Mutational Analysis of Human BLyS in Patients with Common Variable Immunodeficiency

BLyS, a TNF family member, is crucial for B cell proliferation and differentiation by acting through its three receptors, TACI, BCMA and BAFF-R. The knock out model for BLyS is characterized by an immunological phenotype reminiscent of the human phenotype of common variable immunodeficiency (CVID). CVID is characterized by a defective B cell compartment, evidencing the putative importance of BLyS in its pathogenesis. On the contrary, the transgenic model for BLys is characterized by autoimmune manifestations, underlying its role in B cell regulation. In fact, mutations in TACI, one of the three BLyS receptors, are associated with CVID. Based on these facts, we hypothesized that BLyS could be a candidate gene for CVID. We screened 78 patients with CVID using DHPLC and direct sequencing: No disease causing mutations were identified. A novel heterozygous single nucleotide polymorphism (SNP) was found in exon 1 of one individual, however this SNP (G189A) does not lead to an amino acid substitution.     

Predictive Factors for and Complications of Bronchiectasis in Common Variable Immunodeficiency Disorders

Journal of Clinical Immunology - Bronchiectasis is a frequent complication of common variable immunodeficiency disorders (CVID). In a cohort of patients with CVID, we sought to identify predictors...     

Vitamin A Deficiency in Patients with Common Variable Immunodeficiency

Vitamin A, a naturally occuring antioxidant micronutrient, has immunomodulating effect in patients with immunodeficiency, including an influence on cytokine production and lymphocyte growth and functions. Vitamin A deficiency is associated with a shift from type 2 cytokines to predominantly type 1 cytokines. The aims of this study were to determine Vitamin A status in Common variable immunodeficiency (CVID) patients and the relationship between Vitamin A status and cytokines production. Serum Vitamin A, neopterin, TNF-alpha, IL-2, IL-4, and IL-10 levels were determined in 19 CVID patients and 15 healthy children. Effects of 9-cis retinal, Vitamin A derivative, on cytokines (TNF-alpha, IL-2, IL-4 and IL-10) production in lymphocytes were tested in vitro condition using lymphocyte cultures obtained from CVID patients and healthy children.Serum Vitamin A level in CVDI patients was, 21.1± 1.5 μg/dL, significantly (p < 0.001) lower than the value, 35.7± 1.8 μg/dL, observed in healthy children. Serum neopterin level in the patients was, 9.8± 2.9 nmol/L, higher (p < 0.05) than the value, 3.9± 0.7 nmol/L, observed in control group. Common variable immunodeficiency patients, serum IL-4 level was significantly (p < 0.05) lower than the value observed for healthy children. Serum TNF-alpha, IL-2 and IL-10 levels were similar in the patients and healthy children. Vitamin A derivative, 9-cis retinal, increased TNF-alpha and IL-4 production in cultured mononuclear cells obtained from control and CVID patients. Vitamin A derivative, also, increased IL-2 and Il-4 production in cultured mononuclear cells obtained from CVID patients.These results show that CVID patients have low serum Vitamin A levels and high serum neopterin levels. A supplementation with Vitamin A may have role in downregulation of inflammatory responses in CVID patients.The contributions by Sara Sebnem Kilic and Esra Yapici Kezer are equal and the order of authorship is arbitrary.     

Diagnostic Findings in 95 Finnish Patients with Common Variable Immunodeficiency

Common variable immunodeficiency is the most frequent of the primary hypogammaglobulinemias. It is manifested by a wide variety of clinical signs and symptoms. In this retrospective, nationwide survey data were collected on all patients with common variable immunodeficiency who were receiving immunoglobulin replacement therapy in Finland to study the prediagnostic clinical picture, diagnostic delay, and diagnostic findings. Ninety-five patients were identified. The median age of the patients was 33 years. Sixteen of the patients were children. Sinopulmonary infections were the most common prediagnostic signs and symptoms; 66% had suffered from recurrent pneumonia, 60% from recurrent maxillary sinusitis, and 45% from recurrent bronchitis. There was a considerable delay in diagnosis. The mean delay was 8 years. At the time of diagnosis chronic pulmonary complications had already developed in 17% of the patients. The diagnosis was based on low serum immunoglobulin concentrations. This study showed that the awareness of common variable immunodeficiency is low. To improve the recognition of hypogammaglobulinemia, it should be suspected in every patient with recurrent bacterial infections. In addition to a low serum IgG concentration, measurement of specific antibody production is recommended to establish the diagnosis before initiation of a life-long and costly replacement therapy.     

Thymic and Bone Marrow Output in Patients with Common Variable Immunodeficiency

Objective  

The study aims to obtain more information about the immune deficit of common variable immunodeficiency (CVID) patients.     

