Functional Defects in B Lymphocytes in Asthmatic Patients With IgG Subclass Deficiency.
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SUBMITTER: Sohn H
PROVIDER: S-EPMC10359641 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
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Functional Defects in B Lymphocytes in Asthmatic Patients With IgG Subclass Deficiency.
Sohn Hyeukjun H Kim Joo-Hee JH Jang Jae-Hyuk JH Kim Seung-Hyun SH Park Hae-Sim HS
Allergy, asthma & immunology research 20230421 4
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Project description:PurposeSpecific antibody deficiency (SAD) involves a deficient response to a polysaccharide vaccine despite having normal immunoglobulin levels. The failure of the polysaccharide response can be observed as a component of various primary antibody deficiencies. However, only a few studies have described the clinical and immunological profiles in SAD and/or other primary immunodeficiencies (PIDs) in adults.MethodsA total of 47 patients who had a clinical history suggestive of antibody deficiency or had already been diagnosed with various antibody deficiencies were enrolled. Polysaccharide responses to 7 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) were measured using the World Health Organization enzyme-linked immunosorbent assay (WHO-ELISA), and postvaccination immunoglobulin G (IgG) titers were compared to clinical and laboratory parameters.ResultsBased on the American Academy of Allergy, Asthma, and Immunology (AAAAI) criteria for the WHO-ELISA, 11 (23.4%) patients were diagnosed as having SAD. Sixteen-three percent of them had combined with other types of PID, such as IgG subclass deficiency and hypogammaglobulinemia. Postvaccination IgG titers for the serotypes 4/9V/18C correlated with IgG2 (P = 0.012, P = 0.001, and P = 0.004) and for 6B/9V/14 with IgG3 (P = 0.003, P = 0.041, and P = 0.036, respectively). The IgG3 subclass levels negatively correlated with forced expiratory volume in 1 second (FEV1, %) and FEV1/forced vital capacity (P < 0.001 and P = 0.001, respectively).ConclusionSAD can be diagnosed in patients with normal IgG levels as well as in those deficient in IgG or the IgG3 subclass, implicating that restricted responses to Streptococcus pneumoniae polysaccharide antigens commonly exist in patients with predominantly antibody deficiency.
| S-EPMC7840874 | biostudies-literature
Project description:BackgroundAdults with IgG subclass deficiency (IgGSD) with subnormal IgG2 are inadequately characterized.MethodsWe retrospectively analyzed observations in unrelated adults with IgGSD evaluated in a single hematology clinic (1991-2019) and selected those with subnormal serum IgG2 (<117 mg/dL (<1.2 g/L)) without corticosteroid therapy to describe: age; prevalence of women; upper/lower respiratory infection; autoimmune condition(s); atopy; other allergy; frequent or severe respiratory tract infection in first-degree relatives; IgG, IgG subclasses, IgA, and IgM; blood lymphocyte subpopulations; human leukocyte antigen (HLA)-A and -B types and haplotypes; and 23-valent pneumococcal polysaccharide vaccination (PPSV23) responses. We determined the prevalence of subnormal IgG2 among unrelated adults with IgGSD without corticosteroid therapy and compared general characteristics of those with and without subnormal IgG2.ResultsThere were 18 patients (94.4% women) with subnormal IgG2. Mean age was 52 ± 11 y. Upper/lower respiratory infection occurred in 94.4%/74.8%, respectively. Autoimmune condition(s), atopy, other allergy, and frequent or severe respiratory infection in first-degree relatives occurred in 44.4%, 44.4%, 61.1%, and 22.2%, respectively. Median IgG2 was 105 mg/dL (83, 116). Subnormal IgG, IgG1, IgG3, IgG4, IgA, and IgM was observed in 66.7%, 50.0%, 100.0%, 5.6%, 33.3%, and 0%, respectively. Lymphocyte subpopulations were normal in most patients. HLA frequencies were similar in patients and controls. Three of 4 patients had no protective S. pneumoniae serotype-specific IgG levels before or after PPSV23. These 18 patients represent 7.6% of 236 adults with IgGSD. Prevalence of subnormal IgG, subnormal IgG3, and subnormal IgA was significantly greater in 18 adults with subnormal IgG2 than 218 adults without subnormal IgG2. Prevalence of subnormal IgM was significantly lower in patients with subnormal IgG2.ConclusionsCharacteristics of adults with IgGSD with subnormal IgG2 include female predominance, other immunologic abnormalities, subnormal IgG3 and/or IgG1, lack of HLA-A and -B association, and suboptimal PPSV23 response.
