Normal IgA Research Articles

Delayed diagnosis in X-linked agammaglobulinemia and its relationship to the occurrence of mutations in BTK non-kinase domains

ABSTRACTBackground: X-linked agammaglobulinemia (XLA) is characterized by the absence of immunoglobulin and B cells. Patients suffer from recurrent bacterial infections from early childhood, and require lifelong immunoglobulin replacement therapy. Mutations in BTK (Bruton’s Tyrosine Kinase) are associated with this phenotype. Some patients that present XLA do not show typical clinical symptoms, resulting in delayed diagnosis due to the lack of a severe phenotype. This study presents a report of five XLA patients from four different families and attempts to determine a relationship between delayed diagnosis and the occurrence of BTK mutations.Methods: Samples from patients with antibody deficiency were analyzed to determine BTK expression, immunophenotyping and mutation analysis. Clinical and laboratory data was analyzed and presented for each patient.Results: Most patients presented here showed atypical clinical and laboratory data for XLA, including normal IgM, IgG, or IgA levels. Most patients expressed detectable BTK protein. Sequencing of BTK showed that these patients harbored missense mutations in the pleckstrin homology and Src-homology-2 domains. When it was compared to public databases, BTK sequencing exhibited a new change, along with three other previously reported changes.Conclusions: Delayed diagnosis and atypical manifestations in XLA might be related to mutation type and BTK expression.

Selective IgM Deficiency-An Underestimated Primary Immunodeficiency.

Although selective IgM deficiency (SIGMD) was described almost five decades ago, it was largely ignored as a primary immunodeficiency. SIGMD is defined as serum IgM levels below two SD of mean with normal serum IgG and IgA. It appears to be more common than originally realized. SIGMD is observed in both children and adults. Patients with SIGMD may be asymptomatic; however, approximately 80% of patients with SIGMD present with infections with bacteria, viruses, fungi, and protozoa. There is an increased frequency of allergic and autoimmune diseases in SIGMD. A number of B cell subset abnormalities have been reported and impaired specific antibodies to Streptococcus pneumoniae responses are observed in more than 45% of cases. Innate immunity, T cells, T cell subsets, and T cell functions are essentially normal. The pathogenesis of SIGMD remains unclear. Mice selectively deficient in secreted IgM are also unable to control infections from bacterial, viral, and fungal pathogens, and develop autoimmunity. Immunological and clinical similarities and differences between mouse models of deficiency of secreted IgM and humans with SIGMD have been discussed. Patients with SIGMD presenting with recurrent infections and specific antibody deficiency responses appear to improve clinically on immunoglobulin therapy.

Coeliac disease in infants: antibodies to deamidated gliadin peptide come first!

BackgroundThe onset of coeliac disease (CD) in the first year of life is uncommon and the diagnosis can be challenging due to the suboptimal sensitivity of tissue transglutaminase antibodies (tTG) at this age and the many other possible causes of malabsorption in infants. Antibodies to deamidated gliadin peptides (anti-DGPs), especially IgG, may appear earlier than IgA anti-tTG in very young children with CD.Case presentationWe report here on an 8-month-old child who was evaluated for failure to thrive, constipation and developmental delay. The symptoms started following gluten introduction in the diet. Laboratory tests showed high fecal elastase concentration, normal serum IgA levels with positive IgG and IgA anti-DGPs, whereas anti-tTG were not detected. The duodenal biopsy revealed a complete villous atrophy (Marsh-Oberhuber 3C). The culture of biopsy fragments in the presence of gliadin peptides did not stimulate the production of IgA anti-endomysial antibodies. Genetic testing proved the child was positive for HLA-DQ2 (DQA1*05; DQB1*02) and HLA-DQ8 (DQA1*03, DQB1*0302). Having initiated the gluten-free diet, the symptoms disappeared and the infant experienced rapid catch-up growth with normalization of psychomotor development.ConclusionsThis case report highlights the utility of anti-DGPs for screening infants with suspected CD. The pattern with positivity for IgG and IgA anti-DGPs only is rare in IgA-competent children with biopsy-proven CD. It could be explained in infancy as immaturity of the adaptive immune system.

