Multiple Autoantibodies Research Articles

Association between the Presence of Autoantibodies Targeting Ficolin-3 and Active Nephritis in Patients with Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of multiple autoantibodies. Antibodies against Ficolin-3 were previously identified in the sera of some SLE patients, but their prevalence and significance have not been yet investigated. The aims of this study were to determine the prevalence of anti-ficolin-3 antibodies among SLE patients and to investigate their potential as diagnostic and/or prognostic biomarkers in SLE. In this retrospective study, sera from SLE patients (n = 165) were selected from a preexisting declared biological collection. Samples from healthy controls (n = 48) were matched with SLE sera. Disease activity was determined according to the SLEDAI score. Anti-ficolin-3, anti-dsDNA and anti-C1q antibodies levels were measured in sera by ELISA. First, a highly significant difference was found in the anti-ficolin-3 levels between SLE patients and healthy subjects. Anti-ficolin-3 antibodies were detected as positive in 56 of 165 (34%) SLE patients. The titer of anti-ficolin-3 antibodies was correlated with the SLEDAI score (r = 0.38, p<0.0001). The presence of anti-ficolin-3 antibodies was associated with anti-C1q and anti-dsDNA antibodies. Regarding associations with clinical manifestations, the presence of active lupus nephritis was significantly associated with the presence of anti-ficolin-3 antibodies (p≤0.001). This association with renal involvement was higher with anti-ficolin-3 or anti-C1q antibodies than with other auto-antibodies. Interestingly, the combination of anti-ficolin-3 and anti-C1q antibodies demonstrated higher specificity than any other serological biomarker. These results suggest that anti-ficolin-3 antibodies could be useful for the diagnosis of active nephritis in SLE patients.

Generation of Two-color Antigen Microarrays for the Simultaneous Detection of IgG and IgM Autoantibodies.

Autoantibodies, which are antibodies against self-antigens, are present in many disease states and can serve as markers for disease activity. The levels of autoantibodies to specific antigens are typically detected with the enzyme-linked immunosorbent assay (ELISA) technique. However, screening for multiple autoantibodies with ELISA can be time-consuming and requires a large quantity of patient sample. The antigen microarray technique is an alternative method that can be used to screen for autoantibodies in a multiplex fashion. In this technique, antigens are arrayed onto specially coated microscope slides with a robotic microarrayer. The slides are probed with patient serum samples and subsequently fluorescent-labeled secondary antibodies are added to detect binding of serum autoantibodies to the antigens. The autoantibody reactivities are revealed and quantified by scanning the slides with a scanner that can detect fluorescent signals. Here we describe methods to generate custom antigen microarrays. Our current arrays are printed with 9 solid pins and can include up to 162 antigens spotted in duplicate. The arrays can be easily customized by changing the antigens in the source plate that is used by the microarrayer. We have developed a two-color secondary antibody detection scheme that can distinguish IgG and IgM reactivities on the same slide surface. The detection system has been optimized to study binding of human and murine autoantibodies.

3 Screen ELISA for High-Throughput Detection of Beta Cell Autoantibodies in Capillary Blood

Testing for beta cell autoantibodies is used for wide-scale identification of early stages of type 1 diabetes. This requires suitable screening assays. We aimed to establish screening that utilized a first step assay (3 Screen) able to detect autoantibodies to the target antigens glutamic acid decarboxylase-65 (GAD), insulinoma-associated antigen 2 (IA-2), and zinc transporter 8 (ZnT8) to identify children positive for multiple beta cell autoantibodies. An ELISA format was used where plates were coated with a mixture of recombinant GAD, IA-2, and ZnT8325W/R-dimer molecules. The performance was determined in venous blood from 686 first-degree relatives of patients with type 1 diabetes, and 200 patients at onset of type 1 diabetes, and applied as a screening assay in capillary blood from 33,639 general population children. The 3 Screen assay sensitivity for detecting autoantibody-positive patients at onset of type 1 diabetes was similar to that achieved by separate radiobinding assays (RBAs) for antibodies to GAD, IA-2, and ZnT8. Results in venous and capillary serum were correlated (R = 0.987). At a threshold corresponding to the 98th centile (29.1 U/mL) of all 33,639 capillary samples, the 3 Screen was positive in 123 samples with two or more RBA-positive antibodies to insulin, GAD, IA-2, or ZnT8, 146 with one antibody, and 479 that were RBA negative for beta cell autoantibodies. A 3 Screen ELISA was developed that was suitable for first step screening of multiple beta cell autoantibodies in capillary blood.

