Serum autoantibodies directed against transglutaminase-2 have a low avidity compared with alloantibodies against gliadin in coeliac disease.

Coeliac disease is characterized by intolerance to gliadin and related gluten components present in wheat, barley and rye. Coeliac disease patients harbour antibodies directed against alloantigens such as gliadin, but also against the autoantigen transglutaminase-2 (TG2). The type and quality of antibody responses provides insight into the underlying immune activation processes. Therefore, in this study we have analysed the avidity of the antibody response directed against the autoantigen TG2 and compared this with antibody responses against the alloantigens gliadin and Escherichia coli. We observed that the immunoglobulin (Ig)A autoantibody response directed against TG2 is of low avidity compared with the IgA response against the alloantigens gliadin and E. coli in the same patients; the same was true for IgG, both in IgA-deficient and in -sufficient coeliac patients. The observed avidities appear not to be related to disease stage, antibody levels, age or duration of exposure to gluten. In conclusion, in coeliac disease there is a clear difference in avidity of the antibody responses directed against the auto- and alloantigens, indicating different regulation or site of initiation of these responses.

Immunological changes after minimally invasive or conventional esophageal resection for cancer: a randomized trial.

BACKGROUND: This study was performed as a substudy analysis of a randomized trial comparing conventional open esophagectomy [open surgical technique (OE)] by thoracotomy and laparotomy with minimally invasive esophagectomy [minimally invasive procedure (MIE)] by thoracoscopy and laparoscopy. This additional analysis focuses on the immunological changes and surgical stress response in these two randomized groups of a single center. METHODS: Patients with a resectable esophageal cancer were randomized to OE (n = 13) or MIE (n = 14). All patients received neoadjuvant chemoradiotherapy. The immunological response was measured by means of leukocyte counts, HLA-DR expression on monocytes, the acute-phase response by means of C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-8 (IL-8), and the stress response was measured by cortisol, growth hormone, and prolactin. All parameters were determined at baseline (preoperatively) and 24, 72, 96, and 168 h postoperatively. RESULTS: Significant differences between the two groups were seen in favor of the MIE group with regard to leukocyte counts, IL-8, and prolactin at 168 h (1 week) postoperatively. For HLA-DR expression, IL-6, and CRP levels, there were no significant differences between the two groups, although there was a clear rise in levels upon operation in both groups. CONCLUSION: In this substudy of a randomized trial comparing minimally invasive and conventional open esophagectomies for cancer, significantly better preserved leukocyte counts and IL-8 levels were observed in the MIE group compared to the open group. Both findings can be related to fewer respiratory infections found postoperatively in the MIE group. Moreover, significant differences in the prolactin levels at 168 h after surgery imply that the stress response is better preserved in the MIE group. These findings indicate that less surgical trauma could lead to better preserved acute-phase and stress responses and fewer clinical manifestations of respiratory infections.

Increased progression of carotid intima media thickness in thyroid peroxidase antibodies-positive rheumatoid arthritis patients.

OBJECTIVE: Autoimmune diseases such as rheumatoid arthritis (RA) and hypothyroidism tend to cluster, and this coexistence amplifies the elevated cardiovascular risk in RA. Whether thyroid peroxidase antibodies (TPOabs) are associated with increased cardiovascular disease (CVD) risk has not been studied extensively. Therefore, this study determined firstly the prevalence of TPOabs in RA and secondly whether TPOabs were associated with CVD. Moreover, this study explored whether TPOabs were related to RA characteristics. DESIGN AND METHODS: Data from the CARRÉ Study, an ongoing study investigating CVDs and its risk factors in RA (n=322), was used to ascertain the prevalence of TPOabs in RA patients. In addition, cardiovascular and RA disease characteristics were compared between TPOabs-positive and -negative patients at baseline and at a second visit after 3 years. RESULTS: TPOabs were present in 47/322 (15%) RA patients and TSH levels were higher in TPOabs-positive patients (1.40 mU/l) compared with TPOabs-negative patients (1.26 mU/l, P=0.048). At baseline and after 3 years no association was observed between TPOabs and (risk factors for) CVD. Regression analyses revealed a significantly larger progression of carotid intima media thickness (cIMT; ß=0.13 mm) in TPOabs-positive compared with TPOabs-negative patients independent of risk factors for cIMT progression. RA disease activity scores (DAS28) were higher in TPOabs-positive compared with TPOabs-negative patients (4.4 vs 3.8 P=0.018). CONCLUSIONS: TPOabs were associated with increased cIMT progression. Moreover, an association between TPOabs and DAS28 was observed. Hence, TPOabs seems to have a role in the amplified cardiovascular risk in RA patients.

