Serum vitamins and homocysteine levels in autoimmune liver disease: A systematic review and meta-analysis.

OBJECTIVE: Vitamins and homocysteine (Hcy) are involved in liver metabolism and related to the pathogenesis of autoimmune liver disease (AILD), but consensus is lacking. This study aims to systematically summarize relevant evidence to clarify the association of serum vitamins and Hcy levels with AILD. METHODS: The English and Chinese literature was searched until August 29, 2023. Studies were included if they were observational studies of investigating serum vitamins and Hcy levels in patients with AILD and their healthy comparisons. Quality assessment was performed by using the Newcastle-Ottawa Scale, and a meta-analysis was conducted using ReviewManager 5.3. The protocol was registered in the international prospective register of systematic reviews (PROSPERO), with registration number CRD42023455367. RESULTS: A total of 25 case-control studies comprising 3487 patients (1673 patients and 1814 healthy controls) were included for analysis. There were 548 autoimmune hepatitis (AIH) cases, 1106 primary biliary cholangitis (PBC) cases, and 19 primary sclerosing cholangitis (PSC) cases. We found that serum A and E were decreased in both AIH and PBC/PSC; but vitamin C was reduced only in patients with PBC, not AIH. In addition, decreased content of 25(OH)D3 was found in both AIH and PBC. However, levels of 25(OH)D did not differ between the patients and controls, and were independent of disease types and the country. Only one study that met the inclusion criteria reported vitamin B6, B9, B12, and Hcy changes, and found that vitamin B6 and B9 were significantly decreased in patients with PBC, while serum vitamin B12 and Hcy levels were significantly elevated in them. One eligible study each confirmed a reduction in plasma vitamin K1 and 1,25(OH)2D3 in patients with PBC. CONCLUSION: Most vitamins are deficient in AILD, so appropriate vitamin supplementation should be necessary. Further studies with larger sample sizes are needed to validate these findings.

The anti-inflammatory effects of exercise on autoimmune diseases: A 20-year systematic review.

BACKGROUND: The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune diseases. The aim of this systematic review was to examine the evidence on the role of exercise training in mitigating inflammation in adolescents and adults with autoimmune disease. METHODS: PubMed, Web of Science, and Embase databases were systematically reviewed for related studies published between January 1, 2003, and August 31, 2023. All randomized and non-randomized controlled trials of exercise interventions with autoimmune disease study participants that evaluated inflammation-related biomarkers were included. The quality of evidence was assessed using the Tool for the assEssment of Study qualiTy and reporting in EXercise scale and Cochrane bias risk tool. RESULTS: A total of 14,565 records were identified. After screening the titles, abstracts, and full texts, 87 were eligible for the systematic review. These studies were conducted in 25 different countries and included a total of 2779 participants (patients with autoimmune disease, in exercise or control groups). Overall, the evidence suggests that inflammation-related markers such as C-reactive protein, interleukin 6, and tumor necrosis factor α were reduced by regular exercise interventions. Regular exercise interventions combined with multiple exercise modes were associated with greater benefits. CONCLUSION: Regular exercise training by patients with autoimmune disease exerts an anti-inflammatory influence. This systematic review provides support for the promotion and development of clinical exercise intervention programs for patients with autoimmune disease. Most patients with autoimmune disease can safely adopt moderate exercise training protocols, but changes in inflammation biomarkers will be modest at best. Acute exercise interventions are ineffective or even modestly but transiently pro-inflammatory.

[Hyperferritinemia in a Chilean Academic Healthcare Network: A Retrospective Study]. / Hiperferritinemia: Experiencia de un Centro Universitario en Chile.

