Immunoglobulin subclasses and HLA alleles in immunoglobulin A deficiency

Objective : The term “IgA Deficiency (IgAD)” should be reserved for the individuals who do not have detectable disorders known to be associated with low IgA levels. IgG subclass deficiency or a lack of the IgG2 subclass that is specific against polysaccharide antigens, can be seen in many cases.Methods : Forty-five patients (27 males and 18 females; mean age 8.6 years, range 6.3 to 12.8 years) with IgA deficiency who had been admitted to the Department of Pediatric Immunology in Uludag University School of Medicine, Turkey, were included in this study. Serum immunoglobulin (Ig) class and IgG subclass levels, and HLA haplotypes were prospectively determined in patients and healthy controls.Results : Of the 45 patients with IgAD, 1 was found to have a low level of IgG in the serum. Serum Ig levels were also examined in the families of 22 patients. Five patients had low-normal levels of IgM, whilst one had low levels of IgA and IgG. The levels of IgG sublasses were assessed in 23 patients. One patient had a low level of IgG1 ; 2 had low levels of both IgG2 and IgG3, and 11 had low levels of IgG3. IgG subclass concentrations were found to be normal in control groups. HLA alleles were tested in 25 patients. An increased prevelence of HLA-A1, -B8, -B14, -DR1, -DR3, and -DR7 were previously observed in patients with Ig A deficiency. In this study, HLA-A1 allel was found in 3 patients (12 %), HLA-B14 in 3 patients (12%), HLA-DR1 in 10 patients (40 %), HLA-DR7 in 4 patients (16 %) and HLA-DR3 in 1 patient (4 %). HLA-B8 allel was not found in any patient. Twenty-five children with normal IgA levels have chosen as a control group. They had HLA-DR1 (36%), HLA-DR7 (16 %), HLA-B8 (8%), HLA-DR3 (16%). HLA-A1 was not found in any member of our control group.Conclusion : No statistically significant difference in HLA susceptibility alleles was found between patients and healthy controls. Our data suggest that there may be heterogenous HLA distribution patterns in IgA deficiency, or that HLA allel-associated tendency to IgA deficiency may be polygenic.     

IgG SUBCLASS LEVELS IN INFANCY AND CHILDHOOD

Abstract. Oxelius, V. (Department of Paediatrics, University Hospital, Lund, Sweden). IgG subclass levels in infancy and childhood. Acta Paediatr Scand, 68: 23, 1979.—The concentrations of IgG1, IgG2, IgG3 and IgG4 were determined by electroimmunoassay in 10 pairs of maternal and cord sera and in sera of 162 healthy children, aged 6 weeks to 15 years. Specific rabbit antisera against the IgG subclasses were used. The content of the normal serum pool WHO 67/97 was used as reference. The mean value, standard deviation and normal range of each IgG subclass were calculated for each age group and compared with the adult values. All IgG subclasses were present in cord serum except for IgG4 in those cases where also the maternal serum lacked demonstrable IgG4. The IgG subclasses followed the pattern of total IgG with a fall during the first 3–6 months and a subsequent gradual rise with age. The IgG1 and IgG3 levels rose faster with age than IgG2 and IgG4. Adult levels were not reached before puberty. No IgG4 was detectable in 12–21% of the children above 7 years of age.     

食物IgG抗体检测在慢性消化系统疾病中的临床意义

目的探讨血清中14种食物过敏原特异性IgG与小儿慢性消化系统疾病的关系。方法应用酶联免疫法检测40例慢性消化系统疾病患儿,血清中食物特异性IgG水平,然后按3∶1分别采用微粒子化学发光法和散射比浊法检测血清总IgE和血清IgG4水平。结果40例患儿食物过敏原特异性IgG升高有1到6种不等,总阳性率为100%,2种以上升高者为87.5%。食物特异性IgG升高以鸡蛋(92.5%)和牛奶(72.5%)最多见,其次为小麦、大豆(分别为40.0%、27.5%),鸡肉、猪肉和玉米均为0。根据试验结果调整所有患儿的饮食,病人症状在3周内明显改善者62.5%,症状有所改善者32.5%,无效5.0%,总有效率为95.0%。血清总IgE大于正常值者为17.5%,与食物特异性IgG无相关性(r=-1.132,P=0.268)。血清总IgG4水平变化与食物特异性IgG无相关性(r=0.863,P=0.396),与年龄呈正相关(r=3.317,P=0.003)。结论测定食物过敏原特异性IgG在小儿慢性消化系统疾病诊治中有重要意义。     

Recurrent pneumococcal meningitis in a patient with transient IgG subclass deficiency

