IgG subclasses in symptomatic IgA deficiency.

We evaluated IgG subclass levels in 11 symptomatic patients (ages between 3 and 22; mean 7.5 years) with IgA deficiency, seven with selective IgA deficiency, and four with low IgA levels. All patients had experienced three or more episodes of sinopulmonary infections a year. Combined IgG2-IgG4 deficiency was detected in two patients, IgG2 deficiency in one patient and IgG4 deficiency in two patients. Elevated IgG1 and IgG3 levels were detected in most of the IgG subclass deficient and sufficient patients. It is known that gammaglobulin replacement therapy reduces the frequency of infections significantly in IgG subclass deficiency. Although immunization against IgA is a risk in IgA deficiency, these patients can be treated with gammaglobulins containing low IgA.     

IgG subclass deficiency in children with IgA deficiency presenting with recurrent or severe respiratory infections

A group of 22 children presenting with recurrent or severe respiratory tract infections who had low IgA levels (more than 2 SD below the mean for age) were examined for IgG subclass deficiency. Patients were screened for possible defects in neutrophil chemotaxis, bactericidal, fungicidal, and quantitative iodination activity, as well as for complement function. The majority of the patients showed IgG subclass levels below the mean for age. Nine of the children showed definite IgG subclass deficiency and at least two showed definite deficiency of more than one IgG subclass. The predominant subclass deficiency was found to be IgG1. While nine children showed IgG4 levels below the level detectable by the technique used, it is not possible to assess whether these patients are deficient in this isotype since some healthy subjects also give values below the level of detection. Most of the patients who had very low (1-6 mg/dl) or undetectable (less than 1 mg/dl) levels of serum IgA did not show IgG subclass deficiencies, while IgG subclass deficiencies were common among those with borderline low IgA levels (slightly more than 2 SD below the mean for age). Nine children showed total IgG levels close to 2 SD below mean for age, and at least six of these showed IgG subclass deficiency. The result suggests that patients with recurrent and/or severe respiratory infections who have borderline IgA and IgG levels may have IgG subclass deficiencies and if they do could benefit from immunoglobulin therapy.     

Increases in serum immunoglobulins to age-related normal levels in children with IgA and/or IgG subclass deficiency

Immunoglobulins (Ig) A and G subclass deficiencies are common immune system disorders which cause morbidity especially between 2 and 6 yr of age. Prognosis of these defects and therapeutic approach is unclear. The aim of the present retrospective study was to review the clinical and laboratory records of 87 children with IgA and/or IgG subclass deficiency to determine whether these patients experience changes in serum Ig concentrations during follow-up and to give more clinic and laboratory information to the families about the course of these diseases. Among 87 patients studied, the most frequent defect was partial IgA deficiency combined with IgG3 subclass deficiency (41%). The other groups were as follows; partial IgA deficiency (32%), selective IgA deficiency (8%), partial IgA combined with IgG2-G4 subclass deficiency (6%), and IgG subclass deficiency (13%). The commonest clinical presentations were recurrent upper respiratory tract infections (76%), pneumonia (14%), acute gastroenteritis (3%), urinary tractus infection (3%), sinusitis (2%), and acute otitis media (2%). Atopy was widely represented in the patients studied (24%). The number of patients who were given prophylactic treatment with benzathine penicilline, prophylactic oral antibiotic, or oral bacterial extract to prevent infections was 68 (78%). Frequency of recurrent infections decreased from 7.9 +/- 4.9 per year to 2.5 +/- 2.3 in 68 patients receiving any prophylactic regimen; however, decrease in frequency of infections did not show any significant difference between different prophylactic groups. None of the patients in the selective IgA deficiency group had reached normal serum levels of IgA. At the age of 58.3 +/- 21.4 months, 52% of patients in partial IgA deficiency group and 51% of patients in partial IgA + IgG subclass deficiency group, serum IgA increased to normal ranges. Serum IgG subclass levels increased to normal range for age in 67% of patients in partial IgA + IgG subclass deficiency group and in 30% of patients in isolated IgG subclass deficiency group. The mean age for reaching age-related normal IgG subclass levels for these patients was 69.0 +/- 14.5 months. In conclusion, findings of this study suggest that IgA and/or IgG subclass deficiency may be either progressive or reversible disorders and emphasize the value of monitoring Ig levels in affected individuals.     

