicles co-expressing G3BP and double-stranded DNA are associated with active lupus nephritis. However, whether the microvesicular G3BP mainly deposits from circulation or is endogenously derived is unknown. In this study, we aim to delineate the origin of G3BP on in-vitro generated microvesicles by using serum as a source of native G3BP.
Methods: G3BP-expressing microvesicles, generated by stimulation of systemic lupus erythematosus patient-derived mononuclear cells with the Toll-like receptor 9-agonist ODN2395, were incubated with normal human serum, heat-inactivated human serum, recombinant human C1q or human albumin. The expression of G3BP by microvesicles was examined by flow cytometry, and the binding of soluble recombinant human C1q to recombinant human G3BP was investigated by ELISA.
Results: Approximately half of the microvesicles released from mononuclear cells expressed G3BP. Surprisingly, the staining was abrogated by incubation of the microvesicles with normal human serum, while incubation with heat-inactivated human serum did not have a similar effect. Reasoning that C1q might be the heat-labile factor blocking access of our G3BP antibody detection system, we incubated microvesicles with recombinant human C1q, which on average inhibited the detectable proportion of G3BP-bearing microvesicles by 87%. Soluble recombinant human C1q bound to immobilized recombinant human G3BP in a dose-dependent manner.
Conclusion: Our data suggest that soluble C1q binds to G3BP on Toll-like receptor 9-induced microvesicles released from systemic lupus erythematosus patient-derived mononuclear cells. This interaction may exarcerbate inflammation in systemic lupus erythematosus but may also serve as a general mechanism for the appropriate clearance of these potentially pathogenic factors.
Eduardo D. Jiménez-Becerra
Laboratorio de Hematología, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Yucatán, México.
Julian Ramírez-Bello
Subdirección de Investigación Clínica, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City, Mexico.
Yumi E. Nakazawa-Ueji
Laboratorio de Hematología, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Yucatán, México.
Lizbeth J. González-Herrera
Laboratorio de Genética, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Yucatán, México.
Rodrigo Rubi-Castellanos
Laboratorio de Genética, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán, Yucatán, México.
Rosa E. Barbosa-Cobos
Servicio de Reumatología, Hospital Juárez de México, Mexico City, Mexico.
Angélica V. Angulo-Ramírez
Servicio de Reumatología, Hospital General “Dr. Agustín O’Horán”, Yucatán, Mexico.
Guillermo Valencia Pacheco
Abstract
Introduction: Systemic lupus erythematosus is an autoimmune disease with higher prevalence in women. Single nucleotide variants in genes involved in the regulation of autoreactive cells, such as PTPN22 rs2488457C˃G, and TRAF1-C5 rs10818488A˃G and rs3761847G˃A, have been associated with the disease in some populations; however, little is known about these variants in the Mexican mestizo population. Aim: We analyzed whether these variants are associated with lupus in women from Central Mexico and Yucatan. Methods: DNA samples from two hundred female patients with lupus (100 from Yucatan and 100 from Central Mexico) and 200 female healthy controls (100 from Yucatan and 100 from Central Mexico) were genotyped. Allelic and genotypic frequencies of variants were calculated and their association with lupus was analyzed. Results: Distribution of risk allele PTPN22 rs2488457G ranged 36% to 48%, while TRAF1-C5 rs10818488A and rs3761847G ranged from 34% to 40%. Heterozygous C/G was the most frequent for PTPN22 rs2488457 in all studied groups, while TRAF1-C5 heterozygous genotype was the most frequent in cases of Yucatan and controls from Central Mexico. However, we did not find significant differences in allelic and genotypic frequencies of PTPN22 and TRAF1-C5 variants, neither its haplotypes between cases and controls, suggesting a lack of association for lupus in the two Mexican populations. Conclusion: The PTPN22 rs2488457C˃G and TRAF1-C5 rs10818488A˃G and rs3761847G˃A variants do not confer susceptibility with the development of lupus in both studiedpopulations. However, the strong linkage disequilibrium observed in the TRAF1-C5 haplotypes suggests that they are co-inherited together and could be involved in the development of the disease in association with other genes or risk factors, as well as the Caucasian influence.
