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Purpose of the review: With increased access and decriminalization of cannabis use, cases of IgE-dependent cannabis allergy (CA) and cross-reactivity syndromes have been increasingly reported. However, the exact prevalence of cannabis allergy and associated cross-reactive food syndromes (CAFS) remains unknown and is likely to be underestimated due to a lack of awareness and insufficient knowledge of the subject among health care professionals. Therefore, this practical roadmap aims to familiarize the reader with the early recognition and correct management of IgE-dependent cannabis-related allergies. In order to understand the mechanisms underlying these cross-reactivity syndromes and to enable personalized diagnosis and management, special attention is given to the molecular diagnosis of cannabis-related allergies. Recent findings: The predominant signs and symptoms of CA are rhinoconjunctivitis and contact urticaria/angioedema. However, CA can also present as a life-threatening condition. In addition, many patients with CA also have distinct cross-reactivity syndromes, mainly involving fruits, vegetables, nuts and cereals. At present, five allergenic components of Cannabis sativa (Can s); Can s 2 (profilin), Can s 3 (a non-specific lipid protein), Can s 4 (oxygen-evolving enhancer protein 2 oxygen), Can s 5 (the Bet v 1 homologue) and Can s 7 (thaumatin-like protein) have been characterized and indexed in the WHO International Union of Immunological Sciences (IUIS) allergen database. However, neither of them is currently readily available for diagnosis, which generally starts by testing crude extracts of native allergens. Summary: The road to a clear understanding of CA and the associated cross-reactive food syndromes (CAFS) is still long and winding, but well worth further exploration. [ABSTRACT FROM AUTHOR]

In 1995, Yoshida et al. proposed first the concept of "autoimmune pancreatitis" (AIP). Since then, AIP has been accepted as a new pancreatic inflammatory disease and is now divided two subtypes. Type 1 AIP affected immunoglobulin G4 (IgG4) and implicates the pancreatic manifestation of IgG4-related disease, while type 2 is characterized by neutrophil infiltration and granulocytic epithelial lesions (GEL). Recent research has clarified the clinical and pathophysiological aspects of type 1 AIP, which is more than type 2 among the Japanese population. However, many details remain unclear about the pathogenesis and progression of this disease. In this review, we discuss the current knowledge and recent advances relating to type 1 AIP. [ABSTRACT FROM AUTHOR]

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Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus associated with an atopic predisposition which appears to be increasing in prevalence over the last few decades. Symptoms stem from fibrosis, swelling, and smooth muscle dysfunction. In the past two decades, the etiology of EoE has been and is continuing to be revealed. This review provides an overview of the effects of genetics, environment, and immune function including discussions that touch on microbiome, the role of diet, food allergy, and aeroallergy. The review further concentrates on the pathophysiology of the disease with particular focus on the important concepts of the molecular etiology of EoE including barrier dysfunction and allergic hypersensitivity. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the effects of dietary supplementation of Nigella sativa L. seeds, Rosmarinus officinalis L. leaves and their combination on rumen metabolism, nutrient intake and digestibility, growth performance, immune response and blood metabolites in Dorper lambs. Twenty-four entire male Dorper lambs (18.68 ± 0.6 kg, 4-5 months old) were randomly assigned to a concentrate mixture containing on a dry matter basis either, no supplement (control, T1), 1% R. officinalis leaves (T2), 1% N. sativa seeds (T3) or 1% R. officinalis leaves +1% N. sativa seeds (T4). The lambs had ad libitum access to urea-treated rice straw (UTRS) and were raised for 90 days. Supplemented lambs had greater (P < 0.05) intake of DM and UTRS than the control lambs. The T4 lambs had lower (P < 0.05) nutrient digestibility than those fed other treatments. Total and daily weight gain was greater (P < 0.05) in T2 lambs than those fed other diets. The T3 and T4 lambs had greater (P < 0.05) ruminal pH than the T1 and T2 lambs. Supplemented lambs had lower (P < 0.05) ruminal total volatile fatty acids, acetate, propionate, NH3-N and C18:0 than the control lambs. The T4 lambs had lower (P < 0.05) population of Fibrobacter succinogenes, Ruminococcus albus, methanogens and total protozoa compared with those fed other diets. Supplemented lambs had lower (P < 0.05) neutrophils, basophils and serum urea and greater (P < 0.05) serum IgA and IgG compared with the control lambs. The current results emphasised the variation in the efficacy of medicinal plants in ruminant nutrition. [ABSTRACT FROM AUTHOR]