Phenytoin-induced IgG2 and IgG4 deficiencies in a patient with epilepsy

A five-year-old girl with epilepsy and recurrent respiratory infections was investigated for serum IgG subclass concentrations. She was diagnosed as having a combined deficiency of IgG2 and IgG4 with a decreased serum concentration of IgA and IgG3 and was given replacement therapy with i.v. immunoglobulins. Since then, she has been free from respiratory infections. After phenytoin therapy was stopped, IgG subclass deficiency improved. This case describes the further action of phenytoin on the immune system, adding IgG subclass deficiency to the list.     

Immunoglobulin G subclass deficiency and predisposition to infection in Down's syndrome

Serum immunoglobulins and IgG subclasses were measured in 26 children with Down's syndrome using an enzyme-linked immunosorbent assay and monoclonal antibodies. Eighteen (69%) of the children had increased susceptibility to infection. None of the children had deficiencies of total IgG and IgM, and only one had an IgA deficiency. IgG4 deficiency was diagnosed in 14 (54%) children. One child had a deficiency of IgG2. There were no children with deficiencies of either IgG1 or IgG3. There was a significant correlation between IgG subclass deficiency and predisposition to infection (P less than 0.05). Ninety percent of the patients with severe infections had low IgG4 whereas only 25% of those with no infections had low concentrations of IgG4. These results suggest that it is important to screen patients with Down's syndrome who have frequent systemic or respiratory infections for IgG subclass deficiencies because this may not be apparent from the assay of total IgG.     

Clinico-immunologic aspects of IgG subclass deficiency

Serum IgG contains 4 subclasses, IgG1 (60-66%), IgG2 (20-30%), IgG3 (less than or equal to 5%) and IgG4. Individual subclasses vary with respect to their physicochemical and biological properties. IgG subclass concentrations in serum are age dependent. IgG1 and IgG3 reach near to adult levels around the age of 3, IgG2 and IgG4 after the age of 6. Antibodies of certain specificities generally belong to a certain isotype (subclass) due to the isotype restriction. Patients with subclass deficiencies often suffer from recurrent infections. Those with IgG2 deficiency (often occurring with IgA and IgG4 deficiency) develop recurrent infection of the upper and lower respiratory tract often caused by pyogenic microorganisms (Haemophilus, Pneumococcus). Since early initiation of IVIG substitution therapy has a beneficial effect on long term prognosis the importance of early diagnosis is apparent.     

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     

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.     

Clinico-immunologic aspects of IgG subclass deficiency

Serum IgG contains 4 subclasses, IgG1 (60-66%), IgG2 (20-30%), IgG3 (less than or equal to 5%) and IgG4. Individual subclasses vary with respect to their physicochemical and biological properties. IgG subclass concentrations in serum are age dependent. IgG1 and IgG3 reach near to adult levels around the age of 3, IgG2 and IgG4 after the age of 6. Antibodies of certain specificities generally belong to a certain isotype (subclass) due to the isotype restriction. Patients with subclass deficiencies often suffer from recurrent infections. Those with IgG2 deficiency coften occurring with IgA and IgG4 deficiency) develop recurrent infection of the upper and lower respiratory tract often caused by pyogenic microorganisms (Haemophilus, Pneumo-(occus). Since early initiation of IVIG substitution therapy has a beneficial effect on long term prognosis the importance of early diagnosis is apparent.     

