IgG Subclass Deficiency Research Articles

SELECTIVE IgA DEFICIENCY AND HYPOGAMMAGLOBULINEMIA IN 4p - (WOLF-HIRSHHORN) SYNDROME. • 51

Immunodeficiency is a predictable (e.g. Chediak-Higashi Syndrome, ataxia-telangiectasia), frequent (e.g. Netherton syndrome, dyskeratosis congenita) or occasional (Chromosome 18p deletion, methylmalonic acidemia) component of 64 recognizable genetic syndromes. (Ming, Stiehm, Graham, Am. J. Human Genetics, 1995). The immunodeficiency can involve the antibody, T cell, natural killer (NK) or phagocytic systems. We have identified severe selective IgA deficiency (IgA < 10 mg/dl) in 3 children, mild selective IgA deficiency (IgA 10-20 mg/dl) in 2 children, and pan-hypogammaglobulinemia in 2 children with the 4p - (Wolf-Hirshhorn) syndrome. These children, ages 1yr. to 5 yr, had frequent respiratory infections and variably deficient antibody responses. One IgA deficient child had an associated IgG2 subclass (2 mg/dl) deficiency. Two have received IVIG with clinical benefit. T cell and B cell studies were normal. Four other children (ages 2½ - 13 yrs) with 4p-syndrome were evaluated and found to be normal.

IgG subclass deficiencies associated with bronchiectasis.

Only a small number of patients with IgG subclass deficiencies (IgGSD) have been observed to have bronchiectasis. Moreover, in the series of patients with bronchiectasis, IgGSD have not been found at any frequency, and the etiology of bronchiectasis remains unclear in 29 to 49% of cases. Serum concentrations of total IgG, IgA, and IgG subclasses as well as pulmonary function were measured in 65 patients (aged: 10 to 74 yr) with bronchiectasis of unknown etiology. An ELISA test was performed to quantify subclasses 1 through 4 using subclass-specific antihuman monoclonal antibodies. IgG subclass estimation in a healthy population with age-stratified normal ranges was derived from 100 adults, 37 children aged between 10 and 12 yr, and 27 adolescents aged between 13 and 16 yr. Serum concentrations of specific IgG antibodies to Haemophilus influenzae type b capsular polysaccharide (Hib-PRP) were also assayed by an ELISA test in 19 of the patients (10 with IgGSD and nine with non-IgGSD) and in 58 healthy individuals before and 3 wk after immunization with Hib-PRP conjugated to meningococcal outer membrane protein complex (OMPC). Thirty-one patients (48%) had low serum concentrations of one or more IgG subclasses (19 IgG2 deficiencies, 2 IgG3 deficiencies, 3 IgG4 deficiencies, and 7 combined subclass deficiencies). All patients showed increased levels of total IgG, IgG1, and IgA, but this rise was significantly higher in patients without IgGSD. Patients with IgGSD showed impaired antibody response to Hib-PRP compared with patients with non-IgGSD and the control group. IgGSD, particularly IgG2 deficiency, are not an unusual cause of bronchiectasis. Therefore, serum levels of IgG subclasses must be assayed whenever other causes of bronchiectasis have been ruled out.

DNA typing of DQ and DR alleles in IgA-deficient subjects.

IgA deficiency (IgA-D) represents the most common immunodeficiency syndrome of infancy. In most cases IgA-D represents an isolated immunological disorder, while sometimes it is associated with IgG subclass deficiency or with the presence of autoantibodies. We investigated the pattern of association of IgA-D with DRB1 and DQB1 loci of the HLA region by DNA molecular typing, which allows the identification of previously serologically undefined specificities. We also compared the gene frequency of DRB1 and DQB1 allelic variants between IgA-D subjects with or without serum autoantibodies. Our results indicate that the gene frequency of the DRB1*0102 subtype and of the DRB1*0102, DQB1*0501 haplotype is significantly higher in IgA-D than in the general population. Furthermore, the IgA-D subjects with autoantibodies showed a positive association with DR4 and DR13 subtypes, thus supporting the hypothesis that genetic factors are also involved in the association between IgA-D and autoantibodies.

