The presence of autoantibodies to multiple islet autoantigens confers high risk for development of Type 1 diabetes. Four major autoantigens are established (insulin, glutamate decarboxylase, IA-2, and zinc transporter-8), but the molecular identity of a fifth, a 38kDa membrane glycoprotein (Glima), is unknown. Glima antibodies have been detectable only by immunoprecipitation from extracts of radiolabeled islet or neuronal cells. We sought to identify Glima to enable efficient assay of these autoantibodies. Mouse brain and lung were shown to express Glima. Membrane glycoproteins from extracts of these organs were enriched by detergent phase separation, lectin affinity chromatography and SDS-PAGE. Proteins were also immunoaffinity purified from brain extracts using autoantibodies from diabetic patients' sera before SDS-PAGE. Eluates from gel regions equivalent to 38kDa were analyzed by LC-MS/MS for protein identification. Three proteins were detected in samples from the brain and lung extracts, and in the immunoaffinity purified sample, but not the negative control. Only tetraspanin-7, a multipass transmembrane glycoprotein with neuroendocrine expression, had physical characteristics expected of Glima. Tetraspanin-7 was confirmed as an autoantigen by demonstrating binding to autoantibodies in Type 1 diabetes. We identify tetraspanin-7 as a target of autoimmunity in diabetes, allowing its exploitation for diabetes prediction and immunotherapy.

Summary Ninety cases of non-Hodgkin's lymphoma diagnosed prior to the use of modern therapeutic regimens and 88 cases treated with such chemotherapy were studied using conventional morphology and flow cytometry. DNA aneuploidy as determined by flow cytometry was more common among high grade (38%) than low grade (19%)

No abstract [Research letter

Autoantibodies to IA-2 in Type 1 diabetes are associated with HLA-DR4, suggesting influences of HLA-DR4 restricted T-cells on IA-2-specific B-cell responses. The aim of this study was to investigate possible T-B-cell collaboration by determining whether autoantibodies to IA-2 epitopes are associated with T-cell responses to IA-2 peptides presented by DR4. T-cells secreting the cytokines interferon-γ and interleukin-10 in response to seven peptides known to elicit T-cell responses in Type 1 diabetes were quantified by cytokine ELISPOT in HLA-typed patients characterised for antibodies to IA-2 epitopes. T-cell responses were detected to all peptides tested, but only interleukin-10 responses to 841-860 and 853-872 peptides were associated with DR4. Phenotyping by RT-PCR of FACS-sorted CD45ROhi T-cells secreting interleukin-10 in response to these two peptides indicated that these expressed GATA-3 or T-bet, but not FoxP3, consistent with these being Th2 or Th1 memory T-cells rather than of regulatory phenotype. T-cell responses to the same two peptides were also associated with specific antibodies; those to 841-860 peptide with antibodies to juxtamembrane epitopes, which appear early in pre-diabetes, and those to peptide 853-872 with antibodies to an epitope located in the 831-862 central region of the IA-2 tyrosine phosphatase domain. Antibodies to juxtamembrane and central region constructs were both DR4-associated. This study identifies a region of focus for B- and T-cell responses to IA-2 in HLA-DR4 diabetic patients that may explain HLA- associations of IA-2 autoantibodies and this region may provide a target for future immune intervention to prevent disease.

Granulosa cell tumour is among the rarest forms of testicular cancer. Only 21 cases have been reported to date and only 4 have metastasised. All documented metastases are intra-abdominal. We present the first case of granulosa cell tumour of the testis metastasising to bone (tibia), presenting 6 years after orchidectomy. This highlights the need to maintain a high index of suspicion for extra-abdominal metastases during long-term follow-up in patients with previous testicular granulosa cell tumour.