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Results for “Common Variable Immunodeficiency”

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PubMed1996

Intracellular cytokine production by human CD4+ and CD8+ T cells from normal and immunodeficient donors using directly conjugated anti-cytokine antibodies and three-colour flow cytometry.

Using three-colour flow cytometry, we have measured intracellular IL-2, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) induced in human CD4+ and CD8+ T cells from normal donors and patients with common variable immunodeficiency (CVID). Since a new range of directly FITC-conjugated anti-cytokine antibodies was used, conditions were optimized for the concentration of antibody, for cell permeabilization and fixation, and for the time of exposure to monensin to retain the cytokines within the cell. Kinetics of intracellular cytokine production were measured for up to 20 h in culture with phorbol myristate acetate (PMA) and ionomycin, or with phytohaemagglutinin (PHA). Kinetic studies of activation with PMA and ionomycin show that a higher proportion of normal CD4+ cells can make IL-2 than the other two cytokines, and that there are more TNF-alpha-positive CD4+ cells than cells with IFN-gamma. For normal CD8+ cells the highest production of cytokine is of IFN-gamma (up to 50% of the cells) especially at longer times (10-20 h) of stimulation. For CD8+ cells, IL-2-positive cells exceed those with TNF-alpha. The other mitogenic stimulus used (PHA) was grossly inferior to PMA and ionomycin in its ability to induce intracellular cytokines. The time of exposure to monensin was also examined. Its continuous presence in the cultures (up to a maximum of 20 h) increased the detection of IL-2-positive cells without apparently reducing the percentage of cytokine-positive CD4+ or CD8+ cells. Finally, using optimal conditions, we compared cytokine production in cells from patients with the disease CVID and showed normal cellular levels of ability to produce IL-2 and TNF-alpha but significantly raised levels of production of IFN-gamma in both CD4+ and CD8+ lymphocytes. This suggests that the pathology of this disease may involve an excessive Th1-type response.

Adult↗

PubMed2004

Failure to clear persistent vaccine-derived neurovirulent poliovirus infection in an immunodeficient man.

BACKGROUND: Individuals who chronically excrete neurovirulent poliovirus of vaccine-origin are of considerable concern to the Global Polio Eradication programme. Chronic infection with such polioviruses is a recognised complication of hypogammaglobulinaemia. METHODS: We did a series of in-vitro and in-vivo therapeutic studies, with a view to clearing persistent neurovirulent poliovirus infection in an individual with common variable immunodeficiency, using oral immunoglobulin, breast milk (as a source of secretory IgA), ribavirin, and the anti-picornaviral agent pleconaril. We undertook viral quantitation, antibody neutralisation and drug susceptibility assays, and viral gene sequencing. FINDINGS: Long-term asymptomatic excretion of vaccine-derived neurovirulent poliovirus 2 was identified in this hypogammaglobulinaemic man, and was estimated to have persisted for up to 22 years. Despite demonstrable in-vitro neutralising activity of immunoglobulin and breast milk, and in-vitro antiviral activity of ribavirin, no treatment was successful at clearing the virus, although in one trial breast milk significantly reduced excretion levels temporarily. During the course of study, the virus developed reduced susceptibility to pleconaril, precluding the in-vivo use of this drug. Sequence analysis revealed the emergence of a methionine to leucine mutation adjacent to the likely binding site of pleconaril in these isolates. INTERPRETATION: Chronic vaccine-associated poliovirus infection in hypogammaglobulinaemia is a difficult condition to treat. It represents a risk to the strategy to discontinue polio vaccination once global eradication has been achieved.

Adult↗

PubMed1998

Genetic basis of abnormal B cell development.

A susceptibility gene in the MHC class III region may underlie the defective B-cell differentiation in familial IgA deficiency and common variable immunodeficiency. Mutations in Bruton's tyrosine kinase, immunoglobulin heavy chain and lambda 5/14.1 surrogate light chain loci disrupt B-cell development to cause profound antibody deficiency. Mutational, biochemical and transgenic studies offer insight into the function of these and other 'antibody deficiency genes'.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2001

[A case of pediatric recurrent acute mastoiditis caused by penicillin-resistant Streptococcus pneumonia complicated by primary immunodeficiency].

