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1.
Pro- and Anti- Effects of Immunoglobulin A- Producing B Cell in Tumors and Its Triggers.
Zhong, Z, Nan, K, Weng, M, Yue, Y, Zhou, W, Wang, Z, Chu, Y, Liu, R, Miao, C
Frontiers in immunology. 2021;:765044
Abstract
B cells are well known as key mediators of humoral immune responses via the production of antibodies. Immunoglobulin A (IgA) is the most abundantly produced antibody isotype and provides the first line of immune protection at mucosal surfaces. However, IgA has long been a divisive molecule with respect to tumor progression. IgA exerts anti- or pro-tumor effect in different tumor types. In this review, we summarize emerging evidence regarding the production and effects of IgA and IgA+ cells in the tumor microenvironment (TME). Moreover, we discuss that the TME cytokines, host diet, microbiome, and metabolites play a pivotal role in controlling the class-switch recombination (CSR) of IgA. The analysis of intratumoral Ig repertoires and determination of metabolites that influence CSR may help establish novel therapeutic targets for the treatment of cancers.
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Tracking of low disease burden in multiple myeloma: Using mass spectrometry assays in peripheral blood.
Chapman, JR, Thoren, KL
Best practice & research. Clinical haematology. 2020;(1):101142
Abstract
Efforts over the last 5 years have demonstrated that it is technically feasible to detect low levels of monoclonal proteins in peripheral blood using mass spectrometry. These methods are based on the fact that an M-protein has a specific amino acid sequence, and therefore, a specific mass. This mass can be tracked over time and can serve as a surrogate marker of the presence of clonal plasma cells. This review describes the use of mass spectrometry to detect M-proteins in multiple myeloma to date, identifies the challenges of using this biomarker, and describes potential strategies to overcome these challenges. We discuss the work that must be done for these techniques to be incorporated into clinical practice for tracking of low disease burden in multiple myeloma.
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3.
AGA Clinical Practice Update on Diagnosis and Monitoring of Celiac Disease-Changing Utility of Serology and Histologic Measures: Expert Review.
Husby, S, Murray, JA, Katzka, DA
Gastroenterology. 2019;(4):885-889
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Abstract
PURPOSE The purpose of this clinical practice update is to define key modalities in the diagnosis and monitoring of celiac disease (CD) in adults as well as in children and adolescents. METHODS The recommendations outlined in this expert review are based on available published evidence, including cohort and case-control studies of the diagnostic process as well as controlled and descriptive studies of disease management. Best Practice Advice 1: Serology is a crucial component of the detection and diagnosis of CD, particularly tissue transglutaminase-immunoglobulin A (TG2-IgA), IgA testing, and less frequently, endomysial IgA testing. Best Practice Advice 2: Thorough histological analysis of duodenal biopsies with Marsh classification, counting of lymphocytes per high-power field, and morphometry is important for diagnosis as well as for differential diagnosis. Best Practice Advice 2a: TG2-IgA, at high levels (> ×10 upper normal limit) is a reliable and accurate test for diagnosing active CD. When such a strongly positive TG2-IgA is combined with a positive endomysial antibody in a second blood sample, the positive predictive value for CD is virtually 100%. In adults, esophagogastroduodenoscopy (EGD) and duodenal biopsies may then be performed for purposes of differential diagnosis. Best Practice Advice 3: IgA deficiency is an infrequent but important explanation for why patients with CD may be negative on IgA isotype testing despite strong suspicion. Measuring total IgA levels, IgG deamidated gliadin antibody tests, and TG2-IgG testing in that circumstance is recommended. Best Practice Advice 4: IgG isotype testing for TG2 antibody is not specific in the absence of IgA deficiency. Best Practice Advice 5: In patients found to have CD first by intestinal biopsies, celiac-specific serology should be undertaken as a confirmatory test before initiation of a gluten-free diet (GFD). Best Practice Advice 6: In patients in whom CD is strongly suspected in the face of negative biopsies, TG2-IgA should still be performed and, if positive, repeat biopsies might be considered either at that time or sometime in the future. Best Practice Advice 7: Reduction or avoidance of gluten before diagnostic testing is discouraged, as it may reduce the sensitivity of both serology and biopsy testing. Best Practice Advice 8: When patients have already started on a GFD before diagnosis, we suggest that the patient go back on a normal diet with 3 slices of wheat bread daily preferably for 1 to 3 months before repeat determination of TG2-IgA. Best Practice Advice 9: Determination of HLA-DQ2/DQ8 has a limited role in the diagnosis of CD. Its value is largely related to its