INTRODUCTION: The distribution of causes of hyperferritinemia in international series is heterogeneous. Also, the association between ferritin and prognosis is controversial. This study aims to describe the diagnosis associated with hyperferritinemia in a retrospective cohort at an academic healthcare network in Chile. METHODS: A retrospective review of adult patients admitted to our academic medical center from June 2014 to February 2017 with ferritin ≥3,000 ng/mL. All patients were classified into nine diagnostic categories. Then, the association between ferritin level and disease category, as well as mortality, was evaluated. RESULTS: Ninety-nine patients were identified. The mean age was 50.8 ± 19.9 years, 54.5% were men. The most frequent categories were "inflammatory and autoimmune diseases" (21.2%) and "hematological malignancies" (19.2%). The average ferritin was 10,539 ± 13,016.9 ng/mL, while the higher mean was 16,707 ng/mL in the "inflammatory and autoimmune diseases" category. There was a statistically significant association between the ferritin value and age but not between ferritin and diagnostic categories. In the group over 50, hematologic neoplasms (19%) and infections (19%) were more frequent. In those under 50, inflammatory and autoimmune diseases were more frequent (26.8%). There was no association between the ferritin level and mortality at 1, 3, and 12 months. CONCLUSIONS: The most frequent categories were "inflammatory and autoimmune diseases" and "hematological malignancies", but ferritin level was similar in both. Further research could validate a prognostic role.

[Utility of the detection of autoantibodies in autoinmune liver diseases using immunoblot]. / Evaluación del panel de enfermedades hepáticas autoinmunes (INMUNOBLOT) en el diagnóstico de enfermedades hepáticas.

INTRODUCTION: For the diagnosis of liver diseases, clinical criteria, biochemical, immunological and histological parameters are included. The autoimmune panel is an immunoblot that contemplates the detection of antibodies against 9 different hepatic antigens, which could guide the diagnosis of these pathologies. OBJECTIVE: To describe the usefulness of the autoimmune panel in the diagnosis of liver diseases. METHODS: Observational, descriptive study. All autoimmune panels performed between January 2020 and August 2021 (n = 279) were reviewed, and the ones with positive result selected (n = 101). Clinical records were reviewed, including: clinical, biochemical, immunological and histological characteristics. Diagnosis was determined by clinical suspicion (clinical, biochemical and immunological parameters), only through autoimmune panel, and according to liver biopsy in available cases. RESULTS: 45 patients with complete clinical history were included in the analysis; 82% women, median age 58 years (16-79). Clinical suspicions included autoimmune hepatitis (AIH) in 12 patients (27%), primary biliary cholangitis (PBC) in 10 patients (22%), overlap syndrome (AIH/PBC) in 17 (38%), and others in 6 (13%). The diagnosis of PBC was confirmed by autoimmune panel in 9/10 and 11/17 patients with clinical suspicion of PBC and HAI/PBC, respectively. Of the 27 patients with initial clinical suspicion of PBC, 14 had negative AMA and AMA-M2 (6 had Sp100 and 5 gp210 as the only markers and 3 had positive Sp100 and PML). In 10/14 patients, the diagnosis was confirmed by panel and/or compatible liver biopsy. CONCLUSION: The autoimmune panel turns out to be a useful diagnostic tool for liver diseases, especially PBC in isolation or in overlap syndrome.

Non-invasive Screening of Autoimmune Atrophic Gastritis in Asymptomatic Subjects by Serological Biomarker Test (GastroPanel®).

BACKGROUND/AIM: To estimate the prevalence of autoimmune atrophic gastritis (AAG) in the Russian Federation, a systematic screening of asymptomatic healthy adults by non-invasive biomarker testing was conducted. The aim was i) To test the validity of non-invasive serological screening for AAG; ii) to establish the prevalence of AAG among asymptomatic adults. PATIENTS AND METHODS: Altogether, 1,283 asymptomatic, healthy adults (mean age: 38 years) were screened by GastroPanel® test. Those with a biomarker profile indicating AG (n=46) were invited for further examinations; 21 consented to gastroscopy with biopsies classified using the Updated Sydney System and Operative Link to Gastric Atrophy. Blood tests included parietal cell, intrinsic factor and thyroid peroxidase antibodies, and analysis of vitamin B12 and iron. RESULTS: Gastroscopy and biopsies confirmed AG in 20 of the individuals. Parietal cell, intrinsic factor and thyroid peroxidase antibodies were present in five, one and eight individuals, respectively. AAG-associated co-morbidities (iron deficiency and pernicious anemia) were diagnosed in 10 out of 21. The final diagnosis of AAG was made in 15 out of 1,283 subjects (1.2%), of whom four were Helicobacter pylori-positive. When corrected for verification bias (non-attendees in the confirmatory tests; n=25), the adjusted prevalence of AAG was 2.6% (33/1,283). CONCLUSION: AAG prevalence of 2.6% is among the highest reported using non-invasive tests. GastroPanel® is an optimal screening tool, providing the first link in the diagnostic protocol leading to the final diagnosis of this condition. The role of Helicobacter pylori as a trigger of AAG cannot be ruled out.

