Molecular interactions involved in the transactivation of the human T-cell leukemia virus type 1 promoter mediated by Tax and CREB-2 (ATF-4).

The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates viral transcription through three 21-bp repeats located in the U3 region of the HTLV-1 long terminal repeat and called Tax-responsive elements (TxREs). Each TxRE contains nucleotide sequences corresponding to imperfect cyclic AMP response elements (CRE). In this study, we demonstrate that the bZIP transcriptional factor CREB-2 is able to bind in vitro to the TxREs and that CREB-2 binding to each of the 21-bp motifs is enhanced by Tax. We also demonstrate that Tax can weakly interact with CREB-2 bound to a cellular palindromic CRE motif such as that found in the somatostatin promoter. Mutagenesis of Tax and CREB-2 demonstrates that both N- and C-terminal domains of Tax and the C-terminal region of CREB-2 are required for direct interaction between the two proteins. In addition, the Tax mutant M47, defective for HTLV-1 activation, is unable to form in vitro a ternary complex with CREB-2 and TxRE. In agreement with recent results suggesting that Tax can recruit the coactivator CREB-binding protein (CBP) on the HTLV-1 promoter, we provide evidence that Tax, CREB-2, and CBP are capable of cooperating to stimulate viral transcription. Taken together, our data highlight the major role played by CREB-2 in Tax-mediated transactivation.

Nocturnal hypoglycaemias in type 1 diabetic patients : what can we learn with continuous glucose monitoring ?

Rapport de synthèse : Hypoglycémies nocturnes chez les patients diabétiques de type 1 : que pouvons-nous apprendre de la mesure de la glycémie en continu ? But : les hypoglycémies nocturnes sont une complication majeure du traitement des patients diabétiques de type 1; des autocontrôles de la glycémie capillaire sont donc recommandés pour les détecter. Cependant, la majorité des hypoglycémies nocturnes ne sont pas décelées par un autocontrôle glycémique durant la nuit. La mesure de la glycémie en continu (CGMS) est une alternative intéressante. Les buts de cette étude rétrospective étaient d'évaluer la véritable incidence des hypoglycémies nocturnes chez des patients diabétiques de type 1, la meilleure période pour effectuer un autocontrôle permettant de prédire une hypoglycémie nocturne, la relation entre les hyperglycémies matinales et les hypoglycémies nocturnes (phénomène de Somogyi) ainsi que l'utilité du CGMS pour réduire les hypoglycémies nocturnes. Méthode : quatre-vingt-huit patients diabétiques de type 1 qui avaient bénéficié d'un CGMS ont été inclus. Les indications au CGMS, les hypoglycémies nocturnes et diurnes ainsi que la corrélation entre les hypoglycémies nocturnes et les hyperglycémies matinales durant le CGMS ont été enregistrées. L'efficacité du CGMS pour réduire les hypoglycémies nocturnes a été évaluée six à neuf mois après. Résultats : la prévalence des hypoglycémies nocturnes était de 67% (32% non suspectées). La sensibilité d'une hypoglycémie à prédire une hypoglycémie nocturne était de 37% (OR = 2,37, P = 0,001) lorsqu'elle survient au coucher (22-24 h) et de 43% lorsqu'elle survient à 3 h (OR = 4,60, P < 0,001). Les hypoglycémies nocturnes n'étaient pas associées à des hyperglycémies matinales, mais à des hypoglycémies matinales (OR = 3.95, P < 0.001). Six à neuf mois après le CGMS, les suspicions cliniques d'hypoglycémies nocturnes ont diminué de 60% à 14% (P < 0.001). Abstract : Aim. - In type 1 diabetic patients (TIDM), nocturnal hypoglycaemias (Nlï) are a serious complication of T1DM treatment; self-monitoring of blood glucose (SMBG) is recommended to detect them. However, the majority of NH remains undetected on an occasional SMBG done during the night. An alternative strategy is the Continuous glucose monitoring (CGMS), which retrospectively shows the glycaemic profile. The aims of this retrospective study were to evaluate the true incidence of NH in TiDM, the bèst SMBG time to predict NH, the relationship between morning hyperglycaemia and N$ (Somogyi phenomenon) and the utility of CGMS to reduce NH. Methods. -Eighty-eight T1DM who underwent a CGMS exam were included. Indications for CGMS evaluarion, hypoglycaemias and correlation with morning hyperglycaemias were recorded. The efficiency of CGMS to reduce the suspected NH was evaluated after 6-9 months. Results. -The prevalence of NH was 67% (32% of them unsuspected). A measured hypoglycaemia at bedtime (22-24 h) had a sensitivity of 37% to detect NH (OR = 2.37, P = 0.001), while a single measure <_ 4 mmol/l at 3-hour had a sensitivity of 43% (OR = 4.60, P < 0.001). NH were not associated with morning hyperglycaemias but with morning hypoglycaemias (OR = 3.95, P < 0.001). After 6-9 months, suspicions of NH decreased from 60 to 14% (P < 0.001). Conclusion. - NH were highly prevalent and often undetected. SMBG at bedtime, which detected hypoglycaemia had sensitivity almost equal to that of 3-hour and should be preferred because it is easier to perform. Somogyi phenomenon was not observed. CGMS is useful to reduce the risk of NH in 75% of patients.