Cernunnos deficiency associated with BCG adenitis and autoimmunity: First case from the national Iranian registry and review of the literature

Non-homologous end-joining (NHEJ) is a pathway that repairs double-strand breaks (DSB) in DNA and plays a vital role in V(D)J recombination of immunoglobulin genes. Cernunnos is a DNA repair factor that is involved in nonhomologous end-joining (NHEJ) process. Impairment in Cernunnos leads to a genetic disease characterized by neural disorders, immunodeficiency and increased radiosensitivity. We herein describe a severe combined immunodeficiency (SCID) patient with T- B+ phenotype who had a mutation in Cernunnos gene and manifested recurrent infections, microcephaly and growth retardation with hypogammaglobulinemia. Furthermore, our patient was associated with BCG adenitis and autoimmunity that less is observed in patients with Cernunnos deficiency. In contrast to previous reported Cernunnos-deficient patients, our patient had normal B-cell number along with normal IgA and IgM, suggesting a leaky form of the Cernunnos deficiency due to residual count of B cells in our patient. Cernunnos deficiency should be considered in children with recurrent bacterial infections, microcephaly and growth retardation, in spite of having normal B-cell as well as normal IgM and IgA level.

Specific Antibody Deficiency: Controversies in Diagnosis and Management.

Specific antibody deficiency (SAD) is a primary immunodeficiency disease characterized by normal immunoglobulins (Igs), IgA, IgM, total IgG, and IgG subclass levels, but with recurrent infection and diminished antibody responses to polysaccharide antigens following vaccination. There is a lack of consensus regarding the diagnosis and treatment of SAD, and its clinical significance is not well understood. Here, we discuss current evidence and challenges regarding the diagnosis and treatment of SAD. SAD is normally diagnosed by determining protective titers in response to the 23-valent pneumococcal polysaccharide vaccine. However, the definition of an adequate response to immunization remains controversial, including the magnitude of response and number of pneumococcal serotypes needed to determine a normal response. Confounding these issues, anti-polysaccharide antibody responses are age- and probably serotype dependent. Therapeutic strategies and options for patients with SAD are often based on clinical experience due to the lack of focused studies and absence of a robust case definition. The mainstay of therapy for patients with SAD is antibiotic prophylaxis. However, there is no consensus regarding the frequency and severity of infections warranting antibiotic prophylaxis and no standardized regimens and no studies of efficacy. Published expert guidelines and opinions have recommended IgG therapy, which are supported by observations from retrospective studies, although definitive data are lacking. In summary, there is currently a lack of evidence regarding the efficacy of therapeutic strategies for patients with SAD. We believe that it is best to approach each patient as an individual and progress through diagnostic and therapeutic interventions together with existing practice guidelines.

The clinical significance of complete class switching defect in Ataxia telangiectasia patients

ABSTRACTBackground: Ataxia telangiectasia (AT) is a primary immunodeficiency associated with recurrent infections. We aimed to investigate clinical and immunological classification in AT patients who suffer from a different spectrum of humoral immune defects.Methods: AT patients were categorized according to the ability of class switching and patients with hyper IgM (HIgM) profile were defined as class switching defect (CSD).Results: Serum immunoglobulin profile in 66 AT patients showed normal immunoglobulin level (22.8%), IgA deficiency (37.9%) and hypogammaglobulinemia (18.1%) in the majority of patients, while 21.2% had HIgM profile revealing CSD. CSD does not affect the frequency of infections, however, the frequency of lymphoproliferation (p < 0.001), and autoimmunity (p = 0.004) were significantly higher in this group. Neurologic symptoms in CSD patients are mild or appear after recurrent infections, therefore these patients were usually misdiagnosed as HIgM syndrome.Conclusions: Although most of AT patients have reduced IgA levels or normal immunoglobulin levels, but a fraction of these patients may show CSD ensuing HIgM-profile. CSD poses affected individuals at higher risk of non-infectious complications.

The case of the interfering IgM

A 53-year-old woman presented with sweats and weight loss. Initial investigations showed a CRP of >1900 mg/L in the absence of infection, rheumatoid factor (RF) of >2230 IU/mL, IgM of 22 g/L, normal IgA but undetectable IgG. An electrophoretogram (EPG) performed externally was reported as a ‘trace of monoclonal IgM’. On repeat EPG/immunofixation, the sample was treated with beta-mercaptoethanol and a significant IgM lambda paraprotein was revealed. A cryocrit of 9% was also typed as IgM lambda. She was subsequently diagnosed with a low-grade B-cell non-Hodgkin’s lymphoma.

