Abstract Complex regional pain syndrome (CRPS) is a term used to describe a variety of disorders characterized by spontaneous or stimulus-induced pain that is disproportional to the inciting event ...and accompanied by a myriad of autonomic and motor disturbances in highly variable combinations. There are no standards which can be applied to the diagnosis and would fulfill definitions of evidence-based medicine. Indeed, there are almost as many diagnostic criteria as there are names to this disorder. The umbrella term CRPS has been subdivided into type I and type II. CRPS I is intended to encompass reflex sympathetic dystrophy and similar disorders without a nerve injury; while CRPS II occurs after damage to a peripheral nerve. There are numerous etiological pathophysiological events that have been incriminated in development of CRPS, including inflammation, autoimmune responses, abnormal cytokine production, sympathetic-sensory disorders, altered blood flow and central cortical reorganization. However, the number of studies that have included appropriate controls and have sufficient numbers of patients to allow statistical analysis with appropriate power calculations is vanishingly small. This has led to over-diagnosis and often excessive pharmacotherapy and even unnecessary surgical interventions. In this review we provide a detailed critical overview of not only the history of CRPS, but also the epidemiology, the clinical features, the pathophysiological studies, the proposed criteria, the therapy and, in particular, an emphasis that future research should apply more rigorous standards to allow a better understanding of CRPS, i.e. what it is, if it is, and when it is.
Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but ...includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.
Microbial cells significantly outnumber human cells in the body, and the microbial flora at mucosal sites are shaped by environmental factors and, less intuitively, act on host immune responses, as ...demonstrated by experimental data in germ-free and gnotobiotic studies. Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown, as observed in rheumatic fever triggered by Streptococci via molecular mimicry, epitope spread and bystander effects. The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, multiple sclerosis and autoimmune liver disease. It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena. In fact, there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity, and microbial therapeutics is being investigated to prevent or halt autoimmune diseases. As a putative mechanism, it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens, giving rise to the differentiation of autoreactive Th17 cells and other T helper cells. This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity, with an emphasis on how dysbiosis may influence systemic autoimmunity. In particular, a gut-liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm, considering its anatomic and physiological connections.
The geoepidemiology of type 1 diabetes Borchers, Andrea T; Uibo, Raivo; Gershwin, M.E
Autoimmunity reviews,
03/2010, Letnik:
9, Številka:
5
Journal Article
Recenzirano
Abstract Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by absolute insulin deficiency resulting from the progressive immune-mediated destruction of pancreatic islet β cells. It ...is thought to be triggered by as yet unidentified environmental factors in genetically susceptible individuals, the major genetic contribution coming from loci within the HLA complex, in particular HLA class II. The worldwide incidence of T1D varies by at least 100-fold, being highest in Finland and Sardinia (Italy) and lowest in Venezuela and China. The incidence has been increasing worldwide at an annual rate of approximately 3%. While genetic factors are thought to explain some of the geographic variability in T1D occurrence, they cannot account for its rapidly increasing frequency. Instead, the declining proportion of newly diagnosed children with high-risk genotypes suggests that environmental pressures are now able to trigger T1D in genotypes that previously would not have developed the disease during childhood. Although comparisons between countries and regions with low and high-incidence rates have suggested that higher socioeconomic status and degree of urbanization are among the environmental factors that play a role in the rising incidence of T1D, the findings are too inconsistent to allow firm conclusions. Morbidity and mortality as well as causes of death also show considerable geographic variation. While glycemic control has been identified as a major predictor of the micro- and macrovascular complications of T1D and shows considerable geographical variability, it does not appear to be the only factor involved in the regional differences in complication rates. The role of genetics in susceptibility to nephropathy, retinopathy and other diabetic complications largely remains to be explored.
Summary
The diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication ...of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC. The levels of 667 miRNAs were evaluated in 90 human serum samples (30 PSC, 30 CC and 30 control subjects) to identify disease‐associated candidate miRNAs (discovery phase). The deregulated miRNAs were validated in an independent cohort of 140 samples 40 PSC, 40 CC, 20 primary biliary cirrhosis (PBC) and 40 controls. Receiver operating characteristic (ROC) curves were established and only miRNAs with an area under the curve (AUC) > 0·70 were considered useful as biomarkers. In the discovery phase we identified the following: 21 miRNAs expressed differentially in PSC, 33 in CC and 26 in both in comparison to control subjects as well as 24 miRNAs expressed differentially between PSC and CC. After the validation phase, miR‐200c was found to be expressed differentially in PSC versus controls, whereas miR‐483‐5p and miR‐194 showed deregulated expression in CC compared with controls. We also demonstrate a difference in the expression of miR‐222 and miR‐483‐5p in CC versus PSC. Combination of these specific miRNAs further improved the specificity and accuracy of diagnosis. This study provides a basis for the use of miRNAs as biomarkers for the diagnosis of PSC and CC.
