Immunoglobulin G Subclasses Research Articles

Serum Immunoglobulin G Levels Are Associated with Risk for Exacerbations: An Analysis of SPIROMICS.

Serum Immunoglobulin G (IgG) deficiency is associated with morbidity in chronic obstructive pulmonary disease (COPD) but it is unclear whether concentrations in the lower end of the normal range still confer risk. To determine if levels above traditional cutoffs for serum IgG deficiency are associated with exacerbations among current and former smokers with or at risk for COPD. Former and current smokers in SPIROMICS (n=1,497) were studied, n=1,026 with and n=471 at risk for COPD. In a subset (n=1,031), IgG subclasses were measured. Associations between total IgG or subclasses and prospective exacerbations were evaluated with multivariable models adjusting for demographics, current smoking, smoking history, FEV1% predicted, inhaled corticosteroids, and serum IgA. The 35th percentile (1225 mg/dL in this cohort) of IgG was the best cutoff by Akaike Information Criterion (AIC). Below this, there was increased exacerbation risk (IRR 1.28, 95% CI 1.08-1.51). Among subclasses, IgG1 and IgG2 below 35th percentile (354 and 105 mg/dL, respectively) were both associated with increased risk of severe exacerbation (IgG1: IRR 1.39, 95% CI 1.06-1.84; IgG2: IRR 1.50, 95% CI 1.14-1.1.97). These associations remained significant when additionally adjusting for history of exacerbations. Lower serum IgG is prospectively associated with exacerbations in individuals with or at risk for COPD. Among subclasses, lower IgG1 and IgG2 are prospectively associated with severe exacerbations. The optimal IgG cutoff was substantially higher than traditional cutoffs for deficiency, suggesting subtle impairment of humoral immunity may be associated with exacerbations.

The importance of IgG glycosylation-What did we learn after analyzing over 100,000 individuals.

All four subclasses of immunoglobulin G (IgG) antibodies have glycan structures attached to the protein part of the IgG molecules. Glycans linked to the Fc portion of IgG are found in all IgG antibodies, while about one-fifth of IgG antibodies in plasma also have glycans attached to the Fab portion of IgG. The IgG3 subclass is characterized by more complex glycosylation compared to other IgG subclasses. In this review, we discuss the significant influence that glycans exert on the structural and functional properties of IgG. We provide a comprehensive overview of how the composition of these glycans can affect IgG's effector functions by modulating its interactions with Fcγ receptors and other molecules such as the C1q component of complement, which in turn influence various immune responses triggered by IgG, including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In addition, the importance of glycans for the efficacy of therapeutics like monoclonal antibodies and intravenous immunoglobulin (IVIg) therapy is discussed. Moreover, we offer insights into IgG glycosylation characteristics and roles derived from general population, disease-specific, and interventional studies. These studies indicate that IgG glycans are important biomarkers and functional effectors in health and disease.

A mechanistic PK/PD model of AZD0171 (anti-LIF) to support Phase II dose selection.

AZD0171 (INN: Falbikitug) is being developed as a humanized monoclonal antibody (mAb), immunoglobulin G subclass 1 (IgG1), which binds specifically to the immunosuppressive human cytokine leukemia inhibitory factor (LIF) and inhibits downstream signaling by blocking recruitment of glycoprotein 130 (gp130) to the LIF receptor (LIFR) subunit (gp190) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and is intended to treat adult participants with advanced solid tumors. LIF is a pleiotropic cytokine (and a member of the IL-6 family of cytokines) involved in many physiological and pathological processes and is highly expressed in a subset of solid tumors, including non-small cell lung cancer (NSCLC), colon, ovarian, prostate, and pancreatic cancer. The aim of this work was to develop a mechanistic PK/PD model to investigate the effect of AZD0171 on tumor LIF levels, predict the level of downstream signaling complex (LIF:LIFR:gp130) inhibition, and examine the dose-response relationship to support dose selection for a Phase II clinical study. Modeling results show that tumor LIF is inhibited in a dose-dependent manner with >90% inhibition for 95% of patients at the Phase II clinical dose of 1500 mg Q2W.

