Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance.

Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the "weep" response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine.

Tuft cell-derived acetylcholine regulates epithelial fluid secretion.

Tuft cells are solitary chemosensory epithelial cells that can sense lumenal stimuli at mucosal barriers and secrete effector molecules to regulate the physiology and immune state of their surrounding tissue. In the small intestine, tuft cells detect parasitic worms (helminths) and microbe-derived succinate, and signal to immune cells to trigger a Type 2 immune response that leads to extensive epithelial remodeling spanning several days. Acetylcholine (ACh) from airway tuft cells has been shown to stimulate acute changes in breathing and mucocilliary clearance, but its function in the intestine is unknown.

T-Cell Receptor/HLA Humanized Mice Reveal Reduced Tolerance and Increased Immunogenicity of Posttranslationally Modified GAD65 Epitope.

Accumulating evidence supports a critical role for posttranslationally modified (PTM) islet neoantigens in type 1 diabetes. However, our understanding regarding thymic development and peripheral activation of PTM autoantigen-reactive T cells is still limited. Using HLA-DR4 humanized mice, we observed that deamidation of GAD65115-127 generates a more immunogenic epitope that recruits T cells with promiscuous recognition of both the deamidated and native epitopes and reduced frequency of regulatory T cells.

Heat Transfer and Residence Time Distribution in Plug Flow Continuous Oscillatory Baffled Crystallizers.

Heat transfer coefficients in a continuous oscillatory baffled crystallizer (COBC) with a nominal internal diameter of 15 mm have been determined as a function of flow and oscillatory conditions typically used under processing conditions. Residence time distribution measurements show a near-plug flow with high Peclet numbers on the order of 100-1000 s, although there was significant oscillation damping in longer COBC setups. Very rapid heat transfer was found under typical conditions, with overall heat transfer coefficients on the order of 100 s W m K.

Computer Aided Design of Solvent Blends for Hybrid Cooling and Antisolvent Crystallization of Active Pharmaceutical Ingredients.

Choosing a solvent and an antisolvent for a new crystallization process is challenging due to the sheer number of possible solvent mixtures and the impact of solvent composition and crystallization temperature on process performance. To facilitate this choice, we present a general computer aided mixture/blend design (CAMD) formulation for the design of optimal solvent mixtures for the crystallization of pharmaceutical products. The proposed methodology enables the simultaneous identification of the optimal process temperature, solvent, antisolvent, and composition of solvent mixture.

PGD2 and CRTH2 counteract Type 2 cytokine-elicited intestinal epithelial responses during helminth infection.

Type 2 inflammation is associated with epithelial cell responses, including goblet cell hyperplasia, that promote worm expulsion during intestinal helminth infection. How these epithelial responses are regulated remains incompletely understood. Here, we show that mice deficient in the prostaglandin D2 (PGD2) receptor CRTH2 and mice with CRTH2 deficiency only in nonhematopoietic cells exhibited enhanced worm clearance and intestinal goblet cell hyperplasia following infection with the helminth Nippostrongylus brasiliensis.

Tuft-Cell-Derived Leukotrienes Drive Rapid Anti-helminth Immunity in the Small Intestine but Are Dispensable for Anti-protist Immunity.

Helminths, allergens, and certain protists induce type 2 immune responses, but the underlying mechanisms of immune activation remain poorly understood. In the small intestine, chemosensing by epithelial tuft cells results in the activation of group 2 innate lymphoid cells (ILC2s), which subsequently drive increased tuft cell frequency. This feedforward circuit is essential for intestinal remodeling and helminth clearance.

A three course menu for ILC and bystander T cell activation.

The varied list of agonists that activate innate lymphoid cells (ILCs) continues to grow, but whether and how these signals interact is not well defined, especially in vivo. ILC subsets share master transcription factors, chromatin landscapes, and effector cytokines with their corresponding T helper (Th) cell subsets. Here we discuss how studies of these two cell types can inform each other.

Discriminative T cell recognition of cross-reactive islet-antigens is associated with HLA-DQ8 transdimer-mediated autoimmune diabetes.

Human leukocyte antigen (HLA)-DQ8 transdimer (HLA-DQA1*0501/DQB1*0302) confers exceptionally high risk in autoimmune diabetes. However, little is known about HLA-DQ8 transdimer-restricted CD4 T cell recognition, an event crucial for triggering HLA-DQ8 transdimer-specific anti-islet immunity. Here, we report a high degree of epitope overlap and T cell promiscuity between susceptible HLA-DQ8 and HLA-DQ8 transdimer.

The cysteinyl leukotriene 3 receptor regulates expansion of IL-25-producing airway brush cells leading to type 2 inflammation.

Respiratory epithelial cells (EpCs) orchestrate airway mucosal inflammation in response to diverse environmental stimuli, but how distinct EpC programs are regulated remains poorly understood. Here, we report that inhalation of aeroallergens leads to expansion of airway brush cells (BrCs), specialized chemosensory EpCs and the dominant epithelial source of interleukin-25 (IL-25). BrC expansion was attenuated in mice lacking either LTC synthase, the biosynthetic enzyme required for cysteinyl leukotriene (CysLT) generation, or the EpC receptor for leukotriene E (LTE), CysLTR.

Detection of Succinate by Intestinal Tuft Cells Triggers a Type 2 Innate Immune Circuit.

