Common variable immunodeficiency: how many diseases?
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Common Variable Immunodeficiency↗
Biomedical subjects
G P Spickett
Publications and source records attributed to G P Spickett.
The effects of vitamin A derivatives on in vitro antibody production by peripheral blood mononuclear cells (PBMC) from normal blood donors and patients with common variable immunodeficiency (CVID).
The underlying nature of the defect of CVID is not understood, and the treatment at present is life-long infusion of replacement immunoglobulin. Attempts have been made to use other therapeutic agents, such as IL-2 and retinoic acid (RA), with mixed results. RA is a morphogenetic signalling molecule related to vitamin A and involved in vertebrate development. We report here our in vitro evaluation of the effects of three vitamin A analogues, 9-cis retinal, 13-cis RA and all-trans RA, on antibody production of PBMC from normal donors and patients with CVID. At 10(-5) M, 9-cis retinal strongly augmented IgM production of lymphocytes from normal individuals and to a much lesser extent, mild, non-granulomatous (group C) CVID patients, but IgG production was not affected. In the presence of anti-human IgM and IL-2, 9-cis retinal at 10(-5) M elevated IgM and IgG production by normal PBMC, but the effect on PBMC of mild CVID was minimal. The effect of 9-cis retinal was significantly reduced at 10(-7) and 10(-9) M. Only minimal effects were found using 13-cis RA and all-trans RA under these conditions. No detectable antibody production was found in severe, granulomatous (group A) CVID patients under any conditions tested. Taking all data into account, 9-cis retinal is the most potent stimulator for antibody production compared with 13-cis RA and all-trans RA as tested in this in vitro study.
Blood Donors↗
Cytokine production differs in children and adults.
The susceptibility of normal, healthy children to infection has long been recognized, but the underlying mechanisms are poorly understood. As adequate cytokine production is crucial for optimal immune responses, we assessed antigen and mitogen-induced cytokine production in healthy children. Our results demonstrate that healthy children differ markedly compared with adults in their ability to produce cytokines (IL-2, interferon-gamma, IL-4, and IL-6). Maximal stimulation with mitogen demonstrated impaired cytokine production with markedly lower levels of all four cytokines produced compared with adult levels. When stimulated with antigens, median levels of IL-2 and IL-4 remained lower than adult values, IL-6 production was increased as was interferon-gamma, albeit not significantly. Although the study was carried out on peripheral blood mononuclear cells that represent a restricted compartment of the immune system, these data suggest that, in healthy children, cytokine production is decreased and/or altered and could result in a suboptimal immune response, which could be one of the factors underlying increased susceptibility to infection in children.
Adolescent↗
Abnormal phagocytic function in children under one year of age.
The action of white blood cells (WBC) against Proteus mirabilis was assayed in 22 children following meningitis or septicaemia and compared with that in control groups of: (1) adult volunteers, (2) children undergoing minor surgical procedures for non-infective conditions, and (3) children being investigated for suspected renal disease. WBC bacterial killing tests were normal in all 55 adult volunteers. Abnormal results were obtained in 11 of 22 (50%) children with meningitis or septicaemia, 10 of 21 (47.6%) children undergoing surgery and six of 13 (46%) children with suspected renal disease, thereby indicating that there were no significant differences in phagocytic function among these three groups. Of children aged 1 year or less, 75% had abnormal phagocytic function. The significance of this finding is discussed.
Adult↗
Hepatitis C virus density heterogeneity and viral titre in acute and chronic infection: a comparison of immunodeficient and immunocompetent patients.