Penicillin-resistant Streptococcus pneumoniae (PRSP) is a frequently detected pathogen of intractable acute otitis media and is associated with prolonged or recurrent infection. The use of antibiotics has made the incidence of secondary acute mastoiditis following acute otitis media relatively rare, but when it does occur, its severe complications may be life-threatening. We report a case of pediatric recurrent acute mastoiditis caused by PRSP in a 6-year-old boy suffering from PRSP acute mastoiditis on 4 occasions, twice undergoing simple mastoidectomy. Although we initially suspected PRSP to be the chief factor in iterative infection, immunological analysis demonstrated significantly decreased IgG and IgA antibodies in serum and the patient was diagnosed as having common variable immunodeficiency (CVID). As the first middle ear infection occurred at the age of 6 and there was no history of upper respiratory tract infection, CVID may be the main pathological factor of recurrent mastoiditis, although infection occurred, only in the ear and did not involve other organs. This suggests that recurrent mastoiditis in the present case involved the coexistence of PRSP and CVID.

Acute Disease↗

PubMed1998

Expression of Pax5 gene in human haematopoietic cells and tissues: comparison with immunodeficient donors.

In mice, Pax5 gene is indispensable for B cell development. Pax5-deficient mice fail to produce mature B cells owing to complete arrest of B cell development at a precursor stage. However, the lineage and stage of human Pax5 gene expression have remained elusive. In this investigation expression of the human Pax5 gene was studied. Pax5 gene expression was detected in B cell lines but not in myeloma cell lines. CD19 expression was correlated with Pax5 gene expression. Adult spleen and bone marrow and fetal spleen and liver showed strong Pax5 gene expression, as did the corresponding mouse tissues, as reported previously. In common variable immunodeficiency (CVID) peripheral blood lymphocytes (PBL) with a decreased number of B cells, no Pax5 gene expression was detected. Some CVID PBL stimulated with IL-2, IL-10 and anti-CD40 monoclonal antibody, expressed the Pax5 gene. Defect of Pax5 gene expression in CVID may be caused by regulatory T cell disorder.

Adolescent↗

PubMed2006

The broad spectrum of autoimmune lymphoproliferative disease: molecular bases, clinical features and long-term follow-up in 31 patients.

Autoimmune lymphoproliferative disorders, including autoimmune lymphoproliferative syndrome (ALPS) and Dianzani autoimmune lymphoproliferative disease (DALD), are inherited defects of the Fas apoptotic pathway characterized by lymphoid accumulation and autoimmune manifestations. We report the molecular, clinical, immunologic features and the long-term progress of 31 patients. Four carried Fas gene mutations and one also displayed a caspase 10 polymorphism that probably contributed to the phenotype. Seven patients developed antibody deficiency and their clinical pictures overlapped those of subjects with common variable immunodeficiency (CVID). We postulate the existence of a disorder that involves the Fas pathway and displays the characteristics of both autoimmune lymphoproliferative disease and CVID.

Adolescent↗

PubMed1997

[Successful gamma globulin therapy in a patient with anti-IgA antibodies].

A case report of a patient suffering from common variable immunodeficiency with anti-IgA antibodies is described. These antibodies were probably the cause of repeated anaphylactic reactions during substitution gammaglobulin treatment, and lead to discontinuation the therapy lasting 4 years. The reintroduction the therapy was enabled by the therapy with low-IgA contents intravenous immunoglobulin (Endobulin, Immuno Vienna).

Antibodies, Anti-Idiotypic↗

PubMed2001

Immune dysfunction in refractory sinusitis in a tertiary care setting.

