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PubMed1991

Raised serum levels of CD8, CD25 and beta 2-microglobulin in common variable immunodeficiency.

Soluble CD8, soluble CD4, soluble CD25 (IL-2 receptor), beta 2-microglobulin and the cytokine tumour necrosis factor-alpha (TNF-alpha) were measured in sera from patients with common variable immunodeficiency (CVI). Levels of soluble CD8, soluble CD25 and beta 2-microglobulin but not of soluble CD4 and TNF-alpha were raised significantly above levels in normal sera. Sera from patients with X-linked agammaglobulinaemia, who are also antibody deficient, did not show this marked elevation. The raised levels of soluble CD8, soluble CD25 and beta 2-microglobulin in CVI, correlated with the extent of the defects in the B lymphocytes assessed in vitro, as well as with the clinical severity of the disease. The selective release of these molecules into sera may indicate that abnormal cellular activation occurs in most CVI patients. It is also possible that the raised levels of these soluble molecules play a part in the immunodeficiency.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Common variable immunodeficiency in a horse.

A 12-year-old Quarter Horse mare that was nonresponsive to medical treatment was evaluated for chronic respiratory disease and hepatobiliary disease. Serum immunoglobulin concentrations were measured by use of radial immunodiffusion that revealed trace to nondetectable concentrations of IgG, IgG(T), IgM, and IgA. Use of serum protein electrophoresis confirmed agammaglobulinemia by the absence of the expected peak in the gamma region. In addition, vaccination with tetanus toxoid did not result in specific immunoglobulin production. Flow cytometric analysis of blood lymphocyte subpopulations revealed the absence of B cells in blood. Immunohistochemical analysis of tissue sections revealed the absence of B lymphocytes in bone marrow and spleen, with occasional B cells in the peripheral lymph nodes. Blood lymphocyte proliferation assays revealed weak responses to pokeweed mitogen and no response to stimulation with lipopolysaccharide. Considering the age and sex of the horse, results of the immunologic tests suggested a diagnosis of common variable immunodeficiency.

Agammaglobulinemia↗
PubMed1992

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.

Adolescent↗
PubMedDate not supplied

[Common variable immunodeficiency (author's transl)].

In a boy initially diagnosed as X-linked hypogammaglobulinemia, the later clinical and analytical course and the application of new immunological techniques led to the new diagnosis of common variable immunodeficiency. The patient shows panhypogammaglobulinemia, a scarce number of plasma cells with a normal number of precursors and circulating B lymphocytes with membrane bound immunoglobulins and C3 receptors. Delayed hypersensitivity is absent despite normal amount of circulating T lymphocytes which were able to transform when stimulated by PHA. The anergy seems primary and not related to the clinical malnutrition. The authors make a differential diagnosis between both illnesses as a tentative pathogenetic interpretation of B cell development arrest.

Agammaglobulinemia↗
PubMedDate not supplied

[Common variable immunodeficiency (hypogammaglobulinemia of late onset or acquired hypogammaglobulinemia): initial follow-up of 11 cases].

The present paper describes the clinical and laboratory follow-up of 11 patients with the diagnosis of common variable immunodeficiency. Their age varied from 8 to 45 years. The mean disease time was 12.6 years and mean diagnosis time 4.3 years. Infectious manifestations, mainly of the respiratory and digestive tracts, occurred in all patients. Polyadenomegaly was noted in seven, hepatomegaly in six, splenomegaly in five and arthralgia in four patients. All of them presented serum IgG less than 250 mg/dl. IgA less than 33 mg/dl and IgM less than 31 mg/dl, except one with IgM = 176 mg/dl. The isohaemagglutinin titers were less than 1/20 in all but one patient. The determination of the number of B lymphocytes in the peripheral blood revealed normal counts in three, elevated in one and decreased in five patients. The CD-4/CD-8 ratio was less than 1 in 8 and greater than 1 in three of them. Five patients had positive cutaneous late reactions to at least one of the following antigens: PPD, SK-SD (Varidase), Trichophytin and Levedurin (Candidin). A decrease of the proliferative activity of peripheral blood mononuclear cells stimulated by lectins (PHA, Con-A, PWM) was also noted. Natural killer function was decreased. The association a possible role of regulatory lymphocytes in the immunopathogenesis of this disease. The data presented here emphasize the diversity of clinical and immunological manifestations of this disease, which could be noted between diverse patients and in the follow-up of a single one. In our cases the disease had an evolutive character, with a primarily humoral dysfunction followed by cellular immunity disturbances that determined poorer prognosis and progressive difficulties in the therapeutics. We suggest a conceptual reevaluation of this condition and a new denomination, for instance "Late-Onset Combined Immunodeficiency". The long delay between the initial clinical manifestations of the disease and its diagnosis was a handicap for an adequate treatment. Early intervention could certainly decrease the morbidity and mortality of the disease.

