IgG Subclass Deficiency Research Articles

Coexistence of (Partial) Immune Defects and Risk of Recurrent Respiratory Infections

Respiratory infections are major causes of morbidity and mortality, but determinants of susceptibility are poorly defined. We studied whether and to what extent immunologic and genetic factors are associated with increased susceptibility to respiratory infections. We evaluated the prevalence of IgA, IgM, IgG, and IgG subclass deficiencies, impairment in the antibody response against pneumococcal polysaccharides, G2m(n) allotypes, Fc gamma RIIa polymorphisms, partial C2 and partial C4 deficiency, promoter polymorphisms in MBL2, and lymphocyte subset deficiencies in a control population and in consecutive children with recurrent respiratory infections. IgA and/or IgG subclass deficiency was found in 27 of 55 patients (49%) and 6 of 43 controls (14%) (P = 0.0006). An impaired antibody response to polysaccharides was found in 7 patients (19%) and in 0 of 37 controls (P = 0.002). The Gm(n)marker was absent in 25 of 55 patients (45%) and 6 of 42 controls (14%) (P = 0.009). The MBL2 variants O/O, A/O, and A/A occurred in 9, 14, and 32 of the 55 patients, respectively, and in 1, 19, and 23 of the 43 controls, respectively (P = 0.05). There was no increase in the prevalence of partial C4 deficiency, C2 deficiency, lymphocyte subset deficiency, or Fc gamma RIIa polymorphism in the patients compared to the controls. A combination of at least 2 immune defects was found in 31 of 55 patients (56%) and in 4 of 42 controls (11.6%) (P <0.0001). Specific antipolysaccharide antibody deficiency, IgA and/or IgG subclass deficiency, Gm(n) allotype, and MBL2 genotype are susceptibility factors for recurrent respiratory infections, and coexistence of several immune defects is the strongest risk factor in this study.

Efficacy of IGIV in Patients With IgG Subclass Deficiency and/or Antibody Deficiency in a One-Year Open Label Study of Quality of Life, Innate Immunity, and Correction of Subclass/Antibody Levels

Efficacy of IGIV in Patients With IgG Subclass Deficiency and/or Antibody Deficiency in a One-Year Open Label Study of Quality of Life, Innate Immunity, and Correction of Subclass/Antibody Levels

Immunoglobulin prophylaxis in 350 adults with IgG subclass deficiency and recurrent respiratory tract infections: A long-term follow-up

350 adult patients in Sweden were included in a retrospective study covering more than 2000 patient-y, to evaluate the efficacy of immunoglobulin (Ig) prophylaxis. All patients had selective or combined IgG subclass deficiency, without IgA deficiency, and suffered from recurrent respiratory tract infections (RTIs). The patients had been given Ig prophylaxis for 0.5-21 y (mean 5.5 y). In total, 164/350 of the patients had a concomitant lung disease. Because of the heterogeneity of this retrospective material we evaluated only those patients with 4 or more antibiotic-demanding (i.e. presumably bacterial) episodes of RTI per y treated with an Ig dose of about 100 mg/kg/week (132/350). The frequency of antibiotic treated RTIs prior to and during latest y/s of Ig prophylaxis was compared. No difference in response could be found between patients with and without chronic lung diseases. In 92/132 a > or = 50% reduction of the rate of episodes of antibiotic-demanding RTIs was recorded (p < 0.001). The overall reduction of the RTI frequency was for IgG1 57%, IgG2 59%, IgG3 63% and for the combinations 61% (all p<0.001).