The treatment of chronic sinusitis: a controversial issue

The persistence of sinusitis after upper respiratory tract infection is influenced by a range of aetiological factors such as anatomical variation which may be surgically corrected, mucociliary abnormalities and immune deficiency. The latter is more common than previously realised, encompassing IgG subclass deficiency, reduced opsonization and Fc gamma receptor polymorphism. This has therapeutic implications, with the possibility of IgG replacement therapy and vaccination. CT scanning suggests that the age of the patient and anatomical abnormalities are important aetiological factors in chronic rhinosinusitis. Only when medical therapy fails, is surgery considered. Although a range of surgical procedures are available, an endoscopic approach may be directed at the ostiomeatal complex and is generally very conservative. Scanning is a prerequisite to this surgery, demonstrating both the extent of disease and the anatomy but requires careful interpretation. Furthermore, an endoscopic technique can be employed for a number of other sinus conditions though this should only be undertaken by an experienced surgeon. A long-term prospective study of children undergoing radical sinus surgery for neoplasia strongly suggests that concerns that surgery in the middle meatus might disturb subsequent facial development are unfounded.

Antibody response in patients with osteomyelitis of the mandible

Patients with mandibular osteomyelitis had quantification of 10 antibodies against certain bacterial proteins and polysaccharides. Sera from 31 patients with acute or chronic osteomyelitis of the mandible and from 17 healthy controls were analyzed. Some patients showed low levels of investigated antibodies in general and a lack of specific antiteichoic acid antibodies, as well as of different antipneumococcal antibodies particularly. Two patients with therapy-resistant osteomyelitis showed IgG2 and IgG3 subclass deficiency. They had replacement therapy with intravenous 10 or 15 gm immunoglobulin every 3 weeks for 6 months. Both patients showed considerable improvement in their clinical symptoms after treatment with immunoglobulin. This study indicates that impaired humoral immune response may be of importance in subgroups of patients with osteomyelitis of the mandible.

Cell-mediated immune status of children with recurrent infection

Objective: To evaluate the cell-mediated immune status of children with recurrent respiratory tract infections. Design: We evaluated the cell-mediated immune status of 76 patients referred because of recurrent infection. Patients were divided into those with serologic abnormalities and those without such findings. Twenty-three healthy children served as control subjects. Studies of lymphocyte phenotype included CD4 + CD29 + cells (an immunologically mature phenotype), lymphocyte proliferation studies, cytokine production including interleukin-2 (IL-2), IL-4, IL-6, and interferon γ), and measurement of in vitro IgM and IgG synthesis. Results: Lymphocyte proliferation and T-cell phenotype were similar in both patient groups as well as in control subjects. The proportions of CD4 + CD29 + cells at different ages were similar in all groups. Patients with serologic abnormalities (e.g., partial IgA deficiency, partial IgG subclass deficiency) produced more IL-2 and IL-4 than did other patients. The control population had greater spontaneous IgM and IgG synthesis than the patient groups. Conclusion: Routine studies of T-cell function of patients with recurrent infection provide little information useful in making clinical decisions. ( J PEDIATR 1995;126: 530-6)

IgG2 Deficiency Associated with Defects in Production of Interferon‐Gamma; Comparison with Common Variable Immunodeficiency

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

Familial enteropathy with villous edema and immunoglobulin G2 subclass deficiency

We describe a familial form of recurrent acute, life-threatening secretory diarrhea associated with distinctive jejunal histologic changes and IgG2 subclass deficiency. Symptoms begin abruptly with anorexia and vomiting, and progress within hours to massive secretory diarrhea and shock with profound neutropenia and hypoproteinemia, including hypoalbuminemia and hypogammaglobulinemia. Affected survivors recover quickly and thereafter grow and develop normally. Biopsy specimens obtained during remission from 3 adults and 11 children show club-shaped jejunal villi broadened by edema and histiocytes with imbibed fluid; the overlying intestinal epithelium and brush border appear normal, but the basement membrane is interrupted in some areas. No characteristic microorganisms have been identified in association with the syndrome. Clinical manifestations cease in the second decade, but the abnormal jejunal histologic pattern persists into adult life. Female and male patients are equally affected, although all fatal cases have been in female subjects. Inheritance appears dominant with variable penetrance: one family member without a history of diarrhea has characteristic biopsy findings and another appears to be an obligate carrier with normal biopsy findings. Affected individuals have a reduced serum concentration of IgG2. We believe that this familial enteropathy is a unique entity, not previously described. (J P EDIATR 1994;125:541-8)

