XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

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Modern Applied Statistics With S

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22759

Diagnosis, management, and treatment of hepatitis C: An update

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and a potential cause of substantial morbidity and mortality in the future. The complexity and uncertainty related to the geographic distribution of HCV infection and chronic hepatitis C, determination of its associated risk factors, and evaluation of cofactors that accelerate its progression, underscore the difficulties in global prevention and control of HCV. Because there is no vaccine and no post-exposure prophylaxis for HCV, the focus of primary prevention efforts should be safer blood supply in the developing world, safe injection practices in health care and other settings, and decreasing the number of people who initiate injection drug use.

https://courses.washington.edu/conj504/readings/alter_reading3.pdf

Global epidemiology of hepatitis C virus infection

Regulatory T (T(Reg)) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting antitumour immunity. Given that T(Reg) cells can have both beneficial and deleterious effects, there is considerable interest in determining their mechanisms of action. In this Review, we describe the basic mechanisms used by T(Reg) cells to mediate suppression and discuss whether one or many of these mechanisms are likely to be crucial for T(Reg)-cell function. In addition, we propose the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate T(Reg)-cell function.

/pdf/how-regulatory-t-cells-work-3kg9ber5qg.pdf

How regulatory T cells work.

The priming of T cells in the liver is widely accepted. Nonetheless, it is controversial whether immune activation in autoimmune hepatitis (AIH) occurs in the liver or in the spleen. To address this issue, we splenectomized mice and induced experimental murine AIH (emAIH) with an adenovirus (Ad)-expressing formiminotransferase cyclodeaminase (FTCD). Post-splenectomy, the experimental mice developed emAIH to a higher extent than the control mice. In addition, splenectomized mice harboured more intrahepatic B cells and a disproportionately small number of regulatory T cells (Tregs) within a reduced T cell population at the site of inflammation. These results imply that the spleen is not the site of AIH induction. In contrast, the spleen seems to have a protective function since the pathological score was more severe in splenectomized animals. These findings have important implications for the aetiology of AIH.

Autoimmune hepatitis induction can occur in the liver

Autoimmune polyglandulare Syndrome sind seltene Endokrinopathien, die auch in Kombination mit nicht endokrinen Autoimmunerkrankungen auftreten konnen. Man unterscheidet das autoimmun polyglandulare Syndrom Typ 1 (Autoimmunes Polyendokrinopathie-Candidiasis-Ektodermales Dystrophie-Syndrom; APECED-Syndrom) vom autoimmun polyglandularen Syndrom Typ 2 (APS-2). Hauptkomponenten des APECED-Syndroms sind eine Nebennierenrindeninsuffizienz, ein Hypoparathyreoidismus und eine mukokutane Kandidiasis. Das APECED-Syndrom ist mit Mutationen des Autoimmunregulatorgens (AIRE) assoziiert und betrifft v. a. Kinder und Jugendliche bestimmter ethnischer Gruppen. Das APS-2-Syndrom ist durch das Auftreten einer Autoimmunthyreopathie, Nebennierenrindeninsuffizienz und/oder Diabetes mellitus Typ 1 charakterisiert. Das APS-2-Syndrom ist nicht AIRE-assoziiert und besitzt im Vergleich zum APECED-Syndrom eine hohere Inzidenz. Es betrifft v. a. erwachsene Frauen ohne Bevorzugung einer ethnischen Gruppe. Die Therapie beider Syndrome basiert derzeit hauptsachlich auf der Hormonsubstitution und Behandlung der Symptome. Beim APECED-Syndrom war in einzelnen Fallen eine immunsuppressive Therapie erfolgreich.

Autoimmun polyglanduläre Syndrome

Elevated fractional donor‐derived cell‐free DNA during subclinical graft injury after liver transplantation

For the development of autoimmune hepatitis (AIH), genetic predisposition and environmental triggers are of major importance. Although experimental AIH can be induced in genetically susceptible mice, the low precursor frequency of autoreactive T cells hampers a deeper analysis of liver-specific T cells. Here, we established a system where the model antigen hemagglutinin (HA) is expressed exclusively in hepatocytes of Rosa26-HA mice following administration of a replication deficient adenovirus expressing Cre recombinase (Ad-Cre). Under these conditions, hepatocytes mimic the generation of altered-self neoantigens. To follow autoreactive T cells during AIH, we adoptively transferred HA--specific Cl4-TCR and 6.5-TCR T cells into Ad-Cre infected -Rosa26-HA mice. Alternatively, Rosa26-HA mice have been crossed with TCR transgenic mice that were infected with Ad-Cre to break hepatic tolerance and induce the expression of the HA antigen as a hepatic self-antigen. Surprisingly, neither adoptive transfer nor a very high precursor frequency of autoreactive T cells was able to break tolerance in the context of adenoviral infection. The low proliferation of the antigen experienced autoreactive T cells despite the presence of the autoantigen and inflammation points to anergy as a potential tolerance mechanism. This model underscores the crucial importance of genetic susceptibility to break tolerance against hepatic autoantigens.

Hepatic T Cell Tolerance Induction in An Inflammatory Environment.

OBJECTIVE To study how tolerance to GAD65 affects the development of autoimmunity to other β-cell autoantigens (β-CAAs) in GAD65-transgenic (GAD-tg) NOD mice. RESEARCH DESIGN AND METHODS We used ELISPOT to characterize the frequency and functional phenotype of T-cell responses to GAD65 and other β-CAAs at different ages in GAD-tg mice and their NOD mouse littermates. RESULTS In young GAD-tg mice, Th1 responses to GAD659s dominant determinants were 13−18% of those in young NOD mice. This coincided with a great reduction in Th1 responses to other β-CAAs. Evidently, GAD65-reactive T-cells are important for activating and/or expanding early autoreactivities in NOD mice. As GAD-tg mice aged, their T-cell responses to GAD65 remained low, but they developed supernormal splenic and pancreatic lymph node T-cell autoimmunity to other β-CAAs. Apparently, the elimination/impairment of many GAD65-reactive T-cells allowed other β-CAA–reactive T-cells to eventually expand to a greater extent, perhaps by reducing competition for antigen-presenting cells, or homeostatic proliferation in the target tissue, which may explain the GAD-tg mouse9s usual disease incidence. CONCLUSIONS Transgenically induced reduction of GAD65 autoreactivity curtailed the development of early T-cell responses to other β-CAAs. However, later in life, β-CAA–reactive T-cells expanded to supernormal levels. These data suggest that early β-cell autoreactivities are mutually dependent for support to activate and expand, while later in the disease process, autoantigen-specific T-cell pools can expand autonomously. These findings have implications for understanding type 1 diabetes immunopathogenesis and for designing antigen-based immunotherapeutics.

/pdf/transgenically-induced-gad-tolerance-curtails-the-3nxt3a9jjx.pdf

Transgenically Induced GAD Tolerance Curtails the Development of Early β-Cell Autoreactivities but Causes the Subsequent Development of Supernormal Autoreactivities to Other β-Cell Antigens

Elmar Jaeckel

Papers

Autoimmune hepatitis induction can occur in the liver

Autoimmun polyglanduläre Syndrome

Elevated fractional donor‐derived cell‐free DNA during subclinical graft injury after liver transplantation

Hepatic T Cell Tolerance Induction in An Inflammatory Environment.

Transgenically Induced GAD Tolerance Curtails the Development of Early β-Cell Autoreactivities but Causes the Subsequent Development of Supernormal Autoreactivities to Other β-Cell Antigens