Increased Levels Of Immunoglobulin Research Articles

PF433 SOLUBLE MANNOSE RECEPTOR IS A POTENTIAL NEW BIOMARKER FOR PLASMA CELL DYSCRASIAS AND OTHER SKELETAL COMPLICATIONS IN GAUCHER DISEASE

Background:Gaucher Disease (GD) is a rare autosomal recessive lysosomal storage disorder caused by deficient activity of the lysosomal enzyme beta‐glucocerebrosidase (GBA). Clinical features of disease are heterogeneous as is response to treatment. Skeletal disease is complex and a proportion of patients do not respond or progress, despite GD‐specific therapy. Determinants of skeletal non‐response are not known. Polyclonal gammopathy, monoclonal gammopathy of undeterminded significance (MGUS) and Plasma Cell Myeloma (PCM) are features of GD. Progression from MGUS to PCM is difficult to predict. Biomarkers currently used to assess overall disease burden are not specific to GD and do not reliably reflect individual domains of organ involvement. Soluble mannose receptor (sMR) has been assessed as a biomarker in various diseases where alternatively activated macrophages have been implicated, and shows promise in predicting transformation of MGUS to PCM.Aims:To assess sMR in relation to domains of clinical features of GD. To compare sMR to known biomarkers of GD.Methods:The diagnosis of GD was confirmed in our patients by assessing enzyme activity and genotype, which also excluded GD in our controls. Pertinent clinical data was collected from patient records retrospectively. ELISA analysis of biomarkers were undertaken as per kit instructions: Human sMR (Hycult Biotech); PARC (Life Technologies); human osteoactivin GPNMB (Invitrogen by Thermo Fisher Scientific); CCL3 and CCL4 (Invitogen by Thermo Fisher Scientific); progranulin (Ray Biotech). Chitotriosidase, ferritin, ACE, haemoglobin, platelets, IgA, IgG, and IgM were determined by the diagnostic laboratory at The Royal Free hospital. Spleen volumes and liver volumes were calculated from MRI images of patients.Results:16 treatment naïve type 1 GD patients, 14 with paired post‐treatment sera and 10 non‐GD controls had sMR measured by ELISA. Mean sMR in treatment naïve sera was 291.2 +/‐ 178.8 ng/ml compared to post‐treatment 200.5 ng/ml +/‐ 103.1 (p = 0.02). Mean sMR of the control group was 182.1 +/‐ 48.0 ng/ml. There was no statistical significance between control and post‐treatment groups. Median treatment time was 27 months (range: 11–124). There is good correlation with all domains of GD clinical features: platelet count (rho = 0.47, p = 0.009), haemoglobin (rho = 0.77, p = <0.0001), spleen volume (rho = 0.68, p = 0.002), liver volume (rho = 0.64, p = 0.002), bone marrow burden (BMB) score (rho = 0.78, p = 0.0009). There was strong correlation with immunoglobulin levels: IgA (rho = 0.54, p = 0.002), IgG (rho = 0.58, p = 0.0007), IgM (rho = 0.86, p = <0.0001). sMR correlated well with other biomarkers: PARC (rho = 0.65, p = <0.0001), osteoactivin (rho = 0.58, p = 0.0006), chitotriosidase (rho = 0.52, p = 0.0003), ferritin (rho = 0.71, p = <0.0001), CCL3 (rho = 0.66, p = <0.0001). sMR did not correlate with these biomarkers: angiotensin converting enzyme (ACE) (rho = 0.27, p = 0.13), progranulin (rho = 0.071, p = 0.7), CCL4 (rho = 0.048, p = 0.79).Summary/Conclusion:sMR has been studied as a marker in diseases of alternatively activated macrophages previously, but not in GD to date. sMR is elevated in GD patients measured at baseline (prior to treatment) and reduces with Gaucher‐directed treatment. sMR correlates with all domains of clinical features of GD. sMR is strongly correlated with increased immunoglobulin levels in GD patients. sMR correlates with many established clinically used biomarkers and those in development. Future work will assess sMR over time in patients with polyclonal gammopathy and MGUS who develop PCM to assess its utility to predict evolution to PCM.

High immunoglobulin E level is associated with increased readmission in children with bronchopneumonia.