| S-EPMC7553271 | biostudies-literature
Project description:BackgroundFactors associated with IgG levels in adults with IgG subclass deficiency (IgGSD) are incompletely understood. We studied adults with IgGSD with subnormal IgG1 only, subnormal IgG1/IgG3, or subnormal IgG3 only without other subnormal IgG subclasses, IgA, or IgM. We compiled: age; sex; autoimmune condition(s) (AC); atopy; IgG, IgG subclasses, IgA, IgM; IgGsum (IgG1 + IgG2 + IgG3 + IgG4); and D (percentage difference between IgGsum and IgG). We compared attributes of patients with/without subnormal IgG (< 7.00 g/L; subnormal IgG1 subclass groups only) and analyzed IgGsum and IgG relationships. We performed backward stepwise regressions on IgG using independent variables IgG subclasses, age, and sex and on D using independent variables age and sex.ResultsThere were 39 patients with subnormal IgG1 only (89.7% women), 53 with subnormal IgG1/IgG3 (88.7% women), and 115 with subnormal IgG3 only (91.3% women). Fifteen patients (38.5%) and 32 patients (60.4%) in the respective subnormal IgG1 subclass groups had subnormal IgG. Attributes of patients with/without IgG < 7.00 g/L were similar, except that AC prevalence was lower in patients with subnormal IgG1 only and IgG < 7.00 g/L than ≥ 7.00 g/L (p = 0.0484). Mean/median IgG1 and IgG2 were significantly lower in patients with IgG < 7.00 g/L in both subnormal IgG1 subclass groups (p < 0.0001, all comparisons). Regressions on IgG in three subclass groups revealed positive associations with IgG1 and IgG2 (p < 0.0001 each association). Regressions on D revealed no significant association. IgG1 percentages of IgGsum were lower and IgG2 percentages were higher in patients with subnormal IgG1 subclass levels than subnormal IgG3 only (p < 0.0001 all comparisons).ConclusionsWe conclude that both IgG1 and IgG2 are major determinants of IgG in patients with subnormal IgG1, combined subnormal IgG1/IgG3, or subnormal IgG3 and that in patients with subnormal IgG1 or combined subnormal IgG1/IgG3, median IgG2 levels are significantly lower in those with IgG < 7.00 g/L than those with IgG ≥ 7.00 g/L.
| S-EPMC8353875 | biostudies-literature
Project description:Chronic fatigue syndrome (ME/CFS) is a complex disease frequently triggered by infections. IgG substitution may have therapeutic effect both by ameliorating susceptibility to infections and due to immunomodulatory effects. We conducted a proof of concept open trial with s.c. IgG in 17 ME/CFS patients suffering from recurrent infections and mild IgG or IgG subclass deficiency to assess tolerability and efficacy. Patients received s.c. IgG therapy of 0.8 g/kg/month for 12 months with an initial 2 months dose escalation phase of 0.2 g and 0.4 g/kg/month. Primary outcome was improvement of fatigue assessed by Chalder Fatigue Scale (CFQ; decrease ≥ 6 points) and of physical functioning assessed by SF-36 (increase ≥ 25 points) at month 12. Of 12 patients receiving treatment per protocol 5 had a clinical response at month 12. Two additional patients had an improvement according to this definition at months 6 and 9. In four patients treatment was ceased due to adverse events and in one patient due to disease worsening. We identified LDH and soluble IL-2 receptor as potential biomarker for response. Our data indicate that self-administered s.c. IgG treatment is feasible and led to clinical improvement in a subset of ME/CFS patients.
| S-EPMC8198960 | biostudies-literature
Project description:BackgroundImmunoglobulin G (IgG) deficiency increases the risk of acute exacerbations and mortality in chronic obstructive pulmonary disease (COPD). However, the impact of IgG subclass deficiency on mortality in COPD is unknown. Here, we determined which IgG subclass, if any, is associated with increased risk of mortality in COPD.MethodsWe measured serum IgG subclass concentrations of 489 hospitalized patients with COPD who were enrolled in the Rapid Transition Program (clinicaltrials.gov identifier NCT02050022). To evaluate the impact of IgG subclass deficiency on 1-year mortality, Cox proportional hazards regression analyses were performed with adjustments for potential confounders.ResultsDeficiencies in IgG1, IgG2, IgG3, and IgG4 were present in 1.8%, 12.1%, 4.3%, and 11.2% of patients, respectively. One-year mortality was 56% in patients with IgG1 deficiency, 27% in IgG2 deficiency, 24% in IgG3 deficiency, and 31% in IgG4 deficiency. Cox proportional modeling showed that IgG1 and IgG4 deficiencies increased the 1-year mortality risk with an adjusted hazard ratio of 3.92 (95% confidence interval [CI] = 1.55-9.87) and 1.74 (95% CI = 1.02-2.98), respectively. Neither IgG2 nor IgG3 deficiency significantly increased 1-year mortality. Two or more IgG subclass deficiencies were observed in 5.3%. Patients with 2 or more IgG subclass deficiencies had a higher 1-year mortality than those without any deficiencies (46.2% vs. 19.7%, p < 0.001), with an adjusted hazard ratio of 2.22 (95% CI = 1.18-4.17).ConclusionsIgG1 and IgG4 deficiency was observed in 1.8% and 11.2% of hospitalized patients with COPD, respectively, and these deficiencies were associated with a significantly increased risk of 1-year mortality.