Infliximab for Treatment of Granulomatous Disease in Patients with Common Variable Immunodeficiency

Purpose

Eight to 22 % of common variable immunodeficiency (CVID) patients exhibit granulomas of the lungs, spleen, liver, and/or skin. Granulomas can be the most medically significant day-to-day problem for CVID patients. Currently, there are limited options for treatment of granulomas associated with CVID.

Methods

We treated five patients with CVID who exhibited significant clinical symptoms secondary to granulomas with infliximab. The patients were selected and treated based solely on clinical need and were not otherwise controlled or blinded to the therapy. After obtaining baseline studies (labs, spirometry, radiology) and excluding infection, they were treated with infliximab 5 mg/kg at week 0, 2, 6 and every 4 weeks thereafter.

Results

Post treatment improvements were seen in all 5 patients with significant clinical responses observed for both visceral and cutaneous granulomata. Four of the five patients were maintained on infliximab for 5 to 18 months (mean 9.4 months) without adverse reaction or increased susceptibility to infection. One patient completed 6 months of therapy with improvement of respiratory parameters but discontinued infliximab due to joint stiffness and rash that she attributed to the medication.

Conclusion

In our series, infliximab (5 mg/kg monthly) was an effective treatment for cutaneous and visceral granulomas in patients with CVID.     

Clinical and Immunological Features of 65 Iranian Patients with Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and recurrent bacterial infections. The records of 65 patients with CVID (37 males and 28 females) in the age range of 24 to 537 months were reviewed. By the year 2003, 11 patients had died and seven patients could not be located. The total follow-up period was 221 patient-years. The median diagnostic delay (time between onset and diagnosis) in our patient group was 60 months. At the time of diagnosis, the baseline serum immunoglobulin G (IgG), IgM, and IgA levels were below the level normal for the patients' age; the medians for this group were 120, 10, and 0 mg/dl, respectively. All of the patients presented with infectious diseases at the time of onset, the most common of which were otitis media, diarrhea, pneumonia, and sinusitis. Acute and recurrent infections were also found in almost all of the patients, particularly involving respiratory and gastrointestinal systems. The most common infections, before diagnosis and during follow-up, were pneumonia, acute diarrhea, acute sinusitis, and otitis media. CVID should be considered in any patient with a history of recurrent infections and decreased levels of all serum immunoglobulin isotypes.     

IL-10 Production and CD40L Expression in Patients with Common Variable Immunodeficiency

The authors studied CD40 ligand (CD40L) expression and interleukin-10 (IL-10) production in 16 patients with common variable immunodeficiency (CVI). Mean CD40L expression, determined by using cytofluorimetry, and measured as the mean fluorescence intensity following stimulation of peripheral blood mononuclear cells (PBMC) with phorbol myristate acetate (PMA) and calcium ionophore in 12 patients, was comparable to that of controls. However, three CVI patients showed fluorescence intensity in stimulated cells below 2 standard deviations of normal donors' mean and two other patients had only a slight increase of stimulated versus unstimulated cells (<10 channels). IL-10 production after stimulation of PBMC with both anti-CD3 or anti-CD3 plus PMA gave similar results in CVI patients and normal controls. In vitro stimulation of PBMC with anti-CD40 and various combinations of cytokines (IL-2, IL-4 and IL-10) induced IgG production above 100 ng/ml in one CVI patient out of 13 tested. The data suggest that alterations of IL-10 production are unlikely to play a major role in the pathogenesis of impaired IgG production in most CVI patients. CD40L appears to be normally expressed in two thirds of CVI patients, but it may be functionally defective.     

Long-Term Follow-Up and Outcome of a Large Cohort of Patients with Common Variable Immunodeficiency

Common Variable Immunodeficiency belongs to the group of rare diseases encompassing antibody deficiency syndromes of highly variable clinical presentation and outcome. The multicenter prospective study on a cohort of 224 patients with Common Variable Immunodeficiency provides an updated view of the spectrum of illnesses which occurred at the clinical onset and over a long period of follow-up (mean time: 11 years) and information on the effects of long-term immunoglobulin treatment. The mean age at the time of diagnosis was 26.6 years. Seventy-five patients were younger than 14 years of age. The mean age at the onset of symptoms was 16.9 years. This implicates with a mean diagnostic delay of 8.9 years. Respiratory tract infections were the most prominent clinical problem observed at diagnosis and during the follow-up. Intravenous immunoglobulin administration induced a significant reduction in the incidence of acute infections, mainly acute pneumonia and acute otitis. However, a progressive increase in the prevalence of patients with chronic diseases, mainly sinusitis and lung disease, was observed in all age groups, including the pediatric population. The morbidity of Common Variable Immunodeficiency due to all associated clinical conditions increased over time despite an adequate replacement with intravenous immunoglobulins. Our data stressed the need to develop international guidelines for the prevention and therapy of chronic lung disease, chronic sinusitis, chronic diarrhoea, and chronic granulomatosis in patients with humoral immunodeficiencies. WITHIN THE IPINET (Italian Primary Immunodeficiency Network) IPINET: De Mattia D, Martire B, Bari, Cossu F, Cagliari, Schirilló G, Catania, Castagnola E, Genova, Pietrogrande MC, Delle Piane RM, Milano, Putti C, Padova, Trizzino A, Amato GM, Palermo, Bertolini P, Parma, Zecca M, Pavia, Consolini R, Pisa, Moschese V, Rossi P, Cancrini C, Roma, Cazzola GA, Verona     

