Autoimmunity against INS-IGF2 expressed in human pancreatic islets.

Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine 1) expression of INS-IGF2 in human pancreatic islets and 2) autoantibodies in newly diagnosed type 1 diabetes children and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared to donors with either type 2 diabetes (p=0.006) or high HbA1c levels (p<0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed type 1 diabetes patients (n=304) compared to healthy controls (n=355; p<0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Immunogenetics of Childhood Type 1 Diabetes in Immigrant Patients in Sweden. Migration Studies on Type 1 Diabetes

This thesis examined whether the offspring of immigrants (non-Swedes) to Sweden are at increased risk of Type 1 Diabetes (T1D) when they are born or live in Sweden. It also evaluated if their T1D and T2D-related genes differed from Swedish patients and whether this genetic heritage determined the types and existence of islet autoantibodies at time of diagnosis and affected the classification of diabetes. A total of 3451 (55% males) newly diagnosed T1D patients (=2) autoantibodies and IA-2A in association with the dominant DQ8 and 2/8. The ZnT8-WA (38%) found less in non-Swedes compared to Swedes (50%), consistent with lower frequency in the non-Swedes (37%) of the SLC30A8 CT+TT than in Swedes (54%). The ZnT8-RA (57% and 58%, respectively) did not differ despite a higher frequency of CC (RR) genotypes in non-Swedes (63%) compared to Swedes (46%). In non-Swedes only, the prevailing DQ2/X (40%) compared to Swedes (14%) was negatively associated with ZnT8-WA (p=0.008) and ZnT8-QA (p=0.03) but not ZnT8-RA (p=0.26). Molecular simulation showed non-binding of the relevant ZnT8R peptide to DQ2 explaining in part the possible lack of tolerance to ZnT8-R by DQ2. The DQ8 and DQ6.4 had stronger binding epitopes outside the polymorphic site at amino acid position 325. The INS-SNP rs689 A/A genotype contributed T1D risk in non-Swedes (65%), though less than Swedes (72%). IAA were predicted by A/A (OR=3.5) but negatively associated with increasing age at diagnosis (OR=0.1) and HLA-DQ2 regardless of ethnic background (OR=0.6) explaining, in addition to INS T/T, the lower IAA in non-Swedes. In the Swedes only, IAA were associated with DQ2/8 (40%) and 8/x (32%), which were also stronger predictors of IAA at a younger age than INS genotypes. Non-Swedes were further subdivided into non-Europeans (n=148, 63%) and European-descent (n=86, 37%). Non-European had less T1D risk genes (HLA DQ and PTPN22) and more T2D risk genes (SLC30A8 and FTO genes), therefore they were more prone to be autoantibody-negative (11% compared to 8% in Europeans and 6% in Swedes)and had less multiple autoantibodies (64%% compared to 81% in Europeans and 79% in Swedes). Our data suggest that immigrants from low incidence countries (80% were born in Sweden), especially non-Europeans, are exposed to higher T1D in Sweden, because their genetic heritage affected by the Swedish environment. Non-European immigrants develop T1D in Sweden with lesser T1D-related genes but more T2D-related genes and less islet autoantibodies when compared to Europeans and native Swedes

Autoimmune (type 1) diabetes

Autoimmune (type 1) diabetes (AI-DM) is a multistage disorder. Children are born genetically predisposed to putative environmental exposures. These trigger an aggressive, selective and chronic autoimmune response against the pancreatic islet beta cells. This stage is marked by autoantibodies against insulin, glutamic acid decarboxylase (GAD65), IA-2 and the ZnT8 transporter. Progression to clinical onset of diabetes is highly variable but the time to onset is shortened with an increased number of islet autoantibodies. Both islet autoantibodies and diabetes are associated with HLA-DQ on chromosome 6. More than 50 non-HLA genetic factors, mostly associated with the human immune response also contribute. It remains to be clarified to what extent HLA-DQ and the non-HLA genes contribute to the initiation of the chronic islet autoimmunity, progression to diabetes, or both. Insulin replacement therapy is still the only treatment as all attempts to halt the loss of beta cells by immunosuppression or immune modulation have failed so far

Autoimmune type 1 diabetes.

The pathophysiologic mechanisms in type 1 diabetes (T1DM) involve loss of islet β-cell secretory function caused by selective killing of these cells primarily by aggressive autoimmune responses involving both cellular and humoral immune pathways. Inflammatory cells heavily infiltrate pancreatic islets leading to insulitis where CD8+ T lymphocytes are thought to be responsible for selective and specific killing of β-cells. The complex etiology of T1DM involves a strong genetic predisposition, mainly human leukocyte antigen class II genes, and several putative environmental factors, which are thought to trigger autoimmunity or progression to clinical T1DM. A preclinical prodrome in T1DM may vary in duration in which one or more islet autoantibodies may precede insulitis and predict the disease at the early stages of pathologic insult. In genetically susceptible individuals with islet autoantibodies, metabolic indicators such as insulin release abnormalities and insulin resistance may best predict T1DM especially near clinical onset. Based on the improving understanding of the etiopathogenesis of T1DM, several clinical trials have been launched aiming at halting the autoimmunity responses, retarding disease progression or preserving remaining β-cell function after clinical onset

Type 1 diabetes patients born to immigrants to Sweden increase their native diabetes risk and differ from Swedish patients in HLA types and islet autoantibodies.

Delli AJ, Lindblad B, Carlsson A, Forsander G, Ivarsson S-A, Ludvigsson J, Marcus C, Lernmark A; for the Better Diabetes Diagnosis (BDD) Study Group. Type 1 diabetes patients born to immigrants to Sweden increase their native diabetes risk and differ from Swedish patients in HLA types and islet autoantibodies. Aim: To determine whether type 1 diabetes mellitus (T1DM) patients, having parents who immigrated to Sweden, have increased T1DM risk before 18 yr compared with countries of origin. We also determined whether they have different human leukocyte antigen (HLA) genetic markers and islet autoantibodies at diagnosis compared with Swedish patients. Methods: A total of 1988 (53% males) newly diagnosed and confirmed T1DM patients /=2) autoantibodies (p < 0.04) and specifically IA-2Ab (p < 0.001) were most prevalent among the Swedish patients. Multiple autoantibodies were associated with DQ8 among the Swedish patients only (p < 0.001). Conclusion: Patients born to parents who had immigrated to the high T1DM incidence environment of Sweden have, compared with Swedish patients, more frequent HLA-DQ2 genetic markers and are diagnosed more often with GAD65Ab

Neuropeptide Y is a minor autoantigen in newly diagnosed type 1 diabetes patients.

Autoantibodies (A) against Neuropeptide Y (NPY), was reported in 9% newly diagnosed type 1 diabetes (T1D) patients. A single nucleotide polymorphism (SNP) at rs16139 (T1128C) within the NPY-gene identified an amino acid substitution from leucine (L) to proline (P) (L7P) associated with both glucose tolerance and type 2 diabetes. We aimed to determine: (i) the influence of autoantibodies to leucine neuropeptide Y (NPY-LA) and autoantibodies to proline neuropeptide Y (NPY-PA) on the diagnostic sensitivity of type 1 diabetes (T1D), (ii) the association of NPYA with major islet autoantibodies, and (iii) the association of NPYA with HLA-DQ genotypes in newly diagnosed T1D patients