Continuous glucose monitoring and HbA1c in the evaluation of glucose metabolism in children at high risk for type 1 diabetes mellitus

AimsContinuous glucose monitoring (CGM) parameters, self-monitored blood glucose (SMBG), HbA1c and oral glucose tolerance test (OGTT) were studied during preclinical type 1 diabetes mellitus. MethodsTen asymptomatic children with multiple (⩾2) islet autoantibodies (cases) and 10 age and sex-matched autoantibody-negative controls from the Type 1 Diabetes Prediction and Prevention (DIPP) Study were invited to 7-day CGM with Dexcom G4 Platinum Sensor. HbA1c and two daily SMBG values (morning and evening) were analyzed. Five-point OGTTs were performed and carbohydrate intake was assessed by food records. The matched pairs were compared with the paired sample t-test. ResultsThe cases showed higher mean values and higher variation in glucose levels during CGM compared to the controls. The time spent ⩾7.8mmol/l was 5.8% in the cases compared to 0.4% in the controls (p=0.040). Postprandial CGM values were similar except after the dinner (6.6mmol/l in cases vs. 6.1mmol/l in controls; p=0.023). When analyzing the SMBG values higher mean level, higher evening levels, as well as higher variation were observed in the cases when compared to the controls. HbA1c was significantly higher in the cases [5.7% (39mmol/mol) vs. 5.3% (34mmol/mol); p=0.045]. No differences were observed in glucose or C-peptide levels during OGTT. Daily carbohydrate intake was slightly higher in the cases (254.2g vs. 217.7g; p=0.034). ConclusionsGlucose levels measured by CGM and SMBG are useful indicators of dysglycemia during preclinical type 1 diabetes mellitus. Increased evening glucose values seem to be common in children with preclinical type 1 diabetes mellitus.

Staging the progression to type 1 diabetes with prediagnostic markers.

There are an increasing number of markers that are used to predict the occurrence of type 1 diabetes (T1D), and to study the progression of pathologic changes prior to diagnosis. This review discusses some of those markers, particularly markers for which data are available that pertain to the progression to T1D. A study of birth cohorts showed that young children who develop multiple autoantibodies are at a particularly high risk for developing T1D, and that there appears to be a typical sequence for autoantibody development. The measurement of autoantibodies by electrochemiluminescence can increase the prediction accuracy for T1D. A new marker of changes in glucose over 6 months (PS6 M) has potential utility as an endpoint in short-term prevention trials. Markers which combine C-peptide and glucose, such as the Diabetes Prevention Trial-Type 1 Risk Score and the Index60, can increase the accuracy of prediction, and can potentially be utilized as prediagnostic endpoints. β-cell death measurements could have substantial utility in future T1D research. Markers are highly useful for studying the prediction of and progression to T1D. Moreover, markers can possibly be utilized to diagnose T1D at an earlier stage of disease.

Autoantibodies in Autoimmune Liver Diseases-Methods of Detection and Interpretation: An Update for the Reporting Pathologist.

Autoimmune liver disease (AILD) is a type of chronic liver disease with autoimmune etiology. The diagnosis of the disease is multipronged and detection of autoantibodies in AILDs is an important diagnostic tool and it also helps in the classification of the disease. There are multiple autoantibodies that are detected in AILDs but none is diagnostic. Moreover, these autoantibodies are detected in many other pathological and nonpathological conditions. So the significance of seropositivity for these autoantibodies should be known by both the pathologists as well as the clinicians. In addition, there is prognostic significance associated with some of the antibodies and they also sometimes help in the disease monitoring. The whole array of antibodies detected in AILDs is discussed in detail in this review along with their clinical significance and interpretation.