We report the case of a 3 year old boy who exhibited recurrent serious infections with a transient imbalance of IgG subclass in the second year of life. He suffered from pneumococcal meningitis at 3 months, hepatitis at 9 months, and purulent arthritis at 11 months of age. The second episode of pneumococcal meningitis occurred at 14 months. Serum IgG level was normal for age. Low level of IgG2, undetectable level of IgG4 and negligible level of pneumococcus-specific IgG1-G2 antibodies were found. No other primary immunodeficiency was apparent. Serum IgG2-G4 levels but not pneumococcus-specific IgG1-G2 titers increased by the age of 30 months. At that time, he was inoculated with a polyvalent pneumococcal vaccine along with acellular diphtheria-pertussis-tetanus vaccine. He acquired the immunity against these agents, and had no episodic infections in the following 2 years. This observation stresses the existence of transient IgG subclass deficiency associated with delayed development of the anti-polysaccharide antibody response.     

IgG2 deficiency in children with human immunodeficiency virus infection

Infection with the human immunodeficiency virus (HIV) induces a polyclonal B-cell activation. Despite elevated serum immunoglobulin levels, a significant deterioration of the antigen specific humoral immune response exists in most cases. We studied the influence of HIV infection on the serum levels of IgG subclasses in children. We investigated 76 children (aged 15 months to 18 years) with HIV-1-infection. Most children (88%) showed elevated serum immunoglobulin levels. IgA (87%) and IgM (74%) were more often above normal levels for age than IgG (60%). IgG subclass serum levels were significantly altered. The increase in total IgG was mainly due to a marked augmentation of the IgG1 fraction. In most cases IgG3 was simultaneously elevated. Ten children (13%) had very low IgG4 levels (<0.03 g/l). Out of 61 patients older than 2 years 8 (13%) had a profound IgG2 deficiency with normal or elevated total IgG. Four of them also had low IgG4 levels (<0.03 g/l). A correlation between IgG2 deficiency and HIV infection according to the Centres for Disease Control classification for acquired immunodeficiency syndrome could not be demonstrated (three patients with symptomatic and five with asymptomatic infection).     

Normal levels of IgG subclass in childhood determined by a sensitive ELISA

Normal values of all IgG subclasses were determined using a sensitive ELISA in children aged from newborn to 14 years. The upper and lower limits of normal values of all IgG subclasses were obtained in all the age groups using 29 umbilical cord blood samples from full-term newborns and 308 venous blood samples from normal infants and children. The trends in the levels of IgG1, IgG2 and IgG3 with age were almost similar to previous reports. IgG4 levels decreased gradually until reaching the lowest level at 7 to 12 months and increased gradually with age, reaching a plateau at 12 to 14 years of age. Thus, the lower limit of serum IgG4 levels was determined using our method.     

Anti-immunoglobulin antibodies in children with Schönlein-Henoch syndrome. Absence of serum anti-IgA antibodies

Circulating immune complexes (CIC) that simultaneously contain IgG and IgA are frequently found in IgA nephropathy (IgA-N) and the Schönlein-Henoch syndrome (SHS). The presence of anti-immunoglobulin antibodies (IgA anti-IgG and IgG anti-IgA) was studied by ELISA in the serum of 39 children with SHS and compared to 30 normal children. The mean level of IgG anti-IgA antibodies (240±104 u/ml) in SHS patients was similar to control values (251±85 u/ml); the IgA anti-IgG antibodies were increased, although only the antibodies against Fc fraction of IgG were elevated (185±71 u/ml in patients vs 127±24 /ml in controls,P<0.0001) without a significant increase of IgA anti-IgGFab antibodies (141±54 /ml vs. 137±25 u/ml); 16/39 (41%) of the patients had increased levels of IgA anti-IgGFc and 6 of these had also high IgA anti-IgGFab. None of these patients had high IgA anti-IgGFab antibodies without simultaneous augmentation of IgA anti-IgGFc. Only 3/39 (7.7%) of SHS patients showed high levels of IgG anti-IgA antibodies. The correlation of IgA anti-IgGFc antibodies with IgA anti-IgGFab was very strong (P<0.0001) but lower with IgG anti-IgA antibodies (P<0.002). In addition, 8/39 children had renal involvement, nevertheless in these patients the findings were quite similar, with a non-significant elevation of IgA anti-IgGF ab antibodies. These results show that the IgA anti-IgG antibodies are more frequently increased than IgG anti-IgA antibodies in the SHS; moreover they are mainly directed against Fc fraction and are IgA-FR isotype. Our findings suggest that the CIC in SHS are likely formed by the reaction of IgA antibodies against IgG and not vice versa.     

