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Results for “Common Variable Immunodeficiency”

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PubMed2007

The European internet-based patient and research database for primary immunodeficiencies: results 2004-06.

Because primary immunodeficiencies (PID) are rare diseases, transnational studies are essential to maximize the scientific outcome and lead to improved diagnosis and therapy. Immunologists in Europe have united to determine the prevalence of PID in Europe and to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID as well as to improve the awareness of PID in Europe. In order to achieve this aim we have developed an internet-based database for clinical and research data on patients with PID. This database forms the platform for studies of demographics, the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. The database is completely secure, while providing access to researchers via a standard browser using password and encrypted log-in sessions and conforms to all European and national ethics and data protection guidelines. So far 2386 patients have been documented by 35 documenting centres in 20 countries. Common variable immunodeficiency (CVID) is the most common entity, accounting for almost 30% of all entries. First statistical analyses on the quality of life of patients show the advantages of immunoglobulin replacement therapy, at the same time revealing a mean diagnostic delay of over 4 years. First studies on specific questions on selected PID are now under way. The platform of this database can be used for any type of medical condition.

Adolescent↗

PubMed2006

Immunodeficiency in childhood.

Primary immunodeficiency disorders (PIDs) continue to illuminate mechanisms of human immunity and hypersensitivity. New discoveries in common variable immunodeficiency, the most enigmatic of PID syndromes, reveal molecular pathways of importance in human antibody production. FOXP3 mutations demonstrate the essential role that T-regulatory cells play in controlling autoantibody formation and disease. Interleukin-1 receptor-associated kinase 4 deficiency emphasizes the key role that innate immunity plays in the defense of bacterial disease occurring early in life. With respect to therapy, subcutaneous immunoglobulin treatment may indeed be a better treatment than intravenous immunoglobulin for many patients with antibody deficiency. Finally, PIDs remain in the vanguard for the treatment of inherited disorders by gene therapy. Gene therapy has cured patients with chronic granulomatous disease and severe combined immunodeficiency, but not without morbidity and mortality. Into the 21st century, PIDs continue to instruct us in human health and disease.

Antibody Formation↗

PubMed1994

Analysis of immunoglobulin isotype levels in acute pneumococcal bacteremia and in convalescence.

In 48 patients with a history of a pneumococcal bacteremia, serum taken during the acute phase of the infection was analyzed for IgG and IgG subclasses. Once the patients were free of infection, a serum sample was analyzed for IgG, IgG subclasses, IgA and IgM. In an additional 20 patients, it was only possible to analyze serum from the infection-free phase. Seventeen of 48 (35%) patients had reduced levels of total IgG or of one or more of the IgG subclasses during acute disease. Of the 48 patients in whom both acute phase and infection-free phase serum were analyzed, values of IgG (p < 0.001), IgG1 (p < 0.001), IgG2 (p < 0.001), IgG3 (p < 0.01) and IgG4 (p < 0.01) were decreased during the acute infection. During the infection-free phase, 12 of 68 (18%) patients had a recognizable immunodeficiency, including two patients with common variable immunodeficiency. Routine screening for immunoglobulins during the infection-free period could result in the discovery of previously unrecognized immunoglobulin deficiencies in patients with a history of bacteremic pneumococcal infection.

Acute Disease↗

PubMed2005

Neutropenia in Iranian patients with primary immunodeficiency disorders.

Neutropenia may occur in some of the primary immunodeficiency disorders. We reviewed the records of 56 neutropenic patients. The most common disorders were Shwachman-Diamond syndrome, cyclic neutropenia, Kostmann disease, Chediak-Higashi syndrome, hyper IgM syndromes, severe combined immunodeficiency, hyper IgE syndrome, and common variable immunodeficiency.

Adolescent↗

PubMed1993

Immunoglobulin deficiency.

Twenty three patients with primary immunoglobulin(Ig) deficiency were seen during the last ten years. Nine had hypogamma globulinemia (hypo-Ig) and the rest, selective Ig deficiency. Most were in pediatric age group. There was preponderance of males with only one female. Clinical symptoms pertaining to gastrointestinal and sinupulmonary infections were most common. Complete absence of B cells was not observed in any patient with hypogammaglobulinemia. They could be typed as physiological in one patient, X-linked immunodeficiency in 2 patients and common variable immunodeficiency in the remaining six. Three patients with selective IgA deficiency were above 20 years of age. Two had only secretory IgA deficiency, confirmed by jejunal fluid examination and the rest had both secretory and serum IgA deficiency. Low IgM was seen in one patient. We see a spectrum of immunoglobulin deficiencies varying from subtle defects like absence of secretory IgA only, to severe depletion of all immunoglobulins. Therapy is still not ideal due to economic reasons.

