CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency.

Common variable immunodeficiency (CVI) is characterized by hypogammaglobulinemia and recurrent bacterial infections due to failure of CVI B cells to differentiate in vivo into immunoglobulin-secreting plasma cells. We hypothesized that T-cell dysfunction resulting in abnormal contact-mediated B-cell activation may play a prominent role in the failure of CVI B cells to produce specific antibody. We have previously shown that B-cell proliferation and IgE production after stimulation with anti-CD40 and interleukin (IL) 4 were normal in 22 CVI patients evaluated, indicating that CVI B cells respond to signals delivered via CD40. Here we report that CD40 ligand (gp39) mRNA expression by activated lymphocytes from CVI patients (n = 31) as a group was significantly depressed (P < 0.0001) compared with normal controls (n = 32). gp39 mRNA expression by activated lymphocytes from 13 CVI patients fell below the normal control range. T-cell surface expression of functional gp39 protein was correspondingly low in those patients with gp39 mRNA levels below normal control range and normal in patients with gp39 mRNA levels within normal control range. In CVI patients as a group, gp39 mRNA levels correlated with IL-2 mRNA levels (P < 0.002, r = 0.6) and production (P < 0.001, r = 0.7) but not with gene expression or production of other lymphokines evaluated, suggesting an as-yet-undetermined association between gp39 and IL-2 gene regulation. Of the 13 patients whose activated T cells exhibited gp39 mRNA expression below the normal control range, 2 had normal T-cell-derived lymphokine production, whereas the remaining 11 exhibited broader T-cell dysfunction, resulting in IL-2 deficiency, and in some patients deficient production of other lymphokines as well, reflecting a heterogeneity in the underlying mechanisms leading to depressed gp39 expression in these patients. The observation that both gene and surface expression of gp39 by activated T cells is depressed in a subgroup of CVI patients suggests that inefficient signaling via CD40 may be responsible, in part, for failure of B-cell differentiation in these patients.     

A defect in the early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency

Common variable immunodeficiency (CVID) is characterized by an impairment of specific antibody production and a decrease in all or selected Ig isotypes. Abnormalities at the level of the B cells, T cells, and antigen-presenting cells have been described. In the present study, we have focused our attention on T-cell activation in CVID. T cells from 15 of 24 patients failed to respond to recall antigens (eg, tetanus toxoid, Escherichia coli). Of these 15 patients, 11 were studied in detail and showed significantly decreased T-cell proliferative responses and/or decreased interleukin-2 and interferon- gamma production on T-cell receptor-mediated stimulation with recall antigens and superantigens (staphylococcal enterotoxins [SE]); however, T-cell response to mitogens (anti-CD3 monoclonal antibody, phytohemagglutinin) was normal. The defect in interleukin-2 and interferon-gamma release on tetanus toxoid stimulation could also be documented in purified CD4 T cells of the patients and was present in patients with high and normal CD8 counts alike. Furthermore, patients' T cells failed to mount a significant elevation in free intracellular calcium (Ca++ flux) in response to superantigen, whereas the response to phorbol myristate acetate and ionomycin, bypassing receptor-mediated signaling, was unimpaired. These results indicate a defect in the early phase of T-cell activation after triggering of the T-cell receptor in a significant subgroup of CVID patients.     

Characterization of common variable immunodeficiency: identification of a subset of patients with distinctive immunophenotypic and clinical features

The peripheral blood lymphocyte surface markers and clinical features of 38 patients with common variable immunodeficiency (CVID) were assessed. These studies identified a subset of CVID consisting of 14 of the 38 patients with a distinctive T-cell immunophenotype and clinical findings. The phenotypic changes were characterized by an abnormally low CD4/CD8 ratio (less than or equal to 0.9) due primarily to a significant increase in CD8 T cells. In addition, there was an expansion in CD8 T cells coexpressing CD57 and increased expression of the activation markers HLA-DR and interleukin-2 receptor (IL-2R) by these cells. This group of immunophenotypically abnormal CVID patients also had characteristic clinical features, including splenomegaly (P less than .02) and in vivo T-cell dysfunction based on the evaluation of delayed-type hypersensitivity (P less than .05). Approximately 71% of these patients had splenomegaly and 42% were anergic in contrast to the remaining group of CVID patients, in which 29% had splenomegaly and 7% were anergic. These findings define a subgroup of CVID patients that have specific immunophenotypic features and functional T-cell abnormalities.     