Sequence variants influencing the regulation of serum IgG subclass levels

Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics.

Nephelometry vs. Immunoturbidimetry assay: Analytical performance on IgG subclasses

Interest in measuring immunoglobulin G Subclasses (IgG Subclasses) is increasing as more information is gathered and understanding regarding conditions associated with deficiencies of each IgG Subclass grows. Different methodologies are available for the measurement of IgG Subclasses, but their specificities vary. As a result, laboratories choose the methodology that better suits their routine, but which may not necessarily align with the needs of their population. In addition, the lack of standardization for the quantification of IgG Subclasses causes diagnostic gaps when comparing results provided by different methodologies. Thus, the purpose of our research is to compare the analytical performance of The Binding Site's (TBS) Optilite® human Immunoglobulin G (IgG) and IgG Subclasses Immunoturbidimetry assay, with the Nephelometry method routinely used in our clinical laboratory, Siemens BNII®. Our results show that the Immunoturbidimetry assay appears to be the most reliable to evaluate IgG Subclasses: the sum of IgG Subclasses and Total IgG correlate better than by Nephelometry. Although these methodologies share a similar principle, the comparison of results appears to be compromised. Therefore, prior to switching methodologies, further studies should be conducted to assess which methodology could be better applied to specific populations. It is also essential to standardise IgG Subclasses assays to reduce discrepancies that arise from comparing results.

Neutrophil Depletion Changes the N-Glycosylation Pattern of IgG in Experimental Murine Sepsis.

Sepsis is a life-threatening condition with a rising disease burden worldwide. It is a multifactorial disease and is defined as a dysregulated host response to infection. Neutrophils have been shown to be involved in the pathogenesis of sepsis by exacerbating inflammation. However, the exact effector mechanism of action still remains a mystery. Changes in the glycosylation pattern of the immunoglobulin G (IgG) Fc region are described for several diseases including meningococcal sepsis. In this study, we investigated the possible contribution of neutrophils and neutrophil implication, potentially related to degranulation or neutrophil extracellular trap (NET) formation in changing the IgG Fc N-glycosylation pattern in a murine sepsis model. We have measured the serum level of cytokines/chemokines and immunoglobulins, the serum activity of neutrophil elastase (NE), and analyzed the IgG Fc glycosylation pattern by Liquid Chromatography-Electrospray Ionization-Mass Spectrometry (LC-ESI-MS) and Lectin enzyme-linked immunosorbent assay (ELISA). We observed an increased activity of NE- and neutrophil-associated cytokines such as keratinocyte chemoattractant (KC) with the development of sepsis. Regarding the IgG Fc N-glycosylation, we observed an increase in fucosylation and α1,3-galactosylation and a decrease for sialyation. Interestingly, these changes were not uniform for all IgG subclasses. After depletion of neutrophils, we saw a change in the exposure of fucose and α2,6-linked sialic acid during the time course of our experimental sepsis model. In conclusion, neutrophils can influence changes in the IgG glycosylation pattern in experimental sepsis.