Change in autoantibody and cytokine responses during the evolution of neuromyelitis optica in patients with systemic lupus erythematosus: A preliminary study

Background: Neuromyelitis optica (NMO)–systemic lupus erythematosus (SLE) association is a rare condition characterized by multiple autoantibodies. Objective: To examine if, during the evolution of NMO, anti-AQP4 responses are part of polyclonal B cell activation, and if T cell responses contribute. Methods: In 19 samples of six patients who developed NMO during SLE, we examined the correlation of AQP4-IgG1 and IgM with (i) anti-MOG IgG and IgM, (ii) anti-nuclear, anti-nucleosome and anti-dsDNA IgG antibodies, (iii) cytokines and chemokines in the serum and (iv) longitudinal relation to NMO relapses/remission. Results: AQP4-IgG1 was present 1–2–5 years before the first NMO relapse. During relapse, AQP4-IgG1, ANA, anti-dsDNA and anti-nucleosome antibodies were elevated. Anti-MOG IgG/IgM and AQP4-IgM antibodies were not detected. AQP4-IgG1 antibodies correlated with concentration of anti-nucleosome, IFN-γ,interferon-gamma-induced CCL10/IP-10 and CCL17/TARC (p<0.05, respectively). CCL17/TARC correlated with levels of anti-nucleosome and anti-dsDNA (p<0.05, respectively). Compared to healthy subjects, concentration of IFN-γ and CCL17/TARC was higher in NMO/SLE (p<0.05). Conclusions: AQP4-IgG1 antibodies are present in the sera years before the first NMO attack in patients with SLE; elevation of anti-AQP4 is part of a polyclonal B cell response during NMO relapses; in spite of multiple autoantibodies in the serum, MOG antibodies were not present; Th1 responses accompany autoantibody responses in NMO/SLE.

Adjuvants- and vaccines-induced autoimmunity: animal models.

The emergence of autoimmunity after vaccination has been described in many case reports and series. Everyday there is more evidence that this relationship is more than casual. In humans, adjuvants can induce non-specific constitutional, musculoskeletal or neurological clinical manifestations and in certain cases can lead to the appearance or acceleration of an autoimmune disease in a subject with genetic susceptibility. The fact that vaccines and adjuvants can trigger a pathogenic autoimmune response is corroborated by animal models. The use of animal models has enabled the study of the effects of application of adjuvants in a homogeneous population with certain genetic backgrounds. In some cases, adjuvants may trigger generalized autoimmune response, resulting in multiple auto-antibodies, but sometimes they can reproduce human autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, autoimmune thyroiditis and antiphospholipid syndrome and may provide insights about the potential adverse effects of adjuvants. Likewise, they give information about the clinical, immunological and histologic characteristics of autoimmune diseases in many organs, especially secondary lymphoid tissue. Through the description of the physiopathological characteristics of autoimmune diseases reproduced in animal models, new treatment targets can be described and maybe in the future, we will be able to recognize some high-risk population in whom the avoidance of certain adjuvants can reduce the incidence of autoimmune diseases, which typically results in high morbidity and mortality in young people. Herein, we describe the main animal models that can reproduce human autoimmune diseases with emphasis in how they are similar to human conditions.

A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children.