Functional abnormalities of CD8+ T cells define a unique subset of patients with common variable immunodeficiency

A substantial subgroup of patients with common variable immunodeficiency (CVI) exhibit an abnormal T-cell phenotype characterized by a low CD4/CD8 ratio associated with a significant increase in the absolute number of CD8+ T cells (CVI4/8low patients). In the present study, we examined the phenotypic and functional properties of purified T-cell subsets in this group of CVI patients. CD8+ T cells from CVI4/8low patients manifested increased expression of HLA-DR and CD57 and decreased expression of CD45RA as compared with CD8+ T cells from normal controls. When stimulated with anti-CD3 and phorbol 12-myristate 13-acetate, purified patient CD8+ T cells exhibited significantly decreased proliferation, c-myc expression, and interleukin-2 (IL-2) production compared with that of normal CD8+ T cells. Nevertheless, mitogen-activated patient CD8+ T cells secreted elevated amounts of gamma-interferon and IL-5 and normal amounts of IL- 4. This abnormal pattern of proliferation and cytokine production was limited to the CD8+ T-cell subset as CD4+ T cells from these patients exhibited normal proliferation and cytokine production. In further functional studies, purified CD8+ T cells from CVI4/8low patients manifested increased cytotoxic T-lymphocyte activity and suppressor activity, as compared with normal CD8+ T cells, when they were tested in (1) an anti-CD3 "redirected" cytotoxicity assay and (2) a suppressor assay consisting of CD8+ T cells and Staphylococcus aureus Cowan I (SAC) plus IL-2-stimulated normal (allogeneic) B cells. In the latter case, patient CD8+ T cells suppressed IgG production, but not IgM production. Finally, in studies to evaluate the role of patient CD8+ T cells in the pathogenesis of hypogammaglobulinemia, we determined the capacity of SAC and IL-2 to induce Ig production in highly purified patient B cells, ie, in the absence of patient CD8+ T cells. We found that, whereas B cells from one patient produced normal amounts of IgG, B cells from three patients were unable to produce normal amounts of IgG under these conditions. These data establish the phenotypic and functional characteristics of CD8+ T cells in CVI4/8low and clearly distinguish CVI4/8low patients from other patients with this syndrome. The data do not support the contention that hypogammaglobulinemia in CVI4/8low patients is due to a direct effect of CD8+ T cells on terminal B-cell differentiation, except in the occasional patient. The abnormal CD8+ T cells may, nevertheless, have more subtle effects of lymphoid function that play a role in disease pathogenesis.     

Gastric pathology in patients with common variable immunodeficiency

BACKGROUND/AIMS: Common variable immunodeficiency (CVID) is an immunological disorder characterised by defective antibody production. Patients with CVID have a high risk of gastric cancer. It has been suggested that gastric cancer results from an interaction between environmental factors and a genetic predisposition. The role of Helicobacter pylori as an environmental factor in gastric carcinogenesis is of current interest. Moreover, p53 gene mutations have been reported in gastric cancer. This study focuses on the gastric pathology of patients with CVID and correlation with H pylori infection. METHODS: Thirty four consecutive dyspeptic patients with CVID (mean age 49.6 years, range 14-72; 17 men) were included in the study. An upper gastrointestinal endoscopy was performed and biopsy specimens were taken from the antrum, incisura angularis, and gastric body. Biopsies were used for histological assessment, to identify the presence of H pylori, and to evaluate p53 overexpression. RESULTS: H pylori infection was detected in 14/34 (41%) patients. Chronic active gastritis involving both antrum and body was observed more frequently in H pylori positive (79%) than H pylori negative (20%) patients (p = 0.001). Similarly, a histological feature of multifocal atrophic gastritis was found more frequently in infected (50%) than uninfected patients (10%) (p = 0.012). In addition, one case of gastric adenocarcinoma and another of notable dysplasia were observed in the H pylori positive group. Overexpression of p53 was found in six (18%) patients, including one with normal gastric mucosa. CONCLUSIONS: It can be hypothesised that both H pylori and p53 alterations play a role in the gastric carcinogenesis of patients with CVID.     