Revelance of Gammaglobulin Levels at Diagnosis and during Disease Course in Chronic Lymphocytic Leukemia

Introduction:Hypogammaglobulinemia is commonly observed in chronic lymphocytic leukemia (CLL), likely worsens over time and with chemoimmunotherapy, and eventually leads to infections which are a major cause of death in this disease. Unfortunately, newer therapies, such as ibrutinib, may not prevent the ongoing immunosuppression in CLL as a major cause of discontinuing this drug is increased infections. Nowadays, most patients present with early stage CLL, with an increasing number having monoclonal B cell lymphocytosis (MBL) and being followed for many years. CLL treatment is typically intensive, using chemoimmunotherapy with the therapeutic goal being to minimize tumor load. For these reasons, a reassessment of Ig levels in a CLL Clinic at diagnosis and during disease course in the 'real-life' setting has been carried out, along with an assessment of the need for Ig replacement.Methods:All CLL/SLL/MBL cases referred to the CLL clinic at CancerCare Manitoba, Winnipeg, Canada from 2007 to 2011 were included in this study. Immunoglobulin (Ig) levels (G, A, and M) were measured at the time of referral/diagnosis (baseline) and annually thereafter. Ig levels were correlated with patient characteristics (age at diagnosis, gender, comorbidities), CLL prognostic indicators (Rai stage, lymphocyte doubling time, creatinine, LDH, β2- microglobulin, IGHV mutational status, ZAP-70, CD38) and time to first treatment (TTFT). A subset analysis of patients treated with replacement gammaglobulin was also conducted.Results:There were 293 patents in this cohort with median age at diagnosis of 68 years. Of these, 62.5% were male, 38% had received treatment, and 24% died during the follow up time (median follow up of 71 months). Seventy percent of patients had CLL (of those 85% were diagnosed with Rai 0/I), 15% MBL and 15% SLL.At baseline, 41% had normal Ig levels while 59% had a reduced level of one or more Ig (32% had reduced levels of one Ig type, 18% two, and 9% all three). Overall, 53% of patients had low IgM, 24% low IgG and 17% low IgA. However, no consistent correlation was found between the Ig levels at diagnosis and any of the prognostic markers outlined above.Hypogammaglobulinemia (at least two consecutive values < normal) was associated with need for CLL treatment (HR 3.45, 95% CI 1.63-7.30, p=0.0012), while hypogammaglobinemia at diagnosis predicted a shorter TTFT (p=0.0008). Baseline IgA was also predictive of TTFT as well as overall survival, with patients with normal IgA having a longer TTFT, patients with high/low IgA a shorter TTFT (p=0.0012) and those with high IgA a shorter overall survival (p=0.0032). Furthermore, there was a positive correlation between baseline IgG and number of comorbidities (r=0.17, p = 0.0057) as measured by the Cumulative Index Rating Scale (CIRS) and β2-microglobulin levels.Eighteen patients (6.14%) required Ig replacement therapy, of those 13 (72%) were male and 13 (72%) had received chemotherapy. These patents also had a shorter overall survival than those not requiring IgG replacement therapy (p=0.0006). CLL cases with high baseline IgG are seven times more likely to require IgG replacement therapy (HR 6.92, 95% CI 1.78 - 29.91, p=0.0052) while cases with low baseline IgG are 5 times more likely (HR 4.99, 95% CI 1.59 - 9.43, p=0.0254) as compared to those with normal baseline IgG. Baseline IgA and IgM were not predictive of need for IgG replacement therapy.Interestingly, over a median follow-up of 4 years, one-third of patients with normal baseline IgG developed a low IgG and this was unrelated to receiving chemotherapy (Figure 1).SummaryThis study demonstrates that baseline Ig levels in CLL are informative of the underlying biology of this disease, and could provide valuable information regarding disease progression, survival and need for subsequent IgG replacement therapy or CLL treatment. Importantly, Ig levels may be elevated in CLL and this is associated with increased CIRS and a high β2-microglobulin level, suggesting that the increase is related to underlying comorbidities. Further studies are required to examine the cause for the progressive decline in Ig levels over time, despite an otherwise stable disease, and to determine whether this decline can be eliminated by earlier treatment with novel new therapies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hyper IgM Syndrome: a Report from the USIDNET Registry.

The United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM). The USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality. Fifty-two physicians entered data from 145 patients of ages 2months to 62years (median 12years); 131 were males. Using patients' age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40% had a normal serum IgM and 15%, normal IgA. Infections were reported for 91%, with pulmonary, ear, and sinus infections being the most common. 42% had Pneumocystis jirovecii pneumonia; 6% had Cryptosporidium. 41% had neutropenia. 78% experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14years). Analysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.