The value of immunoglobulin and complement levels in the early diagnosis of neonatal sepsis

Serum IgG, IgGl, G2, G3, G4, IgM, C3c and C4 concentrations were measured in 24 term neonates with sepsis and 17 healthy normal neonates of similar age, sex and weight (control group). The serum IgG, IgG1, G2, G3, G4, IgM, C3c, and C4 levels were similar in the patients with sepsis and the control group ( p > 0. 05). In the neonates with sepsis, serum IgG, G1, G2, IgM and C4 levels were not significantly different between the 1st and 10th days, while there were significant differences for IgG3, G4 and C3c ( p < 0. 05). We conclude that the serum levels of IgG, IgG1, G2, G3, G4, IgM, C3c and C4 concentrations are of no value for the early diagnosis of neonatal sepsis.     

Comparison of IgG subclasses in foetal serum, maternal serum at delivery and milk in IgA-deficient and control women

Immunoglobulin G subclass concentrations were measured in paired foetal (cord) and maternal serum specimens at delivery from 27 IgA-deficient (serum IgA < 0.01 g/l) and 15 control women. IgA-deficient women had significantly higher serum IgGl and IgG3 concentrations than control women but 2 of the group had concomitant IgG2/IgG4 deficiency and a further 12 had low IgG4 concentrations (serum IgG4 < 0.025 g/l). Foetal serum also had significantly higher IgGl concentrations than control foetal serum but lower IgG2 and IgG4 levels. Concentrations of IgG subclasses and IgM were measured in breast milk collected on the fifth day postpartum from 19 of these IgA-deficient and 18 control women. Between-group differences in IgG subclass levels resembled those in serum. Compared with serum, proportionally less IgG3 was present in milk in both groups although the contribution of IgG3 to total IgG was not less than that of IgG4. Slightly higher IgM was found in milk from the IgA-deficient mothers.     

Serum cortisol and thyroid hormone levels in neonates with sepsis

Objective: To evaluate the thyroid hormone and cortisol levels in neonates with sepsis in relation to the final outcome. It was hypothesized that the hormonal level could act as some prognostic guideline.Methods: Forty nine neonates, aged 8–28 days, diagnosed as neonatal sepsis were selected for the study. Neonates below 8 days of age, 35 weeks of gestation and 2000 g of birth weight were excluded from the study. Twenty FT-AGA neonates beyond day 7 of life served as control for the study. The hormones were estimated by radioimmunoassay.Results: The neonates with sepsis had significantly higher mean serum cortisol and lower mean serum total T₄ at admission as compared to healthy neonates. The mean serum total T₃ level was also lower, but the difference was not statistically significant. The mean serum TSH levels were comparable in both groups. The levels normalised following recovery. Sixteen neonates succumbed to the disease process. The non-survivors had significantly lower mean total T₃ and total T₄ levels as compared to the survivors.Conclusion. The endocrinal abnormalities are of transient nature as a response to sepsis. Low total T₃ and total T₄ are the predictors of adverse outcome in neonates with sepsis.     

Elevated thyroid-stimulating hormone level in a euthyroid neonate caused by macro thyrotropin-IgG complex

Elevated thyroid-stimulating hormone (TSH) was discovered by routine neonatal screening in a newborn with no clinical symptoms. Thyroid function tests were repeated and confirmed a high TSH value but normal total thyroxine (T4) and triiodothyronine (T3). However, the mother also had elevated serum TSH with normal levels of T4 and T3. The results suggested a transmitted maternal interfering factor, and no treatment was started while further investigation was performed. Gel filtration chromatography of serum from both the infant and the mother showed a peak TSH with molecular mass consistent with a TSH-IgG complex (macro-TSH). TSH in the infant decreased to a normal level within 8 months in accordance with a normal rate of elimination of maternal IgG, whereas the TSH level of the mother remained high. CONCLUSION: This case suggests that interfering macro-TSH should be considered in a euthyroid neonate with elevated serum TSH and normal T4 and T3 levels to avoid unnecessary treatment.     

Effect of Anti-Epileptic Drugs on Serum Level of IgG Subclasses

Objective

There are some controversial studies on effects of anti-epileptic drugs (AEDs) on serum IgG subclasses; however, the role of these medications is still unclear. The aim of this study was evaluation the effects of anti-epileptic drugs on serum concentration of IgG and its subclasses

Methods

Serum IgG and IgG subclasses of 61 newly diagnosed epileptic patients were measured at the beginning of monotherapy with carbamazepine, sodium valproate, and phenobarbital, and 6 months later. Measurement of IgG and its subclasses was performed using nephlometry and ELISA techniques, respectively.