Lung disease in patients with common variable immunodeficiency

BackgroundCommon Variable Immunodeficiency (CVID) is characterized by an impaired antibody production and a higher susceptibility to encapsulated bacterial infections. Lung disease is considered to be the most important cause of morbidity and mortality.MethodsWe analyzed clinical, radiological and functional characteristics in 80 patients with CVID assisted in the Unidad Inmunologia e Histocompatibilidad at Durand Hospital from 1982 to 2018.ResultsOf the 80 patients, 55 showed pathologic lung Computed Tomography (CT). Twenty of them (36.4%) showed bronchiectasis; 26 (47.3%) interstitial involvement associated with nodules and adenopathies called GLILD (granulomatous-lymphocytic interstitial lung disease); and nine patients (16.3%) showed other lesions. Nine percent of patients with lung disease showed CT progression; none of them had spirometry worsening. GLILD patients had normal and restrictive patterns in lung function tests, in equal proportions. Two patients – one with GLILD and the other one with bronchiectasis – had an increase in spirometric pattern severity without CT progression. Lung biopsy was performed in 19% of GLILD patients, all of whom had histopathologic diagnosis of Lymphoid Interstitial Pneumonia (LIP).ConclusionsGLILD is the major cause of lung disease in CVID. Computed tomography is useful for diagnosis but not necessary in follow-up, in which functional tests should have better correlation with clinical evolution, reducing radiation exposure. Biopsy should be indicated when the clinical diagnosis is unclear. Treatment should be considered whenever there is clear evidence of disease progression.     

Abnormal CD45R expression in patients with common variable immunodeficiency and X-linked agammaglobulinaemia

This study has investigated the patterns of membrane 2H4 (CD45RA) and UCHL1 (CD45RO) expression by CD4+ and CD8+ lymphocyte subpopulations in 10 adults and seven children with common variable immunodeficiency (CVI) and X-linked hypogammaglobulinaemia (XLA). Of the 10 adults (CVI, n = 8; XLA, n = 2), only one with a diagnosis of CVI showed normal CD45R expression. For the remaining seven adult CVI patients the abnormal CD45R profiles were primarily associated with CD4+ lymphocytes in three and CD8+ lymphocytes in four. Specific increases in CD45RA- CD45RO+ fractions were found in four CVI patients and in all of these there was a concomitant reduction in circulating CD19+ B-cell numbers. Two of the CVI cases were identical twin sisters and both had the same CD45R abnormality. The two adults with XLA also showed abnormal CD45R expression (increased CD45RA+ CD45RO- components) but of particular note, in view of the fact that these were brothers, one was associated with the CD4+ subpopulation and the other with the CD8+ fraction. Similar analyses for the paediatric group revealed, in distinct contrast to the adult patients, no significant abnormalities of CD45R expression suggesting that these defects may not become apparent until a later age. Further investigations of in vitro lymphocyte proliferation (PHA and PWM) in the eight adults with CVI showed a significant correlation between abnormal responses and disordered CD45R expression. It is proposed that these abnormal patterns of CD45R expression by lymphocyte subpopulations in CVI and XLA may be of fundamental importance with respect to the pathogenesis of these particular immunodeficiencies.     