| S-EPMC9158163 | biostudies-literature
Project description:PurposeRecurrent respiratory tract infection is a common manifestation of primary immunodeficiency disease, and respiratory viruses or bacteria are important triggers of asthma exacerbations. Asthma often coexists with humoral immunodeficiency in adults, and some asthmatics with immunoglobulin (Ig) G subclass deficiency (IgGSCD) suffer from recurrent exacerbations. Although some studies suggest a benefit from Ig replacement, others have failed to support its use. This study aimed to assess the effect of Ig replacement on asthma exacerbation caused by respiratory infection as well as the asthma control status of adult asthmatics with IgGSCD.MethodsThis is a multi-center, open-label study of adult asthmatics with IgGSCD. All patients received monthly intravenous immunoglobulin (IVIG) for 6 months and were evaluated regarding asthma exacerbation related to infection, asthma control status, quality of life, and lung function before and after IVIG infusion.ResultsA total of 30 patients were enrolled, and 24 completed the study. Most of the patients had a moderate degree of asthma severity with partly (52%) or uncontrolled (41%) status at baseline. IVIG significantly reduced the proportion of patients with asthma exacerbations, lowered the number of respiratory infections, and improved asthma control status, compared to the baseline values (P<0.001). The mean asthma-specific quality of life and asthma control test scores were improved significantly (P=0.009 and P=0.053, respectively); however, there were no significant changes in lung function.ConclusionsIVIG reduced the frequency of asthma exacerbations and improved asthma control status in adult asthmatics with IgGSCD, suggesting that IVIG could be an effective treatment option in this population.
| S-EPMC5603481 | biostudies-literature
Project description:Many adults with IgG subclass deficiency (IgGSD) experience long intervals of frequent/severe respiratory tract infection before IgGSD diagnosis, but reasons for delays in IgGSD diagnoses are incompletely understood. We performed a retrospective study of 300 white adults (ages ≥18 y) with IgGSD including frequency analyses of age at IgGSD diagnosis, duration of frequent/severe respiratory tract infection before IgGSD diagnosis, and age at onset of frequent/severe infection (calculated). We performed multivariable regressions on age at diagnosis, infection duration, and age at infection onset using these variables, as appropriate: sex; age at diagnosis; diabetes; autoimmune condition(s); atopy; allergy; corticosteroid use; body mass index; serum immunoglobulin isotype levels; blood lymphocyte subsets; three IgGSD-associated human leukocyte antigen-A and -B haplotypes; and referring physician specialties. Mean age at diagnosis was 50 ± 12 (standard deviation) y (median 50 y (range 19-79)). There were 247 women (82.3%). Mean infection duration at IgGSD diagnosis was 12 ± 13 y (median 7 y (range 1-66)). Mean age at infection onset was 38 ± 16 y (median 38 y (range 4, 76)). Age at infection onset was ≥18 y in 95.7% of subjects. Regressions on age at diagnosis and infection duration revealed no significant associations. Regression on age at infection onset revealed one positive association: age at diagnosis (p <0.0001). We conclude that the median duration of frequent/severe respiratory tract infection in adults before IgGSD diagnosis was 7 y. Older adults may be diagnosed to have IgGSD after longer intervals of infection than younger adults. Duration of frequent/severe respiratory tract infection before IgGSD diagnosis was not significantly associated with routine clinical and laboratory variables, including referring physician specialties.