The challenge of early diagnosis of autoimmune lymphoproliferative syndrome in children with suspected autoinflammatory/autoimmune disorders.

OBJECTIVES: To test the usefulness of an extended panel of lymphocyte subsets in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a paediatric rheumatology centre. METHODS: Patients referred from 2015 to 2018 to our rheumatology unit for an autoimmune or autoinflammatory condition were retrospectively analysed. Oliveira's required criteria [chronic lymphoproliferation and elevated double-negative T (DNT)] were applied as first screening. Flow cytometry study included double-negative CD4-CD8-TCRαß+ T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+ T cells, B220+ T cells and CD27+ B cells. Data were analysed with a univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated. RESULTS: A total of 264 patients were included in the study and classified as: (i) autoimmune diseases (n = 26); (ii) juvenile idiopathic arthritis (JIA) (35); (iii) monogenic systemic autoinflammatory disease (27); (iv) periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (100); (v) systemic undefined recurrent fever (45); (vi) undetermined-systemic autoinflammatory disease (14); or (vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαß+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed five clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαß+B220+ lymphocytes. CONCLUSIONS: Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαß+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to the paediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS.

Autoimmune Coagulation Factor X Deficiency as a Rare Acquired Hemorrhagic Disorder: A Literature Review.

Coagulation factor X (F10) amplifies the clotting reaction in the middle of the coagulation cascade, and thus F10 deficiency leads to a bleeding tendency. Isolated acquired F10 deficiency is widely recognized in patients with immunoglobulin light-chain amyloidosis or plasma cell dyscrasias. However, its occurrence as an autoimmune disorder is extremely rare. The Japanese Collaborative Research Group has been conducting a nationwide survey on autoimmune coagulation factor deficiencies (AiCFDs) starting in the last decade; we recently identified three patients with autoimmune F10 deficiency (AiF10D). Furthermore, an extensive literature search was performed, confirming 26 AiF10D and 28 possible cases. Our study revealed that AiF10D patients were younger than patients with other AiCFDs; AiF10D patients included children and were predominantly male. AiF10D was confirmed as a severe type of bleeding diathesis, although its mortality rate was not high. As AiF10D patients showed only low F10 inhibitor titers, they were considered to have nonneutralizing anti-F10 autoantibodies rather than their neutralizing counterparts. Accordingly, immunological anti-F10 antibody detection is highly recommended. Hemostatic and immunosuppressive therapies may help arrest bleeding and eliminate anti-F10 antibodies, leading to a high recovery rate. However, further investigation is necessary to understand the basic characteristics and proper management of AiF10D owing to the limited number of patients.

Ferritin - from iron, through inflammation and autoimmunity, to COVID-19.

While it took decades to arrive to a conclusion that ferritin is more than an indicator of iron storage level, it took a short period of time through the COVID-19 pandemic to wonder what the reason behind high levels of ferritin in patients with severe COVID-19 might be. Unsurprisingly, acute phase reactant was not a satisfactory explanation. Moreover, the behavior of ferritin in patients with severe COVID-19 and the subsequent high mortality rates in patients with high ferritin levels necessitated further investigations to understand the role of ferritin in the diseases. Ferritin was initially described to accompany various acute infections, both viral and bacterial, indicating an acute response to inflammation. However, with the introduction of the hyperferritinemic syndrome connecting four severe pathological conditions such as adult-onset Still's disease, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock added another aspect of ferritin where it could have a pathogenetic role rather than an extremely elevated protein only. In fact, suggesting that COVID-19 is a new member in the spectrum of hyperferritinemic syndrome besides the four mentioned conditions could hopefully direct further search on the pathogenetic role of ferritin. Doubtlessly, improving our understanding of those aspects of ferritin would enormously contribute to better coping with severe diseases in terms of treatment and prevention of complications. The origin, history, importance, and the advances of searching the role of ferritin in various pathological and clinical processes are presented hereby in our article. In addition, the implications of ferritin in COVID-19 are addressed.