Adolescent↗

PubMed2026

Genetic Heterogeneity of Inborn Errors of Immunity Revealed by Whole-Genome Sequencing: Insights from a Russian Patient Cohort.

Identifying genetic cause(s) is a key step for management and treatment of patients with inborn errors of immunity (IEI). Here, in an observational cross-sectional genomic study, we analyzed whole-genome sequencing (WGS) data of 72 IEI patients from Saint Petersburg and Northwestern Russia: 42 patients with common variable immunodeficiency (CVID)-like phenotypes, 6 patients with clinically diagnosed X-linked agammaglobulinemia (XLA or Bruton's disease), and 24 patients with other forms of IEI. Causative pathogenic and likely pathogenic variants in BTK, CYBB, CHD7, AIRE, ATM, SBDS, NFKB1, and CTLA4 genes were identified in 14 (19%) patients. Variants of uncertain significance that could be linked to observed clinical phenotypes were detected in 6 patients. These included a BTK variant in a patient with Bruton's disease, variants in SH2D1A, SOCS1, and IKBKB in patients with CVID, and variants in CARD11 and CD40LG in patients with other forms of IEI. Additional rare variants that were mostly unique to individual patients were found in multiple IEI genes from the International Union of Immunological Societies (IUIS) Expert Committee 2024 list. In the CVID-like subcohort, pathway-level analysis of these rare variants revealed patterns associated with clinical manifestations. Taken together, our results expand the genetic characterization of an understudied regional IEI cohort, particularly of patients with CVID-like phenotypes, and identify genetic factors that are implicated in or may contribute to the disease.

Humans↗

PubMed1998

Primary antibody deficiency in Arabs: first report from eastern Saudi Arabia.

Epidemiological studies have shown wide geographical and racial variations in the prevalence and pattern of immunodeficiency diseases. As there is no national registry, very little is known of the prevalence and nature of humoral immunodeficiency in the Arabian peninsula. We report here for the first time the analysis of serum immunoglobulin (Ig) levels in 2000 consecutive patients (age, 1-80 years). They were seen over a period of 6 years and were referred to us from six district hospitals for suspected immunodeficiency, autoimmunity, allergy, or immunoglobulin dyscrasia. Forty-six were found to be immunodeficient, in whom at least one of the Ig class was low; 15 had secondary immunodeficiency. The remaining 31 cases, representing 1.5% of the population studied (giving a prevalence of 1550/100,000 hospital registered patients), were categorized into four primary humoral immunodeficiency groups: these included, in order of frequency, (i) selective IgA deficiency (45%; 700/100,000) (ii) common variable immunodeficiency (CVID) (29%; 450/100,000), (iii) agammaglobulinemia (16%; 250/100,000), and (iv) selective IgG deficiency (10%; 150/100,000). Compared with similar hospital-based surveys in the west the prevalence of humoral immunodeficiency seems to be higher in Arabs; this in part may be related to race and higher rate of consanguinity. Most patients with IgA deficiency had either infection, atopy or autoimmunity. Compared with some other races, agammaglobulinemia (X- and non-X-linked) seems to be more prevalent.

Adolescent↗

PubMed2003

Frequent aberrant promoter hypermethylation of O6-methylguanine-DNA methyltransferase and death-associated protein kinase genes in immunodeficiency-related lymphomas.

Aberrant promoter hypermethylation is a mechanism of tumour suppressor gene inactivation. We explored aberrant promoter hypermethylation of multiple genes in 88 human immunodeficiency virus (HIV)-non Hodgkin lymphomas (NHL), 25 post-transplant lymphoproliferative disorders (PTLD) and five common variable immunodeficiency (CVI)-related NHL. Twenty-six of 79 (32.9%) HIV-NHL, eight of 14 (57.1%) PTLD and two of five (40.0%) CVI-NHL showed aberrant hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT). Aberrant hypermethylation of death-associated protein-kinase (DAP-K) occurred in 70 of 84 (83.3%) HIV-NHL, 19 of 25 (72.0%) PTLD and three of five (60.0%) CVI-NHL. These data implicate MGMT and DAP-K hypermethylation in lymphomagenesis of immunodeficient hosts. In particular, promoter hypermethylation of DAP-K represents the most frequent molecular alteration yet identified in immunodeficiency-related lymphomas.