Background:Increased immunoglobulin E (IgE) is associated with lower respiratory tract infections. The study aimed to evaluate the association between IgE and the rate of bronchopneumonia-related readmission within 12 months in children.Methods:A total of 1099 children aged over 1 year with bronchopneumonia, from 1 January 2015 to 31 December 2016, were enrolled. Unplanned readmissions within 12 months after discharge were observed. Multivariate regression analysis was used to identify independent risk factors for rehospitalization.Results:The rate of rehospitalization was 11.4% (125/1099). Compared to the nonreadmission children, IgE levels, the proportion of children with asthma and hospitalization duration were significantly higher in the readmission children (p < 0.05). Compared to the children with normal IgE (≤ 165 IU/ml) levels, the risk of rehospitalization was significantly higher in children with abnormal IgE [odds ratio (OR) 1.781, 95% confidence interval (CI) 1.209–2.624, p = 0.004]. Children with IgE level more than three times the upper limit had even higher risks of readmission (OR 2.037, 95%CI 1.172–3.540, p = 0.012). Meanwhile, the risk of readmission in children with abnormal IgE combined with or without bronchial asthma was significantly higher (OR 2.548 and 1.918, 95% CI 1.490–4.358 and 1.218–3.020, p = 0.001 and 0.005, respectively).Conclusions:Children aged over 1 year with bronchopneumonia who had higher IgE levels are at increased risk for rehospitalization within the first 12 months of the index hospitalization and IgE level may be used as a predictor of rehospitalization in children with bronchopneumonia.

MIXED INFECTION - HANTAVIRUS HAEMORRHAGIC FEVER WITH RENAL SYNDROME AND HERPES SIMPLEX VIRUS ENCEPHALITIS

Introduction: This case report describes a patient treated at the Clinic of Infectious Diseases of University Hospital “St. George” Plovdiv, with two infections occurring at the same time – haemorrhagic fever with renal syndrome (HFRS) and herpes simplex virus (HSV) encephalitis. Results: A 53-year-old male presented with fever, flu-like syndrome and renal impairment with mild nitrogen elevation. The patient was treated at the Clinic of Nephrology for one week. Several hours after discharge he had three generalised tonic-clonic seizures and was admitted to the intensive care unit with status epilepticus and acute respiratory failure requiring intubation and mechanical ventilation for 4 days. Lumbar puncture results showed: white blood cells – 1.10 6 /l, glucose – 5.3 mmol/l, total protein – 1.6 g/l, increased immunoglobulin levels. The patient was transferred to the Clinic of Infectious Diseases with suspicion of viral encephalitis.&#x0D; HSV type 1 was detected in the cerebrospinal fluid by PCR. Due to suspected hantavirus infection, serum was examined and IgM and IgG antibodies against the HFRS virus were detected by ELISA. Specific treatment with acyclovir was started and there was a rapid improvement in the clinical condition. Convulsions did not recur. Nitrogen levels normalised and there was a short period of polyuria. Thrombocytopenia quickly resolved without occurrence of haemorrhagic syndrome. In the course of the disease, the patient developed mild diarrhoeal syndrome and left thrombophlebitis. He was discharged clinically well with negative PCR results for HSV.&#x0D; In conclusion, we can assume that as a result of immunosuppression due to HFRS, HSV type 1 reactivated and led to herpes encephalitis.

Elevation of immunoglobulin levels is associated with treatment failure in HIV-infected children in Vietnam.

BackgroundHIV-infected children suffer from higher levels of treatment failure compared to adults. Immunoactivation, including humoral immunoactivation reflected by increased immunoglobulin levels, is believed to occur early during HIV infection. Therefore, we wanted investigate alteration in immunoglobulin levels in association with treatment response in HIV-infected children.MethodsA nested case–control study was conducted using clinical data collected from 68 HIV-infected children enrolled at the National Hospital of Pediatrics, Vietnam.ResultsThe results showed that immunoglobulin levels, CD4 T-cell counts, CD4 T-cell percentage, and HIV load were significantly higher in the treatment-failure group than the treatment-success group at treatment initiation. IgG and IgA levels were negatively correlated with CD4 T-cell counts (P=0.049 and P<0.01, respectively) and positively correlated with HIV load (P=0.04 and P=0.02, respectively). In addition, IgG and IgA levels were independently associated with treatment response, analyzed by Cox regression analysis (HR 1.19 [P=0.049] and HR 1.69 [P<0.01], respectively).ConclusionElevation of IgA levels occurred early during HIV infection, and might have a prognostic role in treatment response.