The Usefulness of IgA/IgG DGP/tTG Screen Assay for Celiac Disease Detection among Symptomatic and at Risk Young Children

Background: It has been postulated that IgA anti tissue-transglutaminase (tTG) and anti-endomisium (EMA) antibodies can be false negative in young children.ESPGHAN recommended for seronegative children younger than 2 years old with clinical suspicion of celiac disease to perform duodenal biopsies. Recent studies sugested that the combined assay for IgA/IgG deamidated gliadin peptides (DGP) and tTG can detect celiac disease among seronegative young children. Aim: To assess if the new combined assay with synthetic gliadin derived peptides IgA/IgG-DGP/tTG is useful to detect celiac disease in IgA tTG or EMA seronegative children younger than 2 years old. Methods: The authors screened a lot of children aged 6 months to 2 years old that associated characteristic symptoms/risk factors for gluten enteropathy. 368 children were tested for IgAtTG, EMA and IgA/IgG-tTG/DGP combined assay. All children had normal total IgA concentration and were consuming gluten at the time of enrolment. Children with at least one positive serologic test underwent intestinal biopsy, including seronegative infants, DQ2/DQ8 positive, with clinical suspicion of celiac disease that underwent the 2 biopsies protocol. Results: Celiac disease was diagnosed in 22 children based on histology. 19 children were positive for IgA tTG, 20 were positive for EMA and 21 tested positive for IgA/IgG-DGP/tTG. IgA tTG sensitivity was 86.3%, IgA EMA sensitivity was 91% and IgA/IgG-DGP/tTG sensitivity was 95.4% (p=0.002). Conclusions: The sensitivity of IgA/IgG DGP/tTG assay was significantly higher than that of IgAtTG in celiac patients younger than 2 years old.The better performance of this new combined test can avoid repeated intestinal biopsies in young children with high clinical suspicion of celiac disease but negative tTG/ EMA serology.

Towards Finding More Diagnostic Serological Markers in Celiac Disease: Can Deamidated Gliadin Peptide Antibodies Help to Our Babies?

Dokuz Eylul University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Izmir, TURKEY Celiac disease (CD) is a common immune-mediated enteropathy triggered by gluten in genetically susceptible individuals with an overall prevalence almost 1% in different countries [1]. The diagnosis of the disease is classically based on a combination of serologic tests and characteristic intestinal biopsy findings [2]. In a recent meta-analysis performed by European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Working Group of Celiac Disease Diagnosis, 16 studies have been reviewed and anti-antiendomysial (EmA) and anti-tissue transglutaminase (tTG) IgA antibodies have been found more accurate tests for the diagnosis of CD [2]. In this meta-analysis, their sensitivities have been detected more than 90%, and specifities have been found 98.2% for anti-EmA and >90% for anti-tTG [2]. With the improvement of serological tests, diagnosis of CD without intestinal biopsies has been suggested in some defined situations [3]. On the other hand, despite the high diagnostic performance of anti-tTG and anti-EmA antibodies for CD, they have lower accuracy in children younger than 2 years of age and patients with selective IgA-deficiency [4]. ESPGHAN Working Group of CD Diagnosis prepared new guidelines for CD diagnosis in 2012 [5]. According to these criteria, diagnosis is based on the combined evaluation of symptoms, serological tests, biopsy findings, and human leukocyte antigen (HLA) typing [5]. In symptomatic patients who have anti-tTG titers >10 times the upper limit of normal and positivity for EmA, it is possible to diagnose CD without performing the intestinal biopsy [5]. It has been proposed that, for patients with IgA deficiency the decision should be made from the results of the IgG class antibody tests [5]. Typing of HLA-DQ2 and HLA-DQ8 is a useful tool, which has a diagnostic sensitivity of > 96 %. Therefore, a negative result of HLA-DQ2 and/or DQ8 testing makes a diagnosis of CD highly unlikely [5,6]. Recent studies showed that anti-deamidated gliadin peptide (DGP) antibodies had higher sensitivity and specificity than conventional anti-gliadin antibodies [7], consequently anti-DGP antibodies joined anti-tTG and anti-EmA as tests with high diagnostic performance [8,9,10]. On the other hand, some studies demonstrated superior diagnostic value of anti-tTG to anti-DGP antibodies even in patients younger than 2 years-old [11]. In this first issue of the Journal, Oana et al [12] investigated the accuracy of these antibodies in symptomatic infants. They evaluated the diagnostic value of combined IgA/IgG DGP/tTG screen assay in anti-IgA tTG or anti-EmA negative children younger than 2 yearsold. All children had normal total IgA concentration and were consuming gluten at the time of the study. Diagnosis of celiac disease was made according to intestinal biopsy findings. They found the sensitivity of combined IgA/IgG DGP/tTG screen assay (95.4 %) higher than both antitTGA (86.3%) and anti-EmA (91%) antibodies in this age group of children [12]. They concluded that better performance of this combined tests might preclude repeated intestinal biopsies in young symptomatic children who have negative tTG/EmA serology. Recent ESPGHAN guideline also proposes that anti-DGP antibodies may be used as additional tests in patients who are negative for other celiac spesific antibodies but have symptoms compatible with celiac disease, especially in patients younger than 2 years-old [5]. In conclusion, intestinal biopsy is an invasive diagnostic method especially in young children. Further more sensitive serological tests can provide the definite diagnosis of celiac disease especially in younger age group without this invasive procedure.

