Mast cells' involvement in inflammation pathways linked to depression: evidence in mastocytosis.

Converging sources of evidence point to a role for inflammation in the development of depression, fatigue and cognitive dysfunction. More precisely, the tryptophan (TRP) catabolism is thought to play a major role in inflammation-induced depression. Mastocytosis is a rare disease in which chronic symptoms, including depression, are related to mast cell accumulation and activation. Our objectives were to study the correlations between neuropsychiatric features and the TRP catabolism pathway in mastocytosis in order to demonstrate mast cells' potential involvement in inflammation-induced depression. Fifty-four patients with mastocytosis and a mean age of 50.1 years were enrolled in the study and compared healthy age-matched controls. Depression and stress were evaluated with the Beck Depression Inventory revised and the Perceived Stress Scale. All patients had measurements of TRP, serotonin (5-HT), kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), kynurenic acid (KA) and quinolinic acid (QA). Patients displayed significantly lower levels of TRP and 5-HT without hypoalbuminemia or malabsorption, higher IDO1 activity, and higher levels of KA and QA, with an imbalance towards the latter. High perceived stress and high depression scores were associated with low TRP and high IDO1 activity. In conclusion, TRP metabolism is altered in mastocytosis and correlates with perceived stress and depression, demonstrating mast cells' involvement in inflammation pathways linked to depression.

The importance of EN ISO 15189 accreditation of allergen-specific IgE determination for reliable in vitro allergy diagnosis.

BACKGROUND: Allergen-specific serum immunoglobulin E detection and quantification have become an important step in allergy diagnosis and follow-up. In line with the current trend of laboratory test accreditation to international standards, we set out to design and assess an accreditation procedure for allergen-specific serum IgE. METHODS: Method validation according to the accreditation procedure under the EN ISO 15189 standard was carried out for allergen-specific immunoglobulin E determination using the fluoroimmunoenzymatic method ImmunoCAP(®) (ThermoFisher). Data were produced by 25 hospital laboratories in France. A total of 29 allergen specificities including mixes, extracts, and molecular allergens were assayed. Allergen-specific serum immunoglobulin E concentrations ranged from 0.1 to 100 kUA /l. RESULTS: Repeatability, reproducibility, and accuracy results fulfilled method validation criteria for automated laboratory tests and proved similar irrespective of the allergen specificity, allergen-specific serum immunoglobulin E concentration, or individual laboratory. CONCLUSION: Allergen-specific serum immunoglobulin E determination with the fluoroimmunoenzymatic method ImmunoCAP(®) is a highly repeatable, reproducible, and accurate method which may be considered as a single analyte assay in view of the EN ISO 15189 accreditation procedure.

Clinical significance of anti-Ro52 (TRIM21) antibodies non-associated with anti-SSA 60kDa antibodies: results of a multicentric study.

Ro52 antigen has recently been identified as TRIM21 protein, but the clinical significance of anti-Ro52/TRIM21 antibodies remains controversial. The aim of this multicentric study was to investigate the significance of anti-Ro52 antibodies without anti-SSA/Ro60 antibodies in various connective diseases. Sera were selected by each laboratory using its own method (ELISA, immunodot or Luminex technology), and then performed with ANA Screen BioPlex™ reagent (BIO-RAD). Among the 247 screened sera, 155/247 (63%) were confirmed as anti-Ro52 positive and anti-SSA/Ro60 negative. These sera were analyzed for the detection of other antibodies in relation with clinical settings. Isolated anti-Ro52 antibodies were detected in 89/155 (57%) sera. For the remaining sera (66/155), the main antibodies associations were Sm/SmRNP or Chromatin (n=38; 57%), Jo1 (n=17; 26%) and CenpB (n=9; 14%). Clinical data from the 155 patients showed high prevalence in autoimmune diseases (73%) including myositis or dermatomyositis (n=30), lupus (n=23); Sjögren and/or sicca syndrome (n=27); CREST or Systemic sclerosis (n=11) and autoimmune hepatitis (n=11). We found that pulmonary manifestations were often associated with the presence of anti-Ro52 antibodies (n=34, 22%), in addition with anti-tRNA synthetases, anti-SRP or anti-Ku antibodies (18/34) or isolated in half of cases (16/34). Separate detection of anti-Ro52 antibodies might be useful in related antisynthetase syndrome diagnosis. The presence of anti-Ro52 antibodies should probably precede development of autoimmune disease and must induce sequential follow-up of positive patients, particularly in interstitial lung disease progression.