Adolescent↗
PubMedDate not supplied

Evolution of IgA deficiency to IgG subclass deficiency and common variable immunodeficiency.

FIRST REPORT: male child with repeated pulmonary infections from the age of 4 months. He was diagnosed as IgA deficiency (undetectable IgA levels) at the age of 3 years, when he presented repeated bouts of pneumonia and tonsillitis. Several immunologic evaluations were made between the ages of 4 months and 8 years. At 8 years and 9 months, the diagnosis of IgA deficiency was confirmed, and associated IgG2 and IgG4 deficiency (29.0 mg/dl y 0.01 mg/dl) with normal total IgG serum level was found. With the administration of intravenous gammaglobulin, the lung infections remitted and the subsequent clinical course has been uneventful up to now. SECOND REPORT: a boy with repeated infections since the age of 2 months. IgA deficiency was diagnosed at 1 year 7 months (undetectable serum IgA levels). At age 51/2 years, his clinical course worsened and more serious infections appeared. A new immunologic study revealed IgA deficiency associated with CD4 cell deficiency (432 cells/mm3) and normal CD3, CD19, and CD8 levels. Despite intensive antibiotic treatment and care, the child died. The findings suggest an association of IgA deficiency and common variable immunodeficiency.

Common Variable Immunodeficiency↗
PubMed2007

Drug evaluation: apilimod, an oral IL-12/IL-23 inhibitor for the treatment of autoimmune diseases and common variable immunodeficiency.

Apilimod is a small molecule that inhibits IL-12 and IL-23 production - cytokines that are involved in autoimmune diseases - through the prevention of nuclear translocation of c-Rel. Synta Pharmaceuticals Corp is developing apilimod for the potential treatment of Crohn's disease (CD) and other autoimmune diseases. Preclinical studies demonstrated the successful inhibition of IL-12 and IL-23 production by the drug. In the clinical setting, apilimod has been generally well tolerated, with mild-to-moderate side effects reported, including headaches and nausea. Patients with CD responded within 14 days of treatment with apilimod and, after 28 days, the drug significantly reduced the Crohn's disease activity index (CDAI). Apilimod is currently in phase II clinical trials for rheumatoid arthritis, common variable immunodeficiency and CD. From the data available to date, apilimod appears to be a promising treatment for CD, and the oral formulation of this compound provides an advantage for apilimod over injectable therapies.

Animals↗
PubMed1998

Primary defect in CD8+ lymphocytes in the antibody deficiency disease (common variable immunodeficiency): abnormalities in intracellular production of interferon-gamma (IFN-gamma) in CD28+ ('cytotoxic') and CD28- ('suppressor') CD8+ subsets.