negative predictive value to rule out CD in patients who are seronegative in the face of histologic changes, in patients who did not have serologic confirmation at the time of diagnosis, and in those patients with a historic diagnosis of CD; especially as very young children before the introduction of celiac-specific serology. MANAGEMENT Best Practice Advice 10: Celiac serology has a guarded role in the detection of continued intestinal injury, in particular as to sensitivity, as negative serology in a treated patient does not guarantee that the intestinal mucosa has healed. Persistently positive serology usually indicates ongoing intestinal damage and gluten exposure. Follow-up serology should be performed 6 and 12 months after diagnosis, and yearly thereafter. Best Practice Advice 11: Patients with persistent or relapsing symptoms, without other obvious explanations for those symptoms, should undergo endoscopic biopsies to determine healing even in the presence of negative TG2-IgA.
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A New Vision of IgA Nephropathy: The Missing Link.
Sallustio, F, Curci, C, Di Leo, V, Gallone, A, Pesce, F, Gesualdo, L
International journal of molecular sciences. 2019;(1)
Abstract
IgA Nephropathy (IgAN) is a primary glomerulonephritis problem worldwide that develops mainly in the 2nd and 3rd decade of life and reaches end-stage kidney disease after 20 years from the biopsy-proven diagnosis, implying a great socio-economic burden. IgAN may occur in a sporadic or familial form. Studies on familial IgAN have shown that 66% of asymptomatic relatives carry immunological defects such as high IgA serum levels, abnormal spontaneous in vitro production of IgA from peripheral blood mononuclear cells (PBMCs), high serum levels of aberrantly glycosylated IgA1, and an altered PBMC cytokine production profile. Recent findings led us to focus our attention on a new perspective to study the pathogenesis of this disease, and new studies showed the involvement of factors driven by environment, lifestyle or diet that could affect the disease. In this review, we describe the results of studies carried out in IgAN patients derived from genomic and epigenomic studies. Moreover, we discuss the role of the microbiome in the disease. Finally, we suggest a new vision to consider IgA Nephropathy as a disease that is not disconnected from the environment in which we live but influenced, in addition to the genetic background, also by other environmental and behavioral factors that could be useful for developing precision nephrology and personalized therapy.
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Recognizing the Leaky Gut as a Trans-diagnostic Target for Neuroimmune Disorders Using Clinical Chemistry and Molecular Immunology Assays.
Simeonova, D, Ivanovska, M, Murdjeva, M, Carvalho, AF, Maes, M
Current topics in medicinal chemistry. 2018;(19):1641-1655
Abstract
BACKGROUND Increased intestinal permeability with heightened translocation of Gramnegative bacteria, also known as "leaky gut", is associated with the pathophysiology of neuroimmune disorders, such as Major Depressive Disorder (MDD), Chronic Fatigue Syndrome (CSF) and (deficit) schizophrenia, as well as with general medical disorders, including irritable bowel syndrome. This review aims to summarize clinical biochemistry and molecular immunology tests that may aid in the recognition of leaky gut in clinical practice. METHODS We searched online libraries, including PubMed/MEDLINE, Google Scholar and Scopus, with the key words "diagnosis" or "biomarkers" and "leaky gut", "bacterial translocation", and "intestinal permeability" and focused on papers describing tests that may aid in the clinical recognition of leaky gut. RESULTS To evaluate tight junction barrier integrity, serum IgG/IgA/IgM responses to occludin and zonulin and IgA responses to actomyosin should be evaluated. The presence of cytotoxic bacterial products in serum can be evaluated using IgA/IgM responses to sonicated samples of common Gram-negative gut commensal bacteria and assays of serum lipopolysaccharides (LPSs) and other bacterial toxins, including cytolethal distenting toxin, subunit B. Major factors associated with increased gut permeability, including gut dysbiosis and yeast overgrowth, use of NSAIDs and alcohol, food hypersensitivities (IgE-mediated), food intolerances (IgG-mediated), small bacterial overgrowth (SIBO), systemic inflammation, psychosocial stressors, some infections (e.g., HIV) and dietary patterns, should be assessed. Stool samples can be used to assay gut dysbiosis, gut inflammation and decreased mucosal defenses using assays of fecal growth of bacteria, yeast and fungi and stool assays of calprotectin, secretory IgA, β-defensin, α- antitrypsin, lysozyme and lactoferrin. Blood and breath tests should be used to exclude common causes of increased gut permeability, namely, food hypersensitivities and intolerances, SIBO, lactose intolerance and fructose malabsorption. DISCUSSION Here, we propose strategies to recognize "leaky gut" in a clinical setting using the most adequate clinical chemistry and molecular immunology assays.
