Plasma contact system activation drives anaphylaxis in severe mast cell-mediated allergic reactions.

BACKGROUND: Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell-derived mediators into the circulation. OBJECTIVES AND METHODS: We report here that a plasma protease cascade, the factor XII-driven contact system, critically contributes to the pathogenesis of anaphylaxis in both murine models and human subjects. RESULTS: Deficiency in or pharmacologic inhibition of factor XII, plasma kallikrein, high-molecular-weight kininogen, or the bradykinin B2 receptor, but not the B1 receptor, largely attenuated allergen/IgE-mediated mast cell hyperresponsiveness in mice. Reconstitutions of factor XII null mice with human factor XII restored susceptibility for allergen/IgE-mediated hypotension. Activated mast cells systemically released heparin, which provided a negatively charged surface for factor XII autoactivation. Activated factor XII generates plasma kallikrein, which proteolyzes kininogen, leading to the liberation of bradykinin. We evaluated the contact system in patients with anaphylaxis. In all 10 plasma samples immunoblotting revealed activation of factor XII, plasma kallikrein, and kininogen during the acute phase of anaphylaxis but not at basal conditions or in healthy control subjects. The severity of anaphylaxis was associated with mast cell degranulation, increased plasma heparin levels, the intensity of contact system activation, and bradykinin formation. CONCLUSIONS: In summary, the data collectively show a role of the contact system in patients with anaphylaxis and support the hypothesis that targeting bradykinin generation and signaling provides a novel and alternative treatment strategy for anaphylactic attacks.

Integration of in vitro allergy test results and ratio analysis for the diagnosis and treatment of allergic patients (INTEGRA).

The introduction of molecular diagnosis into routine clinical practice has substantially improved the diagnosis and management of allergic patients by allowing clinicians to precisely identify the allergenic molecule responsible for immunoglobulin E (IgE)-mediated allergies. However, it can be challenging to accurately interpret the results of molecular assays, partly due to the limited evidence base. In this context, a panel of experts with extensive experience in interpreting in vitro measures of total and serum specific IgE reviewed the available scientific evidence. After this review, the panel selected a series of representative case studies to demonstrate how determination of specific and total IgE values and the relationship between them (ratio analysis) can add value to the diagnostic process by more precisely defining the patient's sensitization profile. Finally, the experts developed a series of recommendations on the clinical application of ratio analysis to optimize and complement the classical approach to allergy diagnosis.

Microbiome and Allergic Diseases.

Allergic diseases, such as respiratory, cutaneous, and food allergy, have dramatically increased in prevalence over the last few decades. Recent research points to a central role of the microbiome, which is highly influenced by multiple environmental and dietary factors. It is well established that the microbiome can modulate the immune response, from cellular development to organ and tissue formation exerting its effects through multiple interactions with both the innate and acquired branches of the immune system. It has been described at some extent changes in environment and nutrition produce dysbiosis in the gut but also in the skin, and lung microbiome, inducing qualitative and quantitative changes in composition and metabolic activity. Here, we review the potential role of the skin, respiratory, and gastrointestinal tract (GIT) microbiomes in allergic diseases. In the GIT, the microbiome has been proven to be important in developing either effector or tolerant responses to different antigens by balancing the activities of Th1 and Th2 cells. In the lung, the microbiome may play a role in driving asthma endotype polarization, by adjusting the balance between Th2 and Th17 patterns. Bacterial dysbiosis is associated with chronic inflammatory disorders of the skin, such as atopic dermatitis and psoriasis. Thus, the microbiome can be considered a therapeutical target for treating inflammatory diseases, such as allergy. Despite some limitations, interventions with probiotics, prebiotics, and/or synbiotics seem promising for the development of a preventive therapy by restoring altered microbiome functionality, or as an adjuvant in specific immunotherapy.

Antihistone and anti-double-stranded deoxyribonucleic acid antibodies are associated with renal disease in systemic lupus erythematosus.

PURPOSE: We sought to assess the nephritogenic antibody profile of patients with systemic lupus erythematosus (SLE), and to determine which antibodies were most useful in identifying patients at risk of nephritis. METHODS: We studied 199 patients with SLE, 78 of whom had lupus nephritis. We assayed serum samples for antibodies against chromatin components (double-stranded deoxyribonucleic acid [dsDNA], nucleosome, and histone), C1q, basement membrane components (laminin, fibronectin, and type IV collagen), ribonucleoprotein, and phospholipids. Correlations of these antibodies with disease activity (SLE Disease Activity Index) and nephropathy were assessed. Patients with no initial evidence of nephropathy were followed prospectively for 6 years. RESULTS: Antibodies against dsDNA, nucleosomes, histone, C1q, and basement membrane components were associated with disease activity (P <0.05). In a multivariate analysis, anti-dsDNA antibodies (odds ratio [OR] = 6; 95% confidence interval [CI]: 2 to 24) and antihistone antibodies (OR = 9.4; 95% CI: 4 to 26) were associated with the presence of proliferative glomerulonephritis. In the prospective study, 7 (6%) of the 121 patients developed proliferative lupus glomerulonephritis after a mean of 6 years of follow-up. Patients with initial antihistone (26% [5/19] vs. 2% [2/95], P = 0.0004) and anti-dsDNA reactivity (6% [2/33] vs. 0% [0/67], P = 0.048) had a greater risk of developing proliferative glomerulonephritis than patients without these autoantibodies. CONCLUSION: In addition to routine anti-dsDNA antibody assay, antihistone antibody measurement may be useful for identifying patients at increased risk of proliferative glomerulonephritis.

Induction of cell death by sera from patients with acute brain injury as a mechanism of production of autoantibodies.

OBJECTIVE: To investigate the capacity of blood draining from the central nervous system of patients with acute brain injury to induce cell death, and to determine whether this phenomenon could be a way to induce the production of autoantibodies. METHODS: The induction of cell death of several human leukemia cell lines cultured in vitro in the presence of serum collected from the brain or the systemic circulation of patients with acute brain injury was analyzed by flow cytometry after staining with annexin V and propidium iodide. The percentages of apoptotic lymphocytes derived directly from the patients were also quantified. To investigate the mechanisms responsible for the induction of cell death, the expression of apoptosis-related molecules, as well as the effect of addition of several molecules known to interfere with apoptosis, was evaluated in the cell cultures. The presence of serum autoantibodies at the time of injury and 6 months later was studied. RESULTS: Systemic serum and, especially, serum draining from the brain lesions induced the in vitro death of the leukemia cell lines used. Moreover, there were higher percentages of ex vivo dead lymphocytes in regional blood than in systemic blood 48 hours after injury. These effects seemed to be induced by an exogenous and/or endogenous opioid, since they were blocked by the opioid antagonist, naloxone. Furthermore, such effects were mediated by an increased expression of Bax. Importantly, apoptotic Jurkat cells were bound to autoantibodies, and patients with acute brain injury produced serum autoantibodies some months after the injury. However, they did not develop a full autoimmune disease at that time. CONCLUSION: Serum factors from acute brain injuries induce cell death, both in vivo and in vitro. Apoptotic cells and, even more so, necrotic cells in acute brain injury are potential sources for autoantigen presentation that may stimulate autoimmune responses.