Severe vascular lesions and poor functional outcome in kidney transplant recipients with lupus anticoagulant antibodies.

The impact of antiphospholipid antibodies (APA) on clinical outcome and graft histology following renal transplantation remains poorly known and controversial. We retrospectively explored the functional and histological significance of APA, primarily lupus anticoagulant (LA), in kidney transplant recipients using a systematic evaluation of 3- and 12-month posttransplant screening biopsies and glomerular filtration rate measurements (mGFR). During the study period, 37 patients had APA (2.7%), primarily LA, and 12 fulfilled antiphospholipid syndrome (APS) diagnostic criteria (0.8%) at the time of transplantation. Early after transplantation, 4 of the 12 APS patients died. Early thrombosis of graft vessels and deep venous thrombosis occurred more frequently in APA+ patients than in controls (27% vs. 7%, p < 0.05 and 35% vs. 14%, p < 0.05, respectively). The survival rate was significantly lower in patients with APS. Strikingly, the hallmark lesions of APS-associated nephropathy (APSN) were found in most of screening graft biopsies in APA+ patients but not in the controls. Accordingly, APA+ patients had a dramatic increase in chronic vascular scores and a faster decline in mGFR at 1 year. In conclusion, renal transplantation may be life-threatening in APS patients, and the presence of LA at the time of transplantation is associated with a high rate of allograft APSN and poor transplantation outcomes.

Breast inflammatory gigantomastia in a context of immune-mediated diseases.

CONTEXT: Localized breast lesions have been described in lupic or diabetic patients. However, the description of breast gigantomastia in women presenting with autoimmune diseases has not been reported. SETTING: The study took place within the Department of Endocrinology and Reproductive Medicine, Necker Hospital, Paris, France. PATIENTS: We describe eight patients with inflammatory gigantomastia, occurring in a context of immune-mediated diseases: myasthenia, chronic arthritis, or thyroiditis. MAIN OUTCOME MEASURES: Together with hormonal, immunological, and breast magnetic resonance imaging (MRI) evaluation, breast histology enabled us to perform immunocytochemical and indirect immunofluorescence studies. Control sera were obtained from patients with (n = 10) and without (n = 7) antinuclear antibodies. RESULTS: Six of the eight patients developed gigantomastia either at puberty or during pregnancy. Neither a hormonal oversecretion nor a specific immunological pattern was observed. All patients except one presented antinuclear antibodies. Histological study revealed a diffuse, stromal hyperplasia and a severe atrophy of the lobules. A rarefaction of adipocytes was also noted, as previously suggested on MRI. There was a perilobular lymphocytic infiltrate made of CD3+ lymphocytes. Study of sera from five of six cases of gigantomastia showed a nuclear immunofluorescence pattern in normal mammary ductal and lobular glandular epithelium, as well as in kidney and intestine epithelial cells. In control sera, a nuclear signal was observed only when antinuclear antibodies were present. CONCLUSIONS: We suggest that breast tissue may be a target tissue in autoimmune diseases, this process being favored by the hormonal milieu. However, the precise mechanism of such association is not individualized. The fact that stromal hyperplasia is the main histological feature justifies the search for the involvement of growth factors in such a process.

Pharmacokinetics of total immunoglobulin G and immunoglobulin G subclasses in patients undergoing replacement therapy for primary immunodeficiency syndromes.

