Enfermedad relacionada con IgG4 / IgG4-related disease

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Acquired Immunoglobulin G deficiency in stroke patients and experimental brain ischemia.

BACKGROUND AND PURPOSE: Acute brain injuries induce a systemic immune depression syndrome (SIDS) that predisposes patients to bacterial infections. While cellular compartments of this syndrome have been well characterized, the contribution of humoral immune mechanisms and particularly immunoglobulins to SIDS has not been investigated so far. METHODS: We determined serum immunoglobulin levels and infectious complications at several time points in 159 ischemic and hemorrhagic stroke patients. Additionally, findings were verified in a transient middle cerebral artery occlusion model. A novel immunoassay was established to analyze the IgG excretion ratio in mice. RESULTS: We identified a transient IgG reduction in patients suffering from substantial ischemic or hemorrhagic brain injuries. The IgG-reduction was associated with subsequent bacterial infections. Similarly, transient hypogammaglobulinemia was detected in a murine stroke model. We then used this animal model to further distinguish the mechanism of the IgG reduction by an IgG transfer paradigm. Excretional loss rather than deficient production of IgG was demonstrated to underlay hypogammaglobulinemia. CONCLUSIONS: This is the first report of transient hypogammaglobulinemia after ischemic and hemorrhagic stroke suggesting involvement in infectious complications. These findings pave the road for further studies investigating post-stroke hypogammaglobulinemia as a druggable target for stroke-induced complications.

Role of immunoglobulin supplementation for secondary immunodeficiency associated with chylothorax after pediatric cardiothoracic surgery.

OBJECTIVE: To evaluate whether intravenous immunoglobulin was linked to a reduction in sepsis in patients with prolonged chylothoraces postpediatric cardiothoracic surgery. DESIGN: Retrospective observational cohort study. SETTING: Tertiary pediatric cardiac surgical center. PATIENTS: Children with chylothoraces postcardiothoracic surgery from 1998 to 2006 divided into two groups: with and without intravenous immunoglobulin supplementation. INTERVENTION: Intravenous immunoglobulin supplementation. MEASUREMENTS AND MAIN RESULTS: Thirty-seven with chylothoraces (median duration 14 days; interquartile range, 10-32 and median maximum chyle drainage 1.9 mL/kg/hr; interquartile range, 1-3) were included, and 16 (43%) received intravenous immunoglobulin. The degree of lymphopenia was worse with longer duration of chylothorax (p = .005). There was a trend toward immunoglobulin depletion-IgG (p = .07) and IgM (p = .07) with higher volume chyle loss. Twenty-two of 37 (59%) developed bloodstream infection and 24 of 37 (65%) developed sepsis related to other organ systems. The rate of bloodstream infection and of sepsis in other organ systems was high at 25 (95% confidence interval 17-39) and 23 (95% confidence interval 15-34) episodes per 1,000 intensive care unit days, respectively. Intravenous immunoglobulin was not related to the bloodstream infection rate: adjusted hazard ratio 0.88 (95% confidence interval 0.20-3.94; p = .87) or rate of sepsis in other organ systems: hazard ratio 2.31 (95% confidence interval 0.21-24.29; p = .49) or the proportion surviving to hospital discharge (p = .37). CONCLUSION: Patients with prolonged, large-volume chyle loss had greater secondary immunodeficiency. Although the sample size was small and therefore able to detect only a large treatment effect from intravenous immunoglobulin, infectious outcomes were equal between the two groups.

Immunodeficiencies in children with chronic post tympanic otorrhoea.

INTRODUCTION: A minority of children treated with ventilation tubes develop chronic otorrhoea. To test the hypothesis that this condition might be caused by an underlying primary immunodeficiency, the immunological status was examined in a group of children with longstanding otorrhoea. MATERIAL AND METHODS: Eighteen children who had suffered from otorrhoea for a minimum of six months and who did not respond to relevant therapy were included. Thorough cleansing and suction was performed including removal of ventilation tubes. Swabs were obtained for microbiology and blood was collected for immunological analyses. RESULTS: One child out of 18 had a normal immune status. Five demonstrated isolated humoral deficiencies, four had isolated cellular deficiencies, whereas combined defects were identified among eight children. The humoral deficiencies consisted of selective or partial immunoglobulin A deficiencies, immunoglobulin G subclass and mannanbinding lectin deficiencies. The cellular deficiencies most often involved the cytotoxic T cells and the natural killer cells. CONCLUSION: Primary immunodeficiencies were very prevalent in a highly selected group of children suffering from longstanding post tympanic otorrhoea. The condition should therefore be considered in case of chronic, refractory otorrhoea. The serostatus should be followed carefully to obtain information of the prognosis. FUNDING: Not relevant. TRIAL REGISTRATION: Not relevant.