In 1995, Yoshida and colleagues proposed the concept of "autoimmune pancreatitis" (AIP), which has recently been recognized as a new pancreatic inflammatory disease. Recent studies have suggested the existence of two subtypes of AIP: type 1, which involves immunoglobulin G4 (IgG4) and is the pancreatic manifestation of IgG4-related disease (IgG4-RD); and type 2, which is characterized by granulocytic epithelial lesions. Type 2 AIP is thought to be rare in Japan. Type 1 AIP is characterized by increased serum IgG4 concentrations, lymphoplasmacytic infiltrations, storiform fibrosis, and obliterative phlebitis. However, although type 1 AIP has become increasingly recognized, many clinical and basic issues remain to be solved. This review provides an overview of the recent clinical and basic knowledge of type 1 AIP. [ABSTRACT FROM AUTHOR]

Background: Pathophysiology of type 1 autoimmune pancreatitis (AIP) is still unclear. We previously reported that M2 macrophages might play an important role in type 1 AIP. Recently, it has been reported that basophils regulate differentiation to M2 macrophages. In this study, we investigated basophils from the pancreatic tissue and peripheral blood of individuals with type 1 AIP.Methods: By using immunohistochemistry, we investigated basophils in pancreatic tissue from 13 patients with type 1 AIP and examined expression of toll-like receptors (TLRs) by these cells. Additionally, we obtained peripheral blood samples from 27 healthy subjects, 40 patients with type 1 AIP, 8 patients with alcoholic chronic pancreatitis, 10 patients with bronchial asthma, and 10 patients with atopic dermatitis, and analyzed activation of basophils by stimulating them with ligands of TLR1-9. We also compared TLR expression in basophils from the tissue and blood samples.Results: Basophils were detected in pancreatic tissues from 10 of 13 patients with type 1 AIP. Flow cytometric analysis revealed that the ratios of basophils activated by TLR4 stimulation in type 1 AIP (9.875 ± 1.148%) and atopic dermatitis (11.768 ± 1.899%) were significantly higher than those in healthy subjects (5.051 ± 0.730%; P < 0.05). Levels of basophils activated by TLR2 stimulation were higher in seven type 1 AIP cases. Furthermore, stimulation of TLR2 and/or TLR4, which were expressed by basophils in pancreas, activated basophils in peripheral blood.Conclusions: Basophils activated via TLR signaling may play an important role in the pathophysiology of type 1 AIP. [ABSTRACT FROM AUTHOR]

Adenosine 5′-triphosphate (ATP) is released from dying or damaged cells, as well as from activated cells. Once secreted, extracellular ATP induces several immune responses via P2X and P2Y receptors. Basophils and mast cells release ATP upon FcεRI-crosslinking, and ATP activates basophils and mast cells in an autocrine manner. Nucleotide-converting ectoenzymes, such as E-NTPD1, E-NTPD7, and E-NPP3, inhibit ATP-dependent immune responses by hydrolyzing ATP, thereby contributing to immune response regulation. E-NPP3 is a well-known activation marker for human basophils. E-NPP3's physiologic function has recently been disclosed in mice. E-NPP3 is rapidly induced on basophils and mast cells after FcεRI-crosslinking and hydrolyzes extracellular ATP on cell surfaces to prevent ATP-dependent excess activation of basophils and mast cells. In the absence of E-NPP3, basophils and mast cells are overactivated and mice suffer from severe chronic allergic inflammation. Thus, the ATP-hydrolyzing ectoenzymes E-NPP3 has a nonnegligible role in the regulation of basophil- and mast cell-mediated allergic responses. [ABSTRACT FROM AUTHOR]