Association between Serum Immnunoglobulin E and Pterygium: A Population-Based Study from South Korea

ABSTRACTPurpose: Several studies have shown that pterygium is associated with inflammation, angiogenesis, and fibrosis. However, it should be acknowledged that not enough is known about the association between immunoglobulin E (IgE) and pterygium. The present study was conducted to test the hypothesis that elevated serum IgE is associated with a greater prevalence of pterygium.Material and Methods: A cross-sectional study was performed using data of 1,548 participants aged 30 years or older who were enrolled in the Korea National Health and Nutrition Examination Survey conducted in 2010. Multivariable logistic regression analysis was used to examine the relationship between pterygium and allergic conditions, including total serum IgE and allergen-specific serum IgE levels, after adjusting for potential confounding factors.Results: Participants with pterygium were more likely have increased IgE level (p = 0.009). After adjusting for potential confounders, the odds ratio (OR) for pterygium was greater in participants with higher total serum IgE levels (OR = 1.63; p = 0.047). Multivariable-adjusted ORs of pterygium across the tertile of increasing IgE were 1.00 (reference), 1.18, and 1.45, (P for linear trend = 0.038). Although the ORs for the upper two tertiles of cockroach and dog allergen-specific IgE were higher than those for the lowest tertile, allergen-specific serum IgE showed no clear association with pterygium.Conclusions: Increased total serum IgE concentration is independently related to pterygium after adjusting for confounding factors. To the best of our knowledge, this study is the first research that reveals an association between serum IgE and pterygium.

ESTIMATION OF INFLUENCE OF THE THERAPEUTIC – PROPHYLACTIC COMPLEX ON THE IMMUNE SYSTEM INDICES OF EXPERIMENTAL ANIMALS WITH SIMULATED GINGIVITIS

In order to assess the influence of heavy metals, iodine and fluoride deficiency on the status of periodontal tissues in rats experimental studies were carried out on 100 white rats, which were divided into 5 groups of 20 animals in each. 1-st group included intact rats; 2-nd - rats with gingivitis; 3-rd - rats with gingivitis exposed to heavy metals by means of adding cadmium and lead to drinking water; 4-th - animals with gingivitis exposed to heavy metals, as well as iodine and fluoride deficiency; 5-th - animals with gingivitis exposed to heavy metals, under iodine and fluoride deficiency, receiving therapeutic-prophylactic complex. Immunological status of animals was evaluated by means of measuring the level of immunoglobulins in serum. Immunoglobulins (Ig) G, A, and M were determined by their radial immunodiffusion in agar according to G. Manchini et al. using diagnostic kits of the firm "Microgene". The count of leukocytes in the peripheral blood of animals was determined by means of the Goryaev’s chamber.&#x0D; It was found that under influence of heavy metals in combination with iodine and fluoride deficiency the levels of immunoglobulins A and M in blood serum of rats were decreased by 2.5 times, and Ig G ‒ by 2.6 times. The application of the therapeutic-prophylactic complex in 5-th group of rats significantly corrected immunological status of their blood, which was characterized by a significant increase in levels of immunoglobulins.

Advantage of the subcutaneous immunoglobulin replacement therapy in primary immunodeficient patients with or without secondary protein loss.

Gür-Çetinkaya P, Çağdaş-Ayvaz DN, Öksüz AB, Ertoy A, Hayran U, Özkan F, Erol M, Tezcan İ. Advantage of the subcutaneous immunoglobulin replacement therapy in primary immunodeficient patients with or without secondary protein loss. Turk J Pediatr 2018; 60: 270-276. In recent years subcutaneous immunoglobulin is widely used for primary immunodeficient patients. Subcutaneous administration provides a more stable and higher serum immunoglobulin levels due to continuous and steady transition from lymphatics to the systemic circulation. We aimed to evaluate the changes in serum immunoglobulin levels under subcutaneous immunoglobulin therapy in patients with primary immunodeficiency with or without secondary protein loss. Nine patients with primary immunodeficiency who switched to subcutaneous immunoglobulin were enrolled. Age, gender, diagnosis, reasons of transition to subcutaneous route, reasons of secondary protein loss were recorded. A questionnaire consisting of frequencies and types of infections, side effects observed with intravenous and subcutaneous routes; date and reason of transition to subcutaneous route were asked to all participants. Serum immunoglobulin levels at the 3rd and the 6th months before and after subcutaneous route were recorded. Of the 9 patients (M/F=4/5) the median age was 12 years (6.1-28.7) and 5 of them had protein loss. In total, 444 injections were applied, and all patients experienced local reactions. Infections were more frequent under intravenous than subcutaneous route (p=0.004). We observed an increase in immunoglobulin levels under subcutaneous route (p=0.069 at 3rd; p=0.13 at 6th month). This increase was evident at the 3rd month of transition to subcutaneous route in patients with protein loss (p=0.080). There was an increase in serum immunoglobulin levels under subcutaneous route. However, increase was not statistically significant since the study group was small. This increment was prominent in patients with protein loss. Subcutaneous administration may be a good alternative for primary immunodeficient patients with protein loss who have persistent low serum immunoglobulin levels despite increments in the intravenous immunoglobulin doses.