CORONARY ARTERY ANEURYSM IN IGG4–RELATED DISEASE

Abstract Introduction Coronary artery ectasia is a rare disease defined as a local or diffuse dilatation of the coronary artery more than 1.5 times the diameter of the adiacent normal segment. The etiology is diverse and can be rarely associated with immunoglobulin G4 (IgG4)–related disease. The high levels of serum IgG4 may promote the development of low–density plaques, intimal thickening due to pericoronitis and subsequent coronary ectasia. Case Report We present the case of a 72–year–old male patient with arterial hypertension, dyslipidemia, chronic renal insufficiency, and a family history of cardiovascular diseases. In the previous year, he suffered a cerebral hemorrhage attributed to an unspecified cerebral vascular malformation, which was managed with an endovascular approach. The patient was admitted for Non–ST–segment Elevation Myocardial Infarction (NSTEMI). Coronary angiography revealed widespread ectasia of the coronary vessels, a chronically occluded marginal branch, and an aneurysmatic proximal right coronary artery with the presence of a thrombus on the aneurysmal segment, dissolved following administration of intracoronaric heparin. Furthermore a critical stenosis at the crux involving the posterior interventricular branch was detected and angioplasty with drug–eluting stent implantation was performed on the affected vessel. Given the coronary artery ectasia, aortic ectasia revealed by echocardiography, renal insufficiency and persistently elevated amylase and lipase levels, further diagnostic investigation was conducted suspecting IgG4–related disease. Hematological tests revealed elevated IgG and IgG4 subclass levels (882 mg/dL and 1438 mg/L, respectively), C3 117 mg/dL, C4 30 mg/dL, and total IgE 130 KU/L. The diagnosis of IgG4–related disease was confirmed and the patient was advised to continue cardiological and rheumatological follow–up. Conclusion When the coronary arteries are involved in the IgG4–related disease, risk of acute events such as heart attack may increase and the prognosis is poor. Coronary thickening and ectasia, typical imaging features, other aortic involvement and inflammation indicators, like elevated serum IgG4, should be considered as red flags for an early investigation and subsequent early intervention.

Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

Immunoglobulin G4-related disease presenting with nephrotic syndrome due to minimal change disease: a case report

BackgroundImmunoglobulin G4-related disease is an inflammatory disease affecting multiple organs including the kidney. Immunoglobulin G4-related kidney disease most commonly manifests as a tubulointerstitial nephritis and is associated with glomerular disease in a proportion of cases. Membranous nephropathy is the most frequent glomerular lesion. Herein, we report the first documented case of immunoglobulin G4-related disease presenting with nephrotic syndrome owing to minimal change disease.Case presentationA 67-year-old South Asian male presented to our service with systemic upset and leg swelling. He had heavy proteinuria (urine protein:creatinine ratio 1042 mg/mmol) and was hypoalbuminemic (17 g/L) and hypercholersterolemic (9.3 mmol/L), consistent with the nephrotic syndrome. His serum creatinine was 140 μmol/L, and he was hypocomplementemic (C3 0.59 g/L, C4 < 0.02 g/L) with raised immunoglobulin G4 subclass levels (5.29 g/L). Kidney biopsy demonstrated minimal change disease alongside a plasma-cell-rich tubulointerstitial nephritis with strong positive staining for immunoglobulin G4. A diagnosis of minimal change disease in the setting of immunoglobulin G4-related disease was made. He was commenced on oral prednisolone at 60 mg daily but suffered infectious complications, including necrotizing fasciitis within 3 weeks of starting treatment, ultimately resulting in his death 52 days after initial presentation.ConclusionThis case highlights the potential for immunoglobulin G4-related disease to be associated with a spectrum of glomerular pathologies including minimal change disease. It adds to the differential diagnosis of secondary causes of minimal change disease, and moreover, aids as an important reminder of the potential complications of high-dose steroids used in its treatment.

Combined evaluation of glomerular phospholipase A2 receptor and immunoglobulin G subclass in membranous nephropathy