326 IGG SUBCLASSES AND ANTIBODIES TO STREPTOCOCCUS PNEUMONIAE IN IMMUNODEFICIENT CHILDREN WITH CHRONIC LUNG SUPPURATIONS

We studied 17 immunodeficient children 4-14 years old (9 with hypogammaglobulinemia, 8 with selective IgA deficiency) all having chronic lung suppurations. The highest rate of S.pneumoniae colonization was in children with IgA deficiency (up to 50%) with noncapsular H.influenzae found in 43%. Antibody levels to S.pneumoniae capsular polysaccharides, C-polysaccharide, protein antigens were studied in serum, saliva and bronchoalveolar lavage fluid by ELISA; IgG subclasses in serum - by radial immunodiffusion. All patients had absent or very low levels of pneumococcal IgA-antibody in secretions. In spite of the presence of serum IgG-antibody (even their high levels in selective IgA deficiency) all children had severe suppurations indicating the major role of local immune response in bacterial clearance from the respiratory tract. It also suggests that serum IgG antibodies do not pass in sufficient quantity into bronchial secretion due to a peribronchial fibrosis. Low serum IgG-antibody levels were found in children with hypogammaglobulinemia, however two patients with combined IgA - IgG subclass deficiency (IgA plus IgG1, IgG3, IgG4 and IgA plus IgG4) had almost normal serum antibody level probably due to the relation of pneumococcal antibody to IgG2. Clinical data indicate that different rate of hypogammaglobulinemia expression may explain the diversity in manifestations of primary humoral immunodeficiency.

Age related IgG subclass concentrations in asthma.

The prevalence of IgG subclass deficiency in asthma is still controversial. Earlier studies often included patients receiving treatment with systemic steroids which can induce hypogammaglobulinaemia. Concentrations of IgG subclasses were studies in 200 children (aged 2-17 years) with asthma (mean asthma severity score (ASS) 2, range 1-4) who had not received systemic steroids for at least six weeks before investigation, and in 226 healthy age matched controls. The mean concentrations of IgG subclasses in children with asthma were within the 1SD range of those of the control group. In the group with asthma there was a trend towards higher levels of IgG1 and IgG4, whereas the number of children with low concentrations of IgG2 (< 2 SD of control serum samples; absolute concentrations 0.08-1.25 g/l) was slightly greater than in the group who did not have asthma (4.5 v 2.2%). Patients with subnormal concentrations of IgG2 could not be distinguished clinically or on the basis of case history and additional immunological studies did not show further abnormalities. Patients with severe asthma (ASS 3-4) had significantly higher concentrations of IgG4 (mean (SE) 0.53 (0.09) v 0.26 (0.04) g/l) than patients with mild asthma (ASS 1). No significant difference in subclass concentration was found between patients with atopic and those with non-atopic asthma. It is concluded that in an unselected group of children with asthma the mean IgG subclass concentrations do not differ significantly from a group of healthy age matched controls.

Clinical significance of IgG subclasses.

IgG subclass deficiency has been noted in association with a variety of clinical conditions. It's relative importance as a contributing factor to these conditions is unclear. Despite reservations about the importance of partial IgG subclass deficiency, evidence is beginning to emerge that suggests that in select patients with recurrent infection and subclass deficiency, gamma globulin therapy may be beneficial.

IgG2 deficiency in children with febrile convulsions: a familial study.

The IgG subclasses were investigated in children with febrile convulsions (FC) and in their first degree relatives in the search for a selective immunological deficiency associated with FC and its occurrence in the relatives of affected subjects. The results of the study show lower IgG2 concentrations in FC patients than in controls. But it was not possible to demonstrate familial transmission of the IgG2 subclass deficiency, since it was present only in children with FC and tended to normalize in adulthood. The immunoglobulin subclass deficiency might be responsible for the recurrent infections connected with FC.