Dr. Manjuri Sharma
Prof & Head, Dept. of Nephrology, Gauhati Medical College & Hospital.
Dr. Benjamin S Sangma
Senior Resident, Dept. of Nephrology, Gauhati Medical College & Hospital.
Abstract
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with varied manifestations, significantly impacting women and potentially leading to Lupus Nephritis (LN), a major cause of morbidity and mortality. The review article explores the unique challenges and opportunities in managing lupus nephritis (LN) in North Eastern India, a region characterised by diverse ethnicities, cultures, and socioeconomic challenges. With a higher than average prevalence of systemic lupus erythematosus (SLE) and lupus nephritis (LN), the region presents distinct epidemiological patterns, likely influenced by genetic, environmental, and lifestyle factors. The management and prognosis of LN are further complicated by the region’s geographical and infrastructural limitations, including access to specialised healthcare and socioeconomic barriers, which impacts the patient’s outcome. Despite the challenges, there are emerging opportunities for improvement through innovations in healthcare delivery, governmental and non-governmental initiatives aimed at enhancing healthcare access, and the adaptation of treatment guidelines to the local context. This review article underscores the importance of region-specific research and healthcare strategies to improve care and outcome for lupus nephritis (LN) patients in North Eastern India, thus contributing to the broader understanding of the disease in diverse populations and settings.
Iman Kandil
Department of Rheumatology and Rehabilitation, Faculty of Medicine – Zagazig University, Zagazig, Egypt.
Background: Systemic lupus Erthymatosus (SLE) affects predominantly women of reproductive age, and can lead to both negative effect on their fertility and adverse pregnancy outcomes. Antimullerian hormone (AMH) serum levels have been found to be a reliable marker of ovarian reserve.
Objectives: This research aimed to assess ovarian reserve by measuring AMH level in premenopausal SLE patients and to study different factors that can have an effect on it, and also to evaluate pregnancy outcomes in SLE patients.
Methods: The study was performed on 60 subjects divided into 2 groups; (I): 30 SLE female patients and (II): control group which includes 30 healthy female subjects. Full history taking and examination were carried out including assessment of disease activity by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) score and damage index by Systemic Lupus International Collaborating Clinics American College of Rheumatology Damage index (SLICC/ACR) on SLE patients, pregnancy questionnaire were used for taking history of the pregnancy outcomes. AMH levels were measured in both groups using AMH Gen II ELISA kits.
Results: There was no statistically significant difference between both groups as regard to median AMH levels and there was no statistically significant correlation between AMH and disease duration, BMI, SLEDAI-2K activity score, damage index and the immunosuppressive drugs such as cyclophosphamide, mycophenolate mofetil and azathioprine. There was statistically significant difference between both groups as regards to occurrence of miscarriage (P<0.0166) and hypertension in pregnancy (P<0.04).
Conclusion: From these results we can conclude that AMH values did not differ between SLE patients and healthy subjects, and the disease duration and/or activity did not affect its level. Moreover, the study reflected that immunosuppressive agents such as cyclophosphamide, azathioprine and mycophenolate mofetil did not affect the fertility in SLE patients. However, it was noted that adverse pregnancy outcomes were relatively more common in SLE patients, namely hypertension in pregnancy and miscarriages.