IgG deficiency and expansion of CTG repeats in myotonic dystrophy.

OBJECTIVES: Expansion of CTG repeats in myotonic dystrophy (DM1) alters the regulated expression of numerous genes. It is considered to explain the major clinical features of DM1. IgG deficiency is common in DM1 and is due to altered FcRn-related hypercatabolism. We hypothesized that the IgG catabolic rate is correlated with CTG repeat expansion. METHODS: Correlations between serum immunoglobulin levels, peripheral lymphocyte subset counts and CTG repeat numbers were performed in 52 DM1 patients. RESULTS: Serum IgG and IgG1 levels were below the normal limit respectively in 54% and 72% of patients. Increasing CTG repeat numbers were significantly correlated with decreasing serum IgG and IgG1 levels, and with decreasing CD3(+) T-cell and CD3(+)-CD8(+) cell counts. An abnormal immunoglobulin profile at protein electrophoresis was found in 4 patients. CONCLUSION: We conclude that the catabolic rate of IgG is linked to expanded CTG repeats, possibly involving an altered immune response.

Collagenous duodeno-ileo-colitis with transient IgG deficiency preceded by Yersinia enterocolitica intestinal infection: case report and review of literature.

A case-report of a man with chronic diarrhoea is presented. After an unsuccessful treatment of an intestinal yersioniosis, the diagnosis of collagenous intestinal disease affecting duodenum, ileum and colon was made. In addition, a IgG transient deficiency was observed. The literature about gastrointestinal involvement, concomintant infection by Yersinia and IgG deficiency in collagenous colitis is reviewed.

Coexistent yellow nail syndrome and selective antibody deficiency.

BACKGROUND: Yellow nail syndrome (YNS) is a rare, often underdiagnosed condition of unknown origin. The clinical features of the syndrome include yellow nails, chronic sinusitis, bronchiectasis, pleural effusion, and lymphoedema. Despite the frequent occurrence of upper and lower respiratory tract infections in patients with YNS, comprehensive analysis of their humoral immunity has not been previously reported. OBJECTIVE: To present the case of a patient with YNS whose recurrent upper and lower respiratory tract infections may have been caused by an underlying selective antibody deficiency that manifests as impaired IgG antibody response to polysaccharide antigens. METHODS: The patient underwent cultures of purulent sputum for Streptococcus pneumoniae and Haemophilus influenzae, bronchial washings for H. influenzae, and nail scrapings for fungi. Her serum levels of IgG, IgA, IgM, IgG subclasses, and serum titers of IgG antitetanus toxoid, anti-H. influenzae, and anti-S. pneumoniae antibodies were measured. RESULTS: Cultures of purulent sputum were positive on multiple occasions for S. pneumoniae and H. influenzae and bronchial washings were positive for H. influenzae. Nail scrapings were consistently negative for fungi. She had no reductions in serum levels of IgG, IgA, IgM, or IgG subclasses and had normal serum titers of IgG antitetanus toxoid antibodies. However, she demonstrated impaired IgG antibody responses following immunization with Pneumovax and an H. influenza B vaccine. CONCLUSIONS: This case report describes the first comprehensive analysis of humoral immune function in a patient with YNS. The finding of a selective antibody deficiency in our patient provides a potential explanation for the occurrence of respiratory infections in YNS. Accordingly, we recommend that functional antibody determinations and quantitative serum immunoglobulins be evaluated in patients diagnosed as having this unusual, enigmatic syndrome.

Immunoglobulin deficiency in kidney allograft recipients: comparative effects of mycophenolate mofetil and azathioprine.