Protective effect of rutin on humoral and cell mediated immunity in rat model

Diet and dietary intake can persuade the development, safeguard and proper functioning of immune system. Ruin, an important bioflavonoid, is abundantly found in various foodstuffs. Rutin has been acknowledged for its protective and beneficial effects on various aspects of the biological system. The present study was aimed to examine the effect of rutin on the regulation of the immune response in experimental animal models. Effect of rutin of cellular immunity was determined by delayed-type hypersensitivity (DTH) response, carbon clearance assay, leucocyte mobilization test, and cyclophosphamide-induced myelosuppression, whereas humoral immunity was analyzed by the haemagglutinating antibody (HA) titre assay. Rutin (25, 50 and 100 mg/kg, p.o.) evoked a significant increase in antibody titre in the haemagglutination test, increased immunoglobulin levels, and enhanced the delayed type hypersensitivity reaction induced by sheep red blood cells. It also significantly restored the functioning of leucocytes in cyclophosphamide treated rats and augmented phagocytic index in the carbon clearance assay. The outcomes from the present study indicate that rutin possesses sufficient potential for increasing immune activity by cellular and humoral mediated mechanisms.

Impact of high serum Immunoglobulin E levels on the risk of atherosclerosis in humans.

BackgroundEpidemiological studies show that immunoglobulin E (IgE) levels were higher in subjects with acute coronary events. However, it is unknown if the increased IgE level is a marker of future coronary incidents and whether it may be regarded as a risk factor of an ischemic heart disease.ObjectiveOur aim was to investigate the relationship between IgE levels and some atherosclerotic markers in patients without known atherosclerotic disease.MethodsFifty patients (mean age, 40.96 ± 10.8 years) with high serum IgE levels due to various conditions who did not display evidence of an atherosclerotic disease and 30 healthy control subjects (mean age, 47 ± 8.27 years) were included in the study. Atherosclerotic disease markers including adhesion molecules like vascular cell adhesion molecule-1, intercellular adhesion molecule-1, proinflammatory cytokines such as interleukin-6, endothelin-1, and systemic inflammatory markers such as high sensitivity C-reactive protein were determined by enzyme-linked immunosorbent assay (ELISA). Endothelial functions of the coronary arteries were determined by coronary flow reserve (CFR) measurements and carotid intima media thickness using transthoracic Doppler echocardiography.ResultsCFR was significantly lower in the patient group when compared with the control group (p<0.001; 95% confidence interval, -0.79 to-0.20) while carotid media thicknesses were not different between 2 groups. There were no differences in ELISA test results between the 2 groups.ConclusionOur results showed that CFR as an early marker of endothelial dysfunction was significantly lower in patients with high IgE levels. This finding seems to support the role of IgE in the vascular pathology of atherosclerosis.

A Comparative Biochemical Study of Proteins Profile in Iraqi Children and Adolescent with ?-Thalassemia

The aim of the present research is to study different protein fractions in sera of children and adolescent with β –thalassemia major and minor and to compare the results with that of healthy control.One hundred fifty children and adolescents were enrolled in this study,including 50 patients with β- thalassemia major , 50 patients with β- thalassemia minor as pathological control group and another apparently 50 healthy individuals as a control group. The age of all studied groups ranged from (4-18)years.Total protein, albumin and immunoglobulins were estimated in sera of all subjects. A Significant decrease was found in the total protein and albumin levels in sera of both major and minor thalassemic patients compared to normal groups. A Significant increase in immunoglobulin levels (IgG, IgM and IgA) was found in the sera of major and minor β-thalassemia patients compared to control.Different protein parts in sera of all subjects were detected using cellulose acetate electrophoresis.The results revealed significant reduction in β- globulin fractions in β- thalassemia major patients compared to the normal and pathological control groups. Significant elevations in γ- globulins fractions were observed in both major β- thalassemia and minor β- thalassemia as compared to normal control group. As a Conclusion the alteration in some protein parts occurred which is more obvious in major thalassemia patients compared to the normal and pathological control groups.&#x0D; Key words: Protein Parts , Elecrtrophoresis , β-Thalassemia

Could daratumumab be used to treat severe allergy?

In the management of allergic diseases, targeting IgE using biologicals is a current research focus. This proof of concept shows that plasma cell depletion using daratumumab results in decreased total and allergen-specific IgE levels.

Age-Related Cataract Is Associated with Elevated Serum Immunoglobulin E Levels in the South Korean Population: A Cross-Sectional Study.