Recent studies demonstrated that basophils play crucial and non-redundant roles in the immune system, in spite of the fact that they are the rarest granulocytes and represent less than 1 % of peripheral blood leukocytes. In response to various stimuli, basophils release effector molecules stored in their cytoplasmic granules, including chemical mediators and proteases, and also secrete cytokines and chemokines. In this review, we will focus on the physiological and pathological roles of basophil-derived IL-4. Basophils can readily produce large quantities of IL-4 and are therefore the important source of IL-4. Basophil-derived IL-4 has been shown to regulate other immune cells, including T cells, B cells, group 2 innate lymphoid cells, monocytes, and macrophages. It also acts on non-hematopoietic cells such as fibroblasts and endothelial cells. Those cells stimulated with basophil-derived IL-4 contribute to the positive or negative regulation of a variety of immune responses in health and disease, including protection against parasitic and bacterial infections, allergy, and autoimmune diseases. Thus, basophil-derived IL-4 plays versatile roles in immunity. [ABSTRACT FROM AUTHOR]

Human basophils have been implicated in the pathogenesis of chronic spontaneous urticaria (CSU), and substance P (SP) is a possible candidate as histamine-releasing factor in some patients with CSU. However, little is known of relationship between basophils and SP in CSU. In the present study, we investigated expression of SP and NK1R on basophils from patients with CSU, and influence of SP on basophil functions by using flow cytometry analysis, basophil challenge, and mouse sensitization model techniques. The results showed that plasma SP level and basophil numbers in CSU patients were higher than that in HC subject. The percentages of SP+ and NK1R+ basophils were markedly elevated in CSU blood in comparison with HC blood. Once added, SP induced up to 41.2 % net histamine release from basophils of CSU patients, which was comparable with that provoked by anti-IgE, and fMLP. It appeared that SP induced dramatic increase in blood basophil numbers of mice following peritoneal injection. Ovalbumin (OVA)-sensitized mice had much more SP+ and NK1R+ basophils in blood than non-sensitized mice. In conclusion, the elevated plasma concentration of SP, upregulated expression of SP and NK1R on basophils, and the ability of SP in induction of basophil degranulation and accumulation indicate strongly that SP is most likely a potent proinflammatory mediator, which contributes greatly to the pathogenesis of CSU through basophils. Inhibitors of SP and blockers of NK1R are likely useful agents for treatment of CSU. [ABSTRACT FROM AUTHOR]

For half a century, it has been known that the mast cell is the cell responsible for the majority of anaphylactic events. Its mediators, taken as a whole, are capable of producing all of the clinical manifestations of these events. With the discovery of immunoglobulin E (IgE), it was originally felt that the vast majority of anaphylactic episodes were due to antigen coupling with two cell-bound IgE molecules. More recently it has been learned that many episodes are produced by direct activation of mast cells, not involving antigen binding to IgE, and that monomeric IgE under certain conditions can also cause degranulation. Of note—in regard to antigen independent degranulation—are recent reports that the human G-protein-coupled receptor, MRGPRX2, may be the receptor for many drugs and cationic proteins capable of producing direct mast cell degranulation and anaphylactic events. [ABSTRACT FROM AUTHOR]