Mycophenolate mofetil (MMF) has commonly been substituted for azathioprine (AZA) in kidney transplantation and has been shown to have a greater effect on T cell function and also B cell function than AZA. Although immunoglobulin deficiency has been investigated in patients treated with protocols that include AZA, it has not extensively been studied in MMF-based immunosuppressive protocols. To evaluate this effect, we conducted a prospective study and recruited 49 patients. The patients received either AZA- (group 1) or MMF- (group 2) based therapy. A total of 17 patients in group 1 and 24 patients in group 2 completed the study. Immunoglobulin levels were evaluated before and in every month after transplantation for a 6-month period. Total infectious episodes were recorded and evaluated after 6 months in both groups. While no significant differences have been found in group 1, there were significant decreases in IgG, M, and A levels in group 2 after 6 months (IgG: 11.6+/-1.5-6.8+/-2.0 g/L, P<0.0001; IgM: 2.20+/-1.40-1.40+/-1.16 g/L, P=0.02; IgA: 1.40+/-0.70-1.07+/-0.86 g/L P=0.03). Two patients (11.7%) in group 1 and 11 patients in group 2 (45.8%) were found to have at least one low level of immunoglobulin (P=0.03). When the infectious complications were evaluated, the mean number of infection episodes in each patient was 1.3+/-1.6 and 0.5+/-0.7 for the MMF and AZA groups, respectively (P=0.06). Recurrent urinary tract infection developed in eight patients and seven of those were in group 2. In group 2, 7 of 11 patients with low immunoglobulin levels had recurrent urinary tract infection (63%), while no patient who had normal immunoglobulin levels developed any recurrent urinary tract infections (P<0.001). After 6 months, MMF was changed to AZA in these seven patients, who had both recurrent urinary tract infections and low immunoglobulin levels. All but one patient was found to have normal immunoglobulin levels after 3 months of conversion and only two episodes of infection were recorded during this period. We suggest that serum immunoglobulin levels can be monitored in patients taking MMF, and conversion from MMF to AZA may be an alternative for patients with low immunoglobulin levels and recurrent urinary tract infections.

IgG and IgG subclasses deficiency in children undergoing continuous ambulatory peritoneal dialysis and its provocative factors.

BACKGROUND: Low levels of serum IgG or IgG subclasses may be responsible for the defective peritoneal defense and for peritonitis attacks in continuous ambulatory peritoneal dialysis (CAPD) children. Malnutrition, peritoneal loss or frequent peritonitis may lead to IgG or IgG subclasses deficiency. METHODS: Levels of IgG subclasses were determined in 12 children undergoing CAPD treatment. Radial immunodiffusion technique was used for determination. Patients were aged from 6 to 16 years (mean age 12.3 years) and had been on CAPD for 11-26 months (mean duration 19.4 months). We evaluated whether IgG and IgG subclasses deficiency are related to malnutrition, the peritonitis rate and the duration of CAPD using the SPSS program. RESULTS: Serum total IgG levels were found to be low in eight out of 12 patients. Eight patients showed low levels of IgG1, four patients IgG2, one patient IgG3 and three patients IgG4. Total IgG values were found to be positively correlated to malnutrition status, peritonitis rate and duration of CAPD. The IgG2 values were found to be related to the duration of CAPD. The IgG4 values were found to be correlated to the peritonitis rates. CONCLUSIONS: The IgG and IgG subclasses deficiency may develop in children while on CAPD treatment. Periodical determinations of either serum IgG or the subclasses may be useful in the follow-up of these patients.

Dynamic changes of the immunoglobulins in patients with severe ovarian hyperstimulation syndrome: efficacy of a novel treatment using peritoneo-venous shunt.

PROBLEM: To evaluate the efficacy of continuous auto-transfusion system of ascites (CATSA) for the treatment of patients with severe ovarian hyperstimulation syndrome (OHSS) at the risk of febrile morbidity, the dynamic changes of immunoglobulins in the sera and the peritoneal fluid from patients with severe OHSS treated by CATSA were estimated. METHOD OF STUDY: Ten patients with severe OHSS after superovulation for in vitro fertilization-embryo transfer (IVF-ET) were treated by CATSA. Immunoglobulin concentrations were examined in the serum and in the peritoneal fluid before and after CATSA. As controls, serum samples from 15 infertile women, who did not develop OHSS after the same superovulation protocol, were obtained on the day of mid-luteal period (Control-1). Serum samples from 15 patients with OHSS, who were treated by albumin infusion without paracentesis, were also obtained before and after the treatment (Control-2). RESULTS: Before the treatments, serum immunoglobulin G (IgG) concentrations in patients with severe OHSS treated with CATSA and those in patients of Control-2 were significantly lower than those in patients of Control-1 (P < 0.01). Following CATSA, the concentration of IgG increased in the sera, while it decreased in the peritoneal fluid. CONCLUSIONS: Serum IgG in patients with severe OHSS exuded into their peritoneal cavity, indicating that they might be at the status of immunodeficiency and at the risk of febrile morbidity. However, non-infectious febrile morbidity attributed to endogenous pyrogenic mechanism might be considerable. It is also suggested that CATSA might be effective in improving hypoimmunoglobulinemia of the patients with severe OHSS by the peritoneo-venous shunt.