Percentage of Patient with Celiac Disease among Children with Short Stature

Background: Clinical features of celiac disease vary considerably. Intestinal symptoms are common in children whose disease is diagnosed within the 1st 2 years of life. As the age at presentation of the disease shifts to later in childhood, and with the more liberal use of serologic screening tests, extra-intestinal manifestations and associated disorders, without any accompanying digestive symptoms, have increasingly become recognized, including short stature. We aim in this study to determine the percentage of celiac disease among patients with short stature. Objectives of the Study: (1) to show the percentage of patient with celiac disease in short stature children. (2) to show the effect celiac disease on treatment of short stature children. Methodology: A cross sectional study that carried out at the Endocrine Pediatrics Clinic at A Zahraa Teaching Hospital for a period in 1st of January 2013 to end of October 2013; a total of 167 children and adolescents, aged range of 2 to 18 years were registered with short stature . 91 children of them only have been enrolled in this study according to inclusion criteria. Enzyme immunoassay (Biosystems, Spain) was used to determine IgA tTG using microplate tests. Samples with concentrations &gt;20U/mL were defined as positive. Patients with positive anti-tTGserology were referred to the gastroenterology clinic to continue investigation of celiac disease by endoscopy and biopsy. Data were analyzed by SPSS software in IBM version 20 using chi square and paired T-test. Result: A total of 167 patients were evaluated 91 of them only have been enrolled in our study according to inclusion criteria; 59 (65%) were female and 32 (35%) were male. Median age was 9 years (of 2 - 18 years).The anti-tTG assays were positive in 16.5% of patients (15/91). Out of 15 patient whose diagnosed as anti-tTG positive, 11 (73%) have been diagnosed as celiac disease by endoscopy and biopsy according to modified marsh classification. All children diagnosed to have celiac disease were kept on a gluten-free diet. Patients were followed-up for six months and showed improvement in growth rate. Conclusion: Celiac disease a cause of short stature that should be included in diagnostic investigations of short stature.Recommendation: anti-tTG antibody as routine test recommended for all patients with short statures. All patients with idiopathic short statures and anti-tTG test positive with normal IgA level should be subjected to intestinal biopsy to prove the diagnosis of celiac disease.

Assessment of coeliac disease prevalence in patients with Down syndrome in Poland - a multi-centre study.