Circulating Class-Switched Memory B Cells are Markedly Reduced in Some Patients with Specific Antibody Deficiency (SAD) and/or Mild IgG Subclass Deficiency

Circulating Class-Switched Memory B Cells are Markedly Reduced in Some Patients with Specific Antibody Deficiency (SAD) and/or Mild IgG Subclass Deficiency

Campylobacter sepsis with multiple organ failure in IgG subclass deficiency

Some patients with immunodeficiency develop clinical features of autoimmune disorders. A previously asymptomatic antibody deficiency can underlie the development of autoimmune diseases and a severe course of infection, with a risk of sepsis; such cases are known in selective IgA deficiency. On the other hand, little information is available on selective IgG subclass deficiencies. An unexpectedly severe course of Campylobacter infection in a 19-year-old woman with a previously undiagnosed complex immune disorder, including selective IgG1 immunodeficiency, Hashimoto's autoimmune thyroiditis with hypothyroidism combined with Addison's disease presumably due to autoimmune adrenalitis, autoimmunity and allergy is described. The pathophysiological mechanisms of autoimmunity in latent humoral defects are discussed.

Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology

Human immunoglobulin prepared for intravenous administration (IGIV) has a number of important uses in the treatment of disease. Some of these are in diseases for which acceptable treatment alternatives do not exist. In this review we have evaluated the evidence underlying a wide variety of IGIV uses and make specific recommendations on the basis of these data. Given the potential risks and inherent scarcity of IGIV, careful consideration of the indications for and administration of IGIV is warranted.

Suspected Atypical Common Gamma Chain Severe Combined Immunodeficiency

RATIONALE: A gentleman presented in childhood with recurrent sinopulmonary tract infections and IgG2 subclass deficiency, B cell lymphopenia and natural killer (NK) cell lymphopenia. Fifty years later his grandson presents with similar symptoms and was found to be hypogammaglobulinaemic with a NK lymphopenia. Given the family history, male sexes and lymphocyte phenotype we suspected an X linked inherited immunodeficiency in the common gamma-JAK3 pathway and performed immunological investigations to confirm this.

Underlying Aspiration Exacerbating Asthma in a Boy Treated for IgG Subclass Deficiency

Underlying Aspiration Exacerbating Asthma in a Boy Treated for IgG Subclass Deficiency

Large Scale Production and Characterization of Anti-Human IgG Monoclonal Antibody in Peritoneum of Balb/c MICE

Monoclonal antibodies are key reagents that are used in biomedical researches, diagnosis of immunodeficiency diseases such as IgG subclasses deficiency and treatment of diseases like infections and cancers. For large scale production of monoclonal antibody, hybridoma cells that produce monoclonal antibody against human IgG were injected into the peritoneum of the Balb/c mice which have previously been primed with 0.5 mL Pristane. After 10 days, approximately 3 mL ascitic fluid was harvested from the peritoneum of each mouse. Ascitic fluid was assayed for the titer of monoclonal antibody in reaction with human IgG and its cross reactivity in reaction with IgM and IgA. The titer of mAb was 100,000 and didn’t show cross reactivity with IgM and IgA. Immunobloting was done for confirming the ELISA method. In immunobloting, only one sharp band in the heavy chain position of IgG was developed. The subclass of antibody was IgG1 and its light chain was kappa. Ascitic fluid was purified by ion exchange chromatography and the purified monoclonal antibody was conjugated with HRP. The conjugated monoclonal antibody could had application in diagnosis of infectious diseases like Toxoplasmosis, Rubella and IgG class of all other infectious diseases.

Adult IgG subclass (IgGSC) deficiency in clinical practice

RATIONALE: The normative values for IgGSC and the response to vaccination in adult IgGSC deficiency are incompletely studied. Their use is not clear to the practitioner who usually compares individual values to historical normative values.