Gastrointestinal complications in two patients with common variable immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and recurrent bacterial infections especially in respiratory and gastrointestinal systems. We present here 2 cases of CVID with gastrointestinal complications.Case 1 is a 25-year-old man with a history of chronic diarrhoea from childhood. Ultrasonography revealed ascites, with liver size smaller than normal. Liver biopsy showed non-specific hepatitis. Lymphoid proliferation and Histiocytosis were reported in his ascites cytology. Moreover friability in colonoscopy due to moderate active chronic colitis was detected. Case 2 is a 26-year-old man with chronic diarrhoea since 8 years. Abdominal sonography revealed increased liver echogenicity, increased liver size, and some enlarged lymph nodes beside pancreas. Colonoscopy revealed friability and decreased vascularity while biopsy showed moderate active chronic colitis. Lymph node biopsy showed unusual immunologic reaction. Moreover, small bowel transition test showed nodularity. CVID should be considered in any patient with gastrointestinal manifestations especially chronic diarrhoea in association with recurrent bacterial infections in other organs. Diagnostic delay results in more morbidity and complications in untreated patients..     

CD40 ligand expression on stimulated T-helper lymphocytes in patients with common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most common symptomatic primary antibody deficiency, characterized by reduced serum immunoglobulins levels and increased susceptibility to recurrent pyogenic infections. In this study, we evaluated CD40 ligand expression on stimulated versus unstimulated T-helper lymphocytes of nine Common variable immunodeficient patients in comparison with fifteen normal controls. Phorbol myristate acetate (PMA) and Ionomycin were used to stimulate cells in vitro. After six hours stimulation, the cells were subjected to surface staining with three-color staining procedure. Events were analyzed by flow cytometer, using FloMax software. Results were reported as the percentage of lymphocytes expressing CD markers. We did not find any significant statistical difference in CD40 ligand expression between patients and controls (p > 0.05), despite having stimulation documented by CD69 expression as activation marker in each run. The results of this study are in agreement with some other studies, indicating that CD40 ligand expression on stimulated T-helper lymphocytes of Common variable immunodeficiency patients is similar to normal controls.     

Hodgkin disease in a patient with common variable immunodeficiency

Extensive extralymphatic Hodgkin disease developed in a young man with common variable immunodeficiency manifested by hypogammaglobulinemia, recurrent sinopulmonary infections, and multiple autoimmune phenomena. Both humoral and cell-mediated immune dysfunction were present prior to treatment. After two cycles of chemotherapy, irreversible shock developed, and death occurred secondary to overwhelming infection in spite of prophylactic gammaglobulin replacement. The unusual features of this patient's case of extralymphatic Hodgkin disease in association with a primary immunodeficiency disorder have not been previously reported.     

普通变异型免疫缺陷病相关性间质性肾炎

青年女性患者,因肾功能不全、血红蛋白和血小板减少、脾肿大、多处淋巴结肿大及免疫球蛋白和补体减低入院,肾活检组织学为肾间质弥漫浸润细胞伴肾小管损伤,结合临床及实验室检查诊断普通变异型免疫缺陷病相关性间质性肾炎.     

Severe hypoleptinaemia associated with insulin resistance in patients with common variable immunodeficiency

Objective Common variable immunodeficiency (CVI) is a primary immunodeficiency syndrome characterized by impaired production of antibodies and recurrent infections. Delay in diagnosis leads to metabolic wastage and low body weight. Leptin, a hormone produced by white adipose tissue, modulates insulin action by signal transduction cross‐talk and by direct action on pancreatic beta‐cells. We hypothesized that patients with CVI might present a defective regulation of leptin production and insulin resistance. Patients Thirteen CVI patients (39 ± 11 years) under gammaglobulin replacement were evaluated in parallel with 13 gender‐, age‐, body weight‐ and body mass index (BMI)‐matched healthy voluntaries, and with data from two large population series, the Bruneck and the Hoorn Studies. Measurements Serum leptin and insulin levels, homeostasis model assessment – insulin resistance (HOMA‐IR), body composition, haematological, biochemical and immunoglobulin measurements were obtained. Data were analysed by a one‐way analysis of variance (anova ) and by Pearson's rank analysis. The institutional ethics committee approved the study, and informed consent was obtained from patients and controls. Results No differences were found between CVI and the control group when comparing gender distribution, age, body weight, BMI, waist/hip ratio, relative body fat and fasting glucose levels. Leptin levels were lower (P < 0·05) in CVI patients than in controls and lower than fasting leptin levels detected in a large population study. CVI patients’ serum leptin levels did not correlate with BMI (r = 0·074, P = 0·8) and their high HOMA‐IR indicated insulin resistance. Conclusions CVI patients are relatively hypoleptinaemic and insulin resistant, and their serum leptin levels are not correlated to their BMI.     