Anti-neuron antibody syndrome: clinical features, cytokines/chemokines and predictors.

BACKGROUND: Neuroimmunology is a rapidly expanding field, and there have been recent discoveries of new antibodies and neurological syndromes. Most of the current clinical studies have focused on disorders involving one specific antibody. We have summarized a class of antibodies that target common neuronal epitopes, and we have proposed the term "anti-neuron antibody syndrome" (ANAS). In this study, we aimed to clarify the clinical range and analyse the clinical features, cytokines/chemokines and predictors in ANAS. METHODS: This was a retrospective cohort study investigating patients with neurological manifestations that were positive for anti-neuron antibodies. RESULTS: A total of 110 patients were identified, of which 43 patients were classified as having autoimmune encephalitis (AE) and the other 67 were classified as having paraneoplastic neurological syndrome (PNS). With regards to anti-neuron antibodies, 42 patients tested positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibody, 19 for anti-Hu, 14 for anti-Yo and 12 for anti-PNMA2 (Ma2). There were significant differences between the ANAS and control groups in serum B cell-activating factor (BAFF) levels and in cerebrospinal fluid (CSF) C-X-C motif chemokine10 (CXCL10), CXCL13, interleukin10 (IL10), BAFF and transforming growth factor ß1 (TGFß1) levels. Predictors of poor outcomes included having tumours (P = 0.0193) and having a chronic onset (P = 0.0306), and predictors of relapses included having lower levels of CSF BAFF (P = 0.0491) and having a larger ratio of serum TGFß1/serum CXCL13 (P = 0.0182). CONCLUSIONS: Most patients with ANAS had a relatively good prognosis. Having tumours and a chronic onset were both associated with poor outcomes. CSF BAFF and the ratio of serum TGFß1/serum CXCL13 were associated with relapses.

Impact of T cells on neurodegeneration in anti-GAD65 limbic encephalitis.

OBJECTIVE: Direct pathogenic effects of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in autoimmune limbic encephalitis (LE) have been questioned due to its intracellular localization. We therefore hypothesized a pathogenic role for T cells. METHODS: We assessed magnet resonance imaging, neuropsychological and peripheral blood, and CSF flow cytometry data of 10 patients with long-standing GAD65-LE compared to controls in a cross-sectional manner. These data were related to each other within the GAD65-LE group and linked to neuropathological findings in selective hippocampectomy specimen from another two patients. In addition, full-resolution human leukocyte antigen (HLA) genotyping of all patients was performed. RESULTS: Compared to controls, no alteration in hippocampal volume but impaired memory function and elevated fractions of activated HLADR+ CD4+ and CD8+ T cells in peripheral blood and cerebrospinal fluid were found. Intrathecal fractions of CD8+ T cells negatively correlated with hippocampal volume and memory function, whereas the opposite was true for CD4+ T cells. Consistently, antigen-experienced CD8+ T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin-expressing CD8+ T cells were found attached mainly to small interneurons but also to large principal neurons together with wide-spread hippocampal neurodegeneration. 6/10 LE patients harbored the HLA-A*02:01 allele known to present the immunodominant GAD65114-123 peptide in humans. INTERPRETATION: Our data suggest a pathogenic effect of CD8+ T cells and a regulatory effect of CD4+ T cells in patients with long-standing GAD65-LE.

IgM Deficiency in Autoimmune Blistering Mucocutaneous Diseases Following Various Treatments: Long Term Follow-Up and Relevant Observations.