Findings

Reduction of at least one IgG subclass was found in 6 patients 6 months after treatment with AEDs. Among 27 patients receiving carbamazepine, decrease in at least one serum IgG subclass level was found in 5 patients. Among 20 patients using sodium valproate, only one patient showed decrease in IgG2 subclass. None of the 14 patients using phenobarbital revealed significant decrease in IgG subclasses. No infection was seen in the patients with reduction of subclasses.

Conclusion

Although in our study, children with selective IgG subclass deficiency were asymptomatic, assessment of serum immunoglobulin levels could be recommended at starting the administration of AEDs and in serial intervals afterward in epileptic patients.     

Serum IgG subclass concentrations in healthy subjects at different age: Age normal percentile charts

IgG subclass levels were determined in 448 normal children from 6 months to 18 years of age and in 141 healthy adults by radial immunodiffusion using monoclonal antibodies. Age-normal percentile values were calculated for each year of age up to 18 years for IgG1, IgG2, IgG3 and in adults for all four subclasses. The broad spread of IgG4 values in children did not permit calculation of reference values.     

Undetectable IgG4 in immunoprecipitation: association with repeated infections in children?

A total of 210 patients with repeated infections were screened for IgG4 deficiency. In 30 patients (14%) IgG4 was undetectable by radial immunodiffusion (<30 mg/l). Of these patients 17 (57%) were less than 2 years of age. Concomitant IgA deficiency (IgA<0.05 g/l) was demonstrated in 11 cases (37%). IgG2 serum levels below the normal range were found in 26 children. IgG4 could be demonstrated at a concentration of 0.5–29 mg/l in all 30 patients using a more sensitive enzymelinked immunosorbent assay technique. Although a highly selected group of patients was investigated, the percentage of individuals without detectable IgG4 by immunodiffusion was in the same range as reported in the literature for healthy control persons. It is thus concluded that IgG4 serum reference levels have to be defined using more sensitive methods and that the observed severe infections are more likely to be connected with low serum IgG2 and/or IgA levels than undetectable IgG4 as measured by immunodiffusion.This work was supported by a grant from the Deutsche Forschungsgemeinschaft BA 872/1-1     

Serial IgG and IgM serum levels after infusion of different Ig-preparations (IgG or IgM-enriched) in preterm infants

Intravenous administration of Immunoglobulin (IVIG) has been used for prevention or treatment of neonatal sepsis. However, therapeutic efficacy of IVIG is dependent on pharmacokinetic factors. There have been no comparative studies in neonates between licensed IgG and IgM enriched preparations. The aim of this study was to investigate serial IgG and IgM serum levels during the neonatal period in two groups of non-septic, preterm infants treated prophylactically with IVIG. Twenty-two very low birth weight (VLBW) patients (1001-1500g) (gestational age 31.8±2.0 weeks and 1265±245g birth weight) and 12 extremely low birth weight (ELBW) patients (<1000g) (gestational age 28.6±2.5 weeks and 910-85g birth weight) received at random three standard doses of Sandoglobulin (SG) (0. 5 g/kg/day) or IgM enriehed Pentaglobin (PG) (5 ml/kg/day). IgG and IgM concentrations were assayed by rate nephelometry before treatment and at day 3, 5, 7, 14 and 28 of life. At any time IgG levels were higher in the SG-VLBW group (p < 0.01). no difference being observed in the ELBW group (p>0.5). IgM levels were higher at day 3 and 5 in the PG-VLBW group and until day 7 in the ELBW group (p < 0.01). This study indicates a wide range of IgG and IgM kinetics in the healthy premature and suggests frequent monitoring of immunoglobulin serum levels during efficacy studies.     

Transient IgG subclass deficiencies in newly diagnosed diabetic children

In 27 children (15 males and 12 females) with insulin-dependent diabetes mellitus (IDDM), aged 1.2–13.5 years (mean 9.9±3.6 years) we investigated immunoglobulins (IgG, IgA, IgM), IgG subclass levels and islet-cell antibodies (ICA) at diagnosis and at 6 and 12 months after disease onset. At diagnosis, IgG levels were lower than-2SD in 7 patients (26%), IgA in 1 (3.7%), IgM in 1 (3.7%). IgG subclass levels were below the 3rd percentile in 13 patients (48.1%); in particular IgG1 in 7 (26%), IgG2 in 3 (11.1%), IgG3 in 2 and IgG4 undetectable in 1 case. In 3 out of the 13 patients combined IgG1-IgG3, IgG1-IgG2 and IgG1-IgG4-IgA deficiencies were observed. ICA were >20 Juvenile Diabetes Foundation units in 17/27 patients. The HLA-DR2 frequency was higher in patients with IgG subclass deficiency than in patients with normal IgG subclass levels. During follow up, IgG levels normalized in 6 patients while IgA and IgM did not change. IgG1 normalized in 5 out of the 7 patients, IgG2 in all patients while IgG3 and IgG4 did not change. One year later ICA were still present in 8/27 patients. The hypogammaglobulinaemia and IgG subclass deficiencies observed in our patients could have either a genetic or an acquired basis.     