IntroductionThe results of studies assessing whether patients with Down syndrome have increased risk of coeliac disease are contradictory. The prevalence of coeliac disease in patients with Down syndrome is estimated at a wide range between 1% to as much as 18.6%.AimTo assess coeliac disease prevalence in patients with Down syndrome in Poland.Material and methodsThe study enrolled 301 patients with Down syndrome from six centres in Poland (Wroclaw, Sandomierz, Rzeszow, Grudziadz, Katowice, and Bydgoszcz). We measured the concentration of anti-tissue transglutaminase IgA antibodies and anti-deamidated gliadin peptide IgG antibodies in all patients. Patients with abnormal positive (> 10 U/ml) or inconclusive (7–10 U/ml) result of the serological test were offered endoscopic biopsy of the small intestine in the main centre.ResultsIn 31 (10.3%) patients increased concentrations of the investigated antibodies were found, including 19 (6.3%) patients with increased tTg-IgA concentration, 27 (8.97%) patients with increased concentration of DGP-IgG, and 15 (4.98%) patients with increased concentration of both types of antibodies. Endoscopic biopsy of the small intestine was planned for all 31 patients with abnormal results of at least one antibody test and for 2 patients with inconclusive results. One of them suffered from previously diagnosed and histologically confirmed coeliac disease. Biopsy was not conducted in 9 patients due to contraindications, lack of their consent, or introduction of a gluten-free diet by the parents before the examination. In a group of 23 patients who underwent endoscopic biopsy of the small intestine, in 15 patients the histopathological picture of the small intestinal mucosa was typical for coeliac disease, 2 patients were diagnosed with lesions of grade 1 according to the classification by Marsh-Oberhuber, 1 patient was diagnosed with focal shortening of villi and hypertrophy of the crypts with no intraepithelial lymphocytosis (remains under gastrological observation), 2 patients were diagnosed with mucosal inflammation of the duodenum, and 3 patients were found to have a normal histopathological picture of the small intestine. Analysis of the data included in the questionnaires of all patients showed no statistically significant differences in the body height, body mass index, prevalence of abdominal pain, diarrhoea, constipations, recurrent stomatitis, enamel hypoplasia, thyroid diseases, or hypertransaminasaemia between the groups of patients with normal and abnormal serological test results. Significantly higher prevalence of abdominal flatulence (p < 0.05) and epilepsy (p < 0.05) was found in the group of patients whose serological test results were negative.ConclusionsPatients with Down syndrome are a high-risk group for coeliac disease in the Polish population, with an estimated prevalence of at least 5.4%. Serological tools based on tTG-IgA and DGP-IgG tests are useful for the diagnosis of coeliac disease in Down syndrome patients. tTG-IgA test may be superior to DGP-IgG test in patients with normal total IgA level. Tests for coeliac disease should be carried out in all Polish patients with Down syndrome, regardless of the clinical picture.

Immunoglobulin A deficiency in celiac disease in the United States.

Multiple European studies report increased prevalence of selective immunoglobulin A deficiency (SIgAD) and partial immunoglobulin A deficiency (PIgAD) in patients with celiac disease (CD). However; prospective data representing North American adults are lacking. While SIgAD precludes the use of IgA-tissue-transglutaminase antibody (IgA-tTG), the effect of PIgAD on IgA-tTG sensitivity is not well documented. We aim to determine the prevalence and impact of IgA deficiency on CD presentation and diagnosis in North American adult patients. We reviewed 1000 consecutive patients undergoing IgA-tTG testing and 243 healthy controls. Eligible sera were tested for IgA-tTG, serum immunoglobulins, and IgA/IgG-deamidated gliadin peptide (IgA/IgG-DGP). Prevalence of SIgAD was marginally higher in patients with CD (1.9%) compared with healthy controls (0.4%, P = 0.24) and patients without CD (0.7%, P = 0.173). Prevalence of PIGAD was similar in patients with CD (4.8%) compared with healthy controls (5.9%, P = 0.57) and patients without CD (7.2%, P = 0.22). One (16.7%) of 6 patients with CD with SIgAD and all 15 (100%) with PIGAD tested IgA-tTG positive prior to gluten-free diet initiation. Patients with CD with SIGAD showed lower frequency of gastrointestinal symptoms (33% vs 82%, P = 0.01) and more co-morbid autoimmune disease (67% vs 23%, P = 0.03) when compared with patients with CD with normal IgA. The prevalence of SIgAD in North American patients with CD is comparable with European data but not significantly different than control populations. Patients with CD with SIgAD exhibit decreased IgA-tTG sensitivity and lack of gastrointestinal symptoms. PIgAD is common in patients with gastrointestinal disorders but does not alter CD presentation or IgA-tTG sensitivity.

IgA Levels Can Predict Survival in CLL Patients: A Retrospective Analysis of 183 Cases in a Brazilian Cohort

