Elevated Autoantibodies Research Articles

Clinical aspects of granulomatosis with polyangiitis affecting the head and neck

There are many controversies in head and neck granulomatosis with polyangiitis (HN-GPA). Diagnostic/therapeutic regimens vary due to limited knowledge about the special properties of HN-GPA. 28 patients were diagnosed with GPA accordingly. Anti-neutrophil-cytoplasmatic-antibody (ANCA), anti-peroxidase-antibody (anti-PR3) and biopsies were performed for all patients and set into clinical context. 14 patients had sinonasal symptoms. Otological (n = 8) and laryngeal (n = 2) symptoms were usually associated with complex disease activity. Pulmonary and/or renal impairment was present in 14 patients at the time of diagnosis and developed in a further nine patients within 1 year. 21 patients with systemic disease displayed elevated ANCA/anti-PR3. In contrast, those with persistent isolated HN manifestations (n = 6) lacked auto-antibodies. These patients underwent multiple biopsies to diagnose GPA. Interestingly, five patients without clinical HN manifestations but elevated auto-antibodies were identified by nasal "blind" biopsy. Clinical examination, auto-antibody testing, and histology are effective diagnostic tools in HN-GPA. Histological diagnosis remains the gold standard in patients with persistent isolated head and neck manifestations but missing auto-antibodies. Based on our findings, we suggest early and sufficient systemic therapy for all HN-GPA. Nasal mucosal "blind" biopsy should be performed in patients with elevated auto-antibodies but lacking clinical head and neck manifestations.

Th17 cells play a critical role in the development of experimental Sjögren's syndrome

ObjectiveAlthough Th17 cells have been increasingly recognised as an important effector in various autoimmune diseases, their function in the pathogenesis of Sjögren's syndrome (SS) remains largely uncharacterised. This study aims...

Anti-vascular endothelial growth factor receptor (VEGFR) 2 autoantibody identification in glioblastoma patient using single B cell-based antibody gene cloning

Antibody direct cloning from single B cells is simple and efficient and has been successful in antibody identification of infectious diseases. However, although a recent whole-exome sequencing revealed abundant heterogeneic mutation accumulation in cancers, identification and synthesis of autoantibodies against specific cancer-associated antigens is still difficult in cancer patients owing to the very small number of B cells producing autoantibodies. In the present study, to identify autoantibodies targeting tumor antigens, we measured the titer of autoantibodies in high-grade glioma patients’ plasma and identified two patients with elevated autoantibodies to a few transmembrane proteins. Specific B cells producing autoantibody against vascular endothelial growth factor receptor (VEGFR) 2 were immunostained with labeled protein and anti-human IgG antibody, and then collected by a single cell sorter. Finally, 22 antibody genes were successfully identified using direct IgG cloning from single B cell mRNA, and two antibody clones were found to have significant VEGFR2-specific binding affinity.The current direct human IgG gene cloning technique for identifying human antibodies derived from IgG-memory B cells avoids time-consuming procedures such as phage display-based antibody-library screening, and therefore may be applicable to identifying human autoantibodies in a variety of disorders including cancers even when antibody elevation is not detected because of a very small number of memory B cells.

Abstract W P174: Association of Moyamoya Disease With Thyroid Autoantibodies and Thyroid Function: A Case-control Study and Meta-analysis

Background and Purpose: Evidence suggests that elevated thyroid function and elevated levels of thyroid autoantibodies are associated with risk of Moyamoya disease (MMD). Therefore we performed a meta-analysis of all available evidence, including unpublished data from our own center, in order to assess this association. Methods: We reviewed the English- and Chinese-language literature in major databases to identify studies examining the association between MMD and thyroid function or thyroid autoantibodies. We combined these data with those from our own prospective study conducted in our hospital. Results: In our center, 28 patients with MMD and 28 age-matched control patients with non-MMD stroke were included. Based on our literature searches, we identified two studies for inclusion in our meta-analysis, to which we added our own prospective study described above. Data from our hospital study indicated an association between risk of MMD and elevated thyroid autoantibodies (OR 9.00, 95% CI 1.03 to 78.94), but not between risk of MMD and elevated thyroid function (OR 5.87, 95% CI 0.64 to 53.93). Meta-analysis of our data with findings from the literature further supported the association with elevated thyroid autoantibodies (OR 8.77, 95% CI 4.45 to 17.29) and also indicated an association with elevated thyroid function (OR 9.74, 95% CI 2.18 to 43.49). Conclusions: Evidence strongly suggests that elevated thyroid autoantibodies and elevated thyroid function are independently associated with MMD. These clinical variables may require regular monitoring in patients with MMD.