Progression to type 1 diabetes in children and adolescents is not uniform. Based on individual genetic background and environment, islet autoimmunity may develop at variable age, exhibit different autoantibody profiles and progress to clinical diabetes at variable rates. Here, we aimed to quantify the qualitative dynamics of sequential islet autoantibody profiles in order to identify longitudinal patterns that stratify progression rates to type 1 diabetes in multiple-autoantibody-positive children. Qualitative changes in antibody status on follow-up and progression rate to diabetes were analysed in 88 children followed from birth in the prospective BABYDIAB study who developed multiple autoantibodies against insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and/or zinc transporter 8 (ZnT8A). An algorithm was developed to define similarities in sequential autoantibody profiles and hierarchical clustering was performed to group children with similar profiles. We defined nine clusters that distinguished children with respect to their sequential profiles of IAA, GADA, IA-2A and ZnT8A. Progression from first autoantibody appearance to clinical diabetes between clusters ranged from 6% (95% CI [0, 16.4]) to 73% (28.4, 89.6) within 5years. Delayed progression was observed in children who were positive for only two autoantibodies, and for a cluster of 12 children who developed three or four autoantibodies but were IAA-negative in their last samples, nine of whom lost IAA positivity during follow-up. Among all children who first seroconverted to IAA positivity and developed at least two other autoantibodies (n = 57), the 10year risk of diabetes was 23% (0, 42.9) in those who became IAA-negative during follow-up compared with 76% (58.7, 85.6) in those who remained IAA-positive (p = 0.004). The novel clustering approach provides a tool for stratification of islet autoantibody-positive individuals that has prognostic relevance, and new opportunities in elucidating disease mechanisms. Our data suggest that losing IAA reactivity is associated with delayed progression to type 1 diabetes in multiple-islet-autoantibody-positive children.

Dysregulation of glucose metabolism in preclinical type 1 diabetes.

Long-term prospective studies have provided valuable information about preclinical type 1 diabetes (T1D). Children who have seroconverted to positive for islet autoantibodies have also, in follow-up, had metabolic tests to understand the timing and development of abnormal glucose tolerance and declining insulin secretion before the clinical diagnosis of T1D. First phase insulin response (FPIR) in the intravenous glucose tolerance test (IVGTT) is lower in the progressors positive for multiple islet autoantibodies in all age groups and as early as 4-6 years before the diagnosis when compared with the non-progressors positive for only islet cell antibodies (ICA). An accelerated decline in FPIR is seen in the progressors during the last 1.5 years before the diagnosis. These results indicate that the progressors may have an early intrinsic defect in beta cell development or function. In the oral glucose tolerance test (OGTT) the peak C-peptide response is delayed in the progressors at least 2 years before diagnosis. Glucose levels and HbA1c are increasing about 2 years before clinical diagnosis. An increase in HbA1c and detection of abnormal glucose tolerance in OGTT are useful in the prediction of the timing of clinical onset of T1D. Continuous glucose monitoring (CGM) may be useful in the prediction of T1D as an early indicator of increased glycemic variability but more data from larger series are needed for confirmation. Children followed in the prospective studies are diagnosed earlier and have a decreased frequency of ketoacidosis at the diagnosis of T1D when compared with age-matched cases from the population.

Role of humoral beta-cell autoimmunity in type 1 diabetes.

Islet cell antibodies (ICA) were found for the first time more than 40 yr ago in patients with autoimmune endocrine deficiencies, including type 1 diabetes (T1D). ICA detected by indirect immunofluorescence represent a heterogeneous group of autoantibodies targeting a series of biochemical autoantigens, such as the protein tyrosine phosphatase related islet antigen 2 (IA-2), the 65 kD isoform of glutamic acid decarboxylase (GA65), and zinc transporter 8 (ZnT8) as well as currently unidentified autoantigens. The general view is that the diabetes-associated autoantibodies are not directly involved in beta-cell destruction but function as biomarkers of an ongoing destructive process. The diabetes-associated autoantibodies remain the strongest predictive marker for future development of T1D. Positivity for multiple (≥2) autoantibodies is highly predictive of clinical disease both among first-degree relatives and in the general population. Autoantibody titers are highly variable during the preclinical phase, but in many cases the titers tend to decrease before diagnosis. The first signs of beta-cell autoimmunity may appear early during the first months of life. The majority of those individuals diagnosed with T1D before puberty seroconvert to autoantibody positivity before the age of 3 yr. The natural course and duration of preclinical diabetes vary substantially from one individual to another. The characteristics of the isotype-specific response during preclinical diabetes appear to be antigen-specific. Diabetes-associated autoantibodies may be useful surrogate markers of the subsequent development of T1D in primary prevention trials. T1D may occur, albeit rarely, in the absence of any signs of humoral autoimmunity at diagnosis.