OBJECTIVE: To examine the contribution of the primary immunodeficiency states, which are uncommon in the general population, to refractory sinusitis. STUDY DESIGN: We retrospectively reviewed the charts of 316 patients with sinusitis who were referred to the Allergy and Immunology Clinic for immunological evaluation from 1991 to 1997. METHODS: Of the 316 patients, 79 were selected for further study. Inclusion criteria included at least one sinus surgery and/or sinusitis diagnosed by endoscopy and/or computed tomography (CT) scan at least three times in the previous year. Patients with human immunodeficiency virus (HIV), allergic fungal sinusitis, cystic fibrosis, and primary ciliary dyskinesia were excluded. The results of their immunological evaluation for atopy, T-lymphocyte function, and immunoglobulin levels were examined. RESULTS: The average age of these 79 patients was 44 years (+/- 14.5 standard deviation [SD]). They had, on average, 2.94 (+/- 2.19 SD) previous operations and had mean sinus CT scores (Lund-McKay) of 11.2 (+/- 5.0 SD). Forty of 79 (50.6%) patients had at least one positive result on skin test to an aeroallergen. Delayed hypersensitivity skin testing revealed that 22 of 55 patients (40%) were anergic. Of the 60 patients with in vitro T-lymphocyte function testing, 54.8% showed abnormal proliferation in response to recall antigens, 11.3% had decreased response to alloantigen, and 26.3% demonstrated decreased response to T-cell mitogens. Determination of quantitative immunoglobulins showed low immunoglobulin G in 14 of 78 patients (17.9%), low immunoglobulin A in 13 of 78 (16.7%), and low immunoglobulin M in 4 of 78 (5.1%). Common variable immunodeficiency (CVID) was diagnosed in 9.9% of patients, and selective IgA deficiency was found in 6.2%. CONCLUSIONS: This retrospective review reveals an unexpectedly high incidence of immune dysfunction. These results suggest that immunological testing should be an integral part of the evaluation of patients with refractory sinusitis.

Adult↗

PubMed1999

Treatment of cutaneous sarcoidosis using phonophoresis.

Sarcoidosis is a multiple-system disorder of unknown origin characterized histologically by epithelioid granulomas with little or no necrosis. We describe a 32-year-old female patient with a history of systemic sarcoidosis and common variable immunodeficiency with recurrent, multiple, soft, erythematous and violaceous nodules on the back of her left hand. Her lesions responded to phonophoresis after unsuccessful treatment with topical and intralesional corticosteroids. However, nodules appeared on other parts of her body after phonophoresis was stopped, which suggests that phonophoresis had a localized rather than systemic effect.

Administration, Cutaneous↗

PubMed2003

Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen.

Splenectomized and asplenic patients have a high incidence of infections by encapsulated bacteria and do not respond to polysaccharide vaccines. To understand whether the absence of the spleen is associated with a defined B cell defect, we analyzed B cell subsets in the peripheral blood. We found that a population of B cells known as immunoglobulin (Ig)M memory is lacking in patients without spleen. The absence of IgM memory B cells correlates with an impaired immune response to encapsulated bacteria not only in splenectomized patients, but also in individuals with an intact spleen. We show that the physiological and transient predisposition to pneumococcal infections of young children (0-2 yr) is associated with the lack of circulating IgM memory B cells and of serum antipolysaccharide IgM. We also demonstrate that IgM memory B cells are undetectable in a fraction of patients with common variable immunodeficiency, who have recurrent and invasive infections by encapsulated bacteria. IgM memory B cells, therefore, require the spleen for their generation and/or survival and are responsible for the protection against encapsulated bacteria.

Adult↗

PubMed2005

Cardiac conduction abnormalities and congenital immunodeficiency in a child with Kabuki syndrome: case report.