Enfermedad autoinmune en inmunodeficiencias primarias de anticuerpos

Background Immunodeficiency and autoimmune phenomena may occur concomitantly in the same individual. Many immune deficiency syndromes, mainly humoral defects, are associated with autoimmune disorders. In the present study, we describe the frequency of autoimmune disorders in these patients. Methods and results We performed a retrospective review of the medical records of a cohort of 152 patients with primary antibody deficiency in the Clinical Immunology Unit of the Gregorio Marañon University Hospital in Madrid common variable immunodeficiency (CVID) (n = 35), IgA deficiency (n = 43), specific IgG subclass deficiency (n = 56), antibody deficiency with normal immunoglobulin (n = 14) and X-linked agammaglobulinemia (n = 4). Of the 152 patients with primary antibody deficiencies, autoimmune disorders were found in 35 (23 %). Autoimmune hematologic disease was found in 14 patients (9.2 %), autoimmune diseases of the gastrointestinal tract in eight (5.3 %), autoimmune endocrine diseases in six (3.9 %), autoimmune rheumatic diseases in six (3.9 %) and vitiligo in four. Autoimmune diseases were more frequent in CVID patients (37.1 %) than in those with selective IgA deficiency (25.5 %) or selective IgG subclass deficiency (12.5%). Thirty-seven percent of autoimmune episodes occurred prior to the diagnosis of primary antibody deficiency. Sixteen patients (10.5 %) had autoantibodies without clinical data of an autoimmune disease. Conclusions Primary antibody deficiencies have variable autoimmune manifestations. For early detection and appropriate treatment, autoimmune disease should be suspected in patients with immunodeficiency.

Significance of determining concentrations of subclasses of IgG and IgA: Our experience

Selective IgG and IgA subclass (IgGsc and IgAsc) deficiencies may be either partial or complete, yet, combined subclass deficiencies are common. The serums of 65 patients with various clinical symptoms were investigated for quantitative and qualitative immunoglobulin levels. A high correlation (r=0.93) between the two methods used for measuring total IgG concentration (nephelometry) and IgGsc concentration (RID measurement) was demonstrated. Patients were divided into groups according to IgG and IgA class and subclass concentrations. The serums of 51 patients were investigated for IgGsc deficiencies. Three groups were set up and studied: a group with decreased IgG concentrations (5 patients), a group with elevated IgG concentrations (6 patients), and a group with normal IgG concentrations (40 patients). Within these groups, a total of 14 patients with decreased IgGsc levels and 14 patients with elevated IgGsc levels were discovered. Analyses of gender and age frequency within these groups showed that there were significantly (p<0.025) more children and females in the group with the elevated IgGsc concentrations, IgG2 being the most frequent. IgG1 deficiency was found to be more frequent in the group with decreased total IgG compared to the group with normal total IgG. We found IgGsc deficiency to be significantly associated (43%) with IgAsc deficiency within our population, therefore we recommend IgAsc concentration measurement in all patients with IgGsc deficiency. We confirmed that IgGsc concentrations should be measured in all patients with clinical symptoms and decreased total IgG concentrations and even more so in patients with normal total IgG concentrations. So far, we have not investigated our healthy population, and have not obtained our own reference ranges of IgGsc concentrations for children and adults. Therefore, the results we gained are yet to be explained, since, preliminary analysis shows elevated IgG2sc concentrations, and others to a lesser extent, in our population of children.

Selective IgG2 deficiency due to a point mutation causing abnormal splicing of the C 2 gene

The mechanism underlying selective IgG subclass deficiency is largely unknown in humans. We have previously reported the acquisition of a complete IgG2 deficiency in a leukemia patient after bone marrow transplantation. Southern blot analysis showed a deletion including the Cgamma2 and Cgamma4 genes on one chromosome in the donor, suggesting that the remaining Cgamma2 gene allele was silent. In the patient and his two IgG2 deficient brothers, the silent Cgamma2 gene showed both germ-line transcription and switch recombination and no structural defects were found in the intronic promoter or the switch region of the gene. However, an A-->G transition in the fourth nucleotide in the 5' portion of intron 1 was identified. Transfection of artificial constructs into the human B cell lines demonstrated that this A-->G transition inactivated the normal splice site, and instead, a cryptic splice site in the CH1 exon was used in RNA post-transcriptional processing, leading to a 16 bp deletion of the gamma2 CH1 exon. This aberrantly spliced RNA that is mostly derived from germ-line transcription in vivo was also detected in both homozygous and heterozygous individuals carrying this mutation. These findings suggest a novel genetic mechanism as the cause of IgG subclass deficiency in selected patients.