Summary
Primary biliary cholangitis (PBC) is a multi‐factorial disease caused by the interaction of both genetic predisposition and environmental triggers. Bacterial infection has been investigated ...most intensively, both epidemiologically and experimentally, as a prime environmental aetiology in PBC. The association of recurrent history of urinary tract infection (UTI) with PBC has been frequently confirmed by several large‐scale, case–control studies, despite variation in geographic area or case‐finding methods. Escherichia coli is a predominant pathogen in most cases with UTI. Animal studies and molecular mimicry analysis between the human and E. coli E2 subunit of the 2‐oxo‐acid dehydrogenase complexes demonstrated that E. coli infection is a key factor in breaking immunological tolerance against the mitochondria, resulting in the production of anti‐mitochondrial autoantibodies (AMA), the disease‐specific autoantibodies of PBC. Novosphingobium aromaticivorans, a ubiquitous xenobiotic‐metabolizing bacterium, is another candidate which may be involved in the aetiology of PBC. Meanwhile, improved environmental hygiene and increased prevalence of PBC, especially in males, may argue against the aetiological role of bacterial infection in PBC. Multiple mechanisms can result in the loss of tolerance to mitochondrial autoantigens in PBC; nonetheless, bacterial infection is probably one of the dominant pathways, especially in female patients. Notably, there is a rising prevalence of male patients with PBC. With increasing exposure to environmental xenobiotics in both genders, studies directed towards identifying the environmental culprit with systematically designed case–control studies are much needed to further determine the environmental factors and role of bacterial infections in PBC.
In primary biliary cholangitis (PBC) ,the immunodominant epitopes of the disease‐specific autoantibodies, anti‐mitochondrial autoantibodies (AMA) epitopes and T cell epitopes of are mapped within the inner lipoyl domain of E2 subunit of the 2‐oxo‐acid dehydrogenase complexes (PDC‐E2, BCOADC‐E2, OGDC‐E2 and E3BP). Multiple mechanisms can result in the loss of tolerance to mitochondrial autoantigens in PBC; nonetheless, bacterial infection is probably one of the dominant pathways. Animal studies and molecular mimicry analysis between the human and microbial PDC‐E2 demonstrated that E. coli infection is a key factor in breaking immunological tolerance against the mitochondria, resulting in the production of AMA.
Summary
Scleroderma (SSc) is a rare connective tissue disease characterized by fibrosis, microvasculopathy and autoimmune features. The role of genetics is limited in SSc, as suggested by similar ...concordance rates in monozygotic and dizygotic twin pairs, while environmental factors may act through epigenetic changes, as demonstrated for specific genes. Further, sex chromosome changes have been reported in SSc and may explain the female preponderance. In the present study we compared the methylation profile of all X chromosome genes in peripheral blood mononuclear cells from monozygotic twins discordant (n = 7) and concordant (n = 1) for SSc. Methylated DNA immunoprecipitations from each discordant twin pair were hybridized to a custom‐designed array included 998 sites encompassing promoters of all X chromosome genes and randomly chosen autosomal genes. Biostatistical tools identified sites with an elevated probability to be consistently hypermethylated (n = 18) or hypomethylated (n = 25) in affected twins. Identified genes include transcription factors (ARX, HSFX1, ZBED1, ZNF41) and surface antigens (IL1RAPL2, PGRMC1), and pathway analysis suggests their involvement in cell proliferation (PGK1, SMS, UTP14A, SSR4), apoptosis (MTM1), inflammation (ARAF) and oxidative stress (ENOX2). In conclusion, we propose that X chromosome genes with different methylation profiles in monozygotic twin pairs may constitute candidates for SSc susceptibility.
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to ...mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony-stimulating factor-stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention.
Abstract Primary biliary cirrhosis (PBC) is a chronic cholestatic autoimmune liver disease characterized by selective destruction of the intrahepatic bile ducts and highly specific serum ...anti-mitochondrial autoantibodies (AMA). Several studies have attempted to determine the cytokine pattern characterizing PBC, yet no definitive data have been gathered. The present study was designed to evaluate pro-inflammatory cytokines (IL-1β, IL-6, TNFα), soluble IL-2 receptor (sIL-2R, e.g. soluble CD25), and complement components (C1q, C3, factor B, properdin) levels in sera from 84 patients with PBC and 41 controls. PBC was characterized by significantly higher levels of all pro-inflammatory cytokines when compared to controls; these included IL-1β (433.3 ± 13.2 vs. 316.6 ± 14.7 pg/ml, P < 0.001), IL-6 (701 ± 17.4 vs. 158 ± 22.5 pg/ml, P < 0.001), TNFα (3.38 ± 0.6 pg/ml vs. undetectable, P = 0.001), and sIL-2R (1527.1 ± 106 vs. 566.4 ± 28.7 U/ml, P < 0.001). Similarly, all complement components were also significantly higher in PBC compared to control sera. In conclusion, PBC sera manifest higher levels of sIL-2R and complement components and this may reflect a perpetuated immune activation. As expected, we also report that all major pro-inflammatory cytokine levels are enhanced in PBC. Further longitudinal analyses could demonstrate a correlation between these markers and disease stage or inflammatory activity, to predict histological staging, disease activity, and response to treatment.
Abstract Reactive arthritis is a form of seronegative spondyloarthritis clinically associated with inflammatory back pain, additive or migratory oligoarthritis, and extra-articular symptoms that ...typically follow a gastrointestinal or urogenital infection by a minimum of 1 to a maximum of 3–6 weeks. Once arthritis is observed, however, microbial tests and blood or synovial fluid cultures are negative, and only serum antibodies are detected. Reactive arthritis commonly affects young adults, most frequently white and carrying the HLA-B27 allele. The genetic susceptibility appears as necessary with only 1–15% of cases of infection developing reactive arthritis. Clinical symptoms are different from septic arthritis which manifests with fever, systemic signs of infection, and monoarthritis. The presence of large joint oligoarthritis, urogenital tract infection, and uveitis characterizes Reiter's syndrome as a clinical subtype. Ocular, skin, and heart involvement are not uncommon and may be largely variable in severity. Diagnostic criteria are based on the ACR guidelines and include rheumatological signs along with a proof of infection.
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