Low IgA Levels Research Articles

A Rare Cause of Malabsorption and Weight Loss

Purpose: Background: Celiac disease is a multifactorial disorder triggered by exposure to gluten in genetically susceptible patients and is an important cause of malabsorption. It is diagnosed by a combination of clinical features, serologic workup and duodenal biopsies showing villous atrophy and increased intra-epithelial lymphocytes. Histologic features are not specific and can be seen in a variety of conditions like food allergies,autoimmune enteropathy and giardiasis making the diagnosis challenging. We describe the case of a 50 year old white lady who presented to the GI Nutrition clinic at our Institution. She had a six month history of bulky, greasy, foul smelling stools 3-4 times per day with abdominal bloating and a 25 pound weight loss despite a caloric intake of 35 kcals/kg/day. She had a body mass index (BMI) of 16. Her other past medical history included asthma, osteoporosis, multiple past sinus infections and pneumonias. Laboratory examination showed a normal complete blood count,normal electrolytes and creatinine but a low albumin of 3.4 and low pre-albumin of 15. She had low serum IgA, IgG and IgM levels which coupled with her history of respiratory infections prompted a diagnosis of Common Variable Immunodeficiency (CVID). Stool exam showed increased quantitative stool fat but was negative for ova and parasites, PMNs, and giardia antigen. Celiac serologies were negative. An upper GI series with a small bowel followthrough showed thickened proximal small intestinal folds but no other lesions. She subsequently had an upper endoscopy with duodenal biopsies. The gross endoscopic examination was normal but biopsies showed partial crypt hyperplastic villous atrophy with a paucity of plasma cells. She was initially diagnosed with Celiac disease and started on a gluten free diet however her symptoms failed to improve despite six months of this diet. The diagnosis was subsequently revised to CVID related malabsorption and after failing a trial of prednisone she was started on total parenteral nutrition with appropriate weight gain and resolution of symptoms. Eventually she was weaned gradually off the TPN and continues to do well. Conclusion: Common variable immunodeficiency (CVID) is the second most common primary immunodeficiency syndrome (after selective IgA deficiency) characterized by a dysfunction of B-cell differentiation leading to reduced levels of IgG, IgA, and IgM levels. Though respiratory manifestations in the form of frequent infections predominate, a significant proportion of patients also develop diarrhea and malabsorption. Histopathologically a variety of features may be seen including features similar to Celiac disease, lymphocytic enterocolitis or Crohn's disease.

Defective B-cell Response to Toll-like Receptor-9 Ligands in Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a primary immune defect typified by low levels of IgG, IgM, and IgA and poor antibody responses to carbohydrate and protein antigens that leads to increased risk of sinopulmonary infections [1]. The organisms responsible for these infections are typically encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae [2]. Effective treatment is replacement intravenous IgG [1]. Impaired antibody responses in CVID have been explained for some CVID patients by recent discoveries of genetic mutations and polymorphisms such as TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), CD19, and ICOS (inducible co-stimulator). However, these account for only 10% of CVID patients. For the remaining CVID patients, a molecular defect has not been identified [3, 4]. Toll-like receptors (TLRs) are pathogen-recognition receptors that are crucial for microbial elimination, whether through recruitment of phagocytes or activation of dendritic cells [5]. B cells also use TLRs as a means of activation and differentiation [3]. Of the 10 TLRs expressed in humans, B cells use TLR1, TLR2, TLR6, TLR7, TLR9, and TLR10. Of these, TLR7 and TLR9 are expressed in the endosomal compartment, whereas the other TLRs are expressed on the cell surface. TLR7 and TLR9 are expressed in low levels by naive B cells, and B-cell receptor (BCR) cross-linking leads to rapid upregulation of their expression [6]. Ligation of TLR7 and TLR9 can provide a signal for differentiation of B cells after antigenic stimulation through the BCR [7]. The ligand for TLR7 includes single-stranded RNA, and the ligand for TLR9 is CpG-ODN (CpG motifs in DNA oligodeoxynucleotides), which is more prevalent in prokaryotes. Defects in TLR7 and TLR9 have been reported for the B cells of CVID patients [3].