The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription.

The RNA genome of the human T-cell leukemia virus type 1 (HTLV-1) codes for proteins involved in infectivity, replication, and transformation. We report in this study the characterization of a novel viral protein encoded by the complementary strand of the HTLV-1 RNA genome. This protein, designated HBZ (for HTLV-1 bZIP factor), contains a N-terminal transcriptional activation domain and a leucine zipper motif in its C terminus. We show here that HBZ is able to interact with the bZIP transcription factor CREB-2 (also called ATF-4), known to activate the HTLV-1 transcription by recruiting the viral trans-activator Tax on the Tax-responsive elements (TxREs). However, we demonstrate that the HBZ/CREB-2 heterodimers are no more able to bind to the TxRE and cyclic AMP response element sites. Taking these findings together, the functional inactivation of CREB-2 by HBZ is suggested to contribute to regulation of the HTLV-1 transcription. Moreover, the characterization of a minus-strand gene protein encoded by HTLV-1 has never been reported until now.

Impact of phenotype definition on genome-wide association signals: empirical evaluation in human immunodeficiency virus type 1 infection.

Discussion on improving the power of genome-wide association studies to identify candidate variants and genes is generally centered on issues of maximizing sample size; less attention is given to the role of phenotype definition and ascertainment. The authors used genome-wide data from patients infected with human immunodeficiency virus type 1 (HIV-1) to assess whether differences in type of population (622 seroconverters vs. 636 seroprevalent subjects) or the number of measurements available for defining the phenotype resulted in differences in the effect sizes of associations between single nucleotide polymorphisms and the phenotype, HIV-1 viral load at set point. The effect estimate for the top 100 single nucleotide polymorphisms was 0.092 (95% confidence interval: 0.074, 0.110) log(10) viral load (log(10) copies of HIV-1 per mL of blood) greater in seroconverters than in seroprevalent subjects. The difference was even larger when the authors focused on chromosome 6 variants (0.153 log(10) viral load) or on variants that achieved genome-wide significance (0.232 log(10) viral load). The estimates of the genetic effects tended to be slightly larger when more viral load measurements were available, particularly among seroconverters and for variants that achieved genome-wide significance. Differences in phenotype definition and ascertainment may affect the estimated magnitude of genetic effects and should be considered in optimizing power for discovering new associations.

Surveillance of HIV type 1 drug resistance among naive patients from Venezuela.

We have studied 65 HIV-1-infected untreated patients recruited in Caracas, Venezuela with TCD4 counts > or =350/microl. The reverse transcriptase and protease sequences of the virus were sequenced, aligned with reference HIV-1 group M strains, and analyzed for drug resistance mutations. Most of the viruses were subtype B genotype in both the protease and RT genomic regions. Five of the 62 virus isolates successfully amplified showed evidence of recombination between protease and RT, with their protease region being non-B while their RT region was derived from subtype B. Four strains were found bearing resistance mutations either to NRTIs, NNRTIs, or PIs. The prevalence of HIV-1 isolates bearing resistance mutations was therefore above the 5% threshold of WHO.