BACKGROUND: Since it's recognition in 1981, a more complete phenotype of Kabuki syndrome is becoming evident as additional cases are identified. Congenital heart defects and a number of visceral abnormalities have been added to the typical dysmorphic features originally described. CASE REPORT: In this report we describe the clinical course of a child diagnosed with Kabuki syndrome based on characteristic clinical, radiological and morphologic features who died of a cardiac arrhythmia at 11-months of age. This infant, however, had abnormal pulmonary architecture and alterations in his cardiac conduction system resulting in episodes of bradycardia and asystole. This child also had an immunological phenotype consistent with common variable immunodeficiency. His clinical course consisted of numerous hospitalizations for recurrent bacterial infections and congenital hypogammaglobulinemia characterized by low serum IgG and IgA but normal IgM levels, and decreased antibody levels to immunizations. T-, B- and NK lymphocyte subpopulations and T-cell function studies were normal. CONCLUSION: This child may represent a more severe phenotype of Kabuki syndrome. Recurrent infections in a child should prompt a thorough immunological evaluation. Additionally, electrophysiology testing may be indicated if cardiopulmonary events occur which are not explained by anatomic defects.

Abnormalities, Multiple↗

PubMed1998

Juvenile rheumatoid arthritis and common variable hypogammaglobulinemia.

We describe a 9-year-old white boy with systemic juvenile rheumatoid arthritis (JRA) who developed pancytopenia and hypersplenism at the age of 13 years. He underwent splenectomy and 3 years later he developed Coombs' positive hemolytic anemia, alopecia, juvenile warts, and multiple bacterial infections. At that time, investigations were compatible with severe hypogammaglobulinemia associated with common variable immunodeficiency. Concomitantly with this condition he experienced complete remission of his inflammatory arthritis. Immunologic studies of B and T lymphocyte function showed that the number of circulating T and B lymphocytes were normal, while T cell function was depressed, as evidenced by markedly reduced proliferative responses to mitogens and antigens, and ability to mediate B cell help. In addition, his circulating B cells were unable to secrete IgM or IgG. He also exhibited anergy to intradermal challenge with a battery of common antigens. The literature dealing with this clinical association is reviewed, and possible immunologic mechanisms involved are discussed.

Agammaglobulinemia↗

PubMed1994

[Kaposi's disease in a female patient with acquired HIV-negative immunodeficiency].

A 79-year-old woman of Mediterranean ascent suffered from corticosteroid-dependent chronic obstructive lung disease, hypogammaglobulinemia (IgG 1 and 2), decreased CD16 natural killer cell function and non-HIV related CD4 and CD8 lymphopenia. Such immunodeficiency could be either a variant of common variable immunodeficiency or an early stage of the idiopathic CD4 + T lymphocytopenia syndrome. She developed bilateral lesions of Kaposi's sarcoma on the lower extremities resembling the classic European type of the disease. The tumors contained both CD34 + and Factor XIIIa + cells. The HLA-DR5 haplotype was not found. Weekly low intravenous dosages of vinblastine improved the lesions but the patient died from pontic infarction.

Aged↗

PubMed1999

Acquired perforating dermatosis in diabetes mellitus: an unusual case.

A case of elastosis perforans serpiginosa in a patient who presented with insulin-dependent diabetes mellitus secondary to pancreatic insufficiency in a background of common variable immunodeficiency and endocrinopathy, as evidenced by pernicious anaemia and growth hormone deficiency, is described. In acquired perforating dermatosis occurring in patients with diabetes or renal failure, there is a spectrum of changes that may show an overlap of histological features of the four classic perforating diseases. The biopsy changes of the patient described in the present study most closely resembled those of elastosis perforans serpiginosa.

Adolescent↗

PubMed1998

B-cell development: a comparison between mouse and man.

A common variable immunodeficiency (CVID) patient, who carries mutations on both alleles of the gene encoding the surrogate light chain component lambda 5/14.1, shows a similar phenotype of B-cell deficiency as the lambda 5-deficient mutant mouse. As discussed here by Paolo Ghia and colleagues, this points to a remarkably similar developmental pathway of B cells in humans and mice.

Age Factors↗

PubMed2002

Hypogammaglobulinaemia: cumulative experience in 49 patients in a tertiary care institution.