BackgroundPrevious research has suggested that immunoglobulin E (IgE)-mediated events lead to several chronic diseases. We investigated the association between allergic conditions and age-related cataracts in the South Korean adult population.MethodsA cross-sectional study was performed using data obtained from 1,170 participants aged 40 years or older who were enrolled in the Korean National Health and Nutrition Examination Survey 2010. Multivariable logistic regression was used to examine the relationship between age-related cataracts and allergic conditions, including total serum IgE and allergen-specific serum IgE levels, after adjustment for potential confounders (age, sex, alcohol consumption, smoking, sun exposure, blood pressure, plasma glucose and cholesterol levels, as well as histories of asthma, atopic dermatitis, and rheumatoid arthritis).ResultsAfter adjusting for potential confounders, the odds ratio (OR) for age-related cataract was greater in participants with higher total serum IgE levels (OR = 1.37; P = 0.044). In particular, increased IgE levels were significantly associated with nuclear cataract (OR = 1.42; P = 0.032). However, allergen-specific serum IgE levels did not differ significantly between groups. In the trend analysis, no significant relationship was observed between serum IgE and any type of age-related cataract.ConclusionIncreased total serum IgE level is independently associated with age-related cataracts after adjustment for confounding factors.

Sesamin attenuates allergic airway inflammation through the suppression of nuclear factor-kappa B activation

The aim of the present study is to determine the role of sesamin, the most abundant lignan in sesame seed oil, on the regulation of allergic airway inflammation in a murine asthma model. A BALB/c mouse model with allergic asthma was used to evaluate the effects of sesamin on nuclear factor-kappa B (NF-κB) activation. An enzyme-linked immunosorbent assay was used to determine protein expression in bronchoalveolar lavage (BAL) fluids. Hematoxylin and eosin staining was performed to examine histological changes. Moreover, western blot analysis was used to detect the expression of proteins in tissues. Prior to administering sesamin, the mice developed the following pathophysiological features of asthma: An increase in the number of inflammatory cells, increased levels of interleukin (IL)-4, IL-5 and IL-13, decreased levels of interferon-γ in BAL fluids and lung tissues, increased immunoglobulin E (IgE) levels in the serum and an increased activation of NF-κB in lung tissues. Following treatment with sesamin, the mice had evidently reduced peribronchiolar inflammation and airway inflammatory cell recruitment, inhibited production of several cytokines in BAL fluids and lung tissues, and decreased IgE levels. Following inhalation of ovalbumin, the administration of sesamin also inhibited the activation of NF-κB. In addition, sesamin administration reduced the phosphorylation of p38 mitogen-activated protein kinases (MAPKs). The present study demonstrates that sesamin decreases the activation of NF-κB in order to attenuate allergic airway inflammation in a murine model of asthma, possibly via the regulation of phosphorylation of p38 MAPK. These observations provide an important molecular mechanism for the potential use of sesamin in preventing and/or treating asthma, as well as other airway inflammatory disorders.

Abstract A124: Tertiary lymphoid structures: Predictors of effective antitumor immunity in human breast cancer?

Abstract The clinical relevance of tumor infiltrating lymphocytes (TIL) in breast cancer (BC) is now broadly accepted; however, the relationship between protective immunity, observed in some patients, and critical features of lymphoid subset composition and organization are largely unknown. Our recent work revealed that tertiary lymphoid structures (TLS), principally composed of T and B cells, present in the peri-tumoral regions of BC are associated with increased TIL infiltration in the tumor bed and good clinical outcomes in both the neo-adjuvant and adjuvant settings. To gain insight into the immune components linked with a significant TIL and TLS presence, we initiated a prospective study of T and B cell TIL. Breast tissues from tumors (current n=483) and matched non-adjacent non-tumor tissues (NANT) as well as normal tissue from mammary reductions (n=49) were systematically immunophenotyped by flow cytometry on the day of surgery. Primary tumor supernatants derived from the tissue homogenates (non-enzymatic) and plasma from all patients were stored for cytokine/chemokine and immunoglobulin analysis. TIL organization and spatial distribution was analyzed on paraffin sections using immunohistochemistry (IHC) and immunofluorescence (IF). The fresh tissue analyses revealed that TIL distribution in BC forms a continuum. The infiltration levels detected in normal tissue and NANT were used to define cutoffs that discriminate between TIL positive (TILpos) and negative (TILneg) tumors. TILneg tumors are defined as those with a TIL density &amp;lt;99th percentile of the lymphocyte density in normal breast tissue. TILpos tumors include TIL-high (TILhi) where TIL density is &amp;gt;99th percentile of lymphocyte density in NANT and TIL-intermediate (TILint). Applying these thresholds to the TIL infiltration levels identified approximately 25% of tumors as TILneg with infiltrating lymphocytes similar to normal breast tissue. The TILpos tumors (75%) are subdivided into 36% TILint and 39% TILhi tumors. TILpos tumors are characterized by an increase in CD4+ T cells and CD19+/CD20+ B cells. The median CD4/CD8 ratio was &amp;gt;1 in TILpos compared to &amp;lt;1 in TILneg tumors and NANT. CD4+ and CD8+ T cells were predominantly CD45RO+ memory cells with a significant proportion expressing PD-1. All stages of B cell differentiation were detected in the infiltrate; however, memory B cells were significantly increased in BC (50%) compared to normal tissues (&amp;lt;15%) with the highest levels seen in TILhi tumors. An increase in centroblasts and centrocytes, the germinal center (GC) B cells, was associated with Tfh cells, both resident in peri-tumoral TLS. Their presence was positively correlated with antibody-secreting cells, suggesting local humoral immune responses are generated in TLS, which is supported by the increased immunoglobulin levels detected in tumor supernatants compared to NANT/normal tissue supernatants. Closer examination of Tfh cells infiltrating BC indicates that CXCL13-producing Tfh TIL vary from Tfh cells in secondary lymphoid organs such as tonsils. Tfh TIL express the highest levels of some GC Tfh cell markers (PD-1, CD200 and TIGIT) but intermediate levels of others (ICOS and BCL6) and are essentially negative for CXCR5. Closer examination of Tfh cells in the tumor bed revealed that they directly contact CD20+ B cells, IgG+ and IgA+ plasma cells as well as CXCL13–CD8+ TIL. Taken together, our data suggest that active cross-talk between adaptive immune cells in the tumor microenvironment may be key to establishing immunological memory sufficiently robust to control residual BC over the long term. These data further signify that TLS and/or the presence of GC-associated Tfh and B cells may be important biomarkers that identify effective anti-tumor immunity, which can ultimately be used to independently grade therapeutic responses. Citation Format: Soizic Garaud, Laurence Buisseret, Chunyan Gu-Trantien, Gert Van den Eynden, Alexandre de Wind, Edoardo Migliori, Roberto Salgado, Denis Larsimont, Martine Piccart, Karen Willard-Gallo. Tertiary lymphoid structures: Predictors of effective antitumor immunity in human breast cancer? [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A124.