Palladium-induced Th2 cytokine responses reflect skin test reactivity.

Recently, a crucial role of Th2 responses in nickel allergic contact dermatitis (ACD) was demonstrated. As palladium allergy is an issue of growing interest, the diagnostic potential of Th2 parameters for palladium sensitization was investigated. Palladium (Na(2) [PdCl(4)])-induced lymphocyte proliferation (LPT), Th1 and Th2 cytokine production were correlated with skin test (ST) reactivity in 16 positive and 21 negative controls. Furthermore, the diagnostic potential of these assays was evaluated using receiver operating characteristics (ROC) analysis. For comparison, same experiments were carried out for nickel (NiSO(4)). Correlation coefficients between palladium ST reactivity and IFN-γ, LPT, IL-5, and IL-13 were 0.34, 0.51, 0.69, and 0.78, and overall test accuracies were 68%, 81%, 89%, and 95%, respectively. Both palladium- and nickel-mediated Th2 responses tightly correlate with ST reactivity, supporting recent findings on the crucial role of Th2 involvement in ACD. Therefore, these assays may have great potential as diagnostic tools for future in vitro sensitization testing.

The surgical stress response and postoperative immune function after laparoscopic or conventional total mesorectal excision in rectal cancer: a randomized trial.

PURPOSE: This study evaluated differences in stress response and immunological function following laparoscopic and conventional total mesorectal excision (TME) for rectal cancer. METHODS: Patients with non-metastasized rectal cancer were prospectively randomized to open (n = 18) or laparoscopic (n = 22) TME. Blood samples were taken preoperatively (baseline), 2, 24, and 72 h following surgery. Systemic white blood cell and monocyte count, C-reactive protein, interleukin-6 (IL-6), interleukin-8 (IL-8), HLA-DR expression on monocytes, growth hormone, prolactin, and cortisol were measured. RESULTS: Forty patients with a median age of 66 years (interquartile range, 60-74 years) were included. Eighteen patients (45%) were randomized to open surgery and 22 patients (55%) to laparoscopic surgery. Patient demographics in terms of gender, age, BMI, ASA classification, localization of the tumor, and type of neoadjuvant therapy were comparable for both groups. Laparoscopic surgery resulted in a significantly better short-term preservation of postoperative immune function. HLA-DR expression on monocytes was significantly higher (64% vs 50%, P = 0.014) and IL-6 level increase was significantly lower (4.6 vs 10.8, P = 0.003) 2 h after laparoscopic surgery. No differences between the open and laparoscopic technique were observed in postoperative white blood cell count, monocyte count, C-reactive protein, IL-8, growth hormone, prolactin, and cortisol levels. CONCLUSION: Short-term postoperative immune and inflammatory functions tended to be better after laparoscopic rectal surgery. However, the differences were not consistent at all time intervals, making a definitive conclusion difficult. Better preserved inflammatory function 2 h after surgery may reflect a reduction in operative trauma when the laparoscopic technique is compared with open rectal procedures.

Childhood coeliac disease: towards an improved serological mass screening strategy.

BACKGROUND: In 1997-1998, 6127 asymptomatic children aged 2-4 years were screened for coeliac disease (CD) by anti-endomysium (EmA) testing in the Netherlands. After 6 (+/-2) months, biopsies were performed in 57 seropositive children; 31(54%) had villous atrophy, but 26 (46%), all HLA-DQ2/DQ8 positive, had normal histology. AIMS: To reduce the number of unnecessary biopsies after serological mass screening for CD in asymptomatic young children by optimizing screening procedures. METHODS: Comparing different tests and optimizing their cut-off point: screening samples were tested for EmA, tissue-transglutaminase (tTGA), antigliadin and deamidated-gliadin-peptides (anti-DGP) antibodies. Determining serological persistence over time: persistence of EmA and tTGA was determined by testing serological samples obtained at biopsy. RESULTS: Tissue-transglutaminase and anti-DGP correlated with EmA. Optimization of standard cut-off points not only reduced unnecessary biopsies by 50-96% but also reduced sensitivity. EmA persisted in all CD children, but in only 50% of the non-CD children. tTGA persisted in 83% of CD, but in only 15% of non-CD children. CONCLUSIONS: Coeliac disease antibodies may be present transiently in genetically predisposed children. To avoid unnecessary biopsies, serological mass screening procedures may be improved by repeating EmA and/or tTGA in initially seropositive young children after 6 months, before proceeding to biopsy. This may reduce the number of unnecessary biopsies that are performed.