Seroepidemiology of herpes simplex virus type 1 and 2 in pregnant women in Switzerland: an obstetric clinic based study.

OBJECTIVE: To assess the seroprevalence of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) IgG antibodies and the seroincidence of HSV-1 and HSV-2 infections in pregnant women attending the maternity clinic of the University Hospital Lausanne. STUDY DESIGN: Blood samples from 1030 women were taken at the usual pregnancy visit in the first trimester to assess the prevalence rate of IgG antibodies against HSV-1 and HSV-2 using a type-specific assay. A second blood sample was taken 6-8 weeks postpartum from returning women who were seronegative for HSV-2 or HSV-1 to assess the incidence of seroconversion (primary infection). RESULTS: The seroprevalence rates were 79.4% (95% CI: 76.9-81.9) for HSV-1 and 21.2% (18.7-23.7) for HSV-2 in women 14-46 years old. Type-specific serostatus patterns were as follows: 17.3% HSV-1/-2: +/+, 62.1% HSV-1/-2: +/-, 3.9% HSV-1/-2: -/+, 16.7% HSV-1/-2: -/-. Two hundred and sixty five women (59 of the 212 seronegative for HSV-1 (27.8%) and 265 of the 812 seronegative for HSV-2 (32.6%)) returned to the outpatient clinic for the post-delivery check and a second blood sample was obtained. One HSV-1 seroconversion was detected (HSV-1 seroconversion rate 2.4%/100 patient×year (95% CI: 0.06-13.4)) in a patient who had symptoms compatible with primary genital herpes. No HSV-2 seroconversion was detected (HSV-2 seroconversion rate: 0/100 patient×year (97.5% one-sided CI: 0-2)). CONCLUSION: Compared to a previous population-based study, our study results suggest a rise in the prevalence of HSV-2 among pregnant women in Switzerland. The low incidence of seroconversion detected during pregnancy is consistent with the very low reported incidence of neonatal herpes in Switzerland. CONDENSATION: This study in a public hospital in Western Switzerland suggests an increasing prevalence of HSV-2, but a low incidence of primary infections in women of childbearing age.

Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2(Akita/+) mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2(Akita/+) and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2(Akita/+) mice and sex-matched littermate controls. Our phenotypic analysis of Ins2(Akita/+) mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM.

Type 1 diabetes mellitus in people with pharmacoresistant epilepsy: Prevalence and clinical characteristics.

BACKGROUND: There have been inconsistent reports on the potential association between diabetes mellitus and epilepsy. METHODS: We examined a consecutive cohort of 2016 people with pharmacoresistant epilepsy admitted to a tertiary medical centre. RESULTS: We identified 20 individuals with type 1 diabetes mellitus (T1DM); a point prevalence of 9.9 (95% CI: 6.4, 15.3) cases per 1000 individuals. This represents a more than two-fold increase relative to published prevalence estimates of T1DM in the general population. The onset of T1DM preceded that of epilepsy in 80% of individuals, by a median of 1.5 years. Individuals with T1DM were significantly more likely to have cryptogenic/unknown epilepsy relative to those with type 2 diabetes mellitus or without diabetes (85% versus 35% and 49%, p=0.045). All individuals with T1DM had focal epilepsy, the majority of which were temporal lobe in origin, although there was no evidence that this proportion was any different from those without T1DM (p>0.999). CONCLUSIONS: The prevalence of T1DM appears to be increased in people with pharmacoresistant epilepsy and is associated with cryptogenic/unknown epilepsy. These findings may have pathophysiological implications, especially in the context of anti-glutamic acid decarboxylase antibodies.

Vaccine-Induced Linear Epitope-Specific Antibodies to Simian Immunodeficiency Virus SIVmac239 Envelope Are Distinct from Those Induced to the Human Immunodeficiency Virus Type 1 Envelope in Nonhuman Primates.

To evaluate antibody specificities induced by simian immunodeficiency virus (SIV) versus human immunodeficiency virus type 1 (HIV-1) envelope antigens in nonhuman primate (NHP), we profiled binding antibody responses to linear epitopes in NHP studies with HIV-1 or SIV immunogens. We found that, overall, HIV-1 Env IgG responses were dominated by V3, with the notable exception of the responses to the vaccine strain A244 Env that were dominated by V2, whereas the anti-SIVmac239 Env responses were dominated by V2 regardless of the vaccine regimen.