Follicular Helper T Cells in Autoimmunity.

The development of multiple disease-relevant autoantibodies is a hallmark of autoimmune diseases. In autoimmune type 1 diabetes (T1D), a variable time frame of autoimmunity precedes the clinically overt disease. The relevance of T follicular helper (TFH) cells for the immune system is increasingly recognized. Their pivotal contribution to antibody production by providing help to germinal center (GC) B cells facilitates the development of a long-lived humoral immunity. Their complex differentiation process, involving various stages and factors like B cell lymphoma 6 (Bcl6), is strictly controlled, as anomalous regulation of TFH cells is connected with immunopathologies. While the adverse effects of a TFH cell-related insufficient humoral immunity are obvious, the role of increased TFH frequencies in autoimmune diseases like T1D is currently highlighted. High levels of autoantigen trigger an excessive induction of TFH cells, consequently resulting in the production of autoantibodies. Therefore, TFH cells might provide promising approaches for novel therapeutic strategies.

Reversion of β-Cell Autoimmunity Changes Risk of Type 1 Diabetes: TEDDY Study.

β-Cell autoantibodies are a feature of the preclinical phase of type 1 diabetes. Here, we asked how frequently they revert in a cohort of children at risk for type 1 diabetes and whether reversion has any effect on type 1 diabetes risk. Children were up to 10 years of age and screened more than once for insulin autoantibody, GAD antibody, and insulinoma antigen-2 antibodies. Persistent autoantibody was defined as an autoantibody present on two or more consecutive visits and confirmed in two reference laboratories. Reversion was defined as two or more consecutive negative visits after persistence. Time-dependent Cox regression was used to examine how reversion modified the risk of development of multiple autoantibodies and type 1 diabetes. Reversion was relatively frequent for autoantibodies to GAD65 (19%) and insulin (29%), but was largely restricted to children who had single autoantibodies (24%) and rare in children who had developed multiple autoantibodies (<1%). Most (85%) reversion of single autoantibodies occurred within 2 years of seroconversion. Reversion was associated with HLA genotype, age, and decreasing titer. Children who reverted from single autoantibodies to autoantibody negative had, from birth, a risk for type 1 diabetes of 0.14 per 100 person-years; children who never developed autoantibodies, 0.06 per 100 person-years; and, children who remained single-autoantibody positive, 1.8 per 100 person-years. Type 1 diabetes risk remained high in children who had developed multiple β-cell autoantibodies even when individual autoantibodies reverted. We suggest that monitoring children with single autoantibodies for at least 1 year after seroconversion is beneficial for stratification of type 1 diabetes risk.

New Players in the Field of T1D: Anti-Peripherin B Lymphocytes.

B lymphocytes (B cells) play a key role in type 1A diabetes (T1D) via antigen presentation to T cells, but our understanding of their mechanism of action is still evolving (1–6). Pathogenic B cells recognize autoantigens, indicated by T1D-predictive autoantibodies against insulin, GAD65, transmembrane tyrosine phosphatase (IA-2), and zinc transporter 8 (ZnT8) (7). These autoantibodies are not thought to cause T1D but, rather, provide evidence of autoreactive T cell–B cell interactions. Each B cell recognizes a single antigenic site, or epitope, on folded proteins via the antibody variable (V) region of its B-cell receptors (BCRs), internalizes the protein, and processes it into peptides for presentation on MHC class II (MHCII) to T cells (Fig. 1). Thus, autoreactive B cells are uniquely suited to activate autoreactive T cells. Likewise, T cells provide help to B cells, driving antigen-specific germinal center (GC) formation and differentiation into plasma cells that secrete autoantibodies identical to the BCR. Transgenic models provide evidence that B cells must be autoantigen specific to support T1D: anti-insulin B cells present antigen, activate T cells, and promote T1D in nonobese diabetic (NOD) mice (5,6,8). Conversely, NOD mice with transgenic B cells that do not recognize an autoantigen fail to develop diabetes (5,9). While there are multiple T1D-related autoantibodies in humans, to date, insulin has been the only reliable B cell–related autoantigen in NOD mice. In this issue of Diabetes , Leeth et al. (10) report on a new transgenic model in which B cells recognize peripherin, a neuronal antigen, and are able to …