BACKGROUND AND OBJECTIVES: Careful evaluation of the pharmacokinetic properties of a new immunoglobulin G (IgG) preparation is necessary to ensure that the product will not deviate significantly from existing products, in terms of pharmacological activity. MATERIALS AND METHODS: A prospective, open and uncontrolled trial was performed in 16 patients with primary immunodeficiency syndromes. Patients who had been under replacement therapy with licensed preparations prior to study inclusion, received 280 +/- 60 mg/kg of a solution of IgG, ready for intravenous administration, every 3 weeks for 6 months. Trough and peak plasma levels were measured immediately before and 1 h after each infusion, respectively. Pharmacokinetic parameters were calculated for total IgG and IgG subclasses. RESULTS: Total IgG, IgG1, IgG2 and IgG3 declined mono-exponentially in contrast to IgG4 which showed a bi-exponential decline. Half-lives which were highly variable among patients were similar for total IgG, IgG1 and IgG2 (35.9 +/- 10.8, 36.3 +/- 9.2, and 37.1 +/- 13.9 days, respectively) and shorter for IgG3 and IgG4 (28.6 +/- 10.4 and 15.6 +/- 4.5 days, respectively). CONCLUSIONS: The decline of IgG4 probably reflected a complex catabolic pathway specific for this subclass. As the plasma level of IgG4 is low, the decline of total IgG remained unaffected. Pharmacokinetic properties were consistent with results reported elsewhere in patients undergoing replacement therapy for primary immunodeficiency syndromes.

Cardiac troponin I in diagnosis of perioperative myocardial infarction after cardiac surgery.

OBJECTIVE: The diagnosis of perioperative myocardial infarction (PMI) after cardiac surgery remains an important issue. The present study was designed to determine the relevance of the measurement of serum cardiac troponin I (cTnI, a biochemical marker with high cardiospecificity. Therefore, cTnI was compared with creatine kinase-MB (CK-MB) mass and to the other classical signs of myocardial infarction after cardiac surgery. DESIGN: A prospective study. SETTING: A university hospital. PARTICIPANTS: Forty-one patients undergoing coronary artery bypass grafting (CABG) (n = 17) or valvular replacement (n = 24). These patients were separated into three groups according to postoperative complications: group 1, Q-wave PMI (n = 5); group 2, nonspecific changes (non-Q wave) on the electrocardiogram (ECG) and/or need of inotropic support (n = 12); group 3, no postoperative complication (n = 24). INTERVENTIONS: Postoperative follow-up consisted of serial determination of different biochemical markers (CK, CK-MB, cTnI), ECGs, and echocardiography. Blood samples were drawn before (H0) and 3 (H3), 12 (H12), 20 (H20), 24 (H24), and 48 (H48) hours after the onset of cardiopulmonary bypass (CPB). MEASUREMENTS AND MAIN RESULTS: In all patients in group 3, CK-MB and cTnI concentrations increased, and peaked at H12 after CPB (13.4 +/- 7.7 and 7.1 +/- 4.1 micrograms/L for CK-MB and cTnI, respectively). In group 1, cTnI concentrations were significantly higher than in group 3 from H12 until H48 (p < 0.002), peaked later (H24; 59.0 +/- 38.8 micrograms/L), and remained in plateau. In group 2, cTnI peak concentrations were significantly different than in groups 1 and 3 (26.2 +/- 14.8 micrograms/L) and occurred at H24 (as in patients with Q-wave PMI). CONCLUSION: A cTnI concentration less than 15 micrograms/L (mean + 2 standard deviations [SDs] of peak cTnI in group 3) within 24 to 48 hours after cardiac surgery is highly suggestive of the absence of perioperative myocardial necrosis. Because of its higher cardiospecificity than CK-MB mass, and its prolonged release after myocardial necrosis, cTnI might be a useful tool in the diagnosis of PMI after cardiac surgery.