In the small intestine, type 2 responses are regulated by a signaling circuit that involves tuft cells and group 2 innate lymphoid cells (ILC2s). Here, we identified the microbial metabolite succinate as an activating ligand for small intestinal (SI) tuft cells. Sequencing analyses of tuft cells isolated from the small intestine, gall bladder, colon, thymus, and trachea revealed that expression of tuft cell chemosensory receptors is tissue specific.

Modifying Enzymes Are Elicited by ER Stress, Generating Epitopes That Are Selectively Recognized by CD4 T Cells in Patients With Type 1 Diabetes.

In spite of tolerance mechanisms, some individuals develop T-cell-mediated autoimmunity. Posttranslational modifications that increase the affinity of epitope presentation and/or recognition represent one means through which self-tolerance mechanisms can be circumvented. We investigated T-cell recognition of peptides that correspond to modified β-cell antigens in subjects with type 1 diabetes.

Combinatorial detection of autoreactive CD8 T cells with HLA-A2 multimers: a multi-centre study by the Immunology of Diabetes Society T Cell Workshop.

Aims/hypothesis: Validated biomarkers are needed to monitor the effects of immune intervention in individuals with type 1 diabetes. Despite their importance, few options exist for monitoring antigen-specific T cells. Previous reports described a combinatorial approach that enables the simultaneous detection and quantification of multiple islet-specific CD8 T cell populations.

Chronic cat allergen exposure induces a TH2 cell-dependent IgG4 response related to low sensitization.

Background: In human subjects, allergen tolerance has been observed after high-dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T-cell response that leads to IgG4 induction during chronic allergen exposure remains poorly understood.

Objective: We sought to evaluate the relationship between cat allergen-specific T-cell frequency, cat allergen-specific IgE and IgG4 titers, and clinical status in adults with cat allergy with and without cat ownership and the cellular mechanism by which IgG4 is produced.

T cell epitopes and post-translationally modified epitopes in type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease in which progressive loss of self-tolerance, evidenced by accumulation of auto-antibodies and auto-reactive T cells that recognize diverse self-proteins, leads to immune-mediated destruction of pancreatic beta cells and loss of insulin secretion. In this review, we discuss antigens and epitopes in T1D and the role that post-translational modifications play in circumventing tolerance mechanisms and increasing antigenic diversity. Emerging data suggest that, analogous to other autoimmune diseases such as rheumatoid arthritis and celiac disease, enzymatically modified epitopes are preferentially recognized in T1D.

Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes.

Posttranslational modification (PTM) of self-proteins has been shown to elicit clinically relevant immune responses in rheumatoid arthritis and celiac disease. Accumulating evidence suggests that recognition of modified self-proteins may also be important in type 1 diabetes. Our objective was to identify posttranslationally modified GAD65 peptides, which are recognized by subjects with type 1 diabetes, and to assess their disease relevance.

Adhesion to substrates induces dendritic cell endothelization and decreases immunological response.

Dendritic cells (DCs) are antigen presenting cells capable of inducing specific immune responses against microbial infections, transplant antigens, or tumors. DCs have been shown to possess a high plasticity showing different phenotypes in response to their microenvironment. For example, tumor-associated DCs can acquire an angiogenic phenotype thus promoting tumor growth.

Dendritic cells the tumor microenvironment and the challenges for an effective antitumor vaccination.

Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic-cell- (DC-) based vaccines on cancer patients, and recently the first DC-based vaccine for human cancer was approved by the FDA. Herewith, we describe the general characteristics of DCs and different strategies to generate effective antitumor DC vaccines. In recent years, the relevance of the tumor microenvironment in the progression of cancer has been highlighted.

The interplay between surfaces and soluble factors define the immunologic and angiogenic properties of myeloid dendritic cells.

Background: Dendritic cells (DCs) are antigen presenting cells capable of inducing specific immune responses against microbial infections, transplant antigens, or tumors. Interestingly, microenvironment conditions such as those present in tumor settings might induce a DC phenotype that is poorly immunogenic and with the capability of promoting angiogenesis. We hypothesize that this plasticity may be caused not only by the action of specific cytokines or growth factors but also by the properties of the surfaces with which they interact, such as extracellular matrix (ECM) components.

Intracellular Casp8p41 content is inversely associated with CD4 T cell count.

Casp8p41 is a protein fragment generated by cleavage of procaspase 8 by human immunodeficiency virus (HIV) protease. We measured Casp8p41 content in memory CD4 T cells and analyzed the association of Casp8p41 content with CD4 T cell count, cross-sectionally and longitudinally. Casp8p41 content was inversely correlated with CD4 T cell count, and change in Casp8p41 content was associated with absolute CD4 T cell count with change over time.

CD4 downregulation by memory CD4+ T cells in vivo renders African green monkeys resistant to progressive SIVagm infection.

African green monkeys (genus Chlorocebus) can be infected with species-specific simian immunodeficiency virus (SIVagm) but do not develop AIDS. These natural hosts of SIV, like sooty mangabeys, maintain high levels of SIV replication but have evolved to avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to coexist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis.

Recurrent primary cardiac malignant fibrous histiocytoma following orthotopic heart transplantation.

Malignant fibrous histiocytoma (MFH) is an extremely rare primary cardiac tumor. We describe a young patient who underwent orthotopic heart transplantation for an unresectable right ventricular MFH and presented 7 years later with a local recurrence in the native right atrium. This was treated by complete resection of the right atrial tumor and adjuvant chemotherapy.