We have measured by flow cytometry the ability of subsets of CD8+CD3+ lymphocytes within mononuclear cell preparations to make intracellular cytokines (IL-2, tumour necrosis factor-alpha (TNF-alpha) and IFN-gamma) on stimulation in vitro with phorbol myristate acetate (PMA) and ionomycin for 16 h. These CD8+ subsets were defined by the presence or absence of CD28 or HLA-DR. Subsets of normal CD8+ cells were compared with cells from the antibody deficiency disease common variable immunodeficiency (CVID). In CVID there was a significant increase in the production of IFN-gamma in the CD8+CD28+ subset ('cytotoxic'). This reflects a shift in this disease towards an excessive Th1 response away from B cell help. Paradoxically, some CVID patients also showed a reduction in IFN-gamma production in the CD8+CD28- subset ('suppressor') which was associated with a failure of these cells to maintain a state of activation after a stimulus in vitro. The B cell problem in this disease is known to be related to a failure of T cell help shown by an inability to produce the antigen-specific CD4+ memory T cells needed for successful B cell maturation. The two pathological CD28 subsets of CD8+ cells we have found in CVID may both be detrimental to a normal CD4-dependent immune response. The CD28- suppressor subset expands and is unable to maintain activation and cytokine secretion, and the CD28+ cytotoxic subset is over-producing the Th1 cytokine IFN-gamma.

Adult↗
PubMed2004

Successful anti-CD20 monoclonal antibody treatment of severe autoimmune hemolytic anemia due to warm reactive IgM autoantibody in a child with common variable immunodeficiency.

Autoimmune hemolytic anemia due to warm reactive IgM autoantibodies is unusual, severe, and often fails to respond to standard immunosuppressive therapies in both adults and children. A 6-year-old girl with common variable immunodeficiency had longstanding steroid dependent, splenectomy-unresponsive, warm IgM autoantibody-mediated autoimmune hemolytic anemia. Rituximab, a monoclonal antibody directed against CD20 antigen, was used to deplete B lymphocytes and reduce autoantibody production. She received a total of six doses of rituximab (375 mg/m2). Therapy was well tolerated, and B-lymphocytes were effectively depleted from the peripheral blood. The patient was completely tapered off glucocorticoids. The patient has remained off immunosuppressive agents for 16 months despite the return of B lymphocytes to the peripheral circulation. She continues to require IVIG. Early treatment with rituximab might be an option for patients with warm reactive IgM autoantibody-mediated autoimmune hemolytic anemia not responding to other treatments or experiencing untoward side effects from those treatments.

Anemia, Hemolytic↗
PubMed2005

Common variable immunodeficiency in three horses with presumptive bacterial meningitis.

Three adult horses were evaluated for signs of musculoskeletal pain, dullness, ataxia, and seizures. A diagnosis of bacterial meningitis was made on the basis of results of CSF analysis. Because primary bacterial meningitis is so rare in adult horses without any history of generalized sepsis or trauma, immune function testing was pursued. Flow cytometric phenotyping of peripheral blood lymphocytes was performed, and proliferation of peripheral blood lymphocytes in response to concanavalin A, phytohemagglutinin, pokeweed mitogen, and lipopolysaccharide was determined. Serum IgA, IgM, and IgG concentrations were measured by means of radial immunodiffusion, and serum concentrations of IgG isotypes were assessed with a capture antibody ELISA. Serum tetanus antibody concentrations were measured before and 1 month after tetanus toxoid administration. Phagocytosis and oxidative burst activity of isolated peripheral blood phagocytes were evaluated by means of simultaneous flow cytometric analysis. Persistent B-cell lymphopenia, hypogammaglobulinemia, and abnormal in vitro responses to mitogens were detected in all 3 horses, and a diagnosis of common variable immunodeficiency was made.

Agammaglobulinemia↗
PubMed1990

Elevated serum interleukin-6 associated with a failure in B cell differentiation in common variable immunodeficiency.