Abstract Background Phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic membranous nephropathy (MN). Anti-PLA2R antibodies are mainly of immunoglobulin G (IgG) subclass IgG4, although other IgG subclass depositions in glomeruli also can be detected. However, the importance of the subclass of IgG deposit has not been proven. Thus, we investigated clinical findings from patients with idiopathic MN in relation to glomerular PLA2R deposition and IgG subclass. Methods We enrolled 132 Japanese patients with biopsy-proven idiopathic MN in a multicenter retrospective observational study. We investigated the complete remission rate as primary outcome and the development of end-stage kidney disease (ESKD) as secondary outcome in relation to glomerular PLA2R deposition. Moreover, we evaluated prognostic factors, including glomerular IgG subclass, in the PLA2R-positive group. Results The percentage of cases with glomerular PLA2R deposition was 76.5% (n = 101). The first complete remission rate of the PLA2R-positive group was worse than that of the PLA2R-negative group (log-rank test P &amp;lt; 0.001). ESKD incidence did not significantly differ between the glomerular PLA2R-negative and PLA2R-positive MN groups (log-rank test P = 0.608). In the PLA2R-positive group, higher PLA2R intensities and IgG2 staining were associated with a poorer first complete remission rate (log-rank test P &amp;lt; 0.001 and P = 0.032, respectively). Cox proportional hazards analysis also showed that strong PLA2R deposition and positive IgG2 staining were significantly associated with a failure to reach complete remission (hazard ratio: 2.09 [P = 0.004] and 1.78 [P = 0.030], respectively). Conclusions Our results suggest that intense glomerular PLA2R and IgG2 positivity predict a poor proteinuria remission rate in idiopathic MN.

Protective antibody concentrations in primary immunodeficiency following infusion with 5% or 10% intravenous immunoglobulin.

Inadequate production of immunoglobulin G (IgG) antibodies renders patients with primary immunodeficiencysusceptible to infection by numerous pathogens, some of which can lead to severe asthma exacerbation and possible death. These patients who are immunocompromised are often reliant on intravenous immunoglobulin (IVIG) therapies, which provide passive antibodies against various respiratory pathogens, including measles virus and encapsulated bacteria. We conducted a subanalysis of data from a multicenter, multinational, phase III, open-label bioequivalencestudy to compare protective concentrations of IgG antibodies provided by a 5% and a 10% IVIG product in patients with primaryimmunodeficiency. Patients on stable 21- or 28-day regimens of previous IVIG products were assigned to receive study treatment (adults: 5% IVIG and 10% IVIG; children: 10% IVIG) at doses of 300-800 mg/kg per infusion. Trough concentrations of total IgG, IgG subclasses, measles-neutralizing antibodies, and IgG against Haemophilus influenzae type b and Streptococcus pneumoniae serotypes were evaluated. A total of 48 patients (33 adults ages 16-55 years; 15 children ages 2-15 years) were enrolled and received treatment.No statistically significant differences in trough concentrations of total IgG, IgG subclasses, measles neutralizing antibodies, or IgG directed at encapsulated bacteria were observed between the 5% and 10% formulations in analyses by age (adult or pediatric) or infusion schedule (every 21 or 28 days). All evaluated patients had trough IgG concentrations above accepted thresholds for protection against disease. These findings support the conclusion that, at dose levels and infusion schedules prescribed in clinical practice,this 5% and 10% IVIG product provided consistent, predictable, and bioequivalent IgG concentrations for adult and pediatricpatients with primary immunodeficiency disease. Both formulations delivered trough antibody concentrations of total IgG, measles- neutralizing antibodies, and antibodies against encapsulated bacteria that are above thresholds accepted as protective.

Prevalence and Clinical Significance of Immunoglobulin G1 and Immunoglobulin G3 Subclasses of Anti-D Antibody in Rh D Alloimmunized Antenatal Women

ABSTRACT Background and Objectives: Hemolytic disease of the fetus and newborn (HDFN) occurs as a result of maternal sensitization to paternal antigens. Studies have shown that the immunoglobulin G (IgG) subclass in maternal serum – particularly the presence of IgG1 and IgG3 either singly or in combination, has an impact on the presence and severity of HDFN. The column agglutination technology is used for the identification of IgG1 and IgG3 subclasses. Therefore, the prevalence of IgG1 and IgG3 subclasses in a cohort of alloimmunized Rh (D) antenatal women at our center was studied and was correlated with severity of HDFN. The aims of this study were as follows: (1) to find out the prevalence of IgG1 and IgG3 subclasses among Rh (D) alloimmunized women and (2) to assess the clinical outcome