Health-Related Quality of Life in Adult Patients with Common Variable Immunodeficiency Disorders and Impact of Treatment

Purpose

Common variable immunodeficiency disorder (CVID) is a primary immunodeficiency disease (PIDD) often associated with severe and chronic infections. Patients commonly receive immunoglobulin (Ig) treatment to reduce the cycle of recurrent infection and improve physical functioning. However, how Ig treatment in CVID affects quality of life (QOL) has not been thoroughly evaluated. The purpose of a recent Immune Deficiency Foundation (IDF) mail survey was to assess the factors that are associated with QOL in patients with CVID receiving Ig treatment.

Methods

A 75-question survey developed by the IDF and a 12-item Short Form Health Survey (SF-12) to assess QOL were mailed to adults with CVID. Mean SF-12 scores were compared between patients with CVID and the general US adult population normative sample.

Results

Overall, 945 patients with CVID completed the surveys. More than half of the patients (54.9%) received intravenous Ig and 44.9% received subcutaneous Ig treatment. Patients with CVID had significantly lower SF-12 scores compared with the general US population regardless of sex or age (p < 0.05). Route of IgG replacement did not dramatically improve QOL. SF-12 scores were highest in patients with CVID who have well-controlled PIDD, lacked physical impairments, were not bothered by treatment, and received Ig infusions at home.

Conclusion

These data provide insight into what factors are most associated with physical and mental health, which can serve to improve QOL in patients in this population. Improvements in QOL can result from early detection of disease, limiting digestive system disease, attention to fatigue, and implementation of an individual treatment plan for the patient.

     

胸外科患者围手术期排痰的护理

目的：为防止术后并发症的产生对肺部感染造成更大风险。方法对我院近1年30例胸外科患者进行围手术期的排痰护理,观察其护理结果。结果排痰护理取得了良好的效果,有助于胸外科患者身体机能的恢复。结论排痰护理可以有效减轻胸外科手术后患者的呼吸道压力,有利于患者的康复。     

Increased Serum Levels of Soluble CD30 in Patients with Common Variable Immunodeficiency and Its Clinical Implications

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by hypogammaglobulinemia and increased susceptibility to recurrent pyogenic infections, autoimmunity, and malignancies. Twenty-five cases with CVID (18 male and 7 female) and 25 healthy volunteers were investigate in this study. Soluble CD30 (sCD30) serum levels of the subjects were measured and compared. Serum levels of sCD30 in the patients with CVID were significantly increased in comparison with controls (36.93 ± 32.38 vs 5.27 ± 1.32 U/ml, P < 0.001). The group of patients with splenomegaly and reversed ratio of CD3+CD4+ T cells/CD3+CD8+ T cells had the highest serum levels of sCD30 (66.01 ± 43.34 U/ml) in comparison with other patients (P = 0.010). High levels of sCD30 in the CVID patients with splenomegaly and the presence of lymphoma in a patient with the highest level of sCD30 may suggest a soluble form of this marker as a prognostic tool in such diseases.     

Immunological Characteristics and Two Novel Mutations in TACI in a Cohort of 28 Pediatric Patients with Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production. Mutations in the gene encoding TACI (TNFRSF13B) were previously found to be associated with CVID. Previous studies have identified a variety of sequence variants in TACI where A181E and C104R were the most common, with variable frequencies in different ethnic populations. So far, no mutations were identified in the recently reported “TACI highly conserved” (THC) cytoplasmic domain, important for the induction of class switch recombination. Our study evaluated immunological and clinical data on a cohort of 28 Argentinean pediatric CVID patients and allowed the identification of two novel mutations in TNFRSF13B, including one, S231R, affecting the highly conserved THC domain. In contrast, none of the patients presented with A181E and C104R mutations.     