Assessing the Paradox Between Transmitted and Acquired HIV Type 1 Drug Resistance Mutations in the Swiss HIV Cohort Study From 1998 to 2012.

BACKGROUND: Transmitted human immunodeficiency virus type 1 (HIV) drug resistance (TDR) mutations are transmitted from nonresponding patients (defined as patients with no initial response to treatment and those with an initial response for whom treatment later failed) or from patients who are naive to treatment. Although the prevalence of drug resistance in patients who are not responding to treatment has declined in developed countries, the prevalence of TDR mutations has not. Mechanisms causing this paradox are poorly explored. METHODS: We included recently infected, treatment-naive patients with genotypic resistance tests performed ≤1 year after infection and before 2013. Potential risk factors for TDR mutations were analyzed using logistic regression. The association between the prevalence of TDR mutations and population viral load (PVL) among treated patients during 1997-2011 was estimated with Poisson regression for all TDR mutations and individually for the most frequent resistance mutations against each drug class (ie, M184V/L90M/K103N). RESULTS: We included 2421 recently infected, treatment-naive patients and 5399 patients with no response to treatment. The prevalence of TDR mutations fluctuated considerably over time. Two opposing developments could explain these fluctuations: generally continuous increases in the prevalence of TDR mutations (odds ratio, 1.13; P = .010), punctuated by sharp decreases in the prevalence when new drug classes were introduced. Overall, the prevalence of TDR mutations increased with decreasing PVL (rate ratio [RR], 0.91 per 1000 decrease in PVL; P = .033). Additionally, we observed that the transmitted high-fitness-cost mutation M184V was positively associated with the PVL of nonresponding patients carrying M184V (RR, 1.50 per 100 increase in PVL; P < .001). Such association was absent for K103N (RR, 1.00 per 100 increase in PVL; P = .99) and negative for L90M (RR, 0.75 per 100 increase in PVL; P = .022). CONCLUSIONS: Transmission of antiretroviral drug resistance is temporarily reduced by the introduction of new drug classes and driven by nonresponding and treatment-naive patients. These findings suggest a continuous need for new drugs, early detection/treatment of HIV-1 infection.

Trabecular bone score in type 1 diabetes--a cross-sectional study.

UNLABELLED: Trabecular bone score (TBS) seems to provide additive value on BMD to identify individuals with prevalent fractures in T1D. TBS did not significantly differ between T1D patients and healthy controls, but TBS and HbA1c were independently associated with prevalent fractures in T1D. A TBS cutoff <1.42 reflected prevalent fractures with 91.7 % sensitivity and 43.2 % specificity. INTRODUCTION: Type 1 diabetes (T1D) increases the risk of osteoporotic fractures. TBS was recently proposed as an indirect measure of bone microarchitecture. This study aimed at investigating the TBS in T1D patients and healthy controls. Associations with prevalent fractures were tested. METHODS: One hundred nineteen T1D patients (59 males, 60 premenopausal females; mean age 43.4 ± 8.9 years) and 68 healthy controls matched for gender, age, and body mass index (BMI) were analyzed. The TBS was calculated in the lumbar region, based on two-dimensional (2D) projections of DXA assessments. RESULTS: TBS was 1.357 ± 0.129 in T1D patients and 1.389 ± 0.085 in controls (p = 0.075). T1D patients with prevalent fractures (n = 24) had a significantly lower TBS than T1D patients without fractures (1.309 ± 0.125 versus 1.370 ± 0.127, p = 0.04). The presence of fractures in T1D was associated with lower TBS (odds ratio = 0.024, 95 % confidence interval (CI) = 0.001-0.875; p = 0.042) but not with age or BMI. TBS and HbA1c were independently associated with fractures. The area-under-the curve (AUC) of TBS was similar to that of total hip BMD in discriminating T1D patients with or without prevalent fractures. In this set-up, a TBS cutoff <1.42 discriminated the presence of fractures with a sensitivity of 91.7 % and a specificity of 43.2 %. CONCLUSIONS: TBS values are lower in T1D patients with prevalent fractures, suggesting an alteration of bone strength in this subgroup of patients. Reliable TBS cutoffs for the prediction of fracture risk in T1D need to be determined in larger prospective studies.