Development of pulmonary abnormalities in patients with common variable immunodeficiency: associations with clinical and immunologic factors

Patients with common variable immunodeficiency (CVID) have low serum IgG, IgA, and/or IgM levels and recurrent airway infections. Radiologic pulmonary abnormalities and impaired function are common complications. It is unclear to what extent IgG replacement treatment prevents further pulmonary damage and how factors beside infections may contribute to progression of disease. To study the development of pulmonary damage and determine how clinical and immunologic factors, such as serum IgG, may contribute to possible changes. In a retrospective, longitudinal study of 54 patients with CVID already treated with immunoglobulins, we examined changes of lung function and findings on high-resolution computed tomography (HRCT), obtained at 2 time points (the date of the last pulmonary function measurement before April 2005 [T1] and the date of the measurement performed closest to 5 years earlier [T0]) 2 to 7 years apart and explored possible relations to clinical and immunologic factors such as levels of IgG, tumor necrosis alpha (TNF-alpha), and mannose-binding lectin (MBL) in serum. Despite a mean (SD) serum IgG level of 7.6 (2.3) g/L for all the patients during the entire study period, lung function decreased from T0 to T1. The combination of a low serum IgA level and serum MBL was associated with the presence of bronchiectasis and lower lung function and with worsening of several HRCT abnormalities from T0 to T1. Increased serum levels of TNF-alpha were related to deterioration of gas diffusion. A mean serum IgG level less than 5 g/L between T0 and T1 was associated with worsening of linear and/or irregular opacities seen on HRCT. For a period of 4 years, lung function and HRCT deteriorated in CVID patients treated with immunoglobulins.

Characterisation of complex chromosome 18p rearrangements in two syndromic patients with immunological deficits

There have been reports that a number of patients with a chromosome 18pter deletion have developed autoimmune disorders, including juvenile diabetes, rheumatoid arthritis, thyroiditis and Graves’ disease, and/or show little or no reduction in serum IgA levels. We describe two female patients bearing complex rearrangements involving chromosome 18p. Array-CGH and BAC FISH molecular cytogenetic analyses enabled the precise identification of the affected 18p region. One patient has a 2 Mb terminal deletion associated with a 9.2 Mb inverted duplication of the adjacent region; the other has a more extended 10.1 Mb terminal deletion associated with a 4.1 Mb quadruplication of the adjacent region and a 2.6 Mb duplication of the pericentromeric region. Both patients have dysmorphic features typical of 18p deletion syndrome, such as growth retardation, epicanthal folds, a long philtrum and toe defects, and are also affected by immunological disorders. One has a form of immunological deficiency that takes the form of recurrent pulmonary infections and low IgA levels; the other has an autoimmune form of juvenile rheumatoid arthritis. Relating the refined molecular cytogenetic characterisation of these 18p chromosomal rearrangements to the patients’ specific clinical characteristics can improve our understanding of the role of the 18p region in immune responses.

An investigation into the adjuvanticity and immunogenicity of zein microspheres being researched as drug and vaccine carriers

We have determined whether zein microspheres could act as vaccine adjuvants i.e. increase the immune responses to co-administered immunogens. Ovalbumin (model antigen)-loaded zein microspheres, blank zein microspheres and ovalbumin solution were intramuscularly administered to mice and the sera antibody levels were determined by ELISA. Another group of mice was orally dosed with blank zein microspheres, and serum and faecal antibody levels were determined. As expected, negligible antibody titres were obtained with the ovalbumin solution. Surprisingly, intramuscular administrations of blank zein microspheres elicited high levels of serum IgG which bound to the ovalbumin antigen coated on ELISA microtitre plates. This indicated that anti-zein antibodies had been elicited by blank zein microspheres and that these antibodies were cross-reacting with ovalbumin antigen coated onto ELISA plates. Such cross-reactivity inhibited the determination of the adjuvant activity of zein microspheres, if any. Additional ELISA assays, where zein was used as the coating antigen, confirmed the generation of anti-zein antibodies by blank zein microspheres i.e. zein microspheres were immunogenic following intramuscular administration. Upon oral administration of blank zein microspheres, serum IgG levels remained low but intestinal IgA levels increased following booster doses i.e. systemic tolerance, but not mucosal tolerance, to oral zein particles was achieved. Zein microspheres were immunogenic when administered intramuscularly and orally.

Developmental profiles of mucosal immunity in pre-school children.

