The influence of presensitization (blood transfusions) on B-cell immunity as reflected in the serum of two groups of candidates for cadaveric donor renal allografts was examined. The first group ...initially had a high level of panel-reactive antibody (PRA) greater than 72% but experienced a large decrease in PRA (greater than 70%) 6-34 months prior to transplantation. In contrast, the second group maintained a high PRA (100%) for up to 28 months after sensitization and before transplantation. Three blood Three blood samples from each patient, representing a maximum time span of 34 months, were analyzed. Levels of IgG, IgM isohemagglutinins, and antitetanus antibody were used as indicators of B-cell function. There were no significant differences between the individual values of a single patient with regard to each parameter. However, Group II patients had elevated values of total IgG relative to Group I patients. Total serum IgG-subclass levels (IgG1, IgG2, IgG3, IgG4) were measured and the relationship between a specific IgG subclass and the PRA activity was determined. IgG1 values in Group II were higher than those found for Group I. The other IgG subclasses were all within normal levels and were not significantly different between Group I and Group II. When IgG-subclass typing of PRA was performed, IgG1 accounted for most of the activity in both groups and a fall in PRA-specific IgG1 was associated with the reduced PRA observed in Group I. The data indicate that humoral immunity, as reflected by total and specific immunoglobulin levels, is intact in general in the two groups of presensitized renal allograft candidates examined and that any loss of PRA activity reflects a reduction in a specific immune response.
Splenic lymphocyte proteins from New Zealand Black (NZB) mice, which spontaneously develop autoimmune disease, and several control strains were analyzed by two-dimensional polyacrylamide gel ...electrophoresis. A number of strain- and age-related differences were observed, among which was the persistently elevated synthesis of two peptides, 12.5 KD and 10.5 KD, by spleen cells from older NZB mice. Although synthesis of these peptides was moderately high in young NZB and control mice, it diminished with age in control mice. These proteins were found in the cytoplasm and were not expressed on the plasma membrane nor secreted into the medium. Production of these proteins was restricted to B and null cells; T cells did not synthesize these peptides. These proteins appear to be indicators of disease activity, because their increased synthesis was associated with lymphocyte subset alterations associated with the onset of overt autoimmune disease in NZB mice.
Summary Background New treatments for type 2 diabetes mellitus are needed to retain insulin–glucose coupling and lower the risk of weight gain and hypoglycaemia. We aimed to investigate the safety ...and efficacy of liraglutide as monotherapy for this disorder. Methods In a double-blind, double-dummy, active-control, parallel-group study, 746 patients with early type 2 diabetes were randomly assigned to once daily liraglutide (1·2 mg n=251 or 1·8 mg n=247) or glimepiride 8 mg (n=248) for 52 weeks. The primary outcome was change in proportion of glycosylated haemoglobin (HbA1c ). Analysis was done by intention-to-treat. This trial is registered with ClinicalTrials.gov , number NTC00294723. Findings At 52 weeks, HbA1c decreased by 0·51% (SD 1·20%) with glimepiride, compared with 0·84% (1·23%) with liraglutide 1·2 mg (difference −0·33%; 95% CI −0·53 to −0·13, p=0·0014) and 1·14% (1·24%) with liraglutide 1·8 mg (−0·62; −0·83 to −0·42, p<0·0001). Five patients in the liraglutide 1·2 mg, and one in 1·8 mg groups discontinued treatment because of vomiting, whereas none in the glimepiride group did so. Interpretation Liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and leads to greater reductions in HbA1c , weight, hypoglycaemia, and blood pressure than does glimepiride. Funding Novo Nordisk A/S.
In this review we have summarized several lines of evidence supporting the concept that insulin dependent diabetes (IDDM) is an autoimmune disease. Initially, we have considered the association of ...IDDM with other autoimmune diseases, a fact that indirectly suggests involvement of the immune system. Other evidence implicating the immune system is the presence of auto-antibodies directed against pancreatic islet cells and cellular components of the immune system associated with pancreatic insulitis. Finally, we have examined the reported association of cell-surface proteins named histocompatibility antigens (HLA) with this particular disease. Structural and functional aspects of HLA have been considered along with regulatory mechanisms concerning the expression of these antigens.
Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly ...revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ∼2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P = 5.66×10⁻¹¹) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P = 3.50×10⁻⁹ resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P = 8.06×10⁻⁹ lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D.
HLA
‐C*04:112
differs from
HLA
‐C*04:01:01:01
by one nucleotide at position 270 resulting in an amino acid change, Lysine to Asparagine, at codon 66 of exon 2.
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