Apoptosis Regulatory Proteins↗

PubMed1998

Effects of tobacco smoking on salivary immunoglobulin levels in immunodeficiency.

Salivary immunoglobulins and albumin were analysed in smoking and non-smoking immunocompetent and immunodeficient individuals. Stimulated and unstimulated saliva were compared as between individuals with selective immunoglobulin A deficiency (IgAd), common variable immunodeficiency (CVI) and immunocompetent individuals. Immunocompetent smokers showed increased levels of sIgA in unstimulated saliva, when compared with non-smoking immunocompetent individuals. In stimulated saliva, the immunocompetent smokers showed decreased levels of IgG and IgM. IgAd smokers showed decreased levels of albumin in unstimulated saliva, when compared with non-smoking IgAd individuals. The non-smoking individuals with IgAd showed increased levels of IgM in both unstimulated and stimulated saliva, when compared with immunocompetent smokers. The non-smoking CVI individuals showed decreased levels of IgG, IgA and IgM in unstimulated and stimulated saliva, as expected, when compared with the same group of immunocompetent individuals. The decreased levels of albumin in unstimulated saliva in IgAd smokers and comparable to that of the IgG non-smoking IgAd individuals support the observation of locally produced immunoglobulins that protect the oral mucosa. Instead of sIgA, non-smoking immunodeficient individuals with IgAd compensate with increased IgM levels in stimulated saliva. The increased levels of sIgA in unstimulated saliva in immunocompetent smokers may be a reflection of the protection of the oral mucosa.

Adolescent↗

PubMed1995

Repair of immunoglobulin response in B cell line (JK32.1) originating from immunodeficient patient via implantation of functional plasma membranes.

Human-human B cell hybridoma JK32.1, constructed from B lymphocytes of a common variable immunodeficient patient and nonsecreting cell line, retains the defects of B cell immunodeficiency. Efforts to clarify whether the defect is located within the plasma membranes of this cell line were carried out by implanting them with plasma membrane fraction derived from normal functional cells via intact non-infectious Sendai virus. The implanted cells were activated with various mitogens and their Ig responses and isotype switching were examined. Restoration of IgM secretion was achieved in the implanted JK32.1 cells following stimulation with SAC, PWM, or retinoic acid. Augmented IgM response was also obtained in the implanted cells treated with retinoic acid and lipopolysaccharide (LPS) despite their unresponsiveness to LPS alone. No IgG or IgA response could be detected in the implanted JK32.1 cells. These data suggest that this immunodeficient cell line possesses at least two different malfunctions, one located within the plasma membrane moiety of the cells and the other located within the cytoplasmic and/or nucleic components. The plasma membrane moiety defect can be repaired temporarily by delivering proper signals via the implanted plasma membranes. However, this manipulation of the cells could not overcome the intrinsic defect of the cells which blocks isotype switching and secretion of IgG, IgE, and IgA antibodies.

Animals↗

PubMed1995

Immunodeficiency states and associated rheumatic manifestations.

For immunodeficiency states, the past year has been marked with the discovery of a series of events at the gene level and cell-to-cell interaction, particularly in common variable immunodeficiency, severe combined immunodeficiency, IgA deficiency, and immunodeficiency associated with IgM hyperimmunoglobulinemia. Clinical expression, especially in the musculoskeletal system, as well as infectious complications and therapy, also have been reported.

Common Variable Immunodeficiency↗

PubMed2006

Common variable immune deficiency and autoimmunity.

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by various degrees of hypogammaglobulinemia. Similar to many immunodeficiency disorders, autoimmunity is common with an association with autoimmune cytopenias, a sarcoidosis-like disorder and inflammatory bowel disease. Recent efforts have characterized selective immunological defects and genetic associations in CVID and demonstrate an increased tendency towards loss of tolerance. The mainstay of treatment of autoimmune disease in such patients is often high dose IVIG and corticosteroids, although other therapies, including TNF-alpha antagonists, have been reported. While the etiology of increased autoimmunity in CVID remains elusive, certain genetic predispositions in combination with repeated antigen exposure and overall immune dysregulation inherent in CVID likely play a significant role.