This study investigated the effect of attending pre-school on mucosal immunity. Children 3.5 to 5 years of age who attended pre-school were observed for a 10 month period. Demographic information was collected on previous childcare experiences, the home environment and clinical information relating to the child and the family. A daily illness log was kept for each child. A multivariate longitudinal analysis of the relation between immunoglobulins in saliva and age, gender, childcare experience, pre-school exposure, number of siblings, environmental tobacco smoke (ETS), atopy and hospitalisation was conducted. There was a positive association of higher IgA levels with the winter season and with children being older than 4 years (P < .001), having attended childcare prior to commencing pre-school (P < .05), and having been exposed to ETS at home (P < .05). Lower IgA levels were associated with being atopic (P < .05). Higher IgG levels were associated with exposure to ETS (P < .001), while lower levels were associated to having atopy. Higher IgM levels were associated with previous childcare experience (P < .01) whilst having been hospitalised was associated with having low salivary IgM levels (P < .01). Lagged analyses demonstrated that immunological parameters were affected by the number of respiratory infections in the preceding 2 months.

Long-Term Immune Reconstitution Following Stem Cell Transplantation in Chronic Lymphocytic Leukemia.

Abstract 4649Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of monoclonal CD5+ B lymphocytes. In addition, immune disturbances are commonly present. Although CLL is still considered incurable, long term remissions can be observed after allogeneic stem cell transplantation (SCT). Whether immune function is restored in patients responding to treatment is largely unknown. We report on the immune status in 19 patients with CLL in long-lasting complete remission (CR) after SCT (13 allogeneic, 6 autologous). Median age was 51 (range, 33- 64) and median follow-up since transplantation was 6 years (range, 2-17). Three patients had chronic graft-versus host disease at sample collection, two of whom were receiving immunosuppression. Lymphocyte subsets were studied using multiparameter flow cytometry and compared to healthy controls. We quantified immunoglobulin subtypes, complement proteins, and β2-microglobulin (B2M) by standard techniques and IL-10 and VEGF by using flow-based cytometric bead array technology. CD8+ T cell response to CMV was assessed using a pentameric HLA-A2 binding CMV pp65-derived peptide. Three patients (all following allogeneic SCT) had detectable residual CLL cells (> 10-4) in peripheral blood at the time of the analysis. In the remaining 16 patients with no detectable minimal residual disease (MRD) normal CD19+CD5- and CD19+CD5+ B cell populations were lower than in healthy individuals (10.5% vs. 14.5%; p=0.02 and 1.6% vs. 3.9 %; p=0.002 respectively). A significant increase in the proportion of CD8+ T cells (median 28.1% vs. 18.7%, p=0.03), particularly those with a chronically activated phenotype CD3+CD8+DR+ (10.2% of CD3+ cells vs. 4.9% in controls), was observed (p=0.013). The nine CMV+/HLA-A2 patients all showed specific cytotoxic CD8+ T cells which exhibit predominantly a CD45RA+CD27- phenotype, being better preserved in autologous SCT than in allogeneic SCT patients. Also, higher numbers of CD8+CD45RA+CD27- T cells were observed in patients with a longer follow-up. CD4+ T cell count was < 400/mm3 in 4 patients. An abnormal CD4:CD8 ratio was seen in 7 out of 19 patients. Interestingly, a significant increase of double positive CD4 and CD8 T cells was detected in most patients comprising 2.6% vs.1.6% of lymphocytes in normal subjects (p=0.02). There were no quantitative abnormalities in CD3-CD56+ cells. Not surprisingly, hypogammaglobulinemia was present in all but four patients immediately prior to transplant. Whereas IgM levels normalized in all patients, 4 and 6 patients respectively still had low IgG and IgA levels more than two years after transplantation. Of note, low serum immunoglobulin levels were seen in 6 out of 14 MRD negative-CR patients and all three MRD positive-CR patients, including one who had normal immunoglobulin levels at the time of transplant. Complement proteins C3 and C4 were within the normal range in all cases. The direct Coombs test (DCT) was also negative in all patients although one patient had indirect signs of hemolysis. Regarding serum markers, B2M was increased (>2.5mg/dl) in 5 out of 19 patients. No significant differences were found in IL-10 and VEGF levels between patients and normal controls (median levels, 2.14 vs. 1.06 pg/ml and 156.88 vs. 104.14 pg/ml), but there were 2 patients with markedly elevated IL-10. In summary, these data demonstrate that immune defects persist over time in CLL patients with a long lasting CR (including MRD-negative CRs) after SCT. Disclosures:No relevant conflicts of interest to declare.