Interleukin-6 (IL-6/B cell stimulatory factor 2) has been found to drive activated human B-lymphocytes through the final stages of differentiation to become immunoglobulin-producing cells. Most patients with common variable immunodeficiency (CVI) have B-lymphocytes that fail to differentiate into high-rate immunoglobulin-secreting cells in vivo and in vitro. In view of (1) the known effects of IL-6 to promote B-lymphocyte terminal differentiation and (2) the defect in differentiation in B-lymphocytes of patients with CVI, we believed that it was important to analyze the role of this cytokine in patients with CVI. Using an IL-6-dependent murine hybridoma cell line in a bioassay, serum IL-6 levels were determined in 17 patients with CVI and in eight normal control subjects. Thirteen of the 17 patients with CVI exhibited serum IL-6 levels that were twofold to 18-fold higher than the range (mean, +2 SD) of normal control subjects. Spontaneous IL-6 production by peripheral blood mononuclear cells (PBMC) of patients with CVI was significantly higher than that from normal control subjects, whereas lipopolysaccharide maximally stimulated IL-6 production by PBMCs of patients with CVI or PBMCs of normal control subjects was equivalent. A substance inhibitory of IL-6 bioactivity was found in equivalent amounts in sera of both patients and normal control subjects. Sera from patients with CVI with high IL-6 bioactivity were found to have saturated this IL-6 inhibitory substance, thus resulting in large amounts of free IL-6 in the sera. These studies suggest that the failure of B cells from patients with CVI to terminally differentiate into high-rate immunoglobulin-secreting cells cannot be attributed to a decrease in the serum levels of IL-6 and that the increased circulating IL-6 levels in patients with CVI result from hyperproduction rather than decreased use of IL-6. The persistently elevated levels of IL-6 observed in some patients with CVI may secondarily result in the induction of the neoplastic and autoimmune phenomena associated with this disease.

Agammaglobulinemia↗
PubMed1975

Common variable immunodeficiency, Hodgkin's disease, and other malignancies in a Newfoundland family.

A large inbred family is described in which there were seven cases of Hodgkin's disease, three of lymphosarcoma, two of thymoma, two of common variable immunodeficiency, and single cases of retinoblastoma, neuroblastoma, and rhabdomyosarcoma. There have been no other lymphoma cases in the community during the past decade. Further study of this family may help to define the genetic basis for development of Hodgkin's disease and other disorders.

Adult↗
PubMed1995

IgG2 deficiency associated with defects in production of interferon-gamma; comparison with common variable immunodeficiency.

We report a novel mechanism of IgG2 deficiency. Several investigators have reported patients with IgG subclass deficiencies due to homozygous deletion of immunoglobulin heavy chain constant region genes. However, it is unclear what mechanism is responsible for IgG subclass deficiency in cases where no gene deletions have been detected and which are accompanied by recurrent infections due to aberrant immunoregulation. In the present study, we have focused our attention on production by peripheral blood mononuclear cells (PBMCs) of interferon-gamma (IFN-gamma), which is known to induce IgG2 expression. PBMCs from four patients with IgG2 deficiency and their families were studied. Mitogeninduced IFN-gamma production by PBMCs was decreased in all of the patients, although the proliferative responses of PBMCs and the percentages of CD3, CD4, and CD8 T cell subsets were not decreased. IgG2 production by PBMCs was restored upon addition of IFN-gamma and mitogen to the PBMCs of the patients with IgG2 deficiency though it was not restored in the patients with common variable immunodeficiency. We conclude that defects in production of IFN-gamma play an important role in IgG2 deficiency.

Adult↗
PubMed1992

LFA-1-dependent OKT3-driven T cell clusters in common variable immunodeficiency.

The triggering of the TCR/CD3 complex by anti-CD3 (OKT3) antibody leads to the formation of T cell clusters. In cultures of T lymphocytes from most normal individuals, the peak of cluster formation occurs at 24 h, but with cells from patients with common variable immunodeficiency (CVI) it was seen earlier at 4-9 h; in addition, the clusters were larger than normal, particularly at 9 h. Cluster formation by CVI and normal cells was dependent on temperature and divalent cations, but did not require Fc receptors. Since OKT3 clustering is known to be dependent on the LFA-1/ICAM-1 adhesion system, the effect of monoclonal antibodies directed against these molecules was tested. A potent inhibitor was the antibody against the common beta chain of the integrin family (CD18), but of four MoAbs against the alpha chains (CD11), three inhibited and one stimulated T cell aggregate formation. Increased expression of LFA-1 or ICAM-1 on CVI patients' T cells could not be demonstrated. The accelerated clustering was therefore probably due to an increase in the proportion of cells carrying the activated form of LFA-1. The formation of large numbers of homotypic lymphocyte clusters might reduce the effective interaction between B and T cells, thus contributing to the depression of immunoglobulin synthesis observed in this disease.

Adolescent↗