Duodenal pathology and clinical-immunological implications in common variable immunodeficiency patients

OBJECTIVES: Common variable immunodeficiency (CVID) is an immunological disorder characterized by defective antibody production. An increased prevalence of celiac disease has been suggested in patients with this disorder. This study aimed to assess duodenal pathology and its clinical implications in these patients. METHODS: A total of 32 consecutive CVID patients with anemia or GI symptoms were enrolled. Patients underwent upper endoscopy, and biopsy specimens were taken in the descending duodenum for histological assessment. A blood sample was obtained to determine immunoglobulin and Hb levels and to evaluate the CD4+ T-lymphocyte count. Body mass index was calculated for all patients. RESULTS: Histological assessment of duodenal specimens revealed the presence of villous atrophy in 10 (31.2%) patients, a feature of nodular lymphoid hyperplasia in five (15.6%), and mild duodenitis in two (6.3%), whereas normal histology was observed in the remaining 15 (46.9%) patients. Patients with villous atrophy had anemia more frequently than those without, whereas the frequency of persistent diarrhea did not differ between these two groups. Moreover, both CD4 levels and body mass index were significantly lower in patients with atrophy than in controls. CONCLUSIONS: Duodenal villous atrophy is very frequent in symptomatic CVID patients, with relevant clinical and immunological implications. Specifically, this histological alteration is significantly associated with anemia, malnutrition, and low blood CD4+ lymphocyte levels.     

Intrinsic neutrophil defects in a child with impaired neutrophil chemotaxis and immunodeficiency

A boy with recurrent pyogenic infection was found to have occasional neutropenia, defective neutrophil chemotaxis, hypogammaglobulinemia with increased IgM, and impaired cellular immunity. The T and B lymphocytes were defective in IgG production in vitro. Ultrastructure of the neutrophils was normal. The marrow cells formed normal numbers of granulocytic colonies in culture, but the colonies were apparently small in size. The levels of colony-stimulating activity were normal. The lymphocytes did not impair granulopoiesis of control marrow cells. These data indicate that the neutropenia and defective neutrophil chemotaxis are due to the intrinsic neutrophil defects and are not secondary to T and/or B lymphocyte dysfunctions in the patient.     

Gastrointestinal alterations in a female patient with common variable immunodeficiency

We present the case of a 33-year-old woman who complained of intermittent diarrhea over the previous 8 years and who was diagnosed with common variable immunodeficiency. The woman presented antral atrophic gastritis, partial atrophy of the duodenal villi, nodular lymphoid hyperplasia of the small intestine and lymphocytic colitis. We also review the literature.     

Late complications of chronic respiratory infections in patients with common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most frequent serious humoral deficiency manifested in adulthood in the form of acute and chronic respiratory infections which in most patients lead to respiratory failure. Retrospective analysis of 28 CVID patients was made. Mean age at time of diagnosis was 38.6 +/- 18.6 years. The time which elapsed from the first symptoms to determining the diagnosis was three times as long as that indicated in other studies, i.e., 14.1 +/- 10.2 years. Twenty-three patients (82.1%) had respiratory complications. Chronic obstructive pulmonary diseases, n=16 (57.1%), and bronchiectasis, n=10 (35.7%), were the most frequent types of lung damage. In addition, two patients (7.1%) displayed evidence of interstitial lung process. Morbidity associated with CVID can be reduced by early diagnosis and adequate dosage of immunoglobulins to minimise the occurrence and progression of lung damage.