Mary C. Tobin

Intestinal permeation and gastrointestinal disease.

The gastrointestinal tract constitutes one of the largest sites of exposure to the outside environment. The function of the gastrointestinal tract in monitoring and sealing the host interior from intruders is called the gut barrier. A variety of specific and nonspecific mechanisms are in operation to establish the host barrier; these include luminal mechanisms and digestive enzymes, the epithelial cells together with tight junctions in between them, and the gut immune system. Disruptions in the gut barrier follow injury from various causes including nonsteroidal anti-inflammatory drugs and oxidant stress, and involve mechanisms such as adenosine triphosphate depletion and damage to epithelial cell cytoskeletons that regulate tight junctions. Ample evidence links gut barrier dysfunction to multiorgan system failure in sepsis and immune dysregulation. Additionally, contribution of gut barrier dysfunction to gastrointestinal disease is an evolving concept and is the focus of this review. An overview of the evidence for the role of gut barrier dysfunction in disorders such as Crohns disease, celiac disease, food allergy, acute pancreatitis, non-alcoholic fatty liver disease, and alcoholic liver disease is provided, together with critical insight into the implications of this evidence as a primary disease mechanism.

Neonatal microscopic polyangiitis secondary to transfer of maternal myeloperoxidase-antineutrophil cytoplasmic antibody resulting in neonatal pulmonary hemorrhage and renal involvement

BACKGROUND Microscopic polyangiitis is a systemic vasculitis characterized by small vessel involvement. Studies suggest myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) is involved in its pathogenesis, and the titer may reflect disease activity. OBJECTIVE To report a case of transplacental transfer of MPO-ANCA from a mother to a 33-week gestational age neonate that resulted in neonatal pulmonary hemorrhage and renal involvement that was successfully treated with high-dose steroid therapy and exchange transfusion. METHODS MPO-ANCA titers from the cord blood and the neonate on the 8th, 15th, and 25th days of life (DOLs) were obtained. Metabolic panels and chest x-ray examinations were performed for the neonate and mother and the following values were measured: ANCA, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, serial urinalysis, and complete blood cell count. Anti-glomerular basement membrane, quantitative immunoglobulins, anticardiolipin antibody, and rheumatoid factor were also measured for the neonate. RESULTS The neonate had elevated MPO-ANCA titers at birth. Pulmonary hemorrhage and renal involvement were seen on DOL 2. High-dose steroid therapy decreased symptoms within 1.5 hours of initiation. Exchange transfusion performed on DOL 5 removed all of the remaining MPO-ANCA by DOL 25. The child remains asymptomatic to date. CONCLUSIONS To our knowledge, this is the first reported case of transplacental transfer of MPO-ANCA resulting in pulmonary-renal syndrome that was successfully treated with high-dose steroid therapy and exchange transfusion.

Mastocytic Enterocolitis: Increased Mucosal Mast Cells in Chronic Intractable Diarrhea

CONTEXT In some adult patients with chronic intractable diarrhea, the diagnosis remains elusive even after detailed evaluations, and colonic or duodenal biopsy specimens may appear unremarkable on routine hematoxylin-eosin staining. OBJECTIVES To assess the concentration of mast cells in colonic or duodenal biopsy specimens by immunohistochemical analysis for mast cell tryptase from patients with chronic intractable diarrhea and to evaluate their response to drugs affecting mast cell function. DESIGN Mast cells per high-power field were assessed in biopsy specimens from 47 patients with chronic intractable diarrhea, from 50 control subjects, and from 63 patients with other specific diseases that cause chronic diarrhea (inflammatory bowel disease, celiac disease, collagenous colitis, and lymphocytic colitis). Patients with chronic intractable diarrhea who had more than 20 mast cells per high-power field were administered drugs affecting mast cell mediator function and release. RESULTS The mean +/- SD concentration of mast cells in the 50 control subjects was 13.3 +/- 3.5 cells per high-power field; hence, patients with more than 20 mast cells per high-power field were considered to have increased mast cells. Thirty-three (70%) of 47 patients with chronic intractable diarrhea had increased mast cells, and symptoms were controlled by drug therapy in 22 (67%) of the 33 patients. No patient had systemic or cutaneous mastocytosis. No increase in mast cells was seen in patients with other common causes of chronic diarrhea. CONCLUSIONS In chronic intractable diarrhea, colonic or duodenal biopsy specimens may appear unremarkable on routine hematoxylin-eosin staining, but increased mast cells may be demonstrated by immunohistochemistry for mast cell tryptase, with the novel term mastocytic enterocolitis describing this condition. Similar increases in mast cells are not apparent in control populations or in patients with other specific diseases that cause chronic diarrhea. The cause of the increased mast cells remains to be elucidated.