Multiplex giant magnetoresistive biosensor microarrays identify interferon-associated autoantibodies in systemic lupus erythematosus.

High titer, class-switched autoantibodies are a hallmark of systemic lupus erythematosus (SLE). Dysregulation of the interferon (IFN) pathway is observed in individuals with active SLE, although the association of specific autoantibodies with chemokine score, a combined measurement of three IFN-regulated chemokines, is not known. To identify autoantibodies associated with chemokine score, we developed giant magnetoresistive (GMR) biosensor microarrays, which allow the parallel measurement of multiple serum antibodies to autoantigens and peptides. We used the microarrays to analyze serum samples from SLE patients and found individuals with high chemokine scores had significantly greater reactivity to 13 autoantigens than individuals with low chemokine scores. Our findings demonstrate that multiple autoantibodies, including antibodies to U1-70K and modified histone H2B tails, are associated with IFN dysregulation in SLE. Further, they show the microarrays are capable of identifying autoantibodies associated with relevant clinical manifestations of SLE, with potential for use as biomarkers in clinical practice.

Predictors of slow progression to diabetes in children with multiple islet autoantibodies

Although most children with multiple islet autoantibodies develop type 1 diabetes, rate of progression is highly variable. The goal of this study was to explore potential factors involved in rate of progression to diabetes in children with multiple islet autoantibodies. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 118 children with multiple islet autoantibodies for progression to diabetes. After excluding 27 children currently diabetes-free but followed for <10 years, the study population was grouped into: rapid progressors (N = 39) who developed diabetes in <5 years; moderate progressors (N = 25), diagnosed with diabetes within 5–10 years; and slow progressors (N = 27), diabetes-free for >10 years. Islet autoimmunity appeared at 4.0 ± 3.5, 3.2 ± 1.8 and 5.8 ± 3.1 years of age in rapid, moderate and slow progressors, respectively (p = 0.006). Insulin autoantibody levels were lower in slow progressors compared to moderate and rapid progressors. The groups did not differ by gender, ethnicity, family history, susceptibility HLA and non-HLA genes. The rate of development of individual islet autoantibodies including mIAA, GADA, IA-2A and ZnT8A were all slower in the slow versus moderate/rapid progressors. In multivariate analyses, older age at seroconversion and lower initial mIAA levels independently predicted slower progression to diabetes. Later onset of islet autoimmunity and lower autoantibody levels predicted slower progression to diabetes among children with multiple islet autoantibodies. These factors may need to be considered in the design of trials to prevent type 1 diabetes.

Tetraspanin 7 autoantibodies in type 1 diabetes.