Intrinsic autoimmune capacities of hematopoietic cells from female New Zealand hybrid mice

Most systemic autoimmune diseases occur more frequently in females than in males. This is particularly evident in Sjögren’s Syndrome, Systemic Lupus Erythromatosis (SLE) and thyroid autoimmunity, where the ratio of females to males ranges from 20:1 to 8:1. Our understanding of the etiology of SLE implies important roles for genetics, environmental factors and sex hormones, but the relative significance of each remains unknown. Using the New Zealand hybrid mouse model system of SLE we present here a new fetal liver chimera-based system in which we can segregate effects of immune system genes from that of sex hormones in vivo. We show that female hematopoietic cells express an intrinsic capacity to drive lupus-like disease in both male and female recipient mice, suggesting that this capacity is hormone independent. Particularly, only chimeric mice with a female hematopoietic system showed significantly increased numbers of germinal center B cells, memory B cells and plasma cells followed by a spontaneous loss of tolerance to nuclear components and hence elevated serum anti-nuclear autoantibodies. A protective effect of testosterone was noted with regards to disease onset, not disease incidence. Thus, genetic factors encoded within the female hematopoietic system can effectively drive lupus-like disease even in male recipients.

Autoantibody profile in a cohort of South Indian children with Kawasaki disease

Objective: There is no clear data on autoantibody levels in Kawasaki Disease (KD) especially from the Indian Subcontinent. Aim: To look for the presence of organ nonspecific and organ specific antibodies to strengthen the search for an autoimmune cause of KD. We tested the presence of antinuclear antibody (ANA) and antithyroid microsomal antibody (TMA) in children with KD, 6 months after the acute phase. Anti Neutrophil Cytoplasmic Antibody (pANCA, cANCA), Anti Endothelial Cytoplasm Antibody (AECA) and Anti Smooth Muscle Antibody (SMA) was additionally tested in those with elevated titers of ANA and/or TMA. Materials and Methods: Prospective case-control study of 24 children with KD on follow up and an equal number of age and sex matched controls. Historical data about acute phase of illness was obtained from the medical records. After obtaining institutional ethics committee clearance and informed consent from the parents, blood was tested for ANA and TMA by the indirect immunofluorescence method (IIF), using a kit developed by Euroimmun. Positive samples were additionally tested for pANCA, cANCA, AECA and SMA. Relationship of autoantibody elevation and clinical course in the cases was determined. Results: The age of the study group was 4 ΁ 3.2 years. Incomplete KD was seen in 12.5% of the cases. Five cases (21%) had cardiac involvement. All but one with mitral and tricuspid regurgitation resolved after the acute phase of the disease. Only her ANA was elevated. Two children (8%) positive for TMA did not show any cardiac abnormalities. Further antibody testing was negative. All three children with elevated autoantibodies were females. ( P value = 0.02: statistically significant). Conclusion: Elevated autoantibodies in three (12.5%) children after the acute phase may suggest the role of autoimmunity in the etiopathogenesis of KD, even though our observations were not statistically significant.

Does a biological link exist between periodontitis and rheumatoid arthritis?