Role of human hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) in steroid-dependent diseases in females –novel indications for HSD17B1 inhibitors. Phenotypic analysis of transgenic mice overexpressing human HSD17B1.

Hormone-dependent diseases, e.g. cancers, rank high in mortality in the modern world, and thus, there is an urgent need for new drugs to treat these diseases. Although the diseases are clearly hormone-dependent, changes in circulating hormone concentrations do not explain all the pathological processes observed in the diseased tissues. A more inclusive explanation is provided by intracrinology – a regulation of hormone concentrations at the target tissue level. This is mediated by the expression of a pattern of steroid-activating and -inactivating enzymes in steroid target tissues, thus enabling a concentration gradient between the blood circulation and the tissue. Hydroxysteroid (17beta) dehydrogenases (HSD17Bs) form a family of enzymes that catalyze the conversion between low active 17-ketosteroids and highly active 17beta-hydroxysteroids. HSD17B1 converts low active estrogen (E1) to highly active estradiol (E2) with high catalytic efficiency, and altered HSD17B1 expression has been associated with several hormone-dependent diseases, including breast cancer, endometriosis, endometrial hyperplasia and cancer, and ovarian epithelial cancer. Because of its putative role in E2 biosynthesis in ovaries and peripheral target tissues, HSD17B1 is considered to be a promising drug target for estrogen-dependent diseases. A few studies have indicated that the enzyme also has androgenic activity, but they have been ignored. In the present study, transgenic mice overexpressing human HSD17B1 (HSD17B1TG mice) were used to study the effects of the enzyme in vivo. Firstly, the substrate specificity of human HSD17B1 was determined in vivo. The results indicated that human HSD17B1 has significant androgenic activity in female mice in vivo, which resulted in increased fetal testosterone concentration and female disorder of sexual development appearing as masculinized phenotype (increased anogenital distance, lack of nipples, lack of vaginal opening, combination of vagina with urethra, enlarged Wolffian duct remnants in the mesovarium and enlarged female prostate). Fetal androgen exposure has been linked to polycystic ovary syndrome (PCOS) and metabolic syndrome during adulthood in experimental animals and humans, but the genes involved in PCOS are largely unknown. A putative mechanism to accumulate androgens during fetal life by HSD17B1 overexpression was shown in the present study. Furthermore, as a result of prenatal androgen exposure locally in the ovaries, HSD17B1TG females developed ovarian benign serous cystadenomas in adulthood. These benign lesions are precursors of low-grade ovarian serous tumors. Ovarian cancer ranks fifth in mortality of all female cancers in Finland, and most of the ovarian cancers arise from the surface epithelium. The formation of the lesions was prevented by prenatal antiandrogen treatment and by transplanting wild type (WT) ovaries prepubertally into HSD17B1TG females. The results obtained in our non-clinical TG mouse model, together with a literature analysis, suggest that HSD17B1 has a role in ovarian epithelial carcinogenesis, and especially in the development of serous tumors. The role of androgens in ovarian carcinogenesis is considered controversial, but the present study provides further evidence for the androgen hypothesis. Moreover, it directly links HSD17B1-induced prenatal androgen exposure to ovarian epithelial carcinogenesis in mice. As expected, significant estrogenic activity was also detected for human HSD17B1. HSD17B1TG mice had enhanced peripheral conversion of E1 to E2 in a variety of target tissues, including the uterus. Furthermore, this activity was significantly decreased by treatments with specific HSD17B1 inhibitors. As a result, several estrogen-dependent disorders were found in HSD17B1TG females. Here we report that HSD17B1TG mice invariably developed endometrial hyperplasia and failed to ovulate in adulthood. As in humans, endometrial hyperplasia in HSD17B1TG females was reversible upon ovulation induction, triggering a rise in circulating progesterone levels, and in response to exogenous progestins. Remarkably, treatment with a HSD17B1 inhibitor failed to restore ovulation, yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment. We also demonstrate that HSD17B1 is expressed in normal human endometrium, hyperplasia, and cancer. Collectively, our non-clinical data and literature analysis suggest that HSD17B1 inhibition could be one of several possible approaches to decrease endometrial estrogen production in endometrial hyperplasia and cancer. HSD17B1 expression has been found in bones of humans and rats. The non-clinical data in the present study suggest that human HSD17B1 is likely to have an important role in the regulation of bone formation, strength and length during reproductive years in female mice. Bone density in HSD17B1TG females was highly increased in femurs, but in lesser amounts also in tibias. Especially the tibia growth plate, but not other regions of bone, was susceptible to respond to HSD17B1 inhibition by increasing bone length, whereas the inhibitors did not affect bone density. Therefore, HSD17B1 inhibitors could be safer than aromatase inhibitors in regard to bone in the treatment of breast cancer and endometriosis. Furthermore, diseases related to improper growth, are a promising new indication for HSD17B1 inhibitors.