Angiographic coronary artery disease and high-sensitivity troponin-T in a native Pakistani cohort presenting with chronic chest pain.

To determine the relationship between troponin-T levels and atheroma burden in Pakistanis presenting to an ambulatory centre with chest pain. A prospective case-control study of 400 patients selected for presence/absence of angiographic disease referred between 2001 and 2003. A comprehensive cardiovascular disease (CVD) risk factor profile was assessed including demographics, environmental and biochemical risk factors including insulin resistance and troponin-T levels. Coronary atheroma burden was quantified by Gensini score. Clinically significant elevated troponin-T levels (> 30 pmol/l) were found in 40 patients (10%) with equal numbers in groups selected with or without angiographic disease. Troponin-T elevation (> 13 pmol/l) was present in 59 vs. 47 patients (30% vs. 24%; p = 0.04). Troponin-T levels did not correlate with any measured demographical, environmental, drug therapy or biochemical risk factor. No difference was found in concentrations of lipids, apolipoproteins, insulin resistance, C-reactive protein or sialic acid in cohorts stratified by troponin-T concentrations. In univariate analysis comparing patients with high (> 30 pmol/l) and low troponin-T levels (< 13 pmol/l) higher plasma total protein (91 g/l vs. 85 g/l; p = 0.01), increased immunoglobulin levels (41 g/l vs. 36 g/l; p = 0.02) and prevalence of hyperparathyroidism (40% vs. 21%; p = 0.04) were associated with higher troponin-T concentrations. This study shows that measurement of troponin-T is not an alternative to imaging in an Indian asian population, but that it does identify a separate potentially high-risk population that would not be identified by the use of imaging alone which is potentially at higher risk of CVD events.

P013 : ELEVATED BACKGROUND FLUORESCENCE IN SINGLE-ANTIGEN BEAD ANTI-HLA ANTIBODY ASSAYS IS NOT ASSOCIATED WITH A SPECIFIC AGE, GENDER, ETHNICITY, OR HLA TYPE