Deficiency of humoral immunity in cartilage-hair hypoplasia

OBJECTIVE: Cartilage-hair hypoplasia (CHH), a metaphyseal chondrodysplasia, is usually associated with impaired cellular immunity. This study evaluates humoral immunity in patients with CHH. METHODS: The concentrations of immunoglobulins G, A, and M (IgG, IgA, and IgM) and IgG subclasses were studied in 20 patients. Data for 5 additional patients with recurrent infections were retrospectively reviewed. RESULTS: Seven of the prospectively evaluated patients (35%) had defective humoral immunity. Three patients had IgA deficiency. Four patients had IgG2 deficiency, accompanied by IgA deficiency, IgG4 deficiency, or both in 3 patients. IgG4 was low in most patients. Increased infections were usually associated with supranormal IgG and IgG1 and subnormal IgA, IgG2, or IgG4 concentrations. One retrospectively reviewed patient had severe hypogammaglobulinemia, and 3 had multiple IgG subclass deficiencies. CONCLUSIONS: Humoral immunity is impaired in CHH and contributes to the increased susceptibility to infections.     

IgG subclasses and their clinical significance

IgG are the most common isotype of Ig and include four subclasses which differ from one another in the following ways: their initial amino acid sequence, their physical and chemical properties and the different serum concentrations reached with age. Every subclass has a specific biological function: the response to proteic antigens is prevalently mediated by IgG1 and IgG3, while IgG2 mediates the response to polysaccharide antigens. It is still unclear whether IgG4 are protective or sensitising antibodies; IgG1 and IgG3 also have a major ability to bind to the cells that mediate the immune response, while only IgG4 activate the complement using an alternative route. Although low levels of IgG subclasses may be temporary, deficiencies are often associated with various diseases: 1) recidivating bacterial infections involving the respiratory and digestive tracts, primarily sustained by capsulated or pyogenic microorganisms; 2) IgA deficiency; 3) absence of immune response following vaccination; 4) allergic or autoimmune diseases; 5) diseases of the CNS. IgG subclass deficiencies must therefore be looked for every time these diseases are diagnosed, also because subjects may benefit from gammaglobulin replacement therapy.     

IgG subclass deficiency in children with recurrent bronchitis

We studied the incidence of IgG subclass deficiency in children with recurrent bronchitis. Recurrent bronchitis was defined as three or more episodes a year during at least 2 consecutive years, of bronchopulmonary infection, productive cough with or without fever and/or diffuse rales by physical examination in the absence of asthma or atopy. Fifty three children were selected, of whom 30 (57%) were deficient in one of the IgG subclasses. None had an IgG1 deficiency. Nine (17%) were deficient in IgG2, 9 (17%) in IgG3 and 20 (38%) in IgG4. Isolated IgG subclass deficiencies were most frequently seen for IgG4 (14, 26%), less for IgG3 (6, 12%) and even less for IgG2 (4, 7%). Nine (17%) children were IgA deficient and 8 (15%) IgG deficient with a combined IgG subclass deficiency in 8 and 7 of them respectively. By subdivision into different age groups most patients were encountered in the youngest group. The mean content of IgG2, IgG3 and IgG4 in 3- to 4-year-old children with recurrent bronchitis was significantly lower than in the age matched controls. The mean value for IgG4 in the 5- to 6-year-olds was significantly lower than in the control group. This study demonstrates the correlation between recurrent bronchitis in childhood and IgG subclass deficiency. IgG subclass deficiency and recurrent bronchitis are both quite prominent phenomena in young children but rare in older children, suggesting a transient immaturity of the immune system as one of the possible pathogenetic factors. An IgA or an IgG deficiency is highly suggestive for the existence of a combined IgG subclass deficiency.     

IgG4 deficiency in IgA-deficient patients

IgG subclass deficiency may be an important factor in the infection proneness of some IgA-deficient subjects. Although several studies on IgG subclass deficiency in IgA-deficient subjects have been reported, most have been unable to assess the incidence of IgG4 deficiency because the limitations of the assay methods used have often made a distinction between low normal and subnormal concentrations impossible. Having developed an enzyme-linked immunosorbent assay capable of measuring concentrations of all the IgG subclasses in healthy subjects of all ages and having established age-normal ranges for IgG subclasses using this assay, we measured IgG subclass concentrations in 73 IgA-deficient patients, the majority of whom were children with recurrent respiratory infections. The results showed that IgG4 deficiency occurred in 26% of the patients and was the most common IgG subclass deficiency found. IgG1, IgG2 and IgG3 deficiencies occurred, respectively, in 10, 12 and 8% of the patients. IgA-IgG4 deficiency occurred in 16% of the patients; IgA-IgG2-IgG4 in 4%; and IgG1-IgG2-IgG4, IgA-IgG1 and IgA-IgG2-IgG3 each occurred in 3%. Other subclass deficiencies or combinations of deficiencies were less frequent. Our results suggest that IgG4 deficiency even in the absence of IgG2 deficiency may be an important but hitherto largely unrecognized factor in infection proneness in some IgA-deficient patients.     