IgM deficiency has been reported in patients with many autoimmune diseases treated with Rituximab (RTX). It has not been studied, in detail, in autoimmune mucocutaneous blistering diseases (AIMBD). Our objectives were: (i) Examine the dynamics of IgM levels in patients with and without RTX. (ii) Influence of reduced serum IgM levels on clinical and laboratory parameters. (iii) Explore the possible molecular and cellular basis for reduced serum IgM levels. This retrospective study that was conducted in a single-center from 2000 to 2020. Serial IgM levels were studied in 348 patients with five AIMBD (pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, and ocular cicatricial pemphigoid) and found decreased in 55 patients treated with RTX, IVIG, and conventional immunosuppressive therapy (CIST). Hence the incidence of decreased serum IgM is low. The incidence of decreased IgM in patients treated with RTX was 19.6%, in patients treated with IVIG and CIST, it was 52.8% amongst the 55 patients. IgM levels in the post-RTX group were statistically significantly different from the IVIG group (p<0.018) and CIST group (p<0.001). There were no statistically significant differences between the groups in other clinical and laboratory measures. Decreased serum IgM did not affect depletion or repopulation of CD19+ B cells. Patients in the three groups achieved clinical and serological remission, in spite of decreased IgM levels. Decrease in IgM was isolated, since IgG and IgA were normal throughout the study period. Decreased IgM persisted at the same level, while the patients were in clinical remission, for several years. In spite of persistent decreased IgM levels, the patients did not develop infections, tumors, other autoimmune diseases, or warrant hospitalization. Studies on IgM deficiency in knockout mice provided valuable insights. There is no universally accepted mechanism that defines decreased IgM levels in AIMBD. The data is complex, multifactorial, sometimes contradictory, and not well understood. Nonetheless, data in this study provides novel information that enhances our understanding of the biology of IgM in health and disease.

Is There a Clinical Significance of Very Low Serum Immunoglobulin E Level?

PURPOSE: High serum immunoglobulin (Ig) E levels are associated with allergies, parasitic infections, and some immune deficiencies; however, the potential effects and clinical implications of low IgE levels on the human immune system are not well-known. This study aims to determine the disorders accompanying very low IgE levels in children and adults. METHODS: The patients whose IgE levels were determined between January 2015 and September 2020 were analyzed, and the patients with an IgE level < 2 IU/mL were included in this study. Demographic data, immunoglobulin levels, autoantibody results, and the diagnoses of the patients were noted from the electronic recording system of the hospital. RESULT: The IgE levels were measured in 34,809 patients (21,875 children, 12,934 adults), and 130 patients had IgE levels < 2 IU/mL. Fifty-seven patients were children (0.26%); 73 were adults (0.56%). There was a malignant disease in 34 (9 of them children) (26%), autoimmune diseases in 20 (3 of them children) (15.4%), and immunodeficiency in 17 (14 of them children) (13.1%) of the patients. The most common reasons were other diseases, immunodeficiency and malignancy in children, and malignancy, autoimmune disorders, and other diseases in the adults, in rank order. The IgE level did not show any correlation with the levels of other immunoglobulins. CONCLUSION: Although rare, a low IgE level has been shown to accompany malignancies, autoimmune disorders, and immune deficiencies. Patients with very low IgE levels should be carefully monitored for systemic disorders.

Comparison of the analytical and clinical performances of two different routine testing protocols for antinuclear antibody screening.

BACKGROUND: The diagnosis of systemic autoimmune rheumatic diseases (SARD) is based on the detection of serum antinuclear antibodies (ANA) for which indirect immunofluorescence (IIF) is the golden standard. New solid-phase immunoassays have been developed to be used alone or in combination with the detection of extractable antinuclear antibodies (ENA) to improve SARD diagnosis. The purpose of this study was to compare the clinical performances of different ANA screening methods alone or in combination with ENA screening methods for SARD diagnosis. METHODS: A total of 323 patients were screened for ANA by IIF, EliA™ CTD Screen, and ELISA methods. Agreements were calculated between the methods. Then, EliA™ CTD Screen positive samples were screened for ENA by line immunoassay (LIA) and fluorescence enzyme immunoassay (FEIA). RESULTS: The diagnostic accuracy of EliA™ CTD Screen (79% sensitivity and 91% specificity) was better than that of ELISA or IIF. The combination of EliA™ CTD plus IIF had the highest sensitivity (93%). ENA determination revealed that Ro52 and Ro60 were the most prevalent specificities. The use of IIF alone was not able of detecting up to 36% of samples positive for Ro52, and 41% for Ro60. CONCLUSIONS: EliA™ CTD Screen has a better diagnostic performance when compared to IIF and ELISA. The combined use of EliA™ CTD Screen and IIF clearly improves the rate and accuracy of SARD diagnosis. The use of EliA™ CTD Screen as first-line screening technique allows the detection of antibodies, which could not be detected by IIF alone.

