Triggers and drivers of autoimmunity: lessons from coeliac disease.

Coeliac disease, an inflammatory disease of the small intestine, shares key features with autoimmune disorders, such as susceptibility genes, presence of autoantibodies and T cell-mediated destruction of specific cells. Strikingly, however, continuous exposure to the exogenous dietary antigen gluten and gluten-specific adaptive immunity are required to maintain immunopathology. These observations challenge the notion that autoimmunity requires adaptive immune activation towards self antigens.

Activation of coagulation and platelets by candidate membranes of implantable devices in a whole blood model without soluble anticoagulant.

Implantable devices are challenged with thrombus formation at their biomaterial interface. Thus the importance of identifying compatible biomaterials that will help to improve the performance of these devices are becoming increasingly paramount. The aim of this study was to evaluate the activation of coagulation and platelets by candidate membranes considered for use in implantable devices on the basis of an adapted whole blood model without soluble anticoagulants.

Epithelial-microbial crosstalk in polymeric Ig receptor deficient mice.

Innate and adaptive mucosal defense mechanisms ensure a homeostatic relationship with the large and complex mutualistic gut microbiota. Dimeric IgA and pentameric IgM are transported across the intestinal epithelium via the epithelial polymeric Ig receptor (pIgR) and provide a significant portion of the first line of natural or adaptive antibody-mediated immune defense of the intestinal mucosa. We found that colonic epithelial cells from pIgR KO mice differentially expressed (more than twofold change) more than 200 genes compared with cells from WT mice, and upregulated the expression of antimicrobial peptides in a commensal-dependent manner.

High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions.

Celiac disease is an immune-mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) are generated in response to the exogenous antigen gluten in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8 (ref. 3). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire of ex vivo-isolated intestinal antibody-secreting cells (ASCs).

Activation of polymorphonuclear leukocytes by candidate biomaterials for an implantable glucose sensor.

Background: Continuous monitoring of glucose by implantable microfabricated devices offers key advantages over current transcutaneous glucose sensors that limit usability due to their obtrusive nature and risk of infection. A successful sensory implant should be biocompatible and retain long-lasting function. Polymorphonuclear leukocytes (PMN) play a key role in the inflammatory system by releasing enzymes, cytokines, and reactive oxygen species, typically as a response to complement activation.

Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders.

Posttranslational modification (PTM) of antigen is a way to break T-cell tolerance to self-antigens and promote autoimmunity. However, the precise mechanisms by which modifications would facilitate autoimmune T-cell responses and how they relate to particular autoimmune-associated MHC molecules remain elusive. Celiac disease is a T-cell mediated enteropathy with a strong HLA association where the immune response is directed mainly against deamidated cereal gluten peptides that have been modified by the enzyme transglutaminase 2.

Complement activation by candidate biomaterials of an implantable microfabricated medical device.

Implantable devices realized by microfabrication have introduced a new class of potential biomaterials whose properties would need to be assessed. Such devices include sensors for measuring biological substances like glucose. Thus, 14 different candidate materials intended for design of such a device were investigated with respect to their complement activation potential in human serum.

Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer.

The immune system can both promote and suppress cancer. Chronic inflammation and proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are considered to be tumour promoting. In contrast, the exact nature of protective antitumour immunity remains obscure.

Is secretion of tumour-specific antigen important for cancer eradication by CD4(+) T cells?--Implications for cancer immunotherapy by adoptive T cell transfer.

The potential for cancer immunotherapy by adoptive transfer of CD4(+) T cells is gaining increased attention. Most cancer cells lack major histocompatibility complex (MHC) class II molecules and cannot present tumour-specific antigens (TSA) directly to CD4(+) T cells. We have reported that tumour-specific CD4(+) T cells collaborate with macrophages and dendritic cells.

HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22.

We have analyzed the production of the effector cytokines interleukin (IL)-17, IL-21, and IL-22 in gluten-reactive CD4(+) T cells of celiac disease patients, either cultured from small intestinal biopsies or isolated from peripheral blood after an oral gluten challenge. Combining intracellular cytokine staining with DQ2-α-II gliadin peptide tetramer staining of intestinal polyclonal T-cell lines, we found that gluten-specific T cells produced interferon-γ (IFN-γ) and IL-21, but not IL-17 or IL-22, even if other T cells of the same lines produced these cytokines. Similarly, in DQ2-α-II-specific T cells in peripheral blood of gluten-challenged patients, very few stained for intracellular IL-17, whereas many cells stained for IFN-γ.

The idiotype connection: linking infection and multiple sclerosis.

B cells present idiotopes (Id) from their B cell receptor to Id-specific CD4(+) T cells. Chronic Id-driven T-B cell collaboration can cause autoimmune disease in mice. We propose that Id-driven T-B cell collaboration mediates the development of multiple sclerosis by perpetuating immune responses initiated against infectious agents.

Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation.

Celiac disease driven by an antigluten T cell response is strongly associated with the histocompatibility antigen HLA-DQ2.5 but is barely associated with HLA-DQ2.2.