Islet antigen-specific T cells and regulatory T cells in type 1 diabetes

T cells are the key players in the development of type 1 diabetes (T1D), mediating autoimmune reactions leading to the destruction of insulin producing beta cells in the islets. We aimed to analyze the role of different T-cell subtypes in the autoimmunity and pathogenesis of T1D. The frequency of islet antigen-specific (GAD65-, proinsulin-, and insulin-specific) CD4+ T cells was investigated in vitro in T1D patients, at-risk individuals (diabetes-associated autoantibody positive), and in controls, using MHC class II tetramers. An overall higher frequency of CD4+ T-cells recognizing the GAD65 555−567 peptide was detected in at-risk individuals. In addition, increased CD4+ T-cell responses to the same GAD65 epitope displaying a memory phenotype were observed in at-risk and diabetic children, which demonstrate a previous encounter with the antigen in vivo. Avidity and phenotypic differences were also observed among CD4+ T-cell clones induced by distinct doses of GAD65 autoantigen. T-cell clones generated at the lowest peptide dose displayed the highest avidity and expressed more frequently the TCR Vβ5.1 chain than low-avidity T cells. These findings raise attention to the antigen dose when investigating the diversity of antigen-specific T cells. Furthermore, an increased regulatory response during the preclinical phase of T1D was also found in genetically at-risk children. Higher frequencies of regulatory T (Treg) cells (CD4+CD25_high HLA-DR-/CD69-) and natural killer T (NKT) cells (CD161+Vbeta11+) were observed in children with multiple autoantibodies compared to autoantibody-negative controls. Taken together, these data showed increased frequency of islet-specific CD4+ T-cells, especially to the GAD65 555-567 epitope, and Treg and NKT cell upregulation in children at-risk for T1D, suggesting their importance in T1D pathogenesis

The Influence of Diet and Microbes on Colonic Immune Regulation and their Implications on Type 1 Diabetes

Dietary and microbial factors are thought to contribute to the rapidly increasing prevalence of T1D in many countries worldwide. The impact of these factors on immune regulation and diabetes development in non-obese diabetic (NOD) mice are investigated in this thesis. Diabetes can be prevented in NOD mice through dietary manipulation. Diet affects the composition of intestinal microbiota, which may subsequently influence intestinal immune homeostasis. However, the specific effects of anti-diabetogenic diets on gut immunity and the explicit associations between intestinal immune disruption and type 1 diabetes onset remain unclear. The research presented herein demonstrates that newly weaned NOD mice suffer from a mild level of colitis, which shifts the colonic immune cell balance towards a proinflammatory status. Several aberrations can also be observed in the peritoneal B cells of NOD mice; an increase in activation marker expression, increased trafficking to the pancreatic lymph nodes and significantly higher antigen presenting cell (APC) efficiency towards insulin-specific T cells. A shift towards inflammation is likewise observed in the colon of germ-free NOD mice, but signs of peritoneal B cell activation are lacking in these mice. Remarkably, most of the abnormalities in the colon, peritoneal macrophages and the peritoneal B cell APC activity of NOD mice are abrogated when NOD mice are maintained on a diabetes-preventive, soy-based diet (ProSobee) from the time of weaning. Dietary and microbial factors hence have a significant impact on colonic immune regulation and peritoneal B cell activation and it is suggested that these factors influence diabetes development in NOD mice.