Hematologic Manifestations in Celiac Disease-A Practical Review.

Celiac disease (CD) is a systemic autoimmune disease driven by gluten-ingestion in genetically predisposed individuals. Although it primarily affects the small bowel, CD can also involve other organs and manifest as an extraintestinal disease. Among the extraintestinal features of CD, hematologic ones are rather frequent and consist of anemia, thrombocytosis (thrombocytopenia also, but rare), thrombotic or hemorrhagic events, IgA deficiency, hyposplenism, and lymphoma. These hematologic alterations can be the sole manifestation of the disease and should prompt for CD testing in a suggestive clinical scenario. Recognition of these atypical, extraintestinal presentations, including hematologic ones, could represent a great opportunity to increase the diagnostic rate of CD, which is currently one of the most underdiagnosed chronic digestive disorders worldwide. In this review, we summarize recent evidence regarding the hematological manifestations of CD, with focus on practical recommendations for clinicians.

Autoantibodies against BAFF, APRIL or IL21 - an alternative pathogenesis for antibody-deficiencies?

BACKGROUND: The ability of anti-cytokine antibodies to play a disease-causing role in the pathogenesis of immunodeficiencies is widely accepted. The aim of this study was to investigate whether autoantibodies against BAFF (important B cell survival signal), APRIL (important plasma cell survival signal), or Interleukin-21 (important cytokine for immunoglobulin class switch) present an alternative mechanism for the development of the following primary antibody deficiencies (PADs): common variable immune deficiency (CVID) or selective IgA deficiency (sIgAD). RESULTS: Two hundred thirty-two sera from patients with PADs were screened for autoantibodies against cytokines by ELISA. Statistical data analysis yielded a significant difference (p < 0.01) between the healthy donor sera and both PAD cohorts. The analysis was deepened by subdividing the patient collective into groups with distinct B cell phenotypes but no significant differences were found. For selected sera with notable high ELISA-read outs functional analysis ensued. Anti-BAFF and anti-APRIL antibodies were further examined by a B cell survival assay, whilst the functional relevance of putative anti-IL-21 autoantibodies was investigated by means of a STAT3 phosphorylation assay. However, the results of these experiments revealed no discernible functional effect. CONCLUSION: Whilst statistical analysis of ELISA results showed significant differences between patients and healthy controls, in our set of patients functional tests yielded no evidence for an involvement of autoantibodies against BAFF, APRIL, or IL-21 in the pathogenesis of CVID or sIgAD.

Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling.

RATIONALE: Maintenance of a surface immune barrier is important for homeostasis in organs with mucosal surfaces that interface with the external environment; however, the role of the mucosal immune system in chronic lung diseases is incompletely understood. OBJECTIVES: We examined the relationship between secretory IgA (SIgA) on the mucosal surface of small airways and parameters of inflammation and airway wall remodeling in chronic obstructive pulmonary disease (COPD). METHODS: We studied 1,104 small airways (<2 mm in diameter) from 50 former smokers with COPD and 39 control subjects. Small airways were identified on serial tissue sections and examined for epithelial morphology, SIgA, bacterial DNA, nuclear factor-κB activation, neutrophil and macrophage infiltration, and airway wall thickness. MEASUREMENTS AND MAIN RESULTS: Morphometric evaluation of small airways revealed increased mean airway wall thickness and inflammatory cell counts in lungs from patients with COPD compared with control subjects, whereas SIgA level on the mucosal surface was decreased. However, when small airways were classified as SIgA intact or SIgA deficient, we found that pathologic changes were localized almost exclusively to SIgA-deficient airways, regardless of study group. SIgA-deficient airways were characterized by (1) abnormal epithelial morphology, (2) invasion of bacteria across the apical epithelial barrier, (3) nuclear factor-κB activation, (4) accumulation of macrophages and neutrophils, and (5) fibrotic remodeling of the airway wall. CONCLUSIONS: Our findings support the concept that localized, acquired SIgA deficiency in individual small airways of patients with COPD allows colonizing bacteria to cross the epithelial barrier and drive persistent inflammation and airway wall remodeling, even after smoking cessation.

Evaluation of serum & salivary IgA in patients with type 1 diabetes.