Evaluation of Known Defective Signaling-Associated Molecules in Patients Who Primarily Diagnosed as Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease, associated with defective antibody production and recurrent infections. Several defective signaling-associated molecules related to B-cell receptor, T-cell receptor, toll-like receptor, and other immune cell-associated receptors have been identified so far. In this review, defects of cell signaling associated molecules at three levels of surface cytoplasmic, and nuclear molecules are highlighted in patients who primarily diagnosed as CVID. It could be suggested that impaired cell signaling may be involved in the pathogenesis of CVID.     

Modulation of the Interleukin-21 Pathway with Interleukin-4 Distinguishes Common Variable Immunodeficiency Patients with More Non-infectious Clinical Complications

Purpose

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and clinical manifestations such as infections, autoimmunity, and malignancy. We sought to determine if responsiveness to interleukin-21 (IL-21), a key cytokine for B cell differentiation, correlates with distinct clinical phenotypes in CVID.

Methods

CVID subjects were recruited through the Canadian Primary Immunodeficiency Evaluative Survey registry. Peripheral blood mononuclear cells were cultured with anti-CD40 ± interferon-gamma, interleukin-4 (IL-4), IL-21, and/or IL-4+IL-21. B cell subpopulations and IgG production were determined at baseline and day 7 by flow cytometry and ELISA. Clinical complications were compared using contingency tables.

Results

CVID subjects exhibited decreased CD27⁺ B cells and IgG production after 7 days of stimulation with anti-CD40+IL-21 (p < 0.05). In a subset of subjects [CVID responders (R)], the addition of IL-4 led to significant increases in CD27⁺ B cells and IgG (p < 0.05). In CVID non-responders (NR), CD27⁺ B cells and IgG remained lower despite the addition of IL-4. CVID NR experienced significantly more non-infectious clinical complications of CVID than R [OR 8.8, 95% confidence interval (CI) 1.6 to 48.13]. Previous studies reported that CVID subjects with ≤ 2% class-switched memory B cells were more at risk of these complications, but no significant association was found among this cohort of subjects [OR 3.5, CI 0.9 to 13.3]. In fact, 34.6% of CVID NR had > 2% class-switched memory B cells at baseline.

Conclusions

The IL-4 and IL-21 in vitro assays distinguish two groups of CVID subjects and can be used with baseline B cell subpopulation phenotyping to better identify patients experiencing more vs. fewer clinical non-infectious complications and potentially to modulate therapy.

     

Primary Leiomyosarcoma of Brain in an Adolescent with Common Variable Immunodeficiency Syndrome

A 14-year-old girl with common variable immunodeficiency syndrome was found to have a low-grade malignant neoplasm arising in the left temporal lobe of the brain. Ultra-structural and immunohistochemical studies established a diagnosis of leiomyosarcoma, despite the rarity of this tumor in children. In situ hybridization with the EBER probe revealed essentially all of the neoplastic cells to be infected with Ep-stein-Barr virus (EBV). Children with the acquired immunodeficiency syndrome (AIDS) are known to exhibit an increased incidence of smooth muscle tumors associated with EBV. Similar tumors have been reported in EBV-infected patients undergoing therapeutic immunosuppression. This appears to be the first reported case of childhood leiomyosarcoma where the cause of the underlying immunodeficiency was a genetic rather than acquired disorder. The authors conclude that electron microscopy, immunohistochemistry, and other ancillary techniques are essential in the evaluation of unusual tumors in immunocompromised children, whether the cause is hereditary or acquired.     

Ill-Defined Germinal Centers and Severely Reduced Plasma Cells are Histological Hallmarks of Lymphadenopathy in Patients with Common Variable Immunodeficiency

Given the severely reduced numbers of circulating class-switched memory B cells and plasmablasts in patients with common variable immunodeficiency (CVID) the germinal center (GC) reaction as the source of both populations is expected to be disturbed in many CVID patients. Therefore immunohistochemical studies were performed on lymph node (LN) biopsies from ten CVID patients with benign lymphoproliferation. According to the Sander classification the majority of patients presented with reactive lymphoid hyperplasia (7/10), 6/10 showed granulomatous inflammation. All cases showed some normal GCs but in 9/10 these concurred to a varying degree with hyperplastic, ill-defined GCs in the same LN. The percentage of ill-defined GCs correlated significantly with the percentage of circulating CD21^low B cells suggesting a common origin of both immune reactions. In 9/10 CVID LNs significantly higher numbers of infiltrating CD8⁺ T cells were found in GCs of CVID patients compared to controls, but no HHV-8 and only in 2/10 LNs EBV infection was detected. Class switched plasma cells (PCs) were severely reduced in 8/10 LNs and if present, rarely found in the medulla of the LN. Based on the presence of large GCs in all examined patients, the reduction of circulating memory B cells and PCs points towards a failure of GC output rather than GC formation in CVID patients with lymphadenopathy.