Hypersensitivity reactions (HSRs) to platinum drugs and taxanes are increasing in cancer patients, and rapid drug desensitization has emerged as a safe and effective method to reintroduce these drugs in reactive patients. Optimal management of patients presenting HSRs to chemotherapy depends on the use of various diagnostic tools, which include measurement of mast cell/basophil mediator release following a HSR and skin testing. Serum tryptase should be measured in patients presenting chemotherapy HSRs, and its elevation would support mast cell/basophil activation. Skin testing to platinum drugs has a high sensitivity and specificity and is critical to guide the management of platinum-reactive patients. Taxane skin testing is also emerging as a useful diagnostic and risk stratification tool in the evaluation of patients with HSRs to taxanes. Platinum sIgE assays have been recently developed and can be helpful in combination with skin testing or as an alternative when skin testing is not available. [ABSTRACT FROM AUTHOR]

Basophils have emerged in recent years as a small but potent subpopulation of leukocytes capable of bridging innate and adaptive immunity. They can be activated through IgE-dependent and IgE-independent mechanisms to release preformed mediators and to produce Th2 cytokines. In addition to their role in protective immunity to helminths, basophils are major participants in allergic reactions as diverse as anaphylaxis and immediate hypersensitivity reactions, late-phase hypersensitivity reactions, and delayed hypersensitivity reactions. Additionally, basophils have been implicated in the pathophysiology of autoimmune diseases such as lupus nephritis and rheumatoid arthritis, and the modulation of immune responses to bacterial infections, as well as being a feature of myelogenous leukemias. Distinct signals for activation, degranulation, transendothelial migration, and immune regulation are being defined, and demonstrate the important role of basophils in promoting a Th2 microenvironment. These mechanistic insights are driving innovative approaches for diagnostic testing and therapeutic targeting of basophils. [ABSTRACT FROM AUTHOR]

Urticaria and angioedema are common disorders. Chronic urticaria is defined as lasting longer than 6 weeks. Causes of chronic urticaria fall into the following categories: physical, allergic, hereditary, autoimmune, and idiopathic. Basophils and mast cells are the primary effector cells responsible for clinical symptoms and signs. These cells produce and secrete a variety of mediators including histamine, leukotrienes, prostaglandins, cytokines, chemokines, and other pro-inflammatory mediators. This leads to vasodilation, fluid exudation, increased vascular permeability, and accumulation of additional secondary inflammatory cells. Two mechanisms have been investigated as possibly contributing to the pathogenesis of chronic urticaria. One is the development of autoantibodies to FcεRI or IgE on mast cells and basophils. This appears to be responsible for 30-50 % of cases. The other is dysregulation of intracellular signaling pathways involving Syk, SHIP-1, or SHIP-2 in basophils and mast cells. The primary treatment for chronic urticaria is to treat the underlying pathology, if any can be identified. Otherwise, in idiopathic cases, H1 antihistamines, H2 antihistamines, antileukotrienes, and corticosteroids constitute the main pharmacologic treatment modalities. In severe and recalcitrant cases of chronic and autoimmune urticaria, immunosuppressive drugs have been used, most commonly cyclosporin. More recent experimental studies have also suggested that omalizumab, an anti-IgE therapy, may be of benefit. Currently, inhibitors of Syk are also being developed and tested in the laboratory and in animal models. As our understanding of the pathogenesis of idiopathic urticaria increases, development of additional drugs targeting these pathways may provide relief for the significant physical and psychological morbidity experienced by patients with this disorder. [ABSTRACT FROM AUTHOR]

Background: IgG4-related disease (IRD) is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells into the affected organs. Although T helper type 2 (Th2) cytokines are implicated in enhanced IgG4 responses, molecular mechanisms accounting for the development of IgG4 antibody responses are poorly defined. Since basophils function as antigen-presenting cells for Th2 responses, we tried to clarify the role of basophils in the development of IgG4 responses in this study. Methods: IgG4 and cytokine responses to various nucleotide-binding oligomerization domain-like receptor and Toll-like receptor (TLR) ligands were examined by using basophils isolated from healthy controls and from patients with IgG4-related disease. Results: Activation of TLRs in basophils from healthy controls induced IgG4 production by B cells, which effect was associated with enhanced production of B cell activating factor (BAFF) and IL-13. In addition, activation of TLRs in basophils from patients with IRD induced a large amount of IgG4 by B cells from healthy controls. This enhancement of IgG4 production was again associated with BAFF and IL-13. Conclusions: These data suggest that innate immune responses mediated through TLRs may play a role in the development of IgG4-related disease, in part by production of BAFF from basophils. [ABSTRACT FROM AUTHOR]