Laurent Chiche
Department of Internal Medicine, Lupus Living Lab, Hôpital Européen, Marseille, France
Guillemette Thomas
Department of Internal Medicine, Lupus Living Lab, Hôpital Européen, Marseille, France
Noémie Jourde-Chiche
Aix-Marseille Université, C2VN, INSERM, INRAE; AP-HM, CHU Conception, Centre de Néphrologie et Transplantation Rénale, Marseille, France
Thomas Escoda
Department of Internal Medicine, Lupus Living Lab, Hôpital Européen, Marseille, France
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease, which can be clinically heterogeneous in the same patient over the disease process and has an unpredictable evolution. Although its prevalence is increasing, SLE remains a rare disease with frequent extra-articular manifestations managed by multiple specialists. Among these, the internist is a key player in the overall coordination of the care pathway. The dramatic improvement in the short-term prognosis of SLE observed over the past few decades has favoured the emergence of more chronic disease-associated morbidities, especially infectious, cardiovascular and/or related to sequelae, notably renal. Thus, every lupologist is confronted with the difficulty of having to address, in an educational, individualised but also systematic way, a certain number of key items on which the short-, medium- and long-term medical future of patients who develop SLE at a relatively young age depend. In recent years, in addition to the creation of a network of reference centres and the drafting of regularly updated national therapeutic guidelines and therapeutic education programs, international consensus about the factors to consider in SLE patients has been reached, including the definition of therapeutic objectives according to a treat-to-target (T2T) strategy. However, the translation of these new objectives/paradigms in real-life has encountered a number of difficulties. As part of a multidisciplinary team involving SLE patients, we developed practical tools in the form of CHECKLISTs addressing the problems of refractory SLE (D2T), the management of comorbidities and toxicities (BASICs), and, more recently, therapeutic de-escalation with a shared medical decision (T2U). It appears that there is an opportunity to transform the care pathway of SLE patients by allowing the implementation of these tools within adaptive structuring of the consultation, which has the advantage of defining a starting point within the care pathway as a common denominator for lupologists, regardless of their specialty or where they work.
Abstract
Background: In the majority of lupus patients, lupus nephritis (LN) develops within the first five years of diagnosis. Here we evaluated patients treated in our department during the past 40 years distinguishing those with very early onset [within one year of diagnosis]; early onset [ two to five years post diagnosis]; medium-term onset [between six to ten years after diagnosis]; late onset [presenting six to 15 years after diagnosis] and very late onset LN [presenting 16 years or later after diagnosis]. Early onset [ two to five years post diagnosis]; medium-term onset [between six to ten years after diagnosis]; late onset [presenting six to 15 years after diagnosis] and very late onset LN [presenting 16 years or later after diagnosis].early onset [within two years of diagnosis]; medium-term onset [between two and five years after diagnosis]; late onset [presenting five to ten years after diagnosis] and very late onset LN [presenting ten years after diagnosis].
Aim: To compare the differences in demography, clinical data, serological profile and follow up of patients with LN of early, medium, late and very late onset.
Methods: This was a retrospective study of 226 systemic lupus erythematosus (SLE) patients with biopsy proven nephritis. We focused on a comparison of their epidemiology, serology, clinical and follow-up data.
Results: We identified 97 (43%) very early-onset patients; 69 (31%) early-onset; 28 (12%) medium onset; 22 (10%) late-onset and 10 (4%) very late-onset LN patients. Comparing those patients whose LN was delayed by> 10 years post their lupus diagnosis compared to those with LN onset <10 years we found that these patients were statistically significantly more likely to be Caucasian [p=0.04]; to have arthritis [p=0.001] and to be leucopaenic [p=0.004]. There were no other difference between the groups. Among the 10 patients with very late onset LN there was an increase trend towards them having higher ANA titer (>1:640) [p=0,044] and having biopsy-proven combined type of LN (III+V, IV+V) [p=0.034].
Conclusion: Although the majority of SLE patients who get LN do so within 10 years of diagnosis in our experience 14% [approximately 1:7] developed renal involvement 10 years or more after SLE diagnosis. The observation emphasis the need to be vigilant when caring for SLE patients long term.