BACKGROUND: Heterogeneities in the buoyant density of hepatitis C virus RNA have been reported in different groups of patients, and have been attributed to differential binding of viral particles to beta-lipoproteins and IgG, and the presence of hepatitis C virus nucleocapsids in circulation. It may be that hepatitis C virus density heterogeneity correlates with the severity of liver disease, hepatitis C virus RNA titre, and the immunocompetence of the patient. METHODS AND RESULTS: We have analysed five immunodeficient patients (one with hypogammaglobulinaemia and selective IgA deficiency, one with X-linked agammaglobulinaemia, three with common variable immunodeficiency) who have been acutely infected with the same batch of intravenous immunoglobulin contaminated with hepatitis C virus (genotype 1a). The course of hepatitis C virus infection in these patients was compared to one immunocompetent patient who presented with acute hepatitis C virus and progressed to chronic disease, and seven immunocompetent patients with chronic hepatitis C. Serum samples were analysed by differential flotation ultracentrifugation in NaCl solution (density 1.063 g/ml). The high and low density fractions were tested for the presence of RNA by RT-PCR. Serum samples were also quantified for hepatitis C virus RNA (Amplicor HCV Monitor kit, Roche Diagnostic Systems). Three quarters of the acutely infected patients analysed presented with low density hepatitis C virus. Low density hepatitis C virus was absent in most chronic infections but persisted in two patients with common variable immunodeficiency. High density hepatitis C virus was detected in the chronic phase in all acutely infected patients in whom the disease persisted, and was present in all samples from PCR-positive patients with chronic infection. Immunodeficient patients had significantly higher hepatitis C virus RNA titres on presentation than immunocompetent patients, but there was no correlation between titre and clinical course of infection. CONCLUSIONS: Heterogeneities in the buoyant density of hepatitis C virus RNA have been identified in the patient groups studied. Low density hepatitis C virus is detected more often in acute infection and high density hepatitis C virus is detected more often in chronic infection. Despite acute infection via the same route of infection with the same hepatitis C virus strain, the five immunodeficient patients studied all followed a different clinical course.
Acute Disease↗
L-selectin in patients with common variable immunodeficiency (CVID): a comparative study with normal individuals.
L-selectin in one of the key members of the selectin family of adhesion molecules and initiates leucocyte attachment to specialized high endothelial venules. The shed form, which retains functional activity, can be detected in biological fluids and is increased in diseases of many kinds. In the present study, we investigated L-selectin expression on leucocytes and measured the soluble form in the plasma of healthy individuals and patients with CVID. A significant loss of L-selectin expression is found on CVID B cells, which is marked by the presence of a substantial population of L-selectin-negative B cells in the peripheral blood of some CVID patients. On CD4+ T cells, the loss in L-selectin expression affects mostly the CD45RO+ population. Peripheral blood leucocytes other than lymphocytes express L-selectin molecule normally. Moreover, soluble L-selectin was detected in significantly increased levels in CVID plasma compared with healthy controls. Our data suggest that the loss of L-selectin expressed by lymphocytes may be due to increased or aberrant lymphocyte activation in CVID patients who remain immunodeficient, and down-regulation of L-selectin from these lymphocytes may significantly contribute to the elevated levels of soluble L-selectin in the plasma, which may in turn affect further lymphocyte trafficking.
B-Lymphocytes↗
Chronic mucocutaneous candidiasis. I. Altered antigen-stimulated IL-2, IL-4, IL-6 and interferon-gamma (IFN-gamma) production.
Patients with chronic mucocutaneous candidiasis (CMC) present with persistent infections with the opportunistic yeast Candida. Impaired cell-mediated responses to Candida have been documented in CMC patients, but the defect remains poorly understood. The importance of Th1 cytokines in resistance and Th2 in susceptibility to Candida infections has recently been demonstrated in murine models. In our studies we evaluated production of IL-2 and IFN-gamma (markers of Th1 type responses) as well as IL-4 and IL-6 (Th2 type markers) following stimulation with two kinds of Candida antigens (CAgs), polysaccharide antigens, tetanus toxoid and pokeweed mitogen. Our results demonstrate that CMC patients have impaired cytokine production upon in vitro stimulation with CAgs resulting in low or absent IL-2, increased IL-6 and either absent or increased IFN-gamma production. Cytokine production following stimulation by other antigens was unaltered. The overall cytokine-producing capacity assessed through mitogen stimulation was also intact. Addition of IFN-alpha or IFN-gamma to culture in an attempt to modify cytokine production did not have significant effects. Levels of soluble IL-6 receptors were not increased and could not account for increased IL-6 production. Our studies support the hypothesis that Candida antigens trigger a predominantly Th2 instead of a Th1 cytokine response in patients with CMC.