BACKGROUND: Diabetes mellitus is a common immune mediated disorder. The aim of the present study is to evaluate the level of serum and salivary IgA levels in patients with Type 1 diabetes. MATERIAL AND METHOD: In this case control study, serum and salivary IgA levels of patients with diabetes type 1 and similar non diabetes subjects were measured. Age, gender, duration of diabetes and the last HbA1c level of diabetic patients were also studied. Data was analyzed by SPSS software. RESULTS: Two hundred and fifty subjects (126 diabetics and 124 non diabetics) were enrolled in the study. The mean value of serum IgA in patients with Type 1 Diabetes and controls was 1.77± 1.55 g/lit and 2.39± 1.52 g/lit, respectively. The mean salivary IgA level in diabetics and controls was 276 ± 162.5 40 µg/ml and 129 ± 112.2 40 µg/ml, respectively. Selective IgA deficiency was detected in two (1.6%) and three(2.4%)cases of diabetic and control group; respectively (p=0.68). We found low salivary IgA level in 44.4% diabetic and 33.9% control (p=0.08). There was no significant correlation between serum and salivary IgA level. There was also significant association between serum IgA levels with age. Salivary IgA was significantly correlated with HbA1c level. But considering gender, duration of diabetes we didn't find any association. CONCLUSION: We didn't find any significant difference in serum and salivary IgA level among diabetic and non diabetics and also, no association between serum and salivary IgA levels.

Health-related quality of life (HRQL) in immunodeficient adults with selective IgA deficiency compared with age- and gender-matched controls and identification of risk factors for poor HRQL.

PURPOSE: Selective IgA deficiency (SIgAD) is the most common primary immunodeficiency with a prevalence of 1/600 in the general population. Any targeted health-related quality of life (HRQL) study of adults with SIgAD has never been presented. The objectives of the study were to compare HRQL between SIgAD adults and randomly selected age- and gender-matched population controls, and to identify risk factors for poor HRQL. METHODS: Thirty-two SIgAD individuals and 63 controls answered three questionnaires (clinical data, Short Form-36 Health Survey (SF-36), infection-related HRQL) at baseline before undergoing medical/dental examinations and laboratory assessments. HRQL in SIgAD was re-evaluated after 6 and 12 months. RESULTS: Baseline: Selective IgA deficiency individuals reported significantly increased fear of contracting infections (p < 0.01). Those scoring high on fear also perceived significantly poorer physical health (p < 0.01). SF-36 results indicated that SIgAD individuals perceived poorer HRQL, although this was not statistically significant. FOLLOW-UP: Compared with SF-36 responses at baseline, SIgAD individuals reported significantly more pain (p < 0.01) at 6 months, poorer general health (p < 0.05) and summarised physical HRQL (p < 0.01) at 6 and 12 months and decreased vitality at 12 months. The summarised mental scale remained stable over time. Risk factors for poor HRQL: The number of antibiotic treatments during the previous year (p < 0.001), number of daily medications (p < 0.01), allergic rhinoconjunctivitis (p < 0.05), chronic musculoskeletal symptoms at least every week (p < 0.05) and anxiety and/or insomnia (p < 0.05) were identified as independent risk factors for poor HRQL. CONCLUSION: The study highlights the importance of identifying and thoroughly evaluating, educating and following up individuals with SIgAD, as their HRQL may be negatively affected due to health problems possible to prevent and treat.

IgA deficiency and autoimmunity.

IgA is the most abundant immunoglobulin in the human body, and performs a very specialized role which involves mucosal immunity, development of tolerance and protection against infection. IgA is the key immunoglobulin in the respiratory and gastrointestinal tracts, which provide the most intimate interface between the environment and self. Normal levels of IgA are based on early studies consisting of only small numbers of patients. The international consensus definition of IgA deficiency is a level of 0.07g/l after the age of four years in the absence of IgG and IgM deficiencies. The epidemiology of IgA deficiency reveals interesting variances between geographical regions - the incidence in Caucasians being much higher than that in Asians. IgA deficiency has also been found to co-exist with autoimmune diseases, allergies and malignancies. The association with autoimmunity is particularly interesting because it suggests a common genetic linkage that could potentially also explain the diversity in geoepidemiology. Both MHC and non-MHC associations have been described and the 8.1 haplotype has been significantly associated with autoimmunity in IgA deficiency patients over controls. Non-MHC genetic associations include IFIH1 and CLEC16A. The mutations leading to IgA deficiency have not been defined, but in some cases of IgA deficiency it has been suggested that the pathogenesis involves a failure in switched memory B cells that can lead to this cohort experiencing an increased incidence of recurrent bacterial infections or autoimmune diseases. Attempts to investigate the role of cytokines that can induce IgA synthesis in cells of patients with IgA deficiency, such as IL21 or the combination of CD40L/anti-CD40, IL-4 and IL10, are underway.