Aim Elevated background fluorescence (BF) may occur in single-antigen (SA) anti-HLA antibody (Ab) assays. This may result in difficulty in interpretation, and can potentially obscure relevant anti-HLA Ab. It is well-recognized that many autoimmune disorders have specific HLA type associations, which may predispose to increases in immunoglobulin levels, and development of auto-Ab. These are known to cause increased backgrounds in some testing. We therefore conjectured that specific HLA-types may result in elevated BF in anti-HLA Ab assays. Further, if this proved correct, patients with the identified HLA-type could be tested by alternative techniques to ensure that anti-HLA Ab are better identified. Methods Reagents: OneLambda® products; LABScreen®. Study period: 2010–2013. Patients with recurrent elevated BF values were included in the study. HLA type, age, gender, ethnicity, and type of transplant were analyzed under IRB approval. Results 309 patients had recurrent elevated BF (>7000 assays) (61% C, 36% AA, 3% Other) (59% M, 41% F) (age 1–86 years, mean 47 ± 19 years, median 53 years). In comparison with the US population, a higher proportion of AA were observed (36% vs 15%); other minorities were under-represented (3% vs 17%). However, there were no statistically significant differences in age, gender, and ethnicity with the national transplant population in UNOS. Further, no specific age, gender, or ethnicity statistically associated with an elevated background. The initial analysis indicated: increased HLA-A23, HLA-B42, and decreased HLA-DQ9 in kidney and heart transplant patients with elevated BF, suggesting the possibility of specific HLA type association. Secondary analysis controlling for the increased presence of AA, found no statistically significant differences in HLA types of patients awaiting kidney or heart transplantation. Different patterns were observed in patients awaiting BM transplantation, but no statistically signification HLA type emerged. Conclusions Increased HLA-A23 and HLA-B42, and decreased HLA-DQ9 appear to be detected in patients with elevated BF, but the association is not present when controlling for ethnicity. Therefore, no specific age, gender, ethnicity, or HLA-type can be found to be associated with having elevated BF in SA bead anti-HLA Ab assays. T. Harville: Scientific/Medical Advisor; Company/Organization; Arkansas Regional Organ Recovery Agency, Baxter Biologics, CSL Behring, Grifols.

Schisandra polysaccharide evokes immunomodulatory activity through TLR 4-mediated activation of macrophages

Schisandra chinensis (Turcz.) Baill has been used in traditional Chinese medicine for centuries. Previous studies have shown that Schisandra polysaccharide (SCPP11) has robust antitumor activity in vivo. In this study, the immunomodulatory activity and mechanisms of action of SCPP11 were investigated further to reveal its mechanism of action against tumors. Results showed that SCPP11 increased the thymus and spleen indices, pinocytic activity of peritoneal macrophages, and hemolysin formation in CTX-induced immunosuppressed mice. Moreover, SCPP11 significantly increased immunoglobulin levels, cytokines levels in vivo and induced RAW264.7 cells to secrete cytokines in vitro. RAW264.7 cells pretreated with SCPP11 significantly inhibited the proliferation of HepG-2 cells. In addition, SCPP11 promoted both the expression of iNOS protein and of iNOS and TNF-α mRNA. TLR-4 is a possible receptor for SCPP11-mediated macrophage activation. Therefore, the data suggest that SCPP11 exerted its antitumor activity by improving immune system functions through TLR-4-mediated up-regulation of NO and TNF-α.

Comment on ‘Allergy and acute leukaemia in children with Down syndrome: a population study. Report from the Mexican Inter Institutional Group for the Identification of the Causes of Childhood Leukaemia (MIGICCL)’ – Is increased surveillance by hypersensitive immune system a reality or myth?