IgA and IgG hypogammaglobulinemia in Waldenstrom's macroglobulinemia

Hypogammaglobulinemia is common in Waldenström's macroglobulinemia. The etiology of this finding remains unclear, but it has been speculated to be based on tumor-induced suppression of the 'uninvolved' immunoglobulin production We evaluated the incidence of IgA and IgG hypogammaglobulinemia in 207 untreated patients with Waldenström's macroglobulinemia and investigated the associated clinicopathological findings and impact of therapy. We also sequenced eight genes (AICDA, BTK, CD40, CD154, NEMO, TACI, SH2D1A, UNG) implicated in immunoglobulin deficiency in 19 Waldenström's macroglobulinemia patients with IgA and/or IgG hypogammaglobulinemia. At baseline 63.3%, 58.0% and 49.3% of the 207 patients had abnormally low serum levels of IgA, IgG, or both. No association between IgA and IgG hypogammaglobulinemia and disease burden, serum IgM levels, beta(2)-microglobulin, International Prognostic Scoring System score, or incidence of recurrent infections was observed, although the presence of adenopathy and/or splenomegaly was associated with a lower incidence of hypogammaglobulinemia. Lower IgA and IgG levels were associated with disease progression in patients managed with a 'watch and wait' strategy. IgA and/or IgG levels remained abnormally low despite response to treatment, including complete remissions. A missense mutation in the highly conserved catalytic site of UNG was observed in a patient with hypogammaglobulinemia, warranting further study of this pathway in Waldenström's macroglobulinemia. IgA and IgG hypogammaglobulinemia is common in Waldenström's macroglobulinemia and persists despite therapeutic intervention and response. IgA and IgG hypogammaglobulinemia does not predict the risk of recurrent infections in patients with Waldenström's macroglobulinemia, although lower levels of serum IgA and IgG are associated with disease progression in Waldenström's macroglobulinemia patients being managed with a 'watch and wait' strategy.

The outcome of patients with unclassified hypogammaglobulinemia in early childhood

Symptomatic hypogammaglobulinemia in childhood may be the initial finding of primary immunodeficiency (PID) or may be due to delay in maturation of immunoglobulin synthesis. The aim of this study was to review the clinical and laboratory records of patients with unclassified hypogammaglobulinemia and to evaluate whether these children experience changes in serum immunoglobulin concentrations during long-term followup and have an exact diagnosis in natural course of disease. We reviewed the data of 412 patients who were diagnosed as PID with symptomatic hypogammaglobulinemia. Thirty-seven patients with hypogammaglobulinemia [19 males (51.4%) and 18 females (48.6%), with a followup of 34.1 +/- 22.0 months] who were not classified according to European Society for Immunodeficiencies diagnostic criteria were included in this study. The mean age at the beginning of the symptoms was 21.4 +/- 20.6 months and the mean age at admission was 51.5 +/- 25.8 months. The commonest clinical presentations were recurrent upper (94.6%) and/or lower (40.5%) respiratory infections, urinary infection (27%) and gastroenteritis (10.8%). Percentage of consanguinity was 8%. Of the initial 37 patients, 18 (48.6%) spontaneously corrected their immunoglobulin abnormalities during followup. Clinical symptoms of these patients were also improved. IgG, IgA and IgM levels reached to normal levels at ages 62.5 +/- 21.8, 72.0 +/- 11.2, 55.2 +/- 7.8 months, respectively. In remaining 19 patients with undefined/unclassified hypogammaglobulinemia, three partial IgA deficiency, seven IgG subclass deficiency, two selective IgM deficiency and two common variable immunodeficiency (CVID) were diagnosed by long-term monitoring of immunoglobulin levels. Five (13.5%) of the 37 unclassified patients could not be exactly diagnosed while two of them might have a T-cell defect and three of them still had low IgG and IgA levels but adequate antibody responses against vaccine antigens. In conclusion, it is important to monitor symptomatic patients with hypogammaglobulinemia periodically. Some children may spontaneously correct their immunoglobulin abnormalities not in the first 30 months of age, but during the first decade of life and some of them may have a severe PID like CVID.