| S-EPMC6528998 | biostudies-literature
Project description:BackgroundImmunoglobulin G subclass deficiencies (IgGsd) comprise a wide clinical spectrum from no symptoms to repeated respiratory infections and risk for the development of lung damage. Our aims were to investigate whether the immunological phenotype of IgGsd patients on and off immunoglobulin replacement therapy (IgRT) was reflected in the clinical features of IgGsd.MethodThirty patients with IgGsd were included in this prospective study of 18 months of IgRT, followed by 7-18 months of IgRT discontinuation. Blood samples were collected when patients were on and off IgRT and compared with samples from 34 cross-sectional healthy controls. An in-depth lymphocyte phenotyping was performed by flow cytometry and plasma levels of immune checkpoints were assessed.ResultsIgG3 subclass deficiency was most common. Patients with IgGsd had decreased levels of activated T cells and B cells and plasma levels of negative immune checkpoint molecules correlated negatively with T cell and B cell activation. The decreased T cell activation level was unaffected by IgRT, while the B cell activation was partly restored. Of note, decreased levels of activated regulatory T cells (Tregs) were found in IgGsd patients and was partly restored during IgRT. The profile of comorbidities did not associate with Treg levels.DiscussionIgGsd is associated with decreased B cell and T cell activation including Tregs, and increased plasma levels of negative immune checkpoint molecules. The consequence of reduced activated Tregs in IgGsd remains unclear. Decreased immune cell activation was partly restored during IgRT, demonstrating that IgRT may contribute to improved immune function in patients with IgGsd.
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Project description:IgG-based monoclonal antibody therapeutics, which are mainly IgG1, IgG2, and IgG4 subclasses or related variants, have dominated the biotherapeutics field for decades. Multiple laboratories have reported that the IgG subclasses possess different molecular characteristics that can affect their developability. For example, IgG1, the most popular IgG subclass for therapeutics, is known to have a characteristic degradation pathway related to its hinge fragility. However, there remains a paucity of studies that systematically evaluate the IgG subclasses on manufacturability and long-term stability. We thus conducted a systematic study of 12 mAbs derived from three sets of unrelated variable regions, each cloned into IgG1, an IgG1 variant with diminished effector functions, IgG2, and a stabilized IgG4 variant with further reduced FcγR interaction, to evaluate the impact of IgG subclass on manufacturability and high concentration stability in a common formulation buffer matrix. Our evaluation included Chinese hamster ovary cell productivity, host cell protein removal efficiency, N-linked glycan structure at the conserved N297 Fc position, solution appearance at high concentration, and aggregate growth, fragmentation, charge variant profile change, and post-translational modification upon thermal stress conditions or long-term storage at refrigerated temperature. Our results elucidated molecular attributes that are common to all IgG subclasses, as well as those that are unique to certain Fc domains, providing new insight into the effects of IgG subclass on antibody manufacturability and stability. These learnings can be used to enable a balanced decision on IgG subclass selection for therapeutic antibodies and aid in acceleration of their product development process.
| S-EPMC10038059 | biostudies-literature
Project description:Antibodies against several self-glycans on glycosphingolipids are frequently detected in different neurological disorders. Their pathogenic role is profusely documented, but the keys for their origin remain elusive. Additionally, antibodies recognizing non-self glycans appear in normal human serum during immune response to bacteria. Using HPTLC-immunostaining we aimed to characterize IgM and IgG subclass antibody responses against glycosphingolipids carrying self glycans (GM1/GM2/GM3/GD1a/GD1b/GD3/GT1b/GQ1b) and non-self glycans (Forssman/GA1/"A" blood group/Nt7) in sera from 27 randomly selected neurological disorder patients presenting IgG reactivity towards any of these antigens. Presence of IgG2 (p = 0.0001) and IgG1 (p = 0.0078) was more frequent for IgG antibodies against non-self glycans, along with less restricted antibody response (two or more simultaneous IgG subclasses). Contrariwise, IgG subclass distribution against self glycans showed clear dominance for IgG3 presence (p = 0.0017) and more restricted IgG-subclass distributions (i.e. a single IgG subclass, p = 0.0133). Interestingly, anti-self glycan IgG antibodies with simultaneous IgM presence had higher proportion of IgG2 (p = 0.0295). IgG subclass frequencies were skewed towards IgG1 (p = 0.0266) for "anti-self glycan A" subgroup (GM2/GM1/GD1b) and to IgG3 (p = 0.0007) for "anti-self glycan B" subgroup (GM3/GD1a/GD3/GT1b/GQ1b). Variations in players and/or antigenic presentation pathways supporting isotype (M-G) and IgG-subclass pattern differences in the humoral immune response against glycosphingolipids carrying non-self versus self-glycans are discussed.
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