Céu Tristão Martins Conceição
Psychologist and Psychoanalyst, PhD – Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
Ivone Minhoto Meinão
Rheumatologist, MD, PhD- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
Sérgio Luís Blay
Professor of Psychiatry and Psychoanalysis, MD, PhD – Department of Psychiatry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
Emília Inoue Sato
Professor of Rheumatology MD, PhD – Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
Abstract
Objective: To evaluate the effectiveness in the long-term follow-up of brief group psychoanalytic psychotherapy in improving quality of life, symptoms, coping strategies, anxiety, and depression levels in systemic lupus erythematosus (SLE) patients.
Methods: Prospective, randomized clinical trial including 80 SLE patients divided into two groups: therapy (n=37) and control (n=43), with standard clinical care. Therapy group received weekly therapy for 20 weeks. The assessments were at baseline, after 20 weeks and after 24 months from the end of intervention. Damage and disease activity were assessed by rheumatologists. Self-administered questionnaires were supervised by blind evaluators: quality of life, symptoms, coping strategies, anxiety, and depression. Intent to treat statistical analysis. Comparisons of variance between groups over time (ANOVA repeated measures). P <0.05 significant.
Results: At baseline, both groups were homogeneous. After intervention, therapy group showed significant improvement in most domains of quality of life, symptoms, all domains of anxiety, and depression and several domains of coping strategies. Benefits in quality of life and coping remained at 24 months follow-up. However, the improvement in anxiety, and depression was not maintained. Medications and clinical variables did not change.
Conclusion: This study showed the effectiveness of brief group psychoanalytic psychotherapy in improving quality of life, symptoms and coping strategies in SLE patients even in the long-term follow-up. Depression and anxiety levels reduced at the end of therapy, although, the improvement did not last 24 months.
Sudden Death in a Young Male Patient: When Lupus and Cardiovascular Disease Intersect
Guilherme Guilherme Trindade Martins Moreira Da Silva, Álvaro Luís Steiner Fernandes de Souza, Anna Carolina Alves Guimarães Aragão, Vitor Guedes Bonisson, Valério Fuks, Álvaro Luís Steiner Fernandes de Souza, Ludmilla da Rocha Freitas Vieitas & Thiago Sant’Anna Coutinho
Abstract
Herein we present the case of a 27-year-old male patient who was recently diagnosed with Systemic Lupus Erythematosus (SLE) associated with nephritis with atypical findings on kidney biopsy and premature cardiovascular disease despite scarce traditional risk factors and negative laboratory findings for antiphospholipid syndrome. A literature review on the epidemiology and pathogenesis of coronary disease in SLE was conducted. The patient was admitted for pulse therapy after refractory disease on outpatient care but evolved with ventricular fibrillation secondary to acute thrombosis in the proximal segment of the anterior left descending artery, with no evidence of atherosclerotic disease. Laboratory findings were also negative for antiphospholipid syndrome both upon diagnosis and after the coronary event. He underwent manual thrombus aspiration and angioplasty with a drug-eluting stent, successfully weaning off mechanical ventilation and vasopressors at the intensive care unit and showing no neurological deficits or left ventricular function impairment. Kidney biopsy later resulted positive for immunoglobulin A nephropathy. The patient was discharged asymptomatic on guideline-directed therapy for coronary disease, warfarin associated with clopidogrel, anti-hypertensive drugs and a combination of immunosuppressants, remaining well on three-month follow-up. SLE is a chronic inflammatory disease that has increasingly been recognized as a major cardiovascular risk factor due to a variety of mechanisms involving accelerated atherosclerosis and thrombosis. As patients survive the first years of disease onset from infection and disease-specific complications, cardiovascular outcomes become a great concern. However, early events such as in this case are possible, especially in the context of flaring disease. We emphasize the importance of an interdisciplinary approach to such patients for better outcomes.