Giardia lamblia infection in a patient with myotonic dystrophy.

Myotonic dystrophy is an autosomal dominant muscle disorder characterized by muscle wasting and weakness and a number of other systemic abnormalities. Some patients have hypo-IgG that is asymptomatic in most of them. We report the case of a 42-year-old woman with myotonic dystrophy and hypo-IgG who experienced asthenia and weight loss secondary to Giardia lamblia bowel infection.

IgG subclasses in smokers with chronic bronchitis and recurrent exacerbations.

BACKGROUND: Tobacco smokers have lower serum levels of IgG than non-smokers. IgG subclass deficiency is common in patients with recurrent respiratory infections. Recurrent bronchial infections are common in smokers with chronic bronchitis (CB). We have investigated whether susceptibility to recurrent exacerbations in smokers with CB is associated with altered IgG subclass levels or IgG subclass deficiency. METHODS: Serum levels of IgG, IgA, IgM, and IgG subclasses 1-4 were determined by radial immunodiffusion in 100 subjects: 33 smokers with stable CB and recurrent exacerbations, 24 asymptomatic smokers, and 43 healthy never smokers. Systemic tobacco exposure was verified and excluded using a serum cotinine ELISA. Immunoglobulin data were log transformed to enable use of parametric statistical methods. RESULTS: Compared with never smokers, both patients with CB and asymptomatic smokers had significantly lower levels of IgG (median 9.7 g/l (range 5.6-15.2) and 9.9 (6.1-12.1) g/l v 12.0 (6.9-18.5) g/l) and IgG2 (2.8 (0.9-5.9) g/l and 2.5 (1.0-6.3) g/l v 4.0 (1.7-10.2) g/l). The estimated ratio of median values between the patients with CB and never smokers was 0.78 (95% confidence interval (CI) 0.69 to 0.89) for IgG and 0.65 (95% CI 0.50 to 0.83) for IgG2. The corresponding ratios between asymptomatic smokers and never smokers were 0.79 (95% CI 0.69 to 0.91) and 0.60 (95% CI 0.50 to 0.83), respectively. There were no significant differences between the smoking groups. CONCLUSIONS: Susceptibility to recurrent exacerbations in smokers with CB is not associated with lower levels of IgG subclasses than can be accounted for by smoking per se.

[Polyclonal B lymphocytosis and hyper-IgM: immunodeficiency and/or benign lymphoid proliferation associated with tobacco?]. / Hyperlymphocytose B polyclonale et hyper-IgM: déficit immunitaire et/ou prolifération lymphoïde bénigne associé(s) au tabac?

PURPOSE: To study the association of polyclonal B-cell lymphocytosis with binucleated lymphocytes with clinical manifestations suggesting the existence of an immunodeficiency, to evaluate the effect of cigarette smoking on this 'benign lymphoid proliferation', to analyze the clonality of lymphocytes, to determine the levels of immunoglobulins (Ig) G, A, M. METHODS: Description and analysis of the results obtained in four patients and literature review. RESULTS: Polyclonal B-cell lymphocytosis is associated with both a decrease in IgA and IgG and an increase in IgM. Recurrent infectious episodes (bronchitis) were observed in two patients. Transient smoking cessation allowed a decrease in lymphocytosis and IgM levels in two patients. No hematological malignancy occurred during the follow-up, while biological abnormalities persisted. CONCLUSION: Persistent polyclonal B-cell lymphocytosis may be associated with minor clinical features of immunodeficiency. Smoking cessation may sometimes lead to a decrease in lymphocytosis and IgM.

Heterogeneity of serum IgG subclass deficiencies in B chronic lymphocytic leukemia.