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Tests for Serum Transglutaminase and Endomysial Antibodies Do Not Detect Most Patients With Celiac Disease and Persistent Villous Atrophy on Gluten-free Diets: a Meta-analysis.
Silvester, JA, Kurada, S, Szwajcer, A, Kelly, CP, Leffler, DA, Duerksen, DR
Gastroenterology. 2017;(3):689-701.e1
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Abstract
BACKGROUND & AIMS Tests to measure serum endomysial antibodies (EMA) and antibodies to tissue transglutaminase (tTG) were developed to screen for celiac disease in patients consuming gluten. However, they are commonly used to monitor patients on a gluten-free diet (GFD). We conducted a meta-analysis to assess the sensitivity and specificity of tTG IgA and EMA IgA assays in identifying patients with celiac disease who have persistent villous atrophy despite a GFD. METHODS We searched PUBMED, EMBASE, BIOSIS, SCOPUS, clinicaltrials.gov, Science Citation Index, and Cochrane Library databases through November 2016. Inclusion criteria were studies of subjects with biopsy-confirmed celiac disease, follow-up biopsies, and measurement of serum antibodies on a GFD, biopsy performed on subjects regardless of symptoms, or antibody test results. Our analysis excluded subjects with refractory celiac disease, undergoing gluten challenge, or consuming a prescribed oats-containing GFD. Tests were considered to have positive or negative findings based on manufacturer cut-off values. Villous atrophy was defined as a Marsh 3 lesion or villous height:crypt depth ratio below 3.0. We constructed forest plots to determine the sensitivity and specificity of detection for individual studies. For the meta-analysis, a bivariate random effects model was used to jointly model sensitivity and specificity. RESULTS Our search identified 5408 unique citations. Following review of abstracts, 442 articles were reviewed in detail. Only 26 studies (6 of tTG assays, 15 of EMA assays, and 5 of tTG and EMA assays) met our inclusion criteria. The most common reason studies were excluded from our analysis was inability to cross-tabulate histologic and serologic findings. The serum assays identified patients with persistent villous atrophy with high levels of specificity: 0.83 for the tTG IgA assay (95% CI, 0.79-0.87) and 0.91 for the EMA IgA assay (95% CI, 0.87-0.94). However, they detected villous atrophy with low levels of sensitivity: 0.50 for the tTG IgA assay (95% CI, 0.41-0.60) and 0.45 for the EMA IgA assay (95% CI, 0.34-0.57). The tests had similar levels of performance in pediatric and adult patients. CONCLUSIONS In a meta-analysis of patients with biopsy-confirmed celiac disease undergoing follow-up biopsy on a GFD, we found that tests for serum tTG IgA and EMA IgA levels had low sensitivity (below 50%) in detection of persistent villous atrophy. We need more-accurate non-invasive markers of mucosal damage in children and adults with celiac disease who are following a GFD.
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The mucosa-kidney axis in IgA nephropathy.