[Primary immunodeficiencies are a topical problem of modern medicine].

AIM: To analyze the incidence of primary immunodeficiencies (PIDs), to reveal the specific features of the course of this condition at the present stage, and to estimate the quality of health care to patients with PIDs. SUBJECTS AND METHODS: An open-label prospective trial was performed in 94 patients with different forms of PIDs (63 with selective immunoglobulin A (IgA) deficiency and 31 with other more severe primary immunodeficiencies) who had been permanent residents in the Perm Territory in the period 1990 to 2012. RESULTS: The registered PID cases were noted to be lower than the estimated ones. Over 22 years of follow-ups, the death rates for this group of patients with these diseases were 11%, and the disability rates were 27%. In severe PIDs (exclusive of selective IgA deficiency), these rates were as high as 35.5 and 96%, respectively. The rate of untimely diagnosis of severe PIDs was high (43%). Molecular genetic studies were conducted in only one tenth of the patents with this disease. PID treatment generally complied with the accepted medical standards. However, all patients with X-linked agammaglobulinemia were observed to have periodic irregularities of replacement therapy with intravenous immunoglobulins, which was a cause of death in 2 patients. Adult patients with common variable immune deficiency received no adequate replacement therapy. Timely diagnosis and adequate therapy could not only preserve the life of many patients with severe PIDs (64.5% survived), but could achieve its relatively satisfactory quality. CONCLUSION: As of now, PIDs ceased to be fatal diseases. To improve the quality of health care to patients with this pathology, there is a need to increase the awareness of the diagnosis and treatment of immunodeficiencies among physicians of different specialties, to extend the application of molecular genetic techniques, including those for prenatal diagnosis, and to continuously provide patients with essential drugs.

Educational paper: primary antibody deficiencies.

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies and are characterized by a defect in the production of normal amounts of antigen-specific antibodies. PADs represent a heterogeneous spectrum of conditions, ranging from often asymptomatic selective IgA and IgG subclass deficiencies to the severe congenital agammaglobulinemias, in which the antibody production of all immunoglobulin isotypes is severely decreased. Apart from recurrent respiratory tract infections, PADs are associated with a wide range of other clinical complications. This review will describe the pathophysiology, diagnosis, and treatment of the different PADs.

Increased percentages of autoantibodies in immunoglobulin A-deficient children do not correlate with clinical manifestations.

IgA deficiency (IgAD) is frequently associated with autoimmune phenomena. The aim of this study is to evaluate the frequency of 22 different autoantibodies in 60 patients with IgAD and to examine the physical and other laboratory findings of the suspected cases for autoimmune diseases. The evaluated autoantibodies were Anti-nuclear antibody (ANA) profile (autoantibodies against RNP/Sm, SS-A, Ro-52, SS-B, Scl-70, Pm-Scl, Jo-1, centromere B, PCNA, dsDNA, nucleosomes, histones, ribozomal P-protein, AMA-M2), anti-cardiolipin IgG and IgM, anti-neutrophilic cytoplasmic antibodies (ANCA), rheumatoid factor (RF), anti-thyroglobulin (anti-T) and anti-thyroid microsomal antigen (anti-M) and direct cooms test. Forty-one healthy children were included as a control group. ANA titers < or = 1:80 were accepted as normal and titers > or = 1:80 are accepted as positive. In ANA screening, 14 patients showed positivity in different titres. Seven of them were equal to or below 1:80. The other seven patients (11.6%) had positive ANA titers (>1:160) whereas three of them had anti-dsDNA, anti-histon and anti-centromer antibodies. These patients did not have any clinical and laboratory signs of autoimmune diseases. ANA positivity was found higher in IgA deficient children (p < 0.05) compared to controls. RF and pANCA were found positive during follow-up of two different selective IgAD patients. IgG and IgM antibodies against cardiolipin, direct coombs, anti-T and anti-M tests were not found positive in any subjects. In conclusion, increased frequency of autoantibodies in IgAD patients may often be observed. However, the detection of autoantibodies do not show or predict whether this patient will develop an autoimmune disease.

Selective immunoglobulin A deficiency in Iranian blood donors: prevalence, laboratory and clinical findings.