The occurrence of abnormally low serum immunoglobulin (Ig) levels is well-known in B chronic lymphocytic leukemia (CLL), but published data on IgG subclass levels are virtually absent. We measured serum IgG subclass levels in 52 B CLL outpatients, most in stage A and untreated, using an indirect immunoenzymatic assay with monoclonal antibodies. Mean levels of all Ig isotypes were lower than in normal controls in the whole group of patients, except for IgG2 in those studied at diagnosis. Levels of IgG1, IgG2, IgA, and IgM were lower in patients with a long disease duration than in those studied earlier. IgG subclass deficiencies occurred in 54% of cases and the most frequently affected isotype was IgG1. Every possible combination of IgG subclass and Ig class deficiencies from the selective deficiency of a single subclass to a combined deficiency of all isotypes was observed. This marked heterogeneity argues against the occurrence of isolated defects of one of the cytokines involved in Ig switching as a cause of hypoimmunoglobulinemia in CLL.

Selective IgG1 deficiency.

Measurement of serum IgG subclass levels in 3005 patients disclosed abnormally low IgG1 levels with normal levels of the other IgG subclasses and of IgM and IgA in 119 patients, predominantly adults. Not all patients were hypogammaglobulinemic due to nonrare increases of other isotypes, mostly IgM. A familial context of immunodeficiency was frequent, more often combined than selective IgG1 deficiency. A familial association with IgG2 deficiency was found also and IgG1 replaced IgG2 deficiency in 3 cases (and succeeded to or preceded more complex IgG defects in 3 cases, whereas IgG1 deficiency was consistently found at examinations repeated in the absence of therapy in 10 additional cases). Most but not all (83.2%) patients suffered infections, generally moderate, similar to those observed in other selective IgG subclass deficiencies (IgGSD), with predominantly sinorespiratory infections. Other clinical manifestations such as atopy, congenital cardiopathy, and autoimmune diseases were already known in IgGSD but the incidence of asthma was strikingly high (one-fifth of the cases).

Humoral immunodeficiency in patients after bone marrow transplantation.

Ex vivo IgG production was determined in 17 children and adolescents and in 14 adult patients between 10 months and 6 years after BMT. Twenty-four patients received allogeneic transplants. Seven patients were transplanted with autografts. Seven patients received immunosuppressive therapy. B cells were purified by positive selection with a CD20 antibody. After IL-2 or IL-10 stimulation, IgG production of SAC-preactivated B cells in patients with immunosuppression (median/range: 11/4-15 ng/ml or 14210-29 ng/ml) was significantly reduced compared with patients receiving allogenic (30/3-860 ng/ml or 33/2-3431 ng/ml; P < 0.01) or autologous transplants (75/7-1431 ng/ml or 269-/7-13600 ng/ml, P < 0.01). In 14/31 patients ex vivo IgG production was defective. Investigations of B cell function in patients with defective IgG production was performed significantly earlier after BMT compared with patients with normal IgG production ex vivo (2 +/- 1 years vs 3.3 +/- 1.5 years; P < 0.05). In addition, only patients with a B cell deficiency received immunosuppression. However, patients ex vivo IgG produced by B cells was decreased, but IgG production/sIgG+ B cells was within range of healthy volunteers. The number of IgG-committed B cells in these patients was significantly reduced compared to patients without deficiency (23/19-45/microliter vs 100/14-336/microliter; P < 0.05), indicating an in vivo switching defect. Although IL-10 is known to induce IgG-isotype switching in vitro, production of IL-10 by anti-CD3 activated MNCs obtained from patients with a switching defect did not differ from patients without B cell defects (1699/400-2662 pg/ml vs 724-112-1826 pg/ml). In nine patients IgG production and IgG production/sIgG+ B cells were impaired. The number of sIgG+ B cells was not decreased compared with patients without B cell deficiency (115/18-288/microliter), indicating a defective terminal differentiation of IgG-committed B cells to plasma cells. Although autocrine IL-6 is essential for plasma cell formation of isotype-determined B cells, it was comparable in patients with a terminal deficiency and without deficiency (3838/583-5967 pg/ml vs 2423/1643-6184 pg/ml). However, IL-10 production by anti-CD3 activated MNCs in patients with a terminal B cell defect (426/54-2262 pg/ml, P < 0.05) was significantly lower than in patients without deficiency, indicating a deviant cytokine production by T cells which might in part account for the B cell defect. Defective isotype switching as well as impaired terminal differentiation of B cells were found. Further analysis of factors regulating isotype-switching in vivo as well as cytokine receptor expression or signalling processes of differentiation factors in activated B cells might help to characterize the nature of these B cell deficiencies after BMT.