Periodontitis or Periodontal disease (PD) and Rheumatoid arthritis (RA) are two the most common chronic inflammatory diseases. Periodontitis is a biofilm associ ated destructive inflammatory dise ase of the periodontium caused by specific microorganisms. Rheumatoid arthritis is an autoimmune condition and is identified by elevated serum autoantibody titre directed against citrullinated peptides or rheumatoid factor. Periodontitis may involve some elements of autoimmunity. Recent studies have established that PD and RA show a common pathway and could be closely associated through a common dysregulation and dysfunction in inflamma tory mechanism. The enzyme peptidyl arginine deiminase (PAD), expressed by Porphyromonas gingivalis (P. gingivalis ) is responsible for the enzymatic deimination of arginine residuals to citrulline resulting in protein citrullination and its increased accumulation in RA. Citrullination by PAD may act as a putative biologic link between PD and RA. Association of Human leukocytic antigen-DR4 antigen has been established both with RA and PD. Several interleukins and inflammatory me diators (ILs) and Nuclear factor kappa beta ligand are linked to these common chronic inflammatory diseases. Antibodies directed against heat shock protein (hsp 70 ab) of P. gingivalis , P. melanogenicus and P. intermedia are raised in PD as well as RA. Both the conditions share many pathological and immunological similarities. Bacterial infection, genetic susceptibility, altered immune reaction and inflammatory mediators considered responsible for RA are also associated with PD. So it is plausible that a biological link may exist between PD and RA. Therapies aimed at modifying the expression and effect of inflammatory mediators and effector mol ecules such as matrix metalloproteinases, proinflamma tory cytokines and autoantibodies of structural proteins may probably reduce the severity of both RA and PD.

Periodic Febrile Encephalopathy with Mixed Connective Tissue Disease: a Novel Phenotype?

Activation of the innate immune system due to single gene mutations is a hallmark of the autoinflammatory syndromes. Typically, these disorders are not associated with autoimmune phenomena. Here we describe a Caucasian male with a complex phenotype comprising features of both an autoinflammatory state and autoimmunity. He had a life-long history of recurrent encephalopathic episodes during which fever, anorexia and drowsiness would develop over a period of a few hours and last for up to seven days. His phenotype was additionally characterised by a mixed connective tissue disorder with an inflammatory arthritis, restrictive lung disease and variably elevated autoantibodies. Furthermore, he experienced autoimmune thrombocytopenia, gastro-intestinal bleeding and epilepsy on a background of mild to moderate intellectual compromise. Radiological examination demonstrated periarticular, subcutaneous soft tissue and intracranial calcification, together with cerebellar vermis hypoplasia. EEG showed features of a generalised epilepsy. All other investigations were essentially non-contributory. He died at 19 years of age of acute respiratory failure secondary to restrictive lung disease and pneumonia. We hypothesise that this phenotype represents a previously undescribed autoinflammatory syndrome, with secondary autoimmune sequelae.

Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus

Autoantibodies against cytokines, chemokines, and growth factors inhibit normal immunity and are implicated in inflammatory autoimmune disease and diseases of immune deficiency. In an effort to evaluate serum from autoimmune and immunodeficient patients for Abs against cytokines, chemokines, and growth factors in a high-throughput and unbiased manner, we constructed a multiplex protein microarray for detection of serum factor-binding Abs and used the microarray to detect autoantibody targets in SLE. We designed a nitrocellulose-surface microarray containing human cytokines, chemokines, and other circulating proteins and demonstrated that the array permitted specific detection of serum factor-binding probes. We used the arrays to detect previously described autoantibodies against cytokines in samples from individuals with autoimmune polyendocrine syndrome type 1 and chronic mycobacterial infection. Serum profiling from individuals with SLE revealed that among several targets, elevated IgG autoantibody reactivity to B cell-activating factor (BAFF) was associated with SLE compared with control samples. BAFF reactivity correlated with the severity of disease-associated features, including IFN-α-driven SLE pathology. Our results showed that serum factor protein microarrays facilitate detection of autoantibody reactivity to serum factors in human samples and that BAFF-reactive autoantibodies may be associated with an elevated inflammatory disease state within the spectrum of SLE.

Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N‐Methyl‐D‐aspartate receptor or dopamine‐2 receptor

Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N-methyl-D-aspartate receptor (NMDAR). We measured autoantibodies against NMDAR and dopamine-2 receptor (D2R) expressed at the cell surface in the stored acute serum of 9 children with HSE, 3 of whom had a relapsing course with chorea. The 3 patients with chorea had elevated autoantibodies against NMDAR (n = 1), D2R (n = 1), or both (n = 1), whereas patients without chorea were negative (n = 6). The prospectively identified patient with chorea and NMDAR autoantibodies improved after early treatment with steroids, intravenous immunoglobulin, and cyclophosphamide, with reduction in serum NMDAR antibody titers. These autoantibody findings lend support to the autoimmune hypothesis and the early use of immune suppression in post-HSE chorea.

Elevated Thyroid Autoantibodies and Intracranial Stenosis in Stroke at an Early Age

Previous studies have shown that hyperthyroidism was related to Moyamoya disease and intracranial artery stenosis. However, it is not clear whether thyroid hormone or thyroid autoantibodies was associated with them. Thyroid autoimmunity was previously shown to be associated with Moyamoya disease. Our study aimed to investigate the association between thyroid autoantibodies and intracranial large artery stenosis in young ischemic stroke patients with apparent euthyroid states. We retrospectively reviewed first-onset ischemic stroke patients (age ≤55 years old) consecutively admitted to a single academic center. Intracranial large artery stenosis was defined as ≥50% luminal diameter narrowing. We compared demographic profiles, risk factors (age, hypertension, diabetes, current smoker, atrial fibrillation, hyperlipidemia), thyroid function test, and thyroid autoantibodies including antithyroperoxidase antibody and antithyroglobulin antibody between patients with and without intracranial large artery stenosis. We also performed multivariate logistic regression analysis to evaluate the association between thyroid autoantibodies and intracranial large artery stenosis. A total of 351 patients were analyzed. The mean age of the patients was 47·0 ± 7·7 (range, 10-55 years), and 252 (71·8%) patients were male. We identified intracranial large artery stenosis in 121 (34·5%) patients. Patients with intracranial large artery stenosis showed a higher frequency of elevated antithyroperpxidase antibody levels in comparison with nonintracranial large artery stenosis group (16·5% vs. 3·9%, P < 0·001). After adjusting for covariates, the presence of elevated antithyroperpxidase antibody levels (odds ratio: 5·318; 95% confidence interval: 2·157-13·110, P < 0·001), age (odds ratio: 1·037; 95% confidence interval: 1·002-1·073, P = 0·039), and atrial fibrillation (odds ratio: 0·091; 95% confidence interval: 0·011-0·756, P = 0·027) was independently associated with intracranial large artery stenosis. Thyroid autoantibodies may be associated with the presence of intracranial large artery stenosis in young stroke patients, potentially providing insight on immune pathogenesis of intracranial large artery stenosis.

Abstract 279: Hypertension in Hemolysis, Elevated Liver Enzyme, Low Platelet Syndrome is Associated with Increased Endothelin-1

INTRODUCTION. HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) is a severe form of preeclampsia, a hypertensive disorder that occurs during pregnancy. We have shown that HELLP syndrome in both women and in an animal model causes hypertension and elevated TNF-α, IL-6, and agonistic autoantibodies to the angiotensin II receptor, all of which have been shown to activate the endothelin-1 system (ET-1). Therefore we tested the hypothesis that hypertension in response to HELLP syndrome is associated with ET-1 activation. METHODS. Plasma was collected from women with HELLP syndrome or pregnant women without maternal/fetal complications at the time of delivery. Endothelin (ET-1) was extracted from the plasma and measured with a Quantikine ET-1 enzyme linked immunosorbent assay kit. On gestational day (GD) 12 miniosmotic pumps infusing sEndoglin (7ug/kg/day) and sFlt-1 (4.7ug/kg/day) were implanted into normal pregnant rats to induce HELLP syndrome. On GD18 carotid catheters were inserted into HELLP and normal pregnant (NP) rats and mean arterial pressure (MAP) was recorded on GD19; serum, urine and tissues were collected for molecular analysis. RESULTS. Women with HELLP syndrome (n=4) had significantly more circulating ET-1 (3.35pg/mL) compared to normal pregnant women (0.75pg/mL; n=3; p=0.006) and increased MAP (120.8±6.2 mmHg HELLP vs. 87.33±6.67mmHg NP; p=0.015). In rats MAP increased from 91±2mmHg in NP rats (n=4) to 129.8±4.5mmHg in HELLP rats (n=4; p=0.0002). Preproendothelin mRNA expression was 3 fold higher in placentas and 1.3 fold higher in livers from HELLP rats compared to NP rats (p=0.02; p=0.05). In addition we measured ET-1 secretion from endothelial cells exposed to serum from NP and HELLP rats. ET-1 in response to NP serum was 4.03±.68pg/mg/mL and increased to 9.69±3.5pg/mg/mL with HELLP serum (p=0.04) after 24hrs. CONCLUSION. These data support the hypothesis that hypertension in both women and animals with HELLP syndrome is accompanied by increased ET-1 expression.