Background: Immunosuppression and frequent infections has impact on morbidity and mortality in CLL patients. It is basic related with chronic immune dysregulation or treatment toxicities. Hypogammaglobulin is a frequent event in CLL and can explain some of the infection susceptibility related to the disease. Low IgG levels were associated with a higher frequency of bacterial infections, commonly Streptococcus pneumoniae and Haemophilus influenza. Although hypogammaglobulin can contribute with repeated infections in CLL patients, the prognostic value of this occurrence is controversial. At our center we routinely test Ig levels at time of CLL diagnosis.Methods: A retrospectively analysed was done with 183 patients diagnosed with typical CLL between 2007 to 2013 for clinical and laboratorial features (sex, age, CBC, CD38, Beta-2-microglobulin, albumin, Binet staging, direct coombs test and Ig levels) and survival (overall and time to first treatment). The statistical analysis was done on IBM SPSS v.20. This study received approval on the ethical committee from our institution.Results: Median follow up of this cohort was 52 months. Median age was 65y (34-90) and 98 were male (52.1%). Most of them, 61.1% (n=110) were Binet A, 17.8% (n=32) Binet B and 21.1% (n=38) Binet C. Direct coombs test was positive in 9.9% of cases (n=16). CD38 was positive in 23.3% (n=40). The IgG, IgM and IgA levels were above normal laboratory value in 15.3% (n=29), 6.9% (n=13) and 6.3% (n=12), respectively, and it was below in 26.5% (n=50), 35.6% (n=67) and 36% (n=68), respectively. Twenty-three patients (12.2%) had both low levels of IgG, IgM and IgA and 57.7% had at least one Ig subtype at low level. When we consider only the IgA, 42.3% (n=80) had above or below levels. Albumin level was below 4.5 g/dl, 4.0 g/dl and 3.5 g/dl in 63.2% (n=115), 20.3% (n=37) and 9.3% (n=17), respectively. Beta-2 microglobulin level was higher than 2.5 mg/dl in 55% (n=93). The median overall survival was not reached and 76.8% +- 3.8% were alive at 52 months. On the univariate analysis (Kaplan-meier) of overall survival, high Binet staging (p=0.001), altered (high or low) IgG level (p=0.017), altered IgA level (p<0.001), any low Ig level (p<0.001), positive coombs test (p=0.006), beta-2-microglobulin higher than 2.5 mg/dl (p<0.001) and CD38 membrane expression showed worse prognosis. The multivariate model (cox regression) showed that just IgA at high or low level (p=0.002), coombs (p=0.022) and high Beta-2-microglobulin (p=0.001) had impact on survival. Hundred and eight patients with Binet A were included at time of first treatment survival analysis with median follow up of 58 months. The median TTFT again was not reached, but at 58 months was 58% (+- 5.6%). On the univariate analysis low albumin (p=0.039), IgA high or low levels (p=0.003), any low Ig level (p=0.037) and high Beta-2-microglobulin (p<0.001) were significant, remaining only IgA level (p=0.04) and high beta-2-microglobulin (p=0.006) at multivariate analysis.Conclusion: This analysis suggests that low or high IgA level are associated with a worse prognosis. This could be explained by immune suppression (mucous immune system depression) and higher susceptibility for bacterial infection (mortality cause not evaluated). The fact that this group had a shorter time to first treatment can not be explained by the same reason. Maybe not normal IgA levels itself can be associated with a more aggressive and progressive disease. Despite of all the bias of a retrospective study (loss of follow up, missing values) and lack of FISH and IgVH mutational status at the diagnosis, this data points the importance of Ig level evaluation at the time of diagnosis DisclosuresNo relevant conflicts of interest to declare.

Common variable immunodeficiency and natural killer cell lymphopenia caused by Ets-binding site mutation in the IL-2 receptor γ (IL2RG) gene promoter

Common variable immunodeficiency and natural killer cell lymphopenia caused by Ets-binding site mutation in the IL-2 receptor γ (IL2RG) gene promoter

B cells from nuclear factor kB essential modulator deficient patients fail to differentiate to antibody secreting cells in response to TLR9 ligand

Hypohidrotic ectodermal dysplasia (HED) consists of disorders resulting from molecular alterations of ectodysplasin-A (EDA) pathway. Hypomorphic mutations in NF-kB essential modulator, downstream EDA, result in HED with immunodeficiency (HED-ID), characterized by susceptibility to encapsulated pyogenic bacteria infections. Increased susceptibility to pneumococcal infections and poor response to polysaccharide antigens are associated with defect in T-independent B-cell immunity. We investigated B-cell differentiation and immunoglobulin secretion induced by the TLR9 ligand CpG in two HED-ID and in a HED patient caused by EDA mutations (XLHED). In HED-ID, only few B cells differentiated into plasma cells upon TLR9 stimulation and memory B cells did not produce IgG and IgA, but small amounts of IgM. Unexpectedly, memory B cells from XLHED patient failed to produce normal IgA or IgG amount upon TLR9 stimulation. Our findings expand the knowledge about the pathogenesis of humoral alterations in HED patients and help explain the susceptibility to pneumococcal infections.

The prevalence of celiac disease in children and adolescents in Germany.