In this paper, clinical data of 49 adult patients with agammaglobulinaemia (syn. hypogammaglobulinaemia), 15 cases of X-linked agammaglobulinaemia (XLA) and 34 of common variable immunodeficiency (CVID) are reviewed. Although immunoglobulin substitution largely abolished life-threatening respiratory tract infections, considerable infectious and non-infectious morbidity was still encountered in these patients. Almost all patients suffered from chronic or recurrent upper and lower airway infections, mainly caused by Haemophilus influenzae and pneumococci. The lower respiratory tract infections led to cumulative damage to the respiratory tract, especially in XLA patients. Also the incidence of infections outside the respiratory tract (giardiasis, Campylobacter jejuni infections) was more common in XLA patients than in CVID patients. Nodular lymphoid hyperplasia was only found in CVID. A variety of other non-infectious complications were seen especially in CVID. Neoplastic complications occurred in nine patients (two cases of thymoma, two colorectal cancer, one gastric carcinoma, two haematological malignancies, two cases of skin cancer). Six patients died (five XLA patients and one CVID patient, from infectious and non-infectious causes).

Adult↗

PubMed1999

Long-term outcome of chronic hepatitis C virus infection in primary hypogammaglobulinaemia.

The clinical course of HCV infection in patients with primary hypogammaglobulinaemia appears to be more severe than in immunocompetent patients. We studied the long-term course of chronic HCV infection in 20 Norwegian hypogammaglobulinaemia patients with a 13-15 year known history of HCV infection. Twelve of 20 patients developed cirrhosis during the observation period (1984-1999), and the remaining eight also had chronic liver disease verified by liver biopsy in the majority of the cases. Eleven of the 20 patients are dead. Two died following liver transplantation for HCV cirrhosis. Five died due to terminal liver failure without receiving a liver allograft. Two patients died from other causes, but with advanced liver disease contributing to the outcome, while two deaths were unrelated to the HCV infection. Among patients with common variable immunodeficiency (CVI), five out of six are dead. Two patients cleared the hepatitis C virus 3 years following interferon monotherapy, while three patients achieved a sustained response to combination therapy with interferon and ribavirin. Viral load did not seem to have a major impact on disease progression. Our results emphasize the severity of hepatitis C virus infection in patients with hypogammaglobulinaemia. Patients with CVI appear to have the poorest prognosis.

Adolescent↗

PubMed2006

[A 35-year-old man with aggressive periodontitis].

BACKGROUND: Aggressive and necrotic periodontal diseases may occasionally be associated with undiagnosed systemic diseases and immune deficiencies. We present a 35-year-old man with an undiagnosed hypo-gammaglobulinaemia and severe aggressive periodontitis. MATERIAL AND METHODS: Gingival biopsies and peripheral blood were collected for immunohistochemical and cell culture studies from the patient with aggressive periodontitis, 3 patients with chronic periodontitis and 3 controls. Mast cells and neutrophils were visualised and counted on histological sections. Freshly isolated monocytes were challenged with lipopolysaccharides and supernatants assayed for interleukin (IL)-1beta, IL-8, IL-10, IL-12 and tumour necrosis factor. Analysis of peripheral blood for any hidden systemic diseases was carried out, including blood cell counts and measurement of immunoglobulin levels in serum. RESULTS: The patient had depressed levels of immunoglobulin in serum (IgG: 3.2 g/l, IgA: 0.6 g/l and IgM: 0.4 g/l ) and was diagnosed with common variable immunodeficiency. The inflamed gingiva revealed significantly increased numbers of mast cells and neutrophils. Signs of mast cell degranulation were observed in the aggressive periodontitis patient only, and monocytes secreted significantly more IL-1beta, IL-8, IL-12 and tumour necrosis factor, but less IL-10. INTERPRETATION: Low antibody production concurrent with an obviously increased activity of the innate immune defense with massive release of pro-inflammatory cytokines may partly cause the severe destruction of periodontal tissue as seen in this patient.

Adult↗