The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function

AbstractTNFRSF13B, which encodes TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), is mutated in 10% of patients with common variable immune deficiency (CVID). One of the 2 most common TACI mutations in CVID, A181E, introduces a negative charge into the transmembrane domain. To define the consequence of the A181E mutation on TACI function, we studied the effect of its murine equivalent, mTACI A144E, on TACI signaling in transfected cells and on TACI function in transgenic mice. The mTACI A144E mutant, like its human TACI A181E counterpart, was expressed on the surface of 293T transfectants and was able to bind ligand, but exhibited impaired constitutive and ligand-induced NFκB signaling. In addition, constitutive and ligand-induced clustering of the intracellular domain was deficient for A144E as measured by fluorescence resonance energy transfer. Transgenic mice expressing the A144E mutant on TACI−/− background had low serum IgA levels and significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll. B cells from A144E transgenic mice were impaired in their capacity to proliferate and secrete IgG1 and IgA in response to TACI ligation. These results suggest that mTACI A144E mutation and its human counterpart, A181E, disrupt TACI signaling and impair TACI-dependent B-cell functions.

Humoral Immune Deficiency and Hemifacial Microsomia Seen in One Family

We present a patient with hemifacial microsomia and immune deficiency. The patient is a 5-year-old with grade III microtia and Pruzansky type I right mandibular hypoplasia. She developed 25 pulmonary infections in 3 years, required hospitalization every 6 weeks to receive antibiotics, and experienced recurrent herpes stomatitis and esophagitis, staphylococcal bacteremia, urinary tract, sinus, and ear infections. She had low total IgG, IgG1, IgG2, IgA, and anti-pneumococcal antibody levels. She was unable to maintain protective pneumococcal titers following vaccination. The patient's 7-year-old sister also suffered from recurrent infections, had a left facial skin tag, and a left arachnoid cyst. We conclude that immune deficiency can occur in association with hemifacial microsomia.

Follow-up study of immune defects in patients with dysmorphic disorders

In a previous study, we noted immunologic abnormalities in 46 (54.8%) of 84 individuals with dysmorphic disorders. To reevaluate patients with dysmorphic disorders and immunologic abnormalities 2 to 3 years after an initial study to determine any changes in those abnormalities. Information was gathered regarding significant infections during the previous 12 months. Blood samples were drawn for the immunologic tests that were previously performed (IgG, IgA, and IgM level determinations; complete blood cell count; and lymphocyte subset enumeration) and for determination of IgG subclasses and T-cell activation by CD69 expression. In the 21 patients available, 26 (63.4%) of the previously noted 41 low immunologic values were still present. In 5 patients, all previously noted immunologic abnormalities resolved. Of the 17 low values noted in 6 patients with Down syndrome, 12 (70.6%) were still present. Also, the 2 patients with Turner syndrome continued to have low IgA and IgM levels. Two patients had a low IgG4 level. A history of significant clinical infections within the previous 12 months was noted in 10 (58.8%) of 17 patients; 8 (47%) had current immune defects. There was a significantly lower T-cell response to staphylococcal enterotoxin B than in healthy controls. The T-lymphocyte activation response was low in 8 (38.1%) of the 21 patients. Our study revealed a high rate of immune defects in patients with dysmorphic disorders, both during the initial study and 2 to 3 years later, which may contribute to their increased susceptibility to infections. This association was most obvious in patients with Down syndrome and Turner syndrome. The findings should alert for early immunologic evaluation when such patients have infections.

Disseminated bacille Calmette–Guérin in Iranian children with severe combined immunodeficiency

The bacille Calmette-Guérin (BCG) vaccine is a widely practiced vaccine, which is useful for prophylaxis against tuberculosis. Disseminated BCG infection (BCG-osis) is one of the most important complications of this vaccine and can be seen in patients with an underlying immunodeficiency. This study was performed to determine the underlying defects in patients with BCG-osis. Immunological evaluation was performed in all children who developed BCG-osis after vaccination in Tabriz, Iran. BCG-osis was documented in eight patients following vaccination. Axillary adenitis was detected in seven patients, and hepatosplenomegaly was also found in seven patients. Immunological studies revealed low serum IgG, IgM and IgA levels in all patients. Further investigations for enumeration of the lymphocyte sub-population revealed severe combined immunodeficiency (SCID) in all the patients. Three patients had T-B+NK- SCID, four had T-B-NK+ SCID, and one had T-B+NK+ SCID. Unfortunately, all the patients died due to the severe disseminated BCG infection. Inoculation of live vaccines such as BCG should be postponed for a few months in suspected cases of primary immunodeficiency disease, until appropriate screening tests exclude this diagnosis; vaccination should then be performed in those with an intact immune system.