Untreated celiac disease is associated with increased morbidity and mortality. Until now, no up-to-date figures have been available on the prevalence of celiac disease among children and adolescents in Germany, or on the percentage of undiagnosed cases. To estimate the prevalence of celiac disease, serum samples obtained from 2003 to 2006 from participants in the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were studied for celiac disease-specific autoantibodies and total IgA. Of the 12 741 study participants aged 1 to 17 years (6546 boys, 6195 girls), 9 (0.07%) had a reported history of celiac disease. An elevated concentration of serum autoantibodies to tissue transglutaminase was found in 91 children with a normal IgA concentration and in 7 with IgA deficiency. The prevalence of undiagnosed celiac disease, based on positive autoantibody findings, was 0.8% (95% confidence interval 0.6-1.0%), and the overall prevalence of the disease was 0.9%. Seropositive children and adolescents had lower ferritin and red blood cell folate concentrations than seronegative ones; they also tended to be shorter and to weigh less as reflected by age- and sex-standardized z-scores. The 0.9% prevalence of celiac disease in Germany, as determined from a combination of serological findings and clinical histories, is similar to reported prevalences elsewhere in Europe and North America. Pediatricians, primary care physicians, internists, and other specialists should be aware of the broad spectrum of clinical manifestations of this disease. Children who have symptoms suggestive of celiac disease or belong to a group at risk for it should be tested for antibodies against tissue transglutaminase, as should symptomatic adults after the exclusion of other possible causes. It is not yet clear whether asymptomatic adults from high-risk groups should be tested.

Increased Serum IgA in Children with IgA Nephropathy, Severity of Kidney Biopsy Findings and Long-Term Outcomes.

The aim of the study was to determine whether an elevated IgA level at the time of the diagnosis of IgA nephropathy has an effect on the severity of kidney biopsy findings and long-term outcomes in children. We retrospectively studied 89 children with IgA nephropathy who were stratified into Group 1- elevated serum IgA and Group 2 - normal serum IgA at baseline. The level of IgA, proteinuria, hematuria, glomerular filtration rate (GFR) and hypertension (HTN) were compared at baseline and after the end of the follow-up period of 4.0 ± 3.1 years. Kidney biopsy findings were evaluated using the Oxford classification. The evaluation of treatment included immunosuppressive therapy and renoprotection with angiotensin converting-enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), or no treatment. The elevated serum IgA was found in 46 (52 %) patients and normal serum IgA level was found in 43 (48 %) patients. No differences were found between the two groups regarding the mean age of patients, proteinuria, and the number of patients with reduced GFR or HTN at baseline. In kidney biopsy, mesangial proliferation and segmental sclerosis were significantly more common in Group 1 compared with Group 2 (p < 0.05). Immunosuppressive therapy was used in 67 % children in Group 1 and 75 % children in Group 2. The Kaplan-Meier survival curves for renal function (with normal GFR) and persistent proteinuria did not differ significantly depending on the serum IgA level at baseline. We conclude that in IgA nephropathy the elevated serum IgA at baseline may be associated with mesangial proliferation and segmental sclerosis contribute to glomerulosclerosis, but has no effect on the presence of proteinuria or on the worsening of kidney function during several years of disease course.

Rare Case of a Patient Presenting with Parathyroid Hormone-Related Peptide Mediated Hypercalcemia and IgG Heavy Chain Disease: Case Report and Review of Literature

IgG Heavy Chain Disease (γHCD) is a rare plasma cell disorder. Hypercalcemia related to plasma cell dyscrasias is related to non-PTHrP related mechanisms. Here we describe the first case of a patient with γHCD and PTHrP related hypercalcemia. Methods: Patient case derived from chart review from 2011 to 2015. Literature review performed searching PubMed 1968-current. Results: The patient was diagnosed with hypercalcemia with elevated PTHrP and exclusion of other etiologies of hypercalcemia. She was diagnosed with (γHCD) by M-spike 0.64 g/dL, IFE showing a broad band of IgG heavy chain, without associated light chains and severe depression of the non-mono-clonal IgG. Serum immunoglobulins demonstrated elevated IgG (2110 mg/dL), normal IgA (46 mg/dL) and decreased IgM (<21 mg/dL). Bone marrow biopsy showed 5% PCs, non-clonal by kappa/lambda, but exclusive for IgG by IHC, without any staining for IgA or IgM. The patient was started on therapy with improved hypercalcemia and PTHrP levels. Conclusions: This is the first reported case of γHCD presenting with PTHrP related hypercalcemia. Given that skeletal involvement is uncommon in γHCD, hypercalcemia secondary to γHCD may at times be a PTHrP driven phenomenon and we recommend that this test be ordered in such cases.