B‐Cell Activation in Duodenal Mucosa after Oral Cholera Vaccination in IgA Deficient Subjects with or without IgG Subclass Deficiency

Alterations in duodenal Ig-producing cells induced by two oral cholera vaccinations were studied by two-colour immunofluorescence in mucosal tissue sections from adults with selective IgA deficiency (IgAD), either with (n = 7) or without (n = 9) frequent infections, infection-prone patients with combined IgAD and IgG subclass deficiency (IgGSD) (n = 7), and normal control subjects (n = 11). The proportion of IgG-producing cells prior to immunization tended to be lower in the symptomatic IgAD subjects than in the clinically healthy ones. In the first subgroup the absolute number of IgG cells per intestinal length unit was significantly increased after immunization (P < 0.04), and this tendency was also observed in the healthy IgAD subjects (6/9) and in those with combined deficiency (5/7). Very few IgAD subjects responded with an increase of IgM-producing cells. The normal controls responded variably in all major immunocyte classes, in the order IgA > IgG > IgM. Compared with these controls, the patients with combined IgAD and IgGSD showed significantly increased IgG1 (P < 0.01) and reduced IgG2 (P < 0.006) proportions, which was in accordance with their serum subclass levels. Our study showed that oral cholera vaccination preferentially activates intestinal IgG-producing cells in IgAD subjects. This result agreed with data recently obtained by ELISPOT in the same patients with regard to antibody-forming cells specific for cholera toxin. Both methods suggested that IgG rather than IgM antibodies are elicited as compensation for a lacking IgA response. However, our overall results showed that intestinal B-cell activation is quite variable after oral cholera vaccination. Although such vaccination might be of importance for enhancing mucosal immunity also in IgAD patients, a concurrent gut disease could possibly be aggravated by IgG-mediated mucosal immunopathology in the absence of anti-inflammatory IgA antibodies.

IgG subclasses: importance in pediatric practice.

Although many clinical studies provide evidence of a relation between IgG subclass deficiency and increased susceptibility to infection, a direct cause-and-effect relationship clearly does not exist. Each patient must be managed in the full context of clinical symptomatology, reliable measurement of IgG subclasses, and evaluation of specific antibody production. Future studies may clarify the factors that stimulate and regulate the production of IgG subclasses and improve our understanding of their role in the health of children.

IgG Subclasses: Importance in Pediatric Practice

Although many clinical studies provide evidence of a relation between IgG subclass deficiency and increased susceptibility to infection, a direct cause-and-effect relationship clearly does not exist. Each patient must be managed in the full context of clinical symptomatology, reliable measurement of IgG subclasses, and evaluation of specific antibody production. Future studies may clarify the factors that stimulate and regulate the production of IgG subclasses and improve our understanding of their role in the health of children.

Extensive Deletion of Immunoglobulin Heavy Chain Constant Region Genes in the Absence of Recurrent Infections: When Is IgG Subclass Deficiency Clinically Relevant?

This report describes two children with undetectable serum levels of IgA1, IgG2, IgG4, and IgE due to a homozygous deletion encompassing the A1-E genes. The father is a heterozygous carrier of the same deletion and the mother a heterozygous compound carrying the deletion on one chromosome and duplication on the other. In both children, serum IgG, IgG1, and IgG3 were higher than in normal children and IgG antibody response to tetanus toxoid and polysaccharide antigens was normal with increased IgG1 and IgG3 response compared to controls. The latter can be interpreted as a compensatory mechanism for the subclass deficit and may explain the lack of significant infections in both children. The importance of distinguishing IgG subclass deficiency due to gene deletion from that due to immunoregulatory dysfunction is discussed.

IgA and IgG subclass deficiency in a poor population in a developing country.