New developments implicating IL-21 in autoimmune disease.

Elevated interleukin (IL)-21 is a common finding in the tissues and/or sera of patients with autoimmune disease. CD4 T cells are the primary producers of IL-21; often the IL-21 producing CD4 T cells will express molecules associated with follicular helper cells (TFH). Recent work has shown that the CD4 T cell-derived IL-21 is able to promote effector functions and memory differentiation of CD8 T cells in chronic infections and cancer. Autoimmunity has similarities to chronic infections and cancer. However, CD4 T cell-derived IL-21:IL21R signaling in CD8 T cells has not been fully appreciated in the context of autoimmunity. In this review, we assess the current knowledge regarding CD4 T cell-derived IL-21 and IL21R signaling within CD8 T cells and evaluate what implications it has within several autoimmune diseases including systemic lupus erythematous, rheumatoid arthritis, juvenile idiopathic arthritis, type 1 diabetes mellitus, psoriasis, Sjögren's syndrome, vitiligo, antiphospholipid syndrome, pemphigus, and giant cell arteritis.

Hypothalamic-Pituitary Autoimmunity and Related Impairment of Hormone Secretions in Chronic Fatigue Syndrome.

CONTEXT: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness that reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized. OBJECTIVE: This work aims to investigate the occurrence of antipituitary (APA) and antihypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients. METHODS: This is a case-control study conducted in a university hospital setting (Stanford, California, USA; and Naples, Italy). Thirty women with ME/CSF (group 1) diagnosed according to Fukuda, Canadian, and Institute of Medicine criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls. APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands. APA and AHA titers both were assessed and the prevalence of pituitary hormone deficiencies was also investigated. RESULTS: Patients in group 1 showed a high prevalence of AHA (33%) and APA (56%) and significantly lower levels of adrenocorticotropin (ACTH)/cortisol, and growth hormone (GH) peak/insulin-like growth factor-1 (IGF-1) vs controls (all AHA/APA negative). Patients in group 1A (13 patients positive at high titers, ≥ 1:32) showed ACTH/cortisol and GH peak/IGF-1 levels significantly lower and more severe forms of ME/CFS with respect to patients in group 1B (7 positive at middle/low titers, 1:16-1:8) and 1C (10 antibody-negative patients). CONCLUSION: Both AHA and/or APA at high titers were associated with hypothalamic/pituitary dysfunction, suggesting that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

Unboxing dendritic cells: Tales of multi-faceted biology and function.

Often referred to as the bridge between innate and adaptive immunity, dendritic cells (DCs) are professional antigen-presenting cells (APCs) that constitute a unique, yet complex cell system. Among other APCs, DCs display the unique property of inducing protective immune responses against invading microbes, or cancer cells, while safeguarding the proper homeostatic equilibrium of the immune system and maintaining self-tolerance. Unsurprisingly, DCs play a role in many diseases such as autoimmunity, allergy, infectious disease and cancer. This makes them attractive but challenging targets for therapeutics. Since their initial discovery, research and understanding of DC biology have flourished. We now recognize the presence of multiple subsets of DCs distributed across tissues. Recent studies of phenotype and gene expression at the single cell level have identified heterogeneity even within the same DC type, supporting the idea that DCs have evolved to greatly expand the flexibility of the immune system to react appropriately to a wide range of threats. This review is meant to serve as a quick and robust guide to understand the basic divisions of DC subsets and their role in the immune system. Between mice and humans, there are some differences in how these subsets are identified and function, and we will point out specific distinctions as necessary. Throughout the text, we are using both fundamental and therapeutic lens to describe overlaps and distinctions and what this could mean for future research and therapies.