Regulation of Intestinal Immune Responses through TLR Activation: Implications for Pro- and Prebiotics

The intestinal mucosa is constantly facing a high load of antigens including bacterial antigens derived from the microbiota and food. Despite this, the immune cells present in the gastrointestinal tract do not initiate a pro-inflammatory immune response. Toll-like receptors (TLRs) are pattern recognition receptors expressed by various cells in the gastrointestinal tract, including intestinal epithelial cells (IEC) and resident immune cells in the lamina propria. Many diseases, including chronic intestinal inflammation (e.g., inflammatory bowel disease), irritable bowel syndrome (IBS), allergic gastroenteritis (e.g., eosinophilic gastroenteritis and allergic IBS), and infections are nowadays associated with a deregulated microbiota. The microbiota may directly interact with TLR. In addition, differences in intestinal TLR expression in health and disease may suggest that TLRs play an essential role in disease pathogenesis and may be novel targets for therapy. TLR signaling in the gut is involved in either maintaining intestinal homeostasis or the induction of an inflammatory response. This mini review provides an overview of the current knowledge regarding the contribution of intestinal epithelial TLR signaling in both tolerance induction or promoting intestinal inflammation, with a focus on food allergy. We will also highlight a potential role of the microbiota in regulating gut immune responses, especially through TLR activation.

Atopic irritable bowel syndrome: a novel subgroup of irritable bowel syndrome with allergic manifestations

BACKGROUND Mast cells have a primary role in atopy. Mast cells may play a unique role in a subgroup of patients with irritable bowel syndrome (IBS). This observation suggests a link between atopic disorders and IBS. OBJECTIVE To determine whether there is an association between atopic disorders and IBS. METHODS We undertook a prospective study using structured questionnaires. We administered questionnaires to 125 consecutive patients seen in the following clinics from July 1 through October 31, 2001: allergy/immunology (AI) (n = 39), gastroenterology (n = 36), and general medicine (n = 50). The survey included questions detailing gastrointestinal and allergic symptoms. Diagnosis of IBS was based on Rome II criteria. Diagnosis of atopy was based on clinical parameters. RESULTS The AI clinic reported a significantly (P = .015) higher rate of IBS than the general medicine clinic. The IBS incidence reported in the AI clinic was similar to that reported in the gastroenterology clinic. The likelihood of IBS was significantly higher in patients with seasonal allergic rhinitis (2.67 times; 95% confidence interval [CI], 1.10-6.49; P = .03), patients with allergic eczema (3.85 times; 95% CI, 1.72-8.60; P = .001), and patients with depression (2.56 times; 95% CI, 1.05-6.14; P = .04). Patients reporting atopic symptoms (seasonal allergic rhinitis, allergic eczema, and asthma) were 3.20 times (95% CI, 1.20-8.50) (P = .02) more likely to fulfill the criteria for IBS. CONCLUSIONS Adults with atopic symptoms report a high incidence of IBS, suggesting a link between atopy and IBS. We proposed a subgroup of patients with IBS (atopic IBS) who have typical IBS symptoms in association with atopic manifestations. Identifying atopic vs nonatopic IBS may help in identifyingthe underlying pathophysiologic mechanisms and therapeutic options.

A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS)

Chronic rhinosinusitis (CRS) has been known as a disease with strong infectious and inflammatory components for decades. The recent advancement in methods identifying microbes has helped implicate the airway microbiome in inflammatory respiratory diseases such as asthma and COPD. Such studies support a role of resident microbes in both health and disease of host tissue, especially in the case of inflammatory mucosal diseases. Identifying interactive events between microbes and elements of the immune system can help us to uncover the pathogenic mechanisms underlying CRS. Here we provide a review of the findings on the complex upper respiratory microbiome in CRS in comparison with healthy controls. Furthermore, we have reviewed the defects and alterations of the host immune system that interact with microbes and could be associated with dysbiosis in CRS.

Management of anaphylaxis in child care centers: evaluation 6 and 12 months after an intervention program