Risk factors for invasive aspergillosis and related mortality in recipients of allogeneic SCT from alternative donors: an analysis of 306 patients

Invasive aspergillosis (IA) is a serious complication in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT), particularly from donors other than HLA-identical sibling. All 306 patients who underwent alternative donor HSCT between 01 January 1999 and 31 December 2006 were studied. Late IA was defined as occurring >or=40 days after HSCT. The median follow-up was 284 days (range, 1-2709). Donors were matched unrelated (n=185), mismatched related (n=69), mismatched unrelated (n=35) and unrelated cord blood (n=17). According to European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria, 2 patients already had IA at HSCT, 23 had early IA and 20 had late IA (IA incidence 15%). Eight patients had proven and 37 probable IA. Multivariate analyses showed that significant predictors of IA were delayed neutrophil engraftment, extensive chronic GVHD (cGVHD), secondary neutropenia and relapse after transplant. Early IA was associated with active malignancy at HSCT, CMV reactivation and delayed lymphocyte engraftment. Late IA was predicted by cGVHD, steroid therapy, secondary neutropenia and relapse after HSCT. IA-related mortality among IA patients was 67% and was influenced by use of anti-thymocyte globulin, steroids, higher levels of creatinine, and lower levels of IgA and platelets. The outcome of IA depends on the severity of immunodeficiency and the status of the underlying disease.

Common variable immunodeficiency: 20‐yr experience at a single centre

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. It can present at any age in patients with a history of recurrent bacterial infections, with or without a family history of other primary immunodeficiencies (PID), and shows a wide range of clinical manifestations and immunological data. Diagnosis is based on low IgG, IgM and/or IgA levels. Delayed diagnosis and therapy can lead to bronchiectasis and malabsorption. The aim of this study was to describe a paediatric population diagnosed of CVID and its evolution in the population. Memory B-cell (MB) classification carried out in these patients was correlated with clinical manifestations and outcome. Clinical and immunological data of 22 CVID children under 18 yr treated at our centre between 1985 and 2005 are presented. Immunological studies included those for diagnosis and MB quantification. Differences in form of presentation, familial incidence and MB classification were reviewed. A statistical descriptive analysis was made. Infections were the commonest manifestation, affecting mainly respiratory (19/22) and gastrointestinal (10/22) tracts. Bronchiectasis was present in seven cases, and detected prior to CVID diagnosis in five. Replacement therapy led to a significant reduction in the number of infections. Severe complications appeared mostly in patients without MB. Patients of the same family share the same MB group. Family members had also been diagnosed of CVID in seven cases. Early diagnosis and therapy are essential to improve outcome in these patients. MB studies are useful in children to orient prognosis and further genetic studies.

Defective Double-Strand DNA Break Repair and V(D) J Recombination In Patients With Common Variable Immune Deficiency

RATIONALE: Common variable immune deficiency (CVID) is a heterogeneous immune disorder characterized by low levels of IgG and IgA and/or IgM and lack of protective levels of antibody. We present evidence of defects in DNA repair and recombination in CVID patients.

Changes of blood count, lymphocyte subpopulations and immunoglobulin levels in nephroblastoma long term survivors

The aim of this study was to investigate the frequency of blood count, lymphocyte subpopulations, and immunoglobulin levels alterations in a group of healthy nephroblastoma long-term survivors. The group included 122 nephroblastoma longterm survivors who were at least five years post anticancer therapy and free of any sign of recurrence The proportion of lymphocyte subpopulations was analyzed by flow cytometry using antibodies anti CD45 FITC/CD14 PE, anti CD3 FITC/ CD16+CD56 PE, anti CD4 FITC/ CD8 PE and anti CD20 FITC. Immunoglobulin G, A, and M levels were evaluated by immunoturbidimetry. Total blood count was also examined. The occurrence of decreased immunoglobulin levels, leukocytes, lymphocytes, and granulocytes count, proportion of T lymphocytes and their CD4+ subpopulation are not frequent. The most frequently decreased lymphocyte subpopulation was CD8 (15.5%). The most frequent abnormal findings were increased proportion of NK cells (38.5 %), B lymphocytes (38,52 %), decreased number of erythrocytes (25.2 %), hemoglobin levels (41.7 %) and hematocrit (13.9 %). The only significant differences between results of immunological examination and course of the disease were more frequently decreased proportion of CD4+ lymphocytes in recurrent disease survivors and lower IgA levels in survivors after radiotherapy. We found decreased at least one immunological parameter in one fifth of the survivors. The most frequently altered parameter was hemoglobin, which was decreased in 41.7 % of survivors. Decraesed hemoglobin may worsen quality of survivors life. Key words: nephroblastoma long-term survivors, blood count, lymphocyte subpopulations, immunoglobulin G, A, M serum levels.