The basophil activation test (BAT) is a flow-cytometry-based functional assay that assesses the degree of cell activation after exposure to a stimuli. Though no standardized technique currently exists, recent advances have improved the performance of this assay, including identification of new basophil-specific markers and comparisons of the expression of CD63 to CD203c during activation. The basophil activation test has also been validated for many IgE-mediated disease conditions, which have been extensively reviewed elsewhere. This review focuses on the most recent applications of this test to the diagnosis of allergy to drugs, foods, venoms, and pollens, and the evolving role of the BAT in monitoring immunotherapy. [ABSTRACT FROM AUTHOR]

Histamine and the histamine receptors are important regulators of a plethora of biological processes, including immediate hypersensitivity reactions and acid secretion in the stomach. In these roles, antihistamines have found widespread therapeutic applications, while the last receptor to be discovered, the H4 histamine receptor, has become a major target of novel therapeutics. Recent studies involving human genetic variance and the development of mice lacking specific receptors or the ability to generate histamine have shown roles for the histamine pathway that extend well beyond the established roles. These include identification of previously unappreciated mechanisms through which histamine regulates inflammation in allergy, as well as roles in autoimmunity, infection, and pain. As a result, antihistamines may have wider applications in the future than previously predicted. [ABSTRACT FROM AUTHOR]

Exercise-induced anaphylaxis (EIA) and food-dependent, exercise-induced anaphylaxis (FDEIA) are rare but potentially life-threatening clinical syndromes in which association with exercise is crucial. The range of triggering physical activities is broad, including as mild an effort as a stroll. EIA is not fully repeatable (ie, the same exercise may not always result in anaphylaxis in a given patient). In FDEIA, the combined ingestion of sensitizing food and exercise is necessary to precipitate symptoms. Clinical features and management do not differ significantly from other types of anaphylaxis. The pathophysiology of EIA and FDEIA is not fully understood. Different hypotheses concerning the possible influence of exercise on the development of anaphylactic symptoms are taken into consideration. These include increased gastrointestinal permeability, blood flow redistribution, and most likely increased osmolality. This article also describes current diagnostic and therapeutic possibilities, including changes in lifestyle and preventive properties of antiallergic drugs as well as acute treatment of these dangerous syndromes. [ABSTRACT FROM AUTHOR]

The increase in prevalence of food allergies generates a need for more accurate and reliable quantitative allergy testing in order to help diagnosis. In this short review, we briefly outline the history of food allergy testing and extend our comments to current multiplex techniques. Particular emphasis is given to new developments in the protein microarray area, where the use of recent advances in biotechnology has the potential to produce high-throughput devices with improved clinical significance. [ABSTRACT FROM AUTHOR]

Urticaria is dermal edema resulting from vascular dilatation and leakage of fluid into the skin in response to molecules released from mast cells. The major preformed mediator histamine produces a prototypic, short-lived urticaria. However, the clinical spectrum and pattern of lesions indicate that other molecules, including prostaglandins, leukotrienes, cytokines, and chemokines, produced at different times after mast cell activation contribute to the polymorphism of this symptom and the variable evolution of this disease. It is a common practice to distinguish immunological and nonimmunological urticaria. Immunological urticaria is a hypersensitivity reaction mediated by antibodies and/or T-cells that results in mast cell activation. Although immunoglobulin (Ig)E-mediated type I hypersensitivity (HS) was long postulated to be the major immunological pathway associated with mast cell activation, interaction between IgE-bound mast cells and allergens is unlikely to be the mechanism by which urticaria develops in most patients. It is now well established that urticaria may result from the binding of IgG auto-antibodies to IgE and/or to the receptor for IgE molecules on mast cells, thus corresponding to a type II HS reaction. These auto-immune urticarias represent up to 50% of patients with chronic urticaria. Mast cell activation can also result from type III HS through the binding of circulating immune complexes to mast cell-expressing Fc receptors for IgG and IgM. Finally, under certain circumstances, T-cells can induce activation of mast cells, as well as histamine release (type IV HS). Nonimmunological urticarias result from mast cell activation through membrane receptors involved in innate immunity (e.g., complement, Toll-like, cytokine/chemokine, opioid) or by direct toxicity of xenobiotics (haptens, drugs). In conclusion, urticaria may result from different pathophysiological mechanisms that explain the great heterogeneity of clinical symptoms and the variable responses to treatment. [ABSTRACT FROM AUTHOR]