Serum IgG levels in full term preterm and SFD neonates

Cord blood IgG levels were estimated in fifty normal full term, preterm and small for date babies. The values were significantly lower (p<0·05) both in preterm and SFD babies when compared with normal full term (AGA) newborn. A direct correlation was found to exist between IgG concentration and gestation age in pretern as well as full term (ABA). Small for date babies showed significantly lower (p<0·05) IgG levels as compared to preterm (AGA) neonates suggesting the effect of inadequate placental function as a contributing factor in decreased serum IgG values in small for date babies.     

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.     

Coronary risk factors in acute Kawasaki disease: Correlation of serum immunoglobulin levels with coronary complications

Abstract Background To determine the usefulness of the IgG z-score (age and sex-standardized serum IgG level) before intravenous gamma globulin therapy (1VGG) in predicting the occurrence or severity of coronary complications in Kawasaki disease (KD).
Methods A case-control study of clinical and laboratory findings with 88 children in the early stage of acute KD who received IVGG (100 or 200 mg/kg for2–5 days) therapy. Of these, 20 cases had persistent coronary arterial lesions (small aneurysm, moderate aneurysm or large aneurysm persisting more than 1 month). The controls comprised 68 children with no coronary aneurysms or transient small aneurysm only observed within 1 month after the onset of KD. The association between serum levels of immunoglobulin G (IgG), IgM, IgA as well as other coronary risk factors previously reported and the occurrence of the coronary arterial lesions was evaluated using logistic regression analysis.
Results: After adjustment for age, gender, total IVGG dose before the 9th illness day and other traditional coronary risk factors, the odds ratio for the persistent coronary aneurysm associated with lower serum IgG r-score (<-0.7485 v.v & -0.7485). was 30.3 (95% confidence interval, 3.8–243.2). Furthermore, the serum IgG z-score was inversely correlated with the severity of the coronary arterial lesion.
Conclusions: The IgG z-score before IVGG therapy in the early stage of KD provides useful information on the risk factors for persistent coronary aneurysm and is a novel, additional indicator for therapy to prevent the coronary complications in acute KD.     

Passive immunity acquisition of maternal anti-enterohemorrhagic Escherichia coli (EHEC) O157:H7 IgG antibodies by the newborn

Enterohaemorrhagic Escherichia coli (EHEC) strains are among the main causes of haemorrhagic colitis (HC) and haemolytic-uremic syndrome (HUS) in industrialised countries. In Brazil, EHEC have been detected in the faeces of patients with non-bloody diarrhoea, though an association between EHEC and HUS has been detected recently. These observations suggest that there is a pre-existing immunity triggered by the contact with EHEC and other categories of bacteria, such as EPEC, that share similar virulence factors and to which our population is highly exposed. Our aim was to evaluate the placental transfer of IgG antibodies reactive to EHEC O157:H7 antigens. We evaluated 28 paired maternal and cord sera for the presence of IgG against EHEC O157:H7 protein antigens and IgG and IgM to O157 LPS employing ELISA and IB technique. Total IgG and IgM level analyses were also made. Anti-EHEC O157:H7 and anti-LPS O157 IgG antibody levels in cord sera were equivalent to those of their maternal sera. A good correlation between the mothers’ anti-LPS O157 IgM and total IgM levels was found. Anti-LPS O157 IgM levels were higher than anti-LPS O157 IgG levels in the same samples, and anti-LPS IgM antibodies were not detected in cord sera. Identical patterns of recognition of bacterial protein antigens by specific IgG were found in the paired samples and the recombinant purified variable region of γ intimin was specifically recognized by one paired maternal and cord sample. In conclusion, although the antibody profile varied among individuals, all paired cord and maternal serum samples showed an identical recognition pattern, indicating an efficient placental transfer of IgG antibodies reactive to EHEC O157:H7 antigens. Dr. Patricia Palmeira and Leonardo Y. Ito contributed equally to this work.