Clinical manifestations in selective IgA deficiency in childhood. A follow-up report

Clinical manifestations in 40 children with selective IgA deficiency were studied during a follow-up period of 2-10 years. The patients were divided into two groups: group I consisted of 25 children with "sporadic" IgA deficiency and group II of 15 children with "familial" IgA deficiency. Respiratory tract infections including otitis media were frequent in both groups. Concomitant IgG2-IgG4 deficiency was found in two patients in group I. Longitudinal serum IgG levels were elevated significantly in both groups. Atopic complaints were observed in 10 children of the "sporadic" group, but only in two of the "familial" group. However, elevated serum IgE levels were more often found in group II. Two children of group I were mentally retarded and chromosomal examination showed abnormalities in both. Anti-IgA antibodies were detected in one child in group I and three children in group II. These three patients had an IgA deficient mother with class-specific anti-IgA antibodies. Concomitant IgG4-IgE deficiency was found in all four.     

Variable increases of IgG and IgM antibodies in milk of IgA deficient women

Serum, milk and saliva from seven IgA deficient mothers were studied for the presence of IgA, IgG and IgM antibodies to Escherichia coli and polio virus antigens. Different variable patterns were obtained. One mother had very much increased IgM and IgG antibodies in milk and saliva against both antigens; the milk IgG antibodies were 11–14 times higher than the reference milk pool. Another mother showed also striking increases of both IgM and IgG antibodies in milk, as well as in saliva where the increases were much higher for the poliovirus than the E. coli antibodies. Yet another mother showed a certain increase of IgM but not of IgG antibodies in the milk. The uneven appearance of IgG and IgM antibodies in serum and secretions suggests local production. So do the differences ot antibody avidities, the variations in IgG subclass distribution of antibodies and different patterns after isoelectric focusing (IEF) /immunoblotting analysis of antibody spec-trotypes in secretions and serum.
The study illustrates the variable patterns of compensatory increases of IgG and IgM antibodies which may occur in IgA deficiency. It also shows that the milk from IgA deficient mothers can still be rich in antibodies, in spite of the lack of secretory IgA.     

Disorders of immune function in children with selective IgA deficiency

Numerous additional alterations of immune function in patients with selective IgA deficiency (serum IgA less than 0.05 g/l) have been described. In this group of patients we have investigated the connection with allergic diseases and alterations of the other immunoglobulin isotypes. Sera of 44 children from 1 3/12 to 18 years were analysed. In all patients serum IgA was below the nephelometric detection limit of 0.05 g/l). Using a more sensitive ELISA, IgA could be detected in all sera in concentrations ranging from 10 micrograms/l to 0.04 g/l. 25 children (57%) revealed a profound elevation of IgG serum levels, in 27 (61%) IgM was elevated above the upper age related normal value. In 7 patients (16%) with normal IgG serum levels a combined IgG2-IgG4 deficiency was found. In most cases these patients had unusually frequent and severe infections. Total IgE serum levels were determined by a RIA technique. In addition, an IgE-mediated sensitization to the most common food and inhalation antigens was detected by a standardized procedure (Phadiatop, Pharmacia). In 9/44 children (20%) IgE was less than 2 U/ml (lowest detection limit), 27 patients (62%) revealed levels of 6-86 U/ml within the age-related normal range. In 8 patients (18%) total IgE was above 381 U/ml. Four patients demonstrated a sensitization to inhalants, specific IgE antibodies to nutritive antigens were detected in three children.(ABSTRACT TRUNCATED AT 250 WORDS)     

Deficiency of IgG4 in children: association of isolated IgG4 deficiency with recurrent respiratory tract infection.