HLA haplotype A*03-B*07 in hemochromatosis probands with HFE C282Y homozygosity: frequency disparity in men and women and lack of association with severity of iron overload

Before the discovery of HFE, reports suggested that hemochromatosis patients with the ancestral haplotype (or some element thereof) have more severe iron overload than those without the haplotype. We performed univariate and multivariate analyses of the relationships of human leukocyte antigen (HLA)-A*03 and HLA haplotype A*03-B*07 to iron measures (serum iron concentration, transferrin saturation, and serum ferritin concentration at diagnosis and units of phlebotomy to achieve iron depletion) in hemochromatosis probands homozygous for HFE C282Y diagnosed in medical care. Iron overload was defined by demonstration of hepatic iron index of ≥1.9 or removal of ≥2.0 g Fe by therapeutic phlebotomy. We tabulated the phenotype frequencies of HLA-A*03 and the frequencies of common HLA haplotypes A*01-B*08, A*02-B*44, A*03-B*07, and A*03-B*14 in three groups of white adults: (1) 141 hemochromatosis probands with C282Y homozygosity; (2) 195 index cases with IgG subclass deficiency (IgGSD) or common variable immunodeficiency (CVID), disorders typically linked to Ch6p, and (3) 750 control subjects. Among probands, 86 men and 42 women had iron overload. Frequencies of HLA-A and -B alleles in probands did not depart significantly from Hardy-Weinberg equilibrium. The phenotype frequency of A*03 did not differ significantly between men and women in the each of the respective three groups. The frequency of haplotype A*03-B*07 was greater in men than women with hemochromatosis (0.3081 vs. 0.1455; P = 0.0019). The frequency of A*03-B*014 was significantly greater in women than men with hemochromatosis (0.1182 vs. 0.0407, respectively; P = 0.0134). Mean values of most iron measures were not affected by numbers of copies of A*03 or by presence of A*03-B*07 in either men or women in univariate analysis. ANOVA models of sex, age at diagnosis, and all HLA alleles and haplotypes in probands were used to determine effects of these variables on iron measures. ANOVA models revealed that (1) there were no significant predictors for serum iron concentration; (2) B*14 is associated with higher transferrin saturation in women and lower transferrin saturation in men; (3) A*01-B*08 is associated with a trend of higher serum ferritin levels; and (4) A*03-B*14 is associated with exaggeration of the age-associated upward trend in units of phlebotomy to achieve iron depletion. In hemochromatosis probands with HFE C282Y homozygosity, we conclude that (1) disparate frequencies of HLA haplotypes A*03-B*07 and A*03-B*14 occur in men and women and (2) HLA-A*03 and HLA-A*03-B*07 are not independent variables associated with iron overload severity.

Antibody response to the Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in healthy and infection-prone individuals with IgG3 subclass deficiency.

Searching for a possible explanation for the phenotypic heterogeneity in IgG3 deficiency, we studied the antibody response to a polysaccharide and a protein antigen in IgG3-deficient (IgG3d) adults after vaccination with Haemophilus influenzae type b capsular polysaccharide (Hib CP) conjugated to tetanus toxoid. Distribution of isotypes, idiotypes, clonotypes, and Gm allotypes were compared. All the vaccinated individuals, irrespective of the level of IgG3 and proneness to infections, developed protective levels of anti-Hib CP. Significantly lower prevaccination levels of IgG2 (p < 0.05) and IgG4 anti-Hib CP (p < 0.04 and p < 0.03) were noted among the infection-prone compared to the healthy IgG3d individuals and/or controls. Seventy percent of the IgG3d patients and none of the controls had the low responding Gm(ga-n/ga-n) genotype, while the majority of the controls had the alternative Gm(bfn/bfn) genotype. The conjugate ACT-HIB vaccine efficiently overcomes the IgG3 subclass deficiency state and the genetic predisposition for lower responsiveness, providing protection against Hib and tetanus infections. The proneness to infection in some IgG3d individuals may relate to their low prevaccination antibody levels.