Ghosts prepared from rat basophilic leukemia cells (RBL cell ghosts) and permeabilized with α-toxin from S. aureus are a simplified system for the study of FcRI-mediated activation of phospholipase C (PLC). This activity is dependent upon ATP and magnesium, and is enhanced by the addition of another compound containing an energetic phosphate group, either phosphoenolpyruvate (PEP) or phosphocreatine (PCr). This effect appears to be specific for PEP and PCr in that other compounds with energetic phosphate bonds including fructose 1,6-bisphosphate and additional ATP are not effective. On the contrary, GTP-γ-S, an activator of G proteins, activates PLC in the presence of ATP alone and this is not further enhanced by the addition of PEP. In addition to FcRI and GTP-γ-S, two other stimuli lead to enhanced activity of PLC in permeabilized RBL cell ghosts: 1) an inhibitor of tyrosine phosphatases (NaVO) and 2) an analog of adenosine (NECA). Data presented here extend previous results to show that activation of PLC by GTP-γ-S is not enhanced either by the addition of PCr or by the addition of a more MgATP. Further new findings include the observations that activation of PLC by NaVO is augmented by PEP and PCr in a fashion similar to that observed for FcRI-mediated activation of PLC and that activation of PLC by NECA shows even more marked dependency on PEP than does activation by FcRI or NaVO. Together, these experiments demonstrate that antigen, NaVO, GTP-γ-S, and NECA can all activate PLC in permeabilized RBL cell ghosts in the presence of ATP and that these activities are differentially affected by the addition of a second compound with an energetic phosphate bond. [ABSTRACT FROM AUTHOR]

We examined the dynamic changes of histamine metabolism and infiltrating cell populations in lesional sites of representative cutaneous delayed type hypersensitivity (DTH), including dinitrochlorobenzene (DNCB) allergic dermatitis, purified protein derivative of tuberculin (PPD) reaction, and keyhole limpet homocyanin (KLH)-induced cutaneous basophil hypersensitivity. The concentration of histamine increased with time in all DTH reactions examined, though the time course varied among these reactions. In DNCB allergic dermatitis, the maximum content of the amine at 3 days after the initiation was about three times that of the control baseline. In PPD reaction, the maximum content and the time course were almost similar to that in DNCB allergic dermatitis. However, in KLH-induced cutaneous basophil hypersensitivity the maximum content was about ten times that in DNCB allergic dermatitis or PPD reaction, and was observed earlier, on the 2nd day. There was no remarkable change in the activities of histamine-degrading enzymes in these reactions. There was little infiltration of mast cells, while time-dependent changes of the basophil infiltration were almost parallel those of the histamine concentration in all these reactions. Basophils in DNCB allergic dermatitis showed a piecemeal degranulation, while those in either the PPD reaction or KLH-induced cutaneous basophil hypersensitivity remained intact. These results clearly suggest that the increase of histamine concentration in cutaneous DTH depends on the number of basophils infiltrating the lesional sites, even if the regulatory mechanisms of the activation of the cells differ among the DTH reactions. [ABSTRACT FROM AUTHOR]