Animals↗

PubMed1996

Adult immunodeficiency and rheumatic disease.

Several rheumatic illnesses may develop in adults with primary or acquired immunologic defects. Individuals with primary defects in B-cell antibody production, such as common variable immunodeficiency of selective IgA deficiency, and those with defects of complement components, have an increased prevalence of systemic lupus erythematosus--like syndromes or other autoimmune diseases. Defects in immunoglobulin production may be complicated by inflammatory or infectious arthritis. Infection with HIV-1 may be associated with diverse rheumatic conditions, including diffuse infiltrative lymphocytosis syndrome, myopathies, vasculitides, inflammatory arthritides, and infectious musculoskeletal complications. An approach to these disorders that takes into consideration the underlying mechanism of disease is presented. Appropriate strategies aimed at treatment of the underlying immunodeficiency may improve the clinical course of the associated rheumatic disorder.

Adult↗

PubMed1999

[Cytokines in children with immunodeficiencies].

The underlying immunological defect in humoral immunodeficiency with decreased production of immunoglobulin and normal level of circulating B cells (IgA deficiency, transient hypogammaglobulinemia of infancy, common variable immunodeficiency) remains unknown. There is evidence that B cells maturation and differentiation is regulated by cytokines and hence aberrant cytokine production may be involved in the pathogenesis of these diseases. Among interleukins, IL-1, IL-4, IL-6 and IL-10 may each play a role in regulation of B cell growth. Interferons (IFNs) have been described as having both positive and negative effects on B cell growth. The precise role of tumor necrosis factors (TNF alpha and beta) remains obscure. In the present study the in vitro cytokine production by peripheral blood mononuclear cells (PBMC) from children with different forms of immunodeficiency, in particular with IgA deficiency and transient hypogammaglobulinemia of infancy, was evaluated. In the first stage of the study the release of IL-1, IL-6, IFN and TNF by PBMC was analysed in following groups of patients: transient hypogammaglobulinemia (n = 30), IgA deficiency (n = 29), Bruton's disease (n = 7), decreased proliferative response to mitogenes (n = 10), CD4+ lymphocytopenia (n = 8), CD8+ lymphocytopenia (n = 10). The concurrent control group consisted 52 sex- and age-matched children, in whom no immunological immunological abnormalities were detected. The release of bioactive IL-1, IL-6, IFNs and TNF was measured in the culture supernatants from PBMC stimulated with mitogens for 48 hours. While the release of bioactive IL-1, IL-6, and IFNs was comparable in all studied groups, the secretion of TNF was significantly increased in children with transient hypogammaglobulinemia and IgA deficiency. The next issue was determination of the type of TNF (alpha or beta) involved. The production of other cytokines important for the regulation of B cell function (IL-4, IL-10) was also assessed. Production of TNF alpha, TNF beta and IL-10 was significantly elevated in transient hypogammaglobulinemia. The data from the ELISPOT assay suggested, that in these patients also the number of cells secreting TNF alpha after PHA stimulation was increased. These results indicate, that elevated TNF alpha production was probably due to both an enhanced release and an increased number of circulating secreting cells. As the methods employed in the quantification of cytokine levels in culture supernatants do not allow identification of the cytokine producing cell, the studies on intracellular expression of cytokines were undertaken. The fluorochrome-labelled monoclonal antibodies against the cell surface markers and a given cytokine were used simultaneously to identify the cellular source of cytokine production. The intracellular IL-4 expression in CD4+ lymphocytes from patients with transient hypogammaglobulinemia was comparable to that of control while the number of CD4+ lymphocytes expressing TNF alpha, TNF beta and IFN gamma was elevated. The number of CD14+ cells (monocytes) producing of TNF alpha was comparable to the control. These results suggest that an excessive Th-1 type response may contribute to pathology of this disease. In patients with isolated IgA deficiency the significantly increased release of TNF alpha but not: IL-1, IL-4, IL-6, IL-10 and TNF beta was observed. The proportion of CD4+ lymphocytes that expressed TNF alpha was significantly increased while the number CD14+ cells staining for TNF alpha was unchanged. No changes in the expression of TNF type I and II receptors on PBMC were observed, which suggested that regulatory effects of TNF alpha and beta are associated rather with an increased production of these cytokines than an abnormal receptor expression. Some patients with transient hypogammaglobulinemia were followed-up and the serum level of IgG and production of TNF alpha, TNF beta, and IL-10 by their PBMCs was determined 6 to 12 months after first

Agammaglobulinemia↗

PubMed2001

Assessment of male CVID patients for mutations in the Btk gene: how many have been misdiagnosed?