Echocardiographic abnormalities in primary antibody deficiency

Objective: To document cardiac abnormalities secondary to pulmonary disease in primary antibody deficiency. Patients and methods: A cross sectional audit study of patients from a regional immunology centre. Subjects undergoing...

Acquired IgG subclass deficiency - A gene mutation?

Rationale Acquired IgG subclass deficiency is both a pediatric and adult concern. Accurate diagnosis can be complex because of variability in measurement techniques and interpretation of antibody-forming capacity. Case studies A 49-year old Caucasian male in excellent previous health presented with complaints of recurrent infections of the ear, skin, and prostate. The patient had been treated with multiple courses of antibiotics. A 6-year old African-American female presented with recurrent infections of the ear, sinuses, lungs, and throat. The patient was full-term and healthy up until 8 months of age, with normal IgG and subclasses obtained at age 3 years. Methods Besides routine labs, IgG, IgA, IgM and IgG subclasses were obtained. Pre-pneumococcal antibodies were assessed followed by vaccination with post-pneumococcal antibody titers drawn at 2 and 4 weeks. Results The adult's immunodeficiency revealed normal IgA and IgG, low IgM and IgG-3 subclass deficiency. The child had a low IgA, total IgG level at the low end of normal with IgG-1 subclass deficiency. Both patients had defective antibody responses to the pneumococcal vaccine in all the strains of bacteria. Conclusion The diagnosis of a IgG subclass deficiency should be considered in both children and adults with recurrent infections. IgG subclass deficiency may still be a possibility even when the total IgG is normal. A detailed history of infections and antibody-forming capacity is recommended. IVIG is recommended for treatment of the condition.

The immunologic deficiency of Rubinstein-Taybi syndrome

Rationale Rubinstein-Tabyi syndrome is characterized by broad toes and thumbs. It is estimated that approximately 75% of patient with RTS experience respiratory infections. We have found that an immunologic abnormality may be the true cause of their infections. Methods Four patients with Rubinstein-Taybi syndrome and recurrent infections were evaluated for an immunological deficiency. Results JC experienced several episodes of pneumonia, fever, otitis media and sinusitis. Immunologic evaluation showed that JC had low T cells numbers and decreased function to mitogens. Serum immunoglobulins were normal but antibody response to polysaccharide antigens were absent. The patient was started on IVIgG replacement therapy. AR has experienced chronic otitis media. He has had tympanoplasty, mastoidectomy and removal of cholesteatoma. Immunologic evaluation shows an absent IgA and IgG2 subclass deficiency. Absent responses to polysaccharide antigens were noted. Lymphocyte markers were normal. MB experienced frequent otitis media and one episode of pneumonia. The otitis infections were not alleviated by 4 sets of tympanostomy tubes. Infections persisted till the age of 24, his present age. MB had normal T cells for his age. Serum immunoglobulin and IgG subclass levels were normal. Antibody responses to polysaccharide antigens were abnormally low. One other patient is in the process of immunological evaluation but appears to have a similar defective antibody response to polysaccharides. Conclusions We propose that a primarily humoral defect may exist in this population. The humoral defect primarily is one of a lack of antibody response to polysaccharide antigens. Aggressive investigation and management in patients with RTS may enhance the quality of life that these patients.