Association of Circulating Vascular Endothelial Growth Factor Levels With Autoimmune Diseases: A Systematic Review and Meta-Analysis.

Background: Autoimmune diseases (ADs) are characterized by immune-mediated tissue damage, in which angiogenesis is a prominent pathogenic mechanism. Vascular endothelial growth factor (VEGF), an angiogenesis modulator, is significantly elevated in several ADs including rheumatoid arthritis (RA), systemic sclerosis (SSc), and systemic lupus erythematosus (SLE). We determined whether circulating VEGF levels were associated with ADs based on pooled evidence. Methods: The analyses included 165 studies from the PubMed, EMBASE, Cochrane Library, and Web of Science databases and fulfilled the study criteria. Comparisons of circulating VEGF levels between patients with ADs and healthy controls were performed by determining pooled standard mean differences (SMDs) with 95% confidence intervals (CIs) in a random-effect model using STATA 16.0. Subgroup, sensitivity, and meta-regression analyses were performed to determine heterogeneity and to test robustness. Results: Compared with healthy subjects, circulating VEGF levels were significantly higher in patients with SLE (SMD 0.84, 95% CI 0.25-1.44, P = 0.0056), RA (SMD 1.48, 95% CI 0.82-2.15, P <0.0001), SSc (SMD 0.56, 95% CI 0.36-0.75, P <0.0001), Behcet's disease (SMD 1.65, 95% CI 0.88-2.41, P <0.0001), Kawasaki disease (SMD 2.41, 95% CI 0.10-4.72, P = 0.0406), ankylosing spondylitis (SMD 0.78, 95% CI 0.23-1.33, P = 0.0052), inflammatory bowel disease (SMD 0.57, 95% CI 0.43-0.71, P <0.0001), psoriasis (SMD 0.98, 95% CI 0.62-1.34, P <0.0001), and Graves' disease (SMD 0.69, 95% CI 0.20-1.19, P = 0.0056). Circulating VEGF levels correlated with disease activity and hematological parameters in ADs. Conclusion: Circulating VEGF levels were associated with ADs and could predict disease manifestations, severity and activity in patients with ADs. Systematic Review Registration: PROSPERO, identifier CRD42021227843.

Antirheumatic therapy is not associated with changes in circulating N-terminal pro-brain natriuretic peptide levels in patients with autoimmune arthritis.

BACKGROUND: Patients with autoimmune arthritis (AA) are at increased risk for impaired cardiac function and heart failure. This may be partly due to the effect of inflammation in heart function. The impact of antirheumatic drugs on cardiac dysfunction in AA remains controversial. Therefore, we aimed to examine effects of antirheumatic treatment on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in AA patients and its relationship to inflammatory markers. METHODS: We examined 115 patients with AA (64 rheumatoid arthritis (RA), 31 psoriatic arthritis and 20 ankylosis spondylitis) starting with methotrexate (MTX) monotherapy or tumor necrosis factor inhibitors (TNFi) with or without MTX co-medication. NT-proBNP (measured in serum by ECLIA from Roche Diagnostics), and other clinical and laboratory parameters were evaluated at baseline, after 6 weeks and 6 months of treatment. RESULTS: NT-proBNP levels did not change significantly after 6 weeks and 6 months of antirheumatic therapy (pbaseline-6weeks = 0.939; pbaseline-6months = 0.485), although there was a modest improvement from 6 weeks to 6 months in the MTX only treatment group (median difference = -18.2 [95% CI = -32.3 to -4.06], p = 0.013). There was no difference in the effects of MTX monotherapy and TNFi regimen on NT-proBNP levels. The changes in NT-proBNP after antirheumatic treatment positively correlated with changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Baseline NT-proBNP levels were related to baseline CRP and ESR levels, and some other established markers of disease activities in crude analyses. CONCLUSION: Circulating levels of NT-proBNP were related to established inflammatory markers at baseline, and the changes in NT-proBNP after antirheumatic treatment were positively related to these markers. Nevertheless, antirheumatic therapy did not seem to affect NT-proBNP levels compared to baseline, even though inflammatory markers significantly improved.