No evidence of misdiagnosis in patients with multiple sclerosis and repeated positive anticardiolipin antibody testing based on magnetic resonance imaging and long term follow-up.

OBJECTIVE: To determine whether patients with definite multiple sclerosis (MS) and repeated positive anticardiolipin antibody (aCL Ab) testing fulfil the recently updated criteria for the antiphospholipid syndrome (APS). Also, to determine if these patients form a separate subgroup in terms of long term follow-up and MRI characteristics. DESIGN: A blinded case control study comparing MRI patterns between aCL Ab positive and negative MS patients with a clinical follow-up of 7 years. PARTICIPANTS: 8 (5.6%; male:female ratio 2:6; 6 relapsing-remitting subtype, 1 primary progressive subtype and 1 neuromyelitis optica (NMO)) of 143 consecutive patients with definite MS or NMO (71% relapsing-remitting, 18% secondary progressive and 6% primary progressive disease course; 4% NMO) showed repeated positive aCL Ab testing. SETTING: Outpatient clinic of a tertiary MS centre in The Netherlands. RESULTS: All eight aCL Ab positive patients had levels below 40 MPL/GPL units, with the majority of intervals between tests of at least 12 weeks. After follow-up, none of the patients fulfilled the criteria for APS. No specific MRI features were present compared with 24 matched aCL Ab negative patients. CONCLUSIONS: No aCL Ab positive MS patient fulfilled the criteria for APS, arguing against a possible misdiagnosis or coexistence.

Analysis of effector and regulatory immune reactivity to nickel.

BACKGROUND: Diagnostic patch testing in allergic contact dermatitis faces the risk of boosting existing hypersensitivities or active sensitization. Risk-free and reliable in vitro assays using peripheral blood are, therefore, wanted. OBJECTIVES: Here, we studied new approaches for in vitro monitoring of nickel-specific effector ad regulatory cell functions in allergic patients and potentially tolerized individuals. METHODS: Lymphocyte proliferation assays were carried out with the allergen and additional IL-12/IL-7 or IL-4/IL-7 cytokine supplements. Release of IFN-gamma and IL-5 were assessed as measures for type-1 and type-2 effector T cell function, respectively, and IL-10 and TGF-beta1 to monitor possible regulatory T cell function reflecting immunological tolerance. After optimization of in vitro cut-off values, potency of these parameters was evaluated as compared with conventional nickel patch testing. RESULTS: One hundred and fifty six outpatients were included in this study, 74 of whom presenting with a positive history of nickel allergy. Nickel-sulphate patch test results showed positive reactions in 43 patients, of whom 40 had a positive history (test sensitivity 54%; specificity 96%; overall accuracy 76%). Proliferation tests without cytokine supplementation showed an accuracy of 68%, which was further improved by supplementing IL-4/IL-7 (82%). IFN-gamma and IL-5 cytokine production, as revealed in IL-12/IL-7 and IL-4/IL-7 supplemented cultures, respectively, showed accuracies of 70% and 83%. As to the production of putatively immunoregulatory cytokines, IL-10 was most informative, with highest production rates in nickel-skin test negative individuals with long-lasting mucosal metal contact preceding skin piercing. CONCLUSIONS: These results indicate that measuring both T cell proliferation and cytokine secretion profiles, in particular IL-5 release using IL-4/IL-7 supplemented medium, offers a promising improvement of the in vitro diagnostic options in monitoring nickel contact sensitization. Since oral nickel contact has been shown earlier to induce active tolerization, nickel-induced in vitro IL-10 production may help identify nickel-tolerized individuals.