Evolution of IgG Subclass Deficiency into Common Variable Immunodeficiency in a Child with Pulmonary Interstitial Glycogenosis

We present a 5-year-old boy who initially presented during infancy with pulmonary interstitial glycogenosis (PIG) and recurrent sinopulmonary infections. At 3.5 years old, IgG-2 subclass deficiency associated with low IgA level and selective antibody deficiency was diagnosed. Subsequently, the immune deficiency evolved into common variable immunodeficiency (CVID). This is the first case reported of the association of PIG and CVID. In children with PIG who have recurrent infections, associated immunodeficiency should be suspected.

Allergenic activity of Molicola horridus (Cestoda, Trypanorhyncha), a cosmopolitan fish parasite, in a mouse model

The cestode Molicola horridus is a muscle parasite of teleost fish. The ability of molecules present in this parasite to induce allergic response is not known yet. Since fish-borne parasitic allergens can induce allergic manifestations even when the parasitized fish is well cooked, the knowledge of potential allergens present in food is important in order to provide a save products for consumers. The aim of the study was to determine the allergenic potential of the components present in the crude larval extract (CLE) of M. horridus. Two mouse models were exposed to the CLE: adult BALB/c mice that were intraperitoneally (i.p.) immunized and newborn BALB/c mice that were orally exposed. Specific antibody levels in serum and faeces were measured by ELISA. The cellular immune response was determined by proliferation assay of splenocytes from sensitized mice. The protein profile of CLE was analysed by SDS-PAGE and western blot. In adult mice, specific IgG and IgA were detected in sera and faeces, whereas specific IgE were detected in sera only. In newborn mice, specific IgG were detected in sera and a low level of IgA was detected in faeces. SDS-PAGE revealed the CLE protein profile, with most of the proteins running from 15 to 50 kDa. Specific IgG recognized mainly the 26 and 75 kDa proteins and a molecular complex below 100 kDa by immunoblot. Specific IgE recognized the same 26 kDa protein as IgG did, and, with less intensity, another protein at 30 kDa. Splenocytes from CLE-immunized mice proliferated when stimulated with CLE in a dose-dependent manner. The crude larval extract from M. horridus has potential allergenic molecules which can represent a risk for fish consumers.

Failure of IgG production due to a defect in the opening of the chromatin structure of I gamma 1 region in a patient with IgG and IgA deficiency.

Patients with common variable immunodeficiency (CVID) display reduced levels of two or all three of the major immunoglobulin isotypes, and the deficiency is characterized by failure of B cells to differentiate into plasma cells in many cases. A patient (14 years old, female) showed normal serum IgM levels and low serum IgG and IgA levels, including low levels of all IgG subclasses. Northern blot analysis suggested that the patient's B cells may be defective at the immunoglobulin heavy chain isotype switch. The germ-line C gamma 1 transcript was amplified from cDNA of healthy controls by the addition of recombinant IL-2 (rIL-2) to pokeweed mitogen-stimulated peripheral mononuclear cells or Staphylococcus aureus Cowan I (SAC)-stimulated IgM-producing lymphoblastoid cell lines (LCL) transformed by Epstein-Barr virus, while it was not amplified from cDNA of the patient. In the I gamma 1 region of LCL cultured with SAC plus rIL-2, the inner cytosine in the 5' C-C-G-G 3' sequence nearest the 3' site of the I gamma 1 region, at least, was not completely unmethylated in the patient. Moreover, the DNase I hypersensitive site was not induced in the patient's LCL by SAC plus rIL-2. These results indicate that the defects of the immunoglobulin heavy chain isotype switch in the patient's B cells are due to failure in the synthesis of germ-line C gamma transcripts, and this may be caused by defects in opening of the chromatin structures of specific switch regions.