The general characteristics of our patients with primer immunodeficiency

In this study, we aimed to identify the general characteristics of the patients who came to our department with primer immunodeficiency (PII) between 1993-200. We analyzed the medical files of the patients with PII followed up between 1993-2003 retrospectively. A total of 53 patients had PII. There were 31 males (58.5%), and 22 females (41.5%). The average age for the onset of symptoms was 5.8 months and the average age of the time of referral was 15.8 months. Of these patients, 32 (60.4%)had humoral immunodeficiency, 18 had (33.1%) T-cell immunodeficiency, and 3 had (5.6%) had phagocytic system dysfunction. The types of humoral immunodeficiencies were as follow; 11 patients had IgG subclass deficiency, 7 sIgA deficiency, 4 transient hypogammaglobulinemia of infancy, 4 X-linked agammaglobulinemia, 4 common variable immunodeficiency, and 2 autosomal hyper-IgM syndrome. Of the patients with T-cell deficiency, 7 had ataxia-telangiectasia, 5 SCID, 3 X-linked hyper-IgM syndrome, 2 Wiskott-Aldrich syndrome, and 1 DiGeorge. In phagocyte deficiency, 2 patients had Chediac-Higashi syndrome and 1 had LAD. Infection diseases of the patients according to their frequency were as follows; recurrent upper airway infections, lower recurrent lower airway infections, gastroenteritis, skin infections, deep layer apse, candidiasis, meningitis and septic arthritis. In conclusion, we found the humoral immunodeficiencies as the most common primary immunodeficiency disease, which is consistent with results in the literature. However, we believe that our results may not reflect the actual frequency and types of immunodeficiencies as most patients die without diagnosis or wrong diagnosis.

Clinical Properties of a Novel Liquid Intravenous Immunoglobulin: Studies in Patients with Immune Thrombocytopenic Purpura and Primary Immunodeficiencies

Background: We have developed a novel liquid intravenous immunoglobulin (IVIG-F10). It consists of a nanofiltered 12% immunoglobulin G (IgG) solution, stabilized with nicotinamide, L-proline and L-isoleucine. The efficacy, tolerability, safety, and pharmacokinetics of this product were assessed in patients with chronic immune thrombocytopenic purpura (ITP) and primary humoral immunodeficiencies (PID). Patients and Methods: 33 chronic ITP patients with platelet counts of < 20 × 10⁹/l were treated with IVIG-F10 or Sandoglobulin at doses of 0.4 g/kg body weight on 5 consecutive days. The primary efficacy endpoint was an increase in platelet counts to ≧50 × 10⁹/l. Secondary endpoints were time to and duration of platelet response and regression of bleeding. 34 PID patients with X-linked agammaglobulinemia, common variable immunodeficiency or IgG subclass deficiency were treated for 6 months with IVIG-F10 or Sandoglobulin at doses of 0.3–0.8 g/kg, infused at 3- or 4-week intervals. The primary efficacy endpoint was the number of days absent from school/work. Secondary endpoints were feeling of well-being, days of hospitalization, and use of antibiotics. Results: In ITP patients, the primary endpoint was met by 12/16 patients on IVIG-F10 and by 12/17 patients on Sandoglobulin (p = 1.000). Results of the secondary endpoints were comparable in the two study groups. In the PID study, 10/17 patients on IVIG-F10 and 9/17 patients on Sandoglobulin missed days at school/work, with monthly mean absences of 0.7 and 0.6 days (p = 0.746), respectively. There were no significant differences in the outcome of the secondary endpoints. Pharmacokinetics showed constant peak and trough serum IgG levels in PID patients. The median half-life (t_1/2) of IgG was 33 days in the IVIG-F10 group and 41 days in the Sandoglobulin group. For anti-HBsAg, median t_1/2 values were shorter, i.e. 17 and 19 days for IVIG-F10 and Sandoglobulin, respectively. In the ITP study, adverse events related to study drug were suspected in 9 and 14 patients treated with IVIG-F10 and Sandoglobulin, respectively; in the PID study adverse events occurred in 8 and 9 patients, respectively. Viral safety was ascertained in both studies by serology supplemented with nucleic acid amplification testing. Serum levels of the stabilizers transiently increased after infusion of IVIG-F10, but were back to baseline at the following day. Conclusions: The clinical studies in patients with chronic ITP and PID showed that the efficacy, tolerability, safety, and pharmacokinetics of IVIG-F10 were comparable to the properties of Sandoglobulin.