Sir, We read with great interest the study by Nunez-Enriquez et al (2013)' recently published in this journal. They conducted a multi-institutional population-based case–control study on children with Down syndrome and found that asthma is a risk factor of acute leukaemia development (odds ratio: 4.18 and 95% confidence interval: 1.47–11.87). However, other allergies had no effect on acute leukaemia development or were protective, in their experience. This study has revived an old question about effect of having allergies and chance of cancer development. Previous studies in this regard unveiled that allergies usually do not increase the risk of cancers, and in contrast, might be protective from cancer development (Vojtechova and Martin, 2009; Chen et al, 2011; Dikalioti et al, 2012). In allergic subjects, there is bone marrow involvement with reprogramming of bone marrow stem cells, regarded as ‘reflex nature of allergic disease' (Holt and Strickland, 2010). Allergic phenotype in an atopic child may lead to epigenetic reprogramming that in turn affects immune surveillance by increasing antigen-presenting cell activity (Holt and Strickland, 2010). In addition, recent studies have demonstrated that serum eosinophil count is inversely associated with colorectal cancer development (Prizment et al, 2011). Hence, it seems that increased surveillance by hyperactive immune system of allergic patients is a reality. Here, the main question is ‘why was asthma found as a risk factor of acute leukaemia development?'. The method of allergy diagnosis and definition of allergic conditions affect categorisation of patients into different allergic groups, particularly with regard to recruitment of patients from different institutions. Moreover, considerable proportion of asthmatic patients might also have rhinitis, skin allergies or food allergies. Asthma and allergic rhinitis are too close in which more than half of asthmatic patients have also allergic rhinitis and up to 40% of allergic rhinitis patients experience asthma (Bousquet et al, 2012; Aryan et al, 2013). Skin allergies and food allergies are other allergic conditions that are common in asthmatics, in such a way up to 15% of asthmatics have food allergies (Fiocchi et al, 2013). It is not clear in this study that how investigators categorised patients who had several allergic conditions and it might affect their results. Another point is that wheezing in Down syndrome children is not likely to be asthma and asthma misclassification is possible to be occurred. It has been shown that Down syndrome children might experience episodes of wheezing mimicking asthma phenotype. Weijerman et al 2011 studied recurrent wheeze in 173 Down syndrome children and found that none of Down syndrome children below 4 years of age had asthma according to international guidelines, and only 3.1% of overall Down syndrome children were actually asthmatic. Weijerman et al 2011 demonstrated that 46% of wheezes in Down syndrome children were due to congenital heart defects. In addition, neither of increased immunoglobulin-E level nor evidence of aeroallergen sensitisation was found in these children (Weijerman et al, 2011). Hence, the diagnosis of asthma should be made more carefully in Down syndrome patients and only reliance of parent's memory might probably lead to misclassification of asthma in Down syndrome children. Moreover, not all asthmatic Down syndrome children have allergy, and in contrast, asthma in Down syndrome patients seem to be non-allergic (Weijerman et al, 2011). Collectively, the results of this study regarding asthma might be affected by misdiagnosis and misclassification of asthma as an allergic condition. On the other hand, Down syndrome is a primary immune deficiency characterised by lymphopenia, thrombocytopenia, and vulnerability to autoimmune and infectious diseases. Down syndrome children have increased susceptibility to respiratory syncytial virus infections, a known risk factor of asthma, thus they may experience manifestations quasi-asthma or actually develop asthma (Bloemers et al, 2010). Down syndrome patients have also inherited risk of acute leukaemia development. Accumulating evidences show that several genes on chromosome 21 have relevant functions in haematopoiesis and their qualitative or quantitative changes affect blood cells. Transient abnormal haematopoiesis and acute myeloid leukaemia are more likely to develop in Down syndrome children with GATA1 mutation (Maclean et al, 2012; Toki et al, 2013). It indicates that regardless of role of environmental factors, inborn genetic defects in Down syndrome children affect haematopoietic cell biology and cause leukaemogenesis. Down syndrome might be a confounder in relation between asthma and acute leukemia. Altogether, Down syndrome may be considered as a cause of both asthma and acute leukaemia and drawing a causative link from asthma to acute leukaemia in this setting seems a raw conclusion.

Antibody repertoire development in fetal and neonatal piglets. XVI. Influenza stimulates adaptive immunity, class switch and diversification of the IgG repertoire encoded by downstream Cγ genes.

Infection of germ-free isolator piglets with swine influenza (S-FLU) that generates dsRNA during replication causes elevation of immunoglobulins in serum and bronchoalveolar lavage, a very weak response to trinitrophenyl conjugates but an immune response to S-FLU. The increased immunoglobulin levels result mainly from the polyclonal activation of B cells during the infection, but model antigen exposure may contribute. The 10-fold increase in local and serum IgG accompanies a 10-fold decrease in the transcription of IgG3 in the tracheal-bronchial lymph nodes and in the ileal Peyer's patches. Infection results in class switch recombination to downstream Cγ genes, which diversify their repertoire; both features are diagnostic of adaptive immunity. Meanwhile the repertoires of IgM and IgG3 remain undiversified suggesting that they encode innate, natural antibodies. Whereas IgG3 may play an initial protective role, antibodies encoded by downstream Cγ genes with diversified repertoires are predicted to be most important in long-term protection against S-FLU.

The immunogenicity of Eimeria tenella sporozoite proteins and living oocyst vaccines in broilers.

The purpose of the present study was to evaluate the immunity of broilers inoculated with sporulated oocysts and sporozoite proteins of Eimeria tenella against challenge with homologous infectives oocysts. Broiler chickens of Hubbard strain, females, coccidian-free, were kept in wire cages and inoculated on the third day (day 0). Three treatments were used: T1, the negative control; T2, received 500 sporulated oocysts by gavage; T3, positive control; T4, received 50 ?g of sporozoite protein with Quil A; and T5, received Quil A without sporozoite protein and PBS, the last two protocols were administered via nasal route on days 0, 7, and 21. On the 31st day, all groups, with the exception of T1, were challenged with homologous virulent strain of E. tenella at the dose of 8.0×104 oocysts. Immunogenicity was assessed by carotenoids, ELISA assay, histopathological analysis, oocysts count and lesion score. Antibody kinetics were measured weekly and showed a gradual increase in levels of immunoglobulin for treatment T2 and T4, reaching a peak on day 21. Based on the parameters evaluated, a total protecting immunological effect for the infectant oocysts vaccine (T2) and partial protection for the sporozoite protein vaccine (T4) against homologous virulent strain challenge were observed.