The role of lymphotoxin signaling in the development of autoimmune pancreatitis and associated secondary extra-pancreatic pathologies.

The pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis, have so far remained elusive. Treatment options for AIP are currently limited and disease relapse is frequent. Still, AIP can be characterized by specific clinical and histologic features. It has turned out that as described in other autoimmune diseases the generation of tertiary lymphoid organs is also a hallmark of patients with AIP. We have recently demonstrated that pancreata derived from human AIP patients display overexpression of lymphotoxin (LT) α and ß and LTßR-target genes expressed by immune cells but also by irradiation resistant cells of the pancreas (e.g. acinar cells). Expression of LT α and ß on acinar cells in murine pancreata Tg(Ela1-Lta,b) mice led to chronic pancreatitis and sufficed to reproduce key features of human AIP including the development of autoimmunity and AIP associated secondary extra pancreatic pathologies. Here, we review how aberrant and ectopic expression of LT α and ß can induce inflammation and autoimmune diseases in general and how this knowledge might specifically lead to an alternative treatment for patients suffering from autoimmune pancreatitis.

Nonredundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis.

Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα3) produced by RORγt(+) innate lymphoid cells (ILCs) controls T cell-dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin ß (LTα1ß2) produced by RORγt(+) ILCs is critical for T cell-independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTα in RORγt(+) cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxins produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition.

TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer.

The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signaling pathways. Here, we report that conditional ablation of TAK1 in liver parenchymal cells (hepatocytes and cholangiocytes) causes hepatocyte dysplasia and early-onset hepatocarcinogenesis, coinciding with biliary ductopenia and cholestasis. TAK1-mediated cancer suppression is exerted through activating NF-kappaB in response to tumor necrosis factor (TNF) and through preventing Caspase-3-dependent hepatocyte and cholangiocyte apoptosis. Moreover, TAK1 suppresses a procarcinogenic and pronecrotic pathway, which depends on NF-kappaB-independent functions of the I kappaB-kinase (IKK)-subunit NF-kappaB essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-kappaB-independent function of NEMO in parenchymal liver cells.

Consensus guidelines for primary health care of adults with developmental disabilities.

OBJECTIVE: To develop practical Canadian guidelines for primary health care providers based on the best available evidence for addressing health issues in adults with developmental disabilities (DD). QUALITY OF EVIDENCE: Authors of background papers synthesized information from their own clinical experience, from consultations with other experts, and from relevant professional publications. Based on discussions of these papers at a colloquium of knowledgeable health care providers, a consensus statement was developed. Standard criteria were used to select guidelines for consideration and to rank evidence supporting them. Most evidence was level III. MAIN MESSAGE: People with DD have complex health issues, some differing from those of the general population. Adequate primary health care is necessary to identify these issues and to prevent morbidity and premature death. Physical, behavioural, and mental health difficulties should be addressed, and primary health care providers should be particularly attentive to the interactions of biological, psychological, and social factors contributing to health, since these interactions can easily be overlooked in adults with DD. Attention must also be paid to such ethical issues as informed consent and avoidance of harm. Developmental disabilities are not grounds for care providers to withhold or to withdraw medically indicated interventions, and decisions concerning such interventions should be based on patients' best interests. CONCLUSION: Implementing the guidelines proposed here would improve the health of adults with DD and minimize disparities in health and health care.