Increased Prevalence of Luminal Narrowing and Stricturing Identified by Enterography in Pediatric Crohn’s Disease Patients With Elevated Granulocyte–Macrophage Colony Stimulating Factor Autoantibodies

Crohn's disease (CD) patients with elevated granulocyte-macrophage colony-stimulating factor autoantibodies (GM-CSF Ab) are more likely to develop stricturing behavior requiring surgery. Computed tomography or magnetic resonance enterography (CTE or MRE) may detect luminal narrowing (LN) before stricture development. The objective of this study was to determine whether CD patients with elevated GM-CSF Ab (≥1.6 μg/mL) have a higher prevalence of LN and stricturing on CTE or MRE. A single-center, cross-sectional study of 153 pediatric patients with CD and control subjects undergoing diagnostic CTE or MRE. Examinations were evaluated for disease activity using a novel scoring system and for the presence of LN, stricture, intra-abdominal abscess, or fistulae. Dichotomous outcomes were compared with respect to antibody status (high or low) using Fisher's exact test and logistic regression, whereas continuous outcomes were evaluated using unpaired t test. GM-CSF Ab were elevated in CD patients (n = 114) with a median (interquartile range) GM-CSF Ab level of 2.3 μg/mL (0.5-6.6 μg/mL) compared with 0.6 μg/mL (0.3-1.3 μg/mL) in healthy and disease control subjects (n = 39) (P = 0.001). Ileal disease location was more common in CD patients with high GM-CSF Ab (P < 0.001). LN increased from 39% in CD patients with low GM-CSF Ab to 71% in those with high levels (P = 0.004) and remained significantly associated with high GM-CSF Ab in a multivariate logistic model, which included age, gender, small bowel location, and duration of disease. Stricturing prevalence on CTE or MRE examination increased from 4% in CD patients with low GM-CSF Ab to 19% in those with high GM-CSF Ab (P = 0.03). Pediatric CD patients with high GM-CSF Ab levels have a higher prevalence of LN on CTE or MRE. Further study will be needed to determine whether medical therapy will reduce progression to stricturing behavior in these patients.

A study on the association of autoantibodies, chemokine, and its receptor with disease activity in systemic lupus erythematosus in North Indian population

Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease characterized by the production of autoantibodies against a spectrum of nuclear antigens. RANTES and its receptor CCR5 have been associated with the pathogenesis of SLE. The objective of this study is to analyze autoantibodies (DNA/RNA), allelic distribution of RANTES and the association of levels of RANTES and its receptor CCR5 in SLE patients in North Indian region. The RANTES-403 and RANTES-28 polymorphism in the promoter region of RANTES gene was studied in 80 patients and 80 healthy controls. The levels of chemokine RANTES, its receptor CCR5, anti-dsDNA, and anti-SSA antibodies levels were determined. Disease activity was assessed with the systemic lupus erythematosus disease activity index (SLEDAI) score. All the parameters were studied for statistical analysis by using t test (graph pad prism) and correlation by SPSS data. PCR-RFLP performed showed 28C/C and the 403G/G genotypes in both patients and controls, but no other genotypes such as 28C/G, 28G/G and 403A/G, 403A/A were found. Patients had higher levels of RANTES (1840.48 ± 739.42 vs. 835.44 ± 70.48 pg/ml; P < 0.0001) and its receptor CCR5 expression (26.49 ± 0.16 vs. 24.72 ± 3.02 %; P < 0.05) compared to controls. The levels of autoantibodies anti-dsDNA and anti-SSA were also higher in patients than controls. The patients showing elevated anti-dsDNA had negative correlation with SLEDAI score (P < 0.05) while borderline patients were not found to be correlated. In case of anti-Ro/anti-SSA antibody levels, the borderline patients showed a moderately significant negative correlation as compared to controls than patients with elevated autoantibody (P < 0.01). The levels of RANTES and CCR5 were also higher in case of patients than controls. But there was no significant correlation of RANTES and CCR5 with disease activity. We were unable to find an association of RANTES polymorphism with SLE in North Indian population in our sample. No significant difference in allele distribution of RANTES-28 and RANTES-403 in the sample of 160 individuals was detected. Of the two autoantibodies studied, anti-Ro/anti-SSA levels in borderline lupus patients appeared as an important parameter for monitoring/diagnosis of lupus patients.