Autoantibodies to pancreatic beta cell proteins are markers of asymptomatic type 1 diabetes. The aim was to determine whether autoantibodies to the beta cell protein tetraspanin 7 would improve the ability to identify autoimmunity against pancreatic beta cells. Full length and external domain fragments of tetraspanin 7 were expressed as luciferase-tagged fusion proteins and used in immunoprecipitation assays to measure autoantibodies in samples from 363 patients with type 1 diabetes at onset of disease, 503 beta cell autoantibody negative first-degree relatives of patients, and 212 relatives with autoantibodies to insulin, glutamic acid decarboxylase, insulinoma antigen 2 or zinc transporter 8. Antibody binding was observed against the full length and external domains of tetraspanin 7, and was strongest against the full length protein. Autoantibodies that could be inhibited by untagged tetraspanin 7 were detected in 5 (1%) of 503 autoantibody negative relatives, 3 (3.2%) of 94 autoantibody negative patients, 95 (35.3%) of 269 autoantibody positive patients, 1 (1%) of 98 single autoantibody positive relatives and 25 (21.9%) of 114 multiple autoantibody positive relatives. Progression to diabetes did not differ between multiple autoantibody positive relatives with and without tetraspanin 7 autoantibodies. Tetraspanin 7 is an autoantigen in type 1 diabetes. Tetraspanin 7 autoantibodies are a marker of type 1 diabetes, but provide minor additional value to existing autoantibodies in identifying beta cell autoimmunity.

Zmiany w układzie krążenia u pacjentów z toczniem rumieniowatym układowym

Systemic lupus erythematosus (SLE) is a systemic chronic, inflammatory, autoimmune disease, characterized by various clinical manifestations and production of multiple autoantibodies. Complex immune system dysfunctions as well as chronic inflammatory processes lead to internal organs and tissue failure. The most common cardiovascular manifestations among patients with SLE include accelerated coronary heart disease, pericarditis, myocarditis, valvular disease, Libman–Sacks nonbacterial endocarditis - the most characteristic cardiac manifestation of the SLE, conduction abnormalities, pulmonary hypertension, thromboembolic events, hypertension and heart failure. Accelerated atherosclerosis with coronary heart disease is of key importance for prognosis, particularly among young women. An increased risk of cardiovascular events among patients with SLE has been confirmed in multiple studies. Getting closer to understanding multiple mechanisms of cardiovascular disease and pathogenesis of atherosclerosis in SLE is critical to lower mortality rate in this group population. The aim of this article is to present aetiology and cardiovascular manifestations processes of SLE.

Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study

IntroductionType 1 diabetes can be diagnosed at an early presymptomatic stage by the detection of islet autoantibodies. The Fr1da study aims to assess whether early staging of type 1 diabetes...

Dissecting heterogeneity in paediatric Type 1 diabetes: association of TCF7L2 rs7903146 TT and low-risk human leukocyte antigen (HLA) genotypes.

To test the hypothesis that non-obese individuals with childhood-onset Type 1 diabetes and the rs7903146 TT genotype would be less likely to have high-risk human leukocyte antigen (HLA) genotypes and alleles. We studied a cohort of 105 non-obese participants in the T1D Exchange Biobank Residual Insulin Study who had childhood-onset Type 1 diabetes [mean (sd) age at onset and recruitment, respectively, 9.9 (4.15) and 14.4 (4.13) years; 84.8% non-Hispanic white]. We analysed islet autoantibodies (glutamic acid decarboxylase 65, islet cell autoantigen 512/islet antigen-2 and zinc transporter 8), non-fasting random C-peptide levels, HLA type and TCF7L2 single nucleotide polymorphism rs7903146 in this cohort. None of the 13 individuals with the rs7903146 TT genotype carried the highest Type 1 diabetes risk HLA genotype, i.e. DRB1*03:01/DR4 (DRB1*0401, *04:05 or *04:02), compared with 29.4% (27/92) of those without it (P=0.023). The DRB1*03:01 allele was present in 15.4% (2/13) of individuals with the single nucleotide polymorphism, compared with 59.8% (55/92) of those without it (P=0.003). Analyses restricted to autoantibody-positive individuals (n=80) yielded similar results. The HLA DRB1*15:01 allele, which affords dominant protection against Type 1 diabetes, was found in one participant, who had multiple islet autoantibodies and carried the rs7903146 TT genotype. These findings further support the hypothesis that TCF7L2 gene variation contributes to diabetogenesis in a subset of young people with Type 1 diabetes, opening possible new pathways for therapy and prevention.