Adolescent↗
Chronic mucocutaneous candidiasis. II. Class and subclass of specific antibody responses in vivo and in vitro.
Patients with chronic mucocutaneous candidiasis (CMC) succumb to persistent infections with the opportunistic yeast Candida. Impaired cell-mediated responses to Candida have been repeatedly reported while antibody responses were mostly found to be normal. The underlying defect remains poorly understood. It has recently been shown that CMC patients are also susceptible to infections with encapsulated bacteria, and may have associated IgG2 and IgG4 deficiency. Our previous studies demonstrated altered cytokine production in CMC patients. As cytokines can influence production and isotype of specific antibody, in 10 patients with CMC we measured the levels and isotype distribution of serum antibodies to Candida antigens (CAg), pneumococcal polysaccharide (PPS) and tetanus toxoid (TT) antigens. Peripheral blood lymphocytes were also stimulated in culture and the antibodies made in vitro were measured. Our data demonstrated that in vivo, CMC patients had very high levels of IgG and IgA CAg-specific antibodies. CAg-specific and PPS-specific IgG1 was markedly higher than in controls. Children but not adults with CMC had significantly lower levels of IgG2-specific antibody to CAg and PPS compared with age-matched controls. Patients had significantly higher levels of IgG3-specific antibody to all three antigens tested. These findings were in accordance with increased total IgG and IgG3 levels seen in CMC patients. In vitro, CMC patients, particularly children, did not respond as frequently to antigen stimulation as did their healthy controls. The level of specific antibody produced was also lower to all antigens tested, as was the amount of total immunoglobulins following antigenic and particularly mitogenic stimulation. Addition of interferon-alpha (IFN-alpha) or IFN-gamma to cultures had variable, sometimes marked, effects. Our results demonstrate that CMC patients manifest subtle alterations in specific antibody responses to CAg, PPS and TT, which are most pronounced in children. This may relate to altered cytokine production also seen in these patients.
Adult↗
Contribution of stabilizing agents present in intravenous immunoglobulin preparations to modulation of mononuclear cell proliferation in vitro.
Intravenous immunoglobulin (IVIG) preparations have been shown to suppress lymphocyte proliferation in vitro. This study aimed to investigate the effects of an IVIG produced by fractionation/DEAE-Sephadex adsorption on lymphocyte proliferation in vitro, with particular reference to contributions of the stabilizing agents present in the IVIG to the modulation of mononuclear cell proliferation. It was found that glycine significantly inhibited stimulation by the mitogenic lectin phytohaemagglutinin (PHA; 58% inhibition, P < 0.01). Glucose and human albumin also reduced the response to PHA but to a lesser extent (20% and 30%, respectively). In further experiments the effects of sucrose and maltose, two disaccharides used as stabilizing agents in IVIG preparations, were studied. Three doses were used (2.5 mM, 25 mM and 250 mM), representing levels likely to be found in vivo after infusion of IVIG at immunotherapeutic doses, on four different proliferative stimuli. Maltose was found to inhibit proliferation to PHA, anti-CD3 and PMA in a dose responsive manner. Sucrose also inhibited proliferation to these stimuli, but a dose response was not observed. For both sugars, only the highest dose (250 mM) inhibited the proliferative response of mononuclear cells to PMA and a calcium ionophore (ionomycin). The repurified IgG component of the IVIG preparation did not inhibit PBMC responses to PHA in this system. Kinetic analyses, in which the sugars were added 24 h after proliferative stimuli, indicated that both sugars still inhibited responses to PHA, and, to a lesser extent, PMA, but only maltose inhibited the anti-CD3 response. These findings show that stabilizing agents currently found in commercial IVIG preparations make a significant contribution to modulating mononuclear cell proliferation and need to be considered when assessing the immunomodulatory role of IVIG in vitro.
Cell Division↗
Failure of first-line therapy with intravenous immunoglobulin in a child with scleromyositis.
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Child↗
Chronic fatigue, arthralgia, and malaise.