To study the relationship between serum IgG subclass deficiency and clinical host defense impairment, we reviewed the clinical and immunologic features of 123 patients with a history of recurrent infection who had been examined for immunodeficiency in our laboratory (group 1). We then compared immunoglobulin isotype levels with those in sera from 127 age-matched control subjects without recurrent infection from whom blood had been drawn for evaluation of atopy (group 2). There was a significantly higher prevalence of IgG4 deficiencies among patients with recurrent infections (17% vs 7%; p less than 0.02), solely because of a higher prevalence of isolated IgG4 deficiency (n = 9; 7.3%) than in atopic control subjects (n = 1; 0.8%; p less than 0.05); there was a comparable prevalence of multiple isotype deficiencies that included low levels of IgG4 (9.8% and 6.3%, respectively). All nine group 1 patients with isolated IgG4 deficiency had severe recurrent respiratory tract infections requiring multiple hospitalizations; in addition, five were atopic, five had asthma, and one had chronic diahrrea. Antibody responses to bacterial polysaccharide antigens were normal for age in all patients with isolated IgG4 deficiency; two had defective antibody responses to protein antigens. Isolated IgG4 deficiency appears to be associated with impaired respiratory tract defenses and may occur in the absence of an easily definable antibody deficiency state. This association suggests a physiologic defense role for mucosal IgG4.     

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.     

Clinical Manifestations in Selective IgA Deficiency in Childhood; A Follow-up Report

ABSTRACT. Clinical manifestations in 40 children with selective IgA deficiency were studied during a follow-up period of 2-10 years. The patients were divided into two groups: group I consisted of 25 children with "sporadic" IgA deficiency and group II of 15 children with "familial" IgA deficiency. Respiratory tract infections including otitis media were frequent in both groups. Concomitant IgG,-IgG, deficiency was found in two patients in group I. Longitudinal serum IgG levels were elevated significantly in both groups. Atopic complaints were observed in 10 children of the "sporadic" group, but only in two of the "familial" group. However, elevated serum IgE levels were more often found in group II. Two children of group I were mentally retarded and chromosomal examination showed abnormalities in both. Anti-IgA antibodies were detected in one child in group I and three children in group II. These three patients had an IgA deficient mother with class-specific anti-IgA antibodies. Concomitant IgG₄-IgE deficiency was found in all four.     

Isotype composition of antibodies to streptococcus group B type III polysaccharide and to tetanus toxoid in maternal,cord blood sera and in breast milk

Neonates are protected against group B streptococcal (GBS) infections and tetanus by transplacentally transferred serum antibodies. Antibodies of the immunoglobulin (Ig) G, IgM and IgA classes and IgG subclasses to the capsular polysaccharide (CPS) of type III group B streptococci (GBS III) and to tetanus toxoid (TT) were measured in sera from healthy women of fertile age and in paired maternal and cord blood sera from term and preterm pregnancies. GBS III CPS antibodies of the IgG class were found in sera from 97 out of 100 women of fertile age, but only 15 of them had antibodies above the proposed protective level (2 g/ml). TT IgG antibodies above the protective level (0.01 units/ml) were found in all sera. The IgG antibodies against GBS III CPS were mainly composed of the IgG2 subclass and to a lesser extent of IgG1. Almost all women had IgG1 antibodies against TT and 40% had IgG4 antibodies. Total IgG and IgG1 antibodies against GBS III CPS were higher in cord blood sera from 37 term neonates than in sera from their mothers whereas IgG2 antibody levels were similar. Total IgG and IgG1 antibodies against TT were also higher in the 20 term neonates tested than in their mothers. In contrast, total IgG and IgG1 to both GBS III CPS and TT and IgG2 to GBS III CPS were lower in cord blood sera from preterm neonates than in sera from their mothers. IgA antibodies to GBS III CPS were detected in 63% of breast milk samples while IgA antibodies against TT were detected in only 4%. In conclusion the study shows important differences in IgG subclass composition of antibodies against a polysaccharide and a protein antigen and in placental transfer of IgG antibodies in term and preterm babies.