The presentation of hypogammaglobulinaemia in young males without a family history of immunodeficiency can pose a diagnostic problem. In the past, the presence of B-cells has suggested a diagnosis of common variable immunodeficiency (CVID), although genotypic analysis has now clarified that individuals with B cells may have mutations in their Btk gene. In order to address the issue of how many male individuals with a clinical diagnosis of CVID do in fact have mutations in the Btk gene, we analysed a group of 24 male patients. Single-strand conformation polymorphism (SSCP) analysis was used to screen the patient cohort for mutations in the Btk gene. Given the size of the Btk gene, the number of patients in the cohort and the amount of available DNA, multiplex PCR reactions were utilized to span the 19 exons and promoter region of the gene. Where abnormal migration patterns were observed with multiplex PCR reactions, in nine of the 24 patients, the individual Btk gene fragments were re-amplified and analysed again by SSCP. Following this analysis, four patients continued to demonstrate abnormal SSCP migration patterns. However, direct sequencing of the relevant Btk gene fragments for these four CVID patients revealed a mutation in only one patient. The mutation was the previously described polymorphism at position 2031 of Btk gene within exon 18. These results indicate that caution should be taken with the application of SSCP analysis to mutation detection. While it has a role to play in screening large patient cohorts, direct sequencing is a necessary adjunct to such analysis. Finally, the clinical diagnosis of CVID in this cohort successfully excluded males with Btk mutations.

Adult↗

PubMed2005

Intratypic recombination among lineages of type 1 vaccine-derived poliovirus emerging during chronic infection of an immunodeficient patient.

We determined the complete genomic sequences of nine type 1 immunodeficient vaccine-derived poliovirus (iVDPV) isolates obtained over a 337-day period from a poliomyelitis patient from Taiwan with common variable immunodeficiency. The iVDPV isolates differed from the Sabin type 1 oral poliovirus vaccine (OPV) strain at 1.84% to 3.15% of total open reading frame positions and had diverged into at least five distinct lineages. Phylogenetic analysis suggested that the chronic infection was initiated by the fifth and last OPV dose, given 567 days before onset of paralysis, and that divergence of major lineages began very early in the chronic infection. Key determinants of attenuation in Sabin 1 had reverted in the iVDPV isolates, and representative isolates of each lineage showed increased neurovirulence for PVR-Tg21 transgenic mice. None of the isolates had retained the temperature-sensitive phenotype of Sabin 1. All isolates were antigenic variants of Sabin 1, having multiple amino acid substitutions within or near neutralizing antigenic sites 1, 2, and 3a. Antigenic divergence of the iVDPV variants from Sabin 1 followed two major independent evolutionary pathways. The emergence of distinct coreplicating lineages suggests that iVDPVs can replicate for many months at separate sites in the gastrointestinal tract. Some isolates had mosaic genome structures indicative of recombination across and within lineages. iVDPV excretion apparently ceased after 30 to 35 months of chronic infection. The appearance of a chronic VDPV excretor in a tropical, developing country has important implications for the strategy to stop OPV immunization after eradication of wild polioviruses.

Amino Acid Substitution↗

PubMed2004

The genetics of hypogammaglobulinemia.

Etiologies for human hypogammaglobulinemias are diverse and include genetic and nongenetic causes. Although recent reviews focus on the complex genetics of common variable immunodeficiency, in this review, we survey different causes of hypogammaglobulinemias and discuss possible mechanisms.

Agammaglobulinemia↗

PubMed2006

Retinitis pigmentosa and hypogammaglobulinemia.

This report describes a family demonstrating an unusual association of retinitis pigmentosa and hypogammaglobulinemia. The proband in this family suffered from another rare illness, ie, Sertoli cell only syndrome. The incidence of retinitis pigmentosa is 1 in 5,000 and that of common variable immunodeficiency state is 1 in 100,000, making a chance association of these illnesses very unlikely.

Adult↗