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Adult↗
Granulomatous disease in common variable immunodeficiency: effect on immunoglobulin replacement therapy and response to steroids and splenectomy.
A 40 year old white woman with common variable immunodeficiency of four years duration presented with rapidly increasing splenomegaly. Despite high dose, weekly intravenous immunoglobulin, it was impossible to raise the trough serum IgG concentration to within the normal range. While waiting for a diagnostic splenectomy, low dose corticosteroids were started, leading to a decrease in the size of the spleen and an increase in the trough IgG concentration. Both spleen and liver showed non-caseating granulomas. Following splenectomy, the corticosteroids were tailed off and the trough IgG was maintained well into the normal range on a reduced, fortnightly dose of intravenous immunoglobulin and a low dose of oral corticosteroid.
Adult↗
Hypogammaglobulinaemia with absent B lymphocytes and agranulocytosis after carbamazepine treatment.
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Agranulocytosis↗
Psychology, immunology, and HIV.
The interdisciplinary field of psychoneuroimmunology (PNI), which aims to clarify the relationship between psychological factors and immunity, can also play a role in our understanding of individual susceptibility to, progression of immunologically mediated disease. Mechanisms proposed to account for the profoundly damaging effects of human immunodeficiency virus (HIV) on immune function do only partially explain the variability in individual rates of progression, suggesting, therefore, that other immunomodulatory factors are also involved. Studies have examined the proposal that the effects of stress and HIV may interact in some complex way, and psychological, physiological and virological evidence for the role of stress in HIV progression is discussed in detail. A critical review of HIV-specific research in PNI, which can be broadly divided into cross-sectional, longitudinal, and intervention studies, and studies of long-term survivors, reveals that the relationship between stress and HIV progression remains equivocal, because of limitations due to methodological difficulties and to our inadequate understanding of immunology and HIV. A model is proposed for the influence of psychosocial stress on progression in HIV disease, which takes account of some of these difficulties.
HIV Infections↗
Formalin fixation and patterns of antineutrophil cytoplasmic antibodies.
Recent publications have suggested that fixing neutrophils in formalin is a useful adjunct to the differentiation of antinuclear antibodies from perinuclear antineutrophil cytoplasmic antibodies. In this small comparative study of 30 sera the use of an additional slide of formalin fixed neutrophils did not add any useful information and may be confusing as the results were not reproducible.
Animals↗
Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review.
Chronic enteroviral meningoencephalitis is a well-recognized complication in patients with X-linked agammaglobulinemia (XLA). The majority of published cases refers to its occurrence in patients on no replacement therapy or on only intramuscular immunoglobulin. The advent of intravenous immunoglobulin (IVIg) in the early 1980s and its widespread use in XLA was thought to have virtually eradicated enteroviral meningoencephalitis in these patients. We describe the development of echovirus meningoencephalitis in an 11-year-old boy on regular IVIg replacement whose serum IgG levels were maintained at between 6 and 8 g/L (NR 6-13 g/L). Treatment with daily high-dose IVIg was commenced, with significant clinical improvement being noted within a few weeks in association with a reduction in blood-brain barrier permeability. The persistence of live virus, however, necessitated the use of intraventricular immunoglobulin. The virus proved resistant to two courses of specific intraventricular immunoglobulin and a 6-week course of oral ribavirin and eventually proved fatal 5 months after presentation. In view of the therapeutic uncertainties we have reviewed the use of immunoglobulin in the treatment of enteroviral meningoencephalitis over the past 6 years.
Acyclovir↗
Progressive multifocal leucoencephalopathy, sclerosing cholangitis, bronchiectasis and disseminated warts in a patient with primary combined immune deficiency.
A 24 year old man presented with an unusual primary combined immune deficiency syndrome characterised by a profound lymphopenia of CD4 cells, selective serum IgG2 subclass deficiency, poor polysaccharide antibody responses, disseminated warts, recurrent sinopulmonary infection and bronchiectasis. The developed progressive multifocal leucoencephalopathy (PML) in association with sclerosing cholangitis. Progressive multifocal leucoencephalopathy (PML) usually occurs as an opportunistic infection in patients with secondary defects in cellular immunity.
Adult↗