Autoantibody prevalence in active tuberculosis: reactive or pathognomonic?

ObjectivesTo evaluate the autoantibody in patients without corresponding symptoms, whether these autoantibody are pathognomonic or not. We hypothesised that autoantibody may be reactive to chronic infection, such as tuberculosis (TB).DesignRandomised,...

Immune Therapeutic Potential of Stem Cells from Human Supernumerary Teeth

Discoveries of immunomodulatory functions in mesenchymal stem cells (MSCs) have suggested that they might have therapeutic utility in treating immune diseases. Recently, a novel MSC population was identified from dental pulp of human supernumerary teeth, and its multipotency characterized. Herein, we first examined the in vitro and in vivo immunomodulatory functions of human supernumerary tooth-derived stem cells (SNTSCs). SNTSCs suppressed not only the viability of T-cells, but also the differentiation of interleukin 17 (IL-17)-secreting helper T (Th17) -cells in in vitro co-culture experiments. In addition, systemic SNTSC transplantation ameliorated the shortened lifespan and elevated serum autoantibodies and nephritis-like renal dysfunction in systemic lupus erythematosus (SLE) model MRL/lpr mice. SNTSC transplantation also suppressed in vivo increased levels of peripheral Th17 cells and IL-17, as well as ex vivo differentiation of Th17 cells in MRL/lpr mice. Adoptive transfer experiments demonstrated that SNTSC-transplanted MRL/lpr mouse-derived T-cell-adopted immunocompromised mice showed a longer lifespan in comparison with non-transplanted MRL/lpr mouse-derived T-cell-adopted immunocompromised mice, indicating that SNTSC transplantation suppresses the hyper-immune condition of MRL/lpr mice through suppressing T-cells. Analysis of these data suggests that SNTSCs are a promising MSC source for cell-based therapy for immune diseases such as SLE.

Autoantibodies against cytoskeletal neuronal proteins in sera of arsenic-exposed subjects correlate with neurological symptoms

This descriptive study correlates the presence of serum autoantibodies to five neuronal cytoskeletal proteins with neurologic deficits in subjects exposed to arsenic (As). Arsenic exposure remains a serious problem in many countries producing skin lesions and hair loss. More serious manifestations include: liver and kidney damage, encephalopathy, peripheral neuropathy, gangrene of extremities, and cancer. Bangladesh represents one of the countries where high percentage of population is exposed to As through highly contaminated drinking groundwater. Autoantibodies were determined against the following proteins: neurofilament triplet proteins (NFP), microtubule associated protein-2 (MAP2), and microtubule associated protein tau (tau). Sera were obtained from 14 subjects in the severely affected village of Mianpur, Charghat Thana, Rajshahi. Individuals were further divided into group A with objective complaints of organic neurologic damage and group B without neurologic deficits manifestations and eight healthy controls from Rajshahi city. High levels of autoantibodies were detected in five subjects against low molecular weight neurofilaments (NFL) and in two subjects against high molecular weight neurofilament (NFH). Two subjects displayed significantly increased levels of MAP-2 autoantibodies and two others high levels of tau autoantibodies. All elevated autoantibodies were detected in group A subjects who were diagnosed with neurological disorders ranging from sleep disorders to paralysis. The results demonstrate a good correlation between neurologic defects in As-exposed subjects and presence of sera neuronal autoantibodies to cytoskeletal proteins.