Floege, J, Feehally, J
Nature reviews. Nephrology. 2016;(3):147-56
Abstract
Links between IgA nephropathy (IgAN) and the mucosa have been recognized since the 1970s. In particular, the observation of visible haematuria induced by respiratory infections in patients with IgAN and the association of IgAN with diseases in which the mucosa plays a part, especially coeliac disease, have been taken as evidence of a mucosa-kidney axis. Here, we review current evidence that links the mucosa, in particular the gastrointestinal mucosa, and IgA produced by the bone marrow with IgAN. Genome-wide association studies in patients with IgAN have identified risk loci in genes involved in the intestinal mucosal integrity and immune network. Furthermore, the systemic immune response to mucosal antigens in IgAN is increased. Moreover, patients with IgAN have an increased reactivity to dietary proteins associated with subclinical intestinal mucosal inflammation. Associations between IgAN and gastrointestinal diseases have also been reported in a small number of patients, but whether these diseases share a common pathogenesis or whether gastrointestinal inflammation exacerbates IgAN is uncertain. Indeed, mucosal alterations such as infections could activate the innate immune system, aggravate a pre-existing IgAN and promote disease manifestations such as macrohaematuria. Various clinical interventions and trials targeting the mucosa or presumed mucosa-associated mechanisms have so far not yielded consistent findings and the results of ongoing trials are eagerly awaited.
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Celiac Disease, Wheat Allergy, and Non-Celiac Gluten Sensitivity: What's the Difference?
Mitsinikos, FT, Pietzak, M
Adolescent medicine: state of the art reviews. 2016;(1):19-33
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Contemporary celiac disease diagnosis: is a biopsy avoidable?
Mills, JR, Murray, JA
Current opinion in gastroenterology. 2016;(2):80-5
Abstract
PURPOSE OF REVIEW The duodenal biopsy is the gold standard for the diagnosis of celiac disease. However, given improvements in the performance of serological testing, the possibility of accurately diagnosing celiac disease without the need of a biopsy has attracted interest. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition has revised its recommendations to include a diagnostic algorithm that includes sequential serological testing and human leukocyte antigen genotyping for symptomatic children which would enable a diagnosis of celiac disease to be made in the absence of a confirmatory intestinal biopsy. RECENT FINDINGS Recent studies have evaluated the ESPGHAN guidelines and have mostly corroborated that celiac disease can be accurately diagnosed in specific pediatric patient populations without the need of a biopsy. However, two cautionary points have been raised that warrant further consideration - the success of this approach is highly dependent targeting a population with a high pretest probability of celiac disease, as well, the performance of serology assays must be established and the appropriate use of cutoffs is essential. SUMMARY The duodenal biopsy will remain the gold standard for diagnosing celiac disease in a majority of patients. However, as serology assays evolve and as a greater understanding of the genetic risk factors of celiac disease is achieved, more patients may be accurately diagnosed without the need for a biopsy.
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Dermatitis herpetiformis: pathognomonic transglutaminase IgA deposits in the skin and excellent prognosis on a gluten-free diet.
Reunala, T, Salmi, TT, Hervonen, K
Acta dermato-venereologica. 2015;(8):917-22
Abstract
Dermatitis herpetiformis (DH) is an itchy, blistering skin disease with sites of predilection at the elbows, knees and buttocks. Although DH is mostly asymptomatic, all patients exhibit small bowel villous atrophy or at least coeliac-type inflammatory changes. Deposition of immunoglobulin A (IgA) in the papillary dermis is a key diagnostic feature of DH. Epidermal transglutaminase (TG3) is the antigen for IgA deposited in the skin, and tissue transglutaminase (TG2) is the antigen for IgA deposited in the small bowel mucosa. Clinically silent, but immunologically active coeliac disease in the gut appears to result in IgA TG3 antibody complexes aggregated into DH skin. The prevalence of DH in northern Europe is high (30-75/100,000), but its incidence is decreasing, possibly due to increased recognition of subclinical coeliac disease. The rash and small bowel heal on a gluten-free diet, which is a life-long treatment. The risk of non-Hodgkin's lymphoma is increased, but in patients with DH who adhere strictly to a gluten-free diet long-term prognosis is excellent.