Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children with Recent Onset of Type 1 Diabetes Mellitus.

Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces islet-associated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2'-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of ∼80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans.

Avidity-dependent programming of autoreactive T cells in T1D.

Fate determination for autoreactive T cells relies on a series of avidity-dependent interactions during T cell selection, represented by two general types of signals, one based on antigen expression and density during T cell development, and one based on genes that interpret the avidity of TCR interaction to guide developmental outcome. We used proinsulin-specific HLA class II tetramers to purify and determine transcriptional signatures for autoreactive T cells under differential selection in type 1 diabetes (T1D), in which insulin (INS) genotypes consist of protective and susceptible alleles that regulate the level of proinsulin expression in the thymus. Upregulation of steroid nuclear receptor family 4A (NR4A) and early growth response family genes in proinsulin-specific T cells was observed in individuals with susceptible INS-VNTR genotypes, suggesting a mechanism for avidity-dependent fate determination of the T cell repertoire in T1D. The NR4A genes act as translators of TCR signal strength that guide central and peripheral T cell fate decisions through transcriptional modification. We propose that maintenance of an NR4A-guided program in low avidity autoreactive T cells in T1D reflects their prior developmental experience influenced by proinsulin expression, identifying a pathway permissive for autoimmunity.

Uncoupling of proliferation and cytokines from suppression within the CD4+CD25+Foxp3+ T-cell compartment in the 1st year of human type 1 diabetes.

OBJECTIVE: The mechanistic basis for the breakdown of T-cell tolerance in type 1 diabetes is unclear and could result from a gain of effector function and/or loss of regulatory function. In humans, the CD4+CD25+Foxp3+ T-cell compartment contains both effector and regulatory T cells, and it is not known how their relative proportions vary in disease states. RESEARCH DESIGN AND METHODS: We performed a longitudinal study of CD4+CD25+ T-cell function in children with type 1 diabetes at onset and throughout the 1st year of disease. Function was assessed using single-cell assays of proliferation, cytokine production, and suppression. Type 1 diabetic individuals were compared with age-matched control subjects, and suppression was directly assessed by coculture with control T-cell targets. RESULTS: We identify novel functional changes within the type 1 diabetes CD4+CD25+ compartment. Type 1 diabetic CD4+CD25+ cells exhibited a striking increase in proliferative capacity in coculture with CD4 T cells that was present at onset and stable 9-12 months from diagnosis. Elevated type 1 diabetes CD4+CD25+ cell proliferation correlated with increased inflammatory cytokines interleukin 17 and tumor necrosis factor-α but not γ-interferon. Type 1 diabetes CD4+CD25+ cytokine production occurred coincident with suppression of the same cytokines in the control targets. Indeed, enhanced proliferation/cytokines by CD4+CD25+ cells was uncoupled from their suppressive ability. Longitudinally, we observed a transient defect in type 1 diabetes CD4+CD25+ suppression that unexpectedly correlated with measures of improved metabolic function. CONCLUSIONS: Type 1 diabetes onset, and its subsequent remission period, is associated with two independent functional changes within the CD4+CD25+ T-cell compartment: a stable increase in effector function and a transient decrease in regulatory T-cell suppression.

Continuous subcutaneous insulin infusion in toddlers and children with type 1 diabetes mellitus is safe and effective.

OBJECTIVE: The aim of this study was to investigate the safety and efficacy of continuous subcutaneous insulin infusion (CSII) for type 1 diabetes mellitus (T1DM) in toddlers and children. RESEARCH DESIGN AND METHODS: Seventy children who began CSII at the age of 12 yr or younger (youngest 2 yr old) and who were maintained on CSII for at least 6 months were studied by a retrospective chart review. A pre- or postintervention comparison approach was used to assess the impact of CSII on the measured variables. The control period was defined as 1 yr prior to beginning CSII. Charts were reviewed for hemoglobin A1c (HbA1c) reports of severe hypoglycemia, diabetic ketoacidosis (DKA), height and weight, and range of blood glucoses reported at each visit. Mean values for HbA1c, body mass index (BMI) z-score, and range of blood glucose were computed for each subject over all pre-CSII visits, and again over all post-CSII visits. RESULTS: The mean HbA1c decreased significantly during CSII [7.8 +/- 0.8% pre-CSII vs. 7.3 +/- 0.7% on CSII, p < 0.0001]. Hypoglycemic episodes decreased with CSII in the 10- to 12-yr-old group (p < 0.02) and demonstrated a strong trend (mean of 0.46-0.22 events per patient year, p < 0.06) overall. Two episodes of DKA occurred in the CSII period and none in the control period (p = NS). BMI z-scores increased to 0.21 in the 5- to 9-yr-age group (p < 0.008) and averaged 0.13 overall. The range of blood glucoses decreased during CSII (p < 0.005) in the middle and oldest age groups. CONCLUSIONS: This study supports CSII as a safe and effective alternative to managing T1DM, with no increase in hypoglycemia and a trend to improve control, even in the youngest patients.

Hermaphroditus in Greco-Roman myth: lessons and hypotheses for intersex today.

This discussion reviews the Greco-Roman mythic origins of the eponymic Hermaphroditus. It reviews the two major tales, one Greek, the other from Ovid, regarding the origins of the sexual and gender predicament of Hermaphroditus. It explains the genealogy of Hermaphroditus in Greek mythology, and includes a discussion of Ovid's text on Hermaphroditus. A comparison of the two renditions offers the opportunity to reflect on who Hermaphroditus may have been, and to reflect on the implications of his nature. The discussion also attends to some of the ethical and emotional conflicts for the intersexed today. Finally, the discussion explores whether lessons from, and hypotheses regarding a mythic figure, such as Hermaphroditus, may provide guidance for intersexed individuals and their parents.

Comprehensive assessment of professional competence: the Rochester experiment.

BACKGROUND: A required 2-week comprehensive assessment (CA) for 2nd-year medical students that integrates basic science, clinical skills, information management, and professionalism was implemented. DESCRIPTION: The CA links standardized patients (SPs) with computer-based exercises, a teamwork exercise, and peer assessments; and culminates in student-generated learning plans. EVALUATION: Scores assigned by SPs showed acceptable interrater reliability. Factor analyses defined meaningful subscales of the peer assessment and communication rating scales. Ratings of communication skills were correlated with information gathering, patient counseling, and peer assessments; these, in turn, were strongly correlated with the written exercises. Students found the CA fair, with some variability in opinion of the peer and written exercises. Useful learning plans and positive curricular changes were undertaken in response to the CA results. CONCLUSION: A CA that integrates multiple domains of professional competence is feasible, useful to students, and fosters reflection and change. Preliminary data suggest that this format is reliable and valid.