Type 1 Diabetes Mellitus

1. Justin M. Gregory, MD* 2. Daniel J. Moore, MD, PhD† 3. Jill H. Simmons, MD‡ 1. *Pediatric Endocrinology Clinical Fellow, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. 2. †Assistant Professor of Pediatrics, Assistant Professor of Pathology, Microbiology, and Immunology, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. 3. ‡Assistant Professor of Pediatrics, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. * ADA: : American Diabetes Association DKA: : diabetic ketoacidosis HbA1c: : glycosylated hemoglobin I:C ratio: : insulin-to-carbohydrate ratio IV: : intravenous TDD: : total daily dose T1DM: : type 1 diabetes mellitus T2DM: : type 2 diabetes mellitus 1. All children with type 1 diabetes mellitus (T1DM) should have their blood sugar managed with basal-bolus insulin treatment by either multiple daily injections or an insulin pump. 2. All children with T1DM should have access to a pediatric endocrinologist with a diabetes management team with resources to support patients and families. 3. All children with T1DM should be monitored for symptoms and/or screened for commonly associated conditions such as thyroid and celiac disease. After completing this article, readers should be able to: 1. Recognize the presenting signs and symptoms of type 1 diabetes mellitus (T1DM). 2. Know the key principles of effective diabetes self-management and the diabetes care team’s role in facilitating effective self-management. 3. Know the acute and chronic complications of (T1DM). 4. Identify how different categories of insulin analogues are used in daily insulin regimens. True, it is a fight, but there is pleasure in the struggle. Victory comes to the courageous; and without courage and common sense, success awaits no one. I look upon the diabetic as charioteer and his chariot as drawn by three steeds named Diet, Insulin, and Exercise. It takes skill to drive one horse, intelligence to manage a team of two, but a man must be a very good teamster who can get all three to pull together.EP Joslin, 1933 Type 1 diabetes mellitus (T1DM) is a disorder of glucose homeostasis characterized by autoimmune destruction of the insulin-producing pancreatic β-cell that progressively leads to insulin deficiency and resultant hyperglycemia. If left untreated, insulin deficiency leads to progressive metabolic derangement, with worsening hyperglycemia, ketoacidosis, starvation, and death. In …

Type 1 Diabetes Mellitus

Type 1 Diabetes Mellitus

LMP1 signaling in vivo downregulates DUSP1 and exacerbates inflammatory responses (P5204)

Abstract The EBV oncogenic protein LMP1 is implicated in pathogenesis of B cell malignancies and exacerbation of autoimmune disease. We previously produced mice that express, in B and myeloid cells, a transgene with the external domain of CD40 and signaling domain of LMP1. CD40-LMP1 substitutes for CD40 to induce a humoral response in CD40-/- mice, but they display elevated autoantibodies, enlarged lymphoid organs, and elevated inflammatory cytokines. Co-expression of CD40 and CD40-LMP1 partially ameliorates this inflammatory/autoreactive phenotype. The phosphatase DUSP1 is downregulated in B cells from CD40-LMP1tg mice, and upon induced expression of Wt LMP1 in a B cell line. DUSP1 is implicated in the control of inflammatory signaling pathways, and DUSP1 deficiency has been shown to increase susceptibility of mice to LPS induced sepsis. We hypothesized that inhibition of DUSP1 expression caused by LMP1 signaling contributes to the association of LMP1 with inflammation. We tested the impact of LMP1 expression on in vivo responses to LPS in mice expressing CD40-LMP1, CD40, or both. Two hrs after challenge with a low dose of LPS, serum TNFa and IL1b were increased to a markedly greater degree in mice expressing CD40-LMP1, and this was alleviated by co-expression of CD40. Additionally, &amp;gt;50% of CD40-LMP1 Tg mice, but none of the mice expressing Wt CD40, developed sepsis. These findings suggest a potential mechanism by which LMP1 promotes exacerbation of chronic inflammatory disease.