Selective deficiency of immunoglobulin A (IgA) is the most frequent primary hypogammaglobulinemia. As some IgA-deficient patients have IgA antibodies in their plasma which may cause anaphylactic reactions, blood centers usually maintain a list of IgA-deficient blood donors to prepare compatible blood components. In this study we determined the incidence of selective IgA deficiency (SIgAD) in normal adult Iranian population. 13022 normal Iranian blood donors were included in this study. The assay which we used was adapted to the manual pipetting system and ELISA reader was used for screening. Other classes of immunoglobulins (G, M), as well as secretory IgA and IgG subclasses were tested in IgA deficient cases by ELISA. SPSS was used for statistical analysis.Among 13022 studied cases, 11608 blood donors were males (89.14%) and 1414 were females (10.86%). Their mean (+/-SD) age and weight were 38.5+/-11 years and 82+/-12 Kg respectively. Twenty of the screened samples were found by means of ELISA to be IgA-deficient (less than 5mg/dl), (frequency; 1:651). The data could indicate a compensation for IgA deficiency by serum IgM in one of our IgA deficient cases (Patient 5). We observed a correlation between IgG3 and serum IgA in deficient cases (r=0.498, P=0.025). Our results indicate that in present study the prevalence of S IgA D is in agreement with data from other Caucasians populations (from 1:300 to 1:700). In conclusion, Selective IgA Deficiency could be almost asymptomatic in most cases in general population. Our study suggests that; due to high frequency of IgA deficiency in Iran, it seems necessary to measure IgA levels for every blood donor and blood recipient to find IgA deficient cases.

Bronchial hyper-responsiveness in selective IgA deficiency.

Secretory IgA in mucosal secretions has a broad protective function. The insufficient protection provided by the respiratory mucosa in children with selective IgA deficiency (sIgAD) might facilitate the development of bronchial hyper-responsiveness (BHR) and consequently asthma symptoms. This study was conducted to clarify the prevalence of BHR in sIgAD children and the relationship with atopic status. A cohort of 20 children (group A) aged 6.4-20.1 yr (median: 12.6) with sIgAD (serum IgA <6 mg/dl) were evaluated for BHR using inhaled hypertonic saline test as well as for atopy by skin prick testing (SPT) to eight common aero-allergens. Seventy other children with normal levels of serum IgA, but sensitized to aero-allergens (group B) and 102 with normal IgA and negative SPTs (group C) were also evaluated. Baseline spirometry demonstrated that forced vital capacity (FVC) values in group A were significantly lower than in C. Forced expiratory volume in 1 s values were similar in all groups, but impairment of the forced expiratory flow over the middle half of the FVC was detected in group B. The prevalence of BHR was similar among group A (30.0%) and group B (35.7%) (p = 0.79) but they differed from group C (5.9%) (p = 0.005). An association between BHR and reported current (p = 0.001) but not lifetime asthma symptoms among group A was also observed. There was no association between atopy and BHR in group A but only to mites' sensitization (p = 0.03). In conclusion, these results indicate that sIgAD constitutes a risk factor for development of BHR but it appears to be related to sensitization to mites.

Myelin widenings and MGUS-IgA: an immunoelectron microscopic study.

A few studies have reported a variety of nonspecific histological lesions in patients with IgA monoclonal gammopathies and polyneuropathy. In our case, using electron microscopy, we observed widenings of the myelin lamellae identical to those commonly described in IgM neuropathies with anti-myelin-associated glycoprotein activity. Using immunoelectron microscopy, we demonstrated a direct involvement of IgA in myelin lesions. The search for a direct link between monoclonal dysglobulinemia, regardless of type, and polyneuropathy is important and may influence treatment.

Immunoglobulin secreting cells in lymphocytes of patients with IgA deficiency or hyper-IgA.

To assess the ability of immunoglobulin production in vivo, we enumerated the immunoglobulin secreting cells in the peripheral blood of patients with an IgA deficiency and of those with hyper-IgA-emia. All seven patients with primary IgA deficiency and two of the three patients with secondary IgA deficiency had low numbers of IgA secreting cells. In all five patients with hyper-IgA the number of IgA secreting cells was increased. Our results suggest that measurement of immunoglobulin secreting cells in PBMCs is useful in the assessment of ability of immunoglobulin production in vivo.

Selective IgA deficiency and autoimmunity.

Selective IgA deficiency is the most common primary immunodeficiency. Selective IgA deficiency, as most other immunodeficiencies, is frequently associated with autoimmune phenomena. In this article the authors critically review the literature concerning this association, and discuss the possible mechanisms leading to the increased frequency of autoimmune disorders in subjects with selective IgA deficiency.