Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4

During immune responses, antigen-presenting cells (APCs) process antigens and present peptide epitopes complexed with human leukocyte antigen (HLA) molecules. CD4 cells recognize these naturally processed and presented epitopes (NPPEs) bound to HLA class II molecules. Epitope identification is important for developing diagnostic and therapeutic tools for immune-mediated diseases and providing insight into their etiology, but current approaches overlook effects of natural processing on epitope selection. We have developed a technique to identify NPPEs using mass spectrometry (MS) after antigen is targeted onto APCs using a lectin-based antigen delivery system (ADS). We applied the technique to identify NPPEs of the intracellular domain of the type 1 diabetes mellitus-associated (type 1 DM-associated) autoantigen insulinoma-associated-2 (IA-2ic), presented by HLA-DR4 (0401). IA-2ic-derived NPPEs eluted from HLA-DR4 constitute 6 sets of peptides nested around distinct core regions. Synthetic peptides based on these regions bind HLA-DR4 and elicit primary T-cell proliferation frequently in HLA-DR4-positive type 1 DM patients, but rarely in non-HLA-DR4 patients, and in none of the HLA-DR4 nondiabetic controls we tested. This flexible, direct approach identifies an HLA allele-specific map of NPPEs for any antigen, presented by any HLA class II molecule. This method should enable a greater understanding of epitope selection and lead to the generation of sensitive and specific reagents for detecting autoreactive T cells.     

Pancreas and islet cell transplantation

Currently, for the patient with type 1 diabetes, a definitive treatment without resorting to the use of exogenous insulin can be achieved only with pancreas or islet cell transplantation. These means of restoring beta-cell mass can completely maintain essentially normal long-term glucose homeostasis, although the need for powerful immunosuppressive regimens limits their application to only a subgroup of adult patients. Apart from the shortage of donors that has limited all kinds of transplantation, however, the widespread use of beta-cell replacement has been precluded until recently by the drawbacks associated with both organ and islet cell transplantation. Although the study of recurrence of diabetes has generated attention, the fundamental obstacle to pancreas and islet transplantation has been, and remains, the alloimmune response. With a better elucidation of the mechanisms of alloengraftment achieved during the last 3 years, the stage has been set for further advances.     

Hemicrania Continua: A Case Responsive to Piroxicam-Beta-Cyclodextrin

The case of a 53-year-old woman is described, who since the age of 38 years had been suffering from a unilateral headache that was at first remitting, but then evolved into an unremitting course. The headache was burning in quality, located in the left forehead and face, and was accompanied by mild ipsilateral autonomic symptoms. The clinical picture, as well as the absolute response to indomethacin, suggested a diagnosis of hemicrania continua. The presence of mild gastric discomfort on continuous indomethacin administration made us transfer the patient to another NSAID (piroxicam-beta-cyclodextrin). With this drug, complete relief and good tolerability was obtained.     

Gene- and cell-based therapeutics for type I diabetes mellitus

Type 1 diabetes mellitus, an autoimmune disorder is an attractive candidate for gene and cell-based therapy. From the use of gene-engineered immune cells to induce hyporesponsiveness to autoantigens to islet and beta cell surrogate transplants expressing immunoregulatory genes to provide a local pocket of immune privilege, these strategies have demonstrated proof of concept to the point where translational studies can be initiated. Nonetheless, along with the proof of concept, a number of important issues have been raised by the choice of vector and expression system as well as the point of intervention; prophylactic or therapeutic. An assessment of the current state of the science and potential leads to the conclusion that some strategies are ready for safety trials while others require varying degrees of technical and conceptual refinement.     

Developmental pathways of adolescent cannabis use: Risk factors,outcomes and sex-specific differences

Background: Characterizing patterns of adolescent cannabis use (CU), as well as risk factors and outcomes uniquely associated with these pathways is essential for informing treatment and prevention efforts. Yet, few studies have examined these issues among youth at-risk of engaging in problematic cannabis use. Further, research accounting for use of other substances or sex differences in patterns of CU remains exceedingly sparse. Methods: Trajectory-based modeling was used to identify underlying CU pathways among a predominantly Hispanic (90%) sample of at-risk youth (n?=?401; 46% female) across adolescence (ages～14–18), controlling for baseline substance use and participant demographics. Adolescent psychopathology (i.e., conduct disorder, attention deficit hyperactivity disorder, anxiety, and depression) was examined as a predictor and outcome of CU. Results: Three trajectories of adolescent CU were identified, with most youth (74%) engaging in relatively “low” levels of use, followed by ～12% exhibiting an early-initiating “chronic” course, and 14% “escalating” in use. Although boys and girls both experienced increased levels of CU across adolescence, boys were more likely to exhibit escalating and chronic patterns of use. Findings revealed unique associations between adolescent CU pathways and facets of psychopathology; most notably, the relatively robust and bidirectional association between CU trajectories and conduct problem symptoms. Conclusions: Specific facets of psychopathology may confer unique associations with CU across development, including the initiation and exacerbation of CU during adolescence.     

The relationship of self-esteem and self-efficacy to treatment outcomes of alcohol-dependent men and women

This study investigates whether self-esteem is associated with clinical and demographic characteristics, self-efficacy expectancies, and post-treatment drinking outcomes. Forty-one (40.6%) women and 60 (59.4%) men were recruited during inpatient alcohol dependence treatment. At baseline, lower self-esteem was significantly associated with current depression and other psychiatric disorders. Self-esteem was not related to gender, relapse, other one-year drinking outcomes, or self-efficacy. Age and psychiatric disorders were strong predictors of self-esteem at follow-up. This study suggests that different perceptions of the self have unique roles in recovery from alcohol use disorders.