Kumi Inoue
Department of Anatomical and Physiological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan
Osamu Hoshi
Department of Anatomical and Physiological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan
Tetsuo Kubota
Department of Anatomical and Physiological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan; Department of Medical Technology, Tsukuba International University, Ibaraki, Japan.
Abstract
Accumulating evidence suggests that DNA-anti-DNA antibody immune complexes are endocytosed by immune cells, where they ligate intracellular nucleic acid sensors. This results in production of type I interferon or other cytokines, which may be a significant pathogenetic mechanism in systemic lupus erythematosus (SLE). Most studies thus far have been performed using cell-lines or peripheral blood mononuclear cells, but it remains unclear whether cells from the brain can take up such immune complexes. Because permeability of the blood-brain interfaces is suggested to be increased and autoantibodies are detected in cerebrospinal fluid of SLE patients with neuropsychiatric manifestations, we hypothesize that DNA-anti-DNA immune complexes may be internalized by cells in the central nervous system and cause dysregulation of neural networks. As a first step to test this hypothesis, here we investigated whether anti-DNA antibodies can be internalized by live brain cells in vitro.
Primary culture rat astrocytes were incubated for 1 h at 37°C with or without anti-DNA monoclonal antibodies. After washing, fixation, permeabilization and blocking, internalized anti-DNA antibodies were detected by a fluorescent labeled second antibody. We observed that a dsDNA-specific monoclonal antibody entered the nucleus, while a monoclonal antibody cross-reactive with phospholipid and DNA entered the cytoplasm. Isotype-matched control IgG did not enter the cells, suggesting that they were viable and the cell membrane and nuclear membrane were intact at that time. When the cells were incubated at 4°C, internalization of the anti-DNA antibodies was almost completely abolished. This suggests that antibody internalization was not by passive transfer but is an energy-dependent process. Given that astrocytes play indispensable roles in maintaining the function of neural networks, these results may provide a novel perspective on the pathogenetic mechanisms of the neuropsychiatric manifestations often presented in SLE.
Mukund Tinguria
Department of Pathology and Laboratory Medicine Brantford General Hospital 200 Terrace Hill Street Brantford, Ontario Postal Code – N3R 1G9 Canada
Abstract
Celiac disease (CD) is an immune-mediated disorder characterized by intolerance to glutens in certain grains like wheat, barley, and rye. The exposure to the gliadin protein component in susceptible individuals leads to an inflammatory reaction damaging small bowel mucosa with the progressive disappearance of intestinal villi. The damaged intestinal mucosa leads to malabsorption. The usual symptoms of celiac disease include diarrhea, steatorrhea, weight loss, fatigue, and abdominal pain. Diagnosis is based on clinical features, duodenal biopsy, elevated levels of anti-gliadin antibodies, and response to a gluten-free diet. Contrary to common belief, celiac disease is a protein systemic disease rather than merely a pure digestive alteration. Celiac disease is closely associated with genes that code HLA -II antigens mainly of DQ2 and DQ8 classes, production of disease-specific antibodies (i.e., endomysial antibodies), multiorgan involvement, comorbidity with other autoimmune diseases (shared autoimmunity), familial aggregation, and immune system dysregulation.
The clinical presentation of celiac disease can be variable. In mild form, patients can be almost asymptomatic whereas in the most severe form, the patients are at increased risk of life-threatening complications. Celiac disease has a well-known association with other autoimmune diseases such as autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis), diabetes mellitus, autoimmune thyroid diseases, skin diseases such as dermatitis herpetiformis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, psoriasis, sarcoidosis, immune thrombocytopenic purpura, and pancreatitis. In addition, celiac disease may be associated with rare but potentially serious complications such as collagenous sprue, ulcerative jejunoileitis, refractory celiac disease (RCD), enteropathy associated T-cell lymphoma, small bowel adenocarcinoma (SBA), hyposplenism, and cavitating mesenteric lymph node syndrome (CMLNS). The present article describes the clinicopathologic features of these rare but serious complications of celiac disease.