BACKGROUND Many young children with a history of allergic reactions or anaphylaxis spend considerable time in child care centers. We previously reported that a significant knowledge deficit exists in anaphylaxis recognition, evaluation, and treatment and that greater anaphylaxis education is needed among child care providers. OBJECTIVE To determine whether child care centers can recognize, evaluate, and treat anaphylactic episodes in children aged 1 to 6 years 6 months and 1 year after attending an allergy seminar. METHODS All 39 child care centers participating in the original study were selected to complete 6-month and 1-year follow-up surveys using a similar questionnaire. Those who did not attend the seminar or complete all the previous surveys were excluded. RESULTS At 6 months and 1 year, 37 and 29 centers, respectively, completed surveys. There was a significant improvement regarding when to administer intramuscular epinephrine compared with before the allergy seminar. However, only 48% of the centers at 6 months (P = .02) and 31% at 1 year (P = .002) knew how to correctly administer intramuscular epinephrine compared with 77% four weeks after the seminar. With time, there was a significant decline in correctly recognizing typical anaphylaxis symptoms, including abdominal cramping, chest tightness, shortness of breath, low blood pressure, and diarrhea, whereas symptoms such as hives, swelling, and wheezing continued to be identified correctly. CONCLUSIONS There is a need for renewed anaphylaxis education among child care providers. Initially, this intervention significantly increased the ability of child care center staff to recognize, evaluate, and treat anaphylaxis, but knowledge diminished gradually at 6-month and 1-year follow-up.

Neutrophil-like low-density granulocytes are elevated in patients with moderate to severe persistent asthma

BACKGROUND Elevations in neutrophil-like low-density granulocytes (LDGs) are observed in association with disease severity in some autoimmune and other disorders. This study evaluated whether a similar association with disease severity is observed in asthma. OBJECTIVE To determine LDG levels in peripheral blood mononuclear cells of subjects with intermittent or mild persistent asthma, subjects with moderate persistent or severe persistent (SP) asthma, and control subjects without a history or allergy or asthma. METHODS A brief medical history and physical examination, spirometry, and measurement of fraction of exhaled nitric oxide were performed. The LDGs were quantified by polychromatic flow cytometry. RESULTS The LDGs displaying the same phenotype as those described previously for LDGs in other diseases were significantly elevated in peripheral blood mononuclear cells of subjects with moderate persistent or SP asthma. The LDGs comprised up to 39% of peripheral blood mononuclear cells, with elevated LDG levels most prevalent in subjects with SP asthma. The highest LDG levels were observed in 4 subjects with SP asthma. Fraction of exhaled nitric oxide levels and body mass were significantly increased in subjects with low LDG levels compared with control subjects, whereas fraction of exhaled nitric oxide levels and body mass were not elevated in subjects with moderate persistent or SP asthma and high LDG levels compared with control subjects. CONCLUSION These findings identify a previously unrecognized association between LDG levels and asthma severity. Identification of the factor(s) responsible for the increased LDG levels in moderate persistent or SP asthma may provide a serum biomarker to aid in the identification of neutrophil-associated phenotypes of severe asthma.

Expression of the high affinity IgE receptor by neutrophils of individuals with allergic asthma is both minimal and insensitive to regulation by serum IgE

We evaluated the hypothesis that serum IgE regulates neutrophil FcepsilonRI expression in the same manner as described for other FcepsilonRI+ cells. FcepsilonRI expression by neutrophils of 40 asthma subjects and 20 control subjects did not correlate with serum IgE levels, whereas FcepsilonRI expression by basophils of the same subjects showed a highly significant correlation. The level of FcepsilonRI expression by neutrophils of both asthma and control subjects was approximately 1% of that for basophil FcepsilonRI expression. IgE+ neutrophils were minimally detectable, and FcepsilonRI alpha-subunit was not detected in Western blots of neutrophil membranes and cytosol. The neutrophil FcepsilonRI did not support anti-IgE stimulated superoxide release or IgE-induced increase in neutrophil survival. We conclude that FcepsilonRI expression by neutrophils of both asthma patients and control individuals is minimal at best and that, if present, neutrophil FcepsilonRI expression, unlike that of other human FcepsilonRI+ cells, is not regulated by serum IgE.

Lack of cross-reactivity between IgE to salmon and protamine sulfate

Immediate type-generalized reactions to protamine sulfate are uncommon but may be fatal. The mechanisms of severe or fatal reactions are unknown in most cases. One theory is that contaminating fish (salmon) proteins present in protamine solutions induce anaphylaxis in salmon-sensitive subjects. A second hypothesis is that protamine interacts with anti-salmon IgE to cause anaphylaxis. We assessed these hypotheses by establishing an indirect amplified enzyme-linked immunosorbent assay (ELISA) for IgE to salmon. Sera obtained from two subjects anaphylactically sensitive to salmon demonstrated high binding to salmon that was not inhibited by preincubation of sera with 500 or 1000 micrograms of protamine or Aspergillus fumigatus. Serum from a patient who experienced anaphylactic shock from protamine was indistinguishable from control sera in the ELISA for IgE to salmon. Anti-protamine IgE could not be demonstrated in separate experiments. The assays prove that 1) serum IgE to salmon is not inhibited by protamine and 2) serum from a patient experiencing a severe reaction to protamine did not contain IgE to salmon or protamine. The experiments do not support the notion that there is cross-reactivity between IgE to salmon and protamine sulfate in the cases evaluated.