The levels of IgG, IgG subclasses, IgM and IgA were determined in serum from 17 patients with IgA deficiency and severe or frequent infections, allergy and/or autoimmunity (median age 7 years, range 2-19), 11 healthy IgA-deficient adults and 35 controls (median age 7 years, range 2-19). In serum from all groups IgG, IgM and IgA antibodies were determined against beta-lactoglobulin, E. coli O antigens and poliovirus type 1 antigen. In saliva of 15 IgA-deficient patients and 12 of the controls IgG, IgM and secretory component-carrying antibodies against E. coli O antigens and poliovirus type 1 were determined. The majority of the studied individuals lived under poor socio-economic conditions in Brazil, with consequent heavy microbial exposure. One IgA-deficient patient with rheumatoid arthritis also had IgG2 deficiency but no infectious problems. Four out of the 35 controls without any obvious infectious problems were found with IgA or IgG subclass deficiency. One of the 11 healthy IgA-deficient adults was low in the IgG2 subclass, one in IgG1 and one in IgG3. Those with symptomatic IgA deficiency had significantly higher serum IgG than the controls, especially in the age group 6-11 years. This latter group also had significantly increased serum IgG1 and IgG2 levels when compared with the age-matched controls. Salivary IgM antibodies to E. coli and poliovirus antigens were significantly higher among the symptomatic IgA-deficient individuals than among the controls. It is not clear at present whether these increased Ig levels are secondary to frequent infections and/or part of mechanisms that may compensate for the IgA deficiency.

Serum IgG and IgG Subclass Contents in Different Gm Phenotypes

Different serum IgG and IgG subclass levels were found among Gm phenotypes of a normal population. One hundred and fifty-seven Caucasian blood donors were investigated for the reciprocal Gm allotypes on IgG subclass loci namely: for IgG1, G1m(f) and G1m(a); for IgG2, G2m(n) and G2m("); and for IgG3, G3m(b) and G3m(g), and subgrouped in the seven most common Gm phenotypes. The frequencies of Gm phenotypes and haplotypes were given, including numbers of the previously little known G2m(n,") heterozygous individuals. Mean serum quantities +/- SD and range of IgG, IgG1, IgG2, IgG3 and IgG4 were given for different Gm phenotypes. The IgG content was significantly lower in the Gm(f,",b/f,",b) phenotype in which the IgG2 levels were also significantly lower, compared with values of the other phenotypes. IgG3 levels were significantly lower in the Gm(a,",g/a,",g) phenotype compared with other phenotypes. These data imply the importance of Gm(f,",b/f,",b) and Gm(a,",g/a,",g) phenotypes causing lower amounts of IgG antibodies. In evaluating IgG subclass deficiency, the range for the low responding Gm(f,",b/f,",b) and Gm(a,",g/a,",g) phenotypes should be considered.

IgG SUBCLASSES IN CHILDREN WITH IgA DEFICIENCY

Children having normal serum levels of IgG and IgM but IgA below 5mg/dl were considered as having “selective IgA deficiency”. Those with-2 SD from the normal mean for the age were defined as “partial selective IgA deficients”. Deficiency of IgG subclasses was considered in those patients whose values were below the 5th percentile data from the literature. Igs were determinated by radial immunodifusion and IgG subclasses by ELISA. Preliminary data from 27 children is presented: 22 with classic selective deficiency and 5 with partial deficiency. The former group consisted of 11 males and 11 females between 1 and 14 years of age (x=6.8) while the latter were 4 males and 1 female between 3 and 12 years (x=6.6). All had recurrent infections of the upper respiratory tract. Besides, 8 had asthma, 2 pneumonias and 7 other pathologies such as chronic diarrhea, urinary tract infections, recurrent meningitis, celiac disease and rheumatoid arthritis. Deficiency of one or more IgG subclasses were present in 77.8% of the 27 children. Classic and partial IgA deficiencies had the same frequency as IgG subclas ses deficiency. There was no correlation between clinical features and isotype deficiency, except in asthmatic patients in whom IgG 4 subclasses deficiency was predominant. Patients with other associated pathologies had predominantly normal levels of the IgG subclasses. There was no IgG 1 subclass deficiency, probably because of the criteria applied for selection of patients. The frequent association between deficiencies of IgG subclasses and of IgA will probably require a new definition of this latter.

IgG subclass deficiency.

IgG subclasses have been recognized since the early 1960s. Four such subclasses, designated IgG1, IgG2, IgG3, and IgG4, are known to exist. Approximately 65 to 70% of the total circulating IgG in normal persons is of the IgG1 subclass. IgG2 constitutes 20 to 25% of circulating IgG, and IgG3 and IgG4 each represent less than 10%. Deficiencies in the various IgG subclasses have been detected in adults and children with common variable hypogammaglobulinemia as well as in those with relatively normal total IgG levels. An important issue facing clinicians today is to determine what, if any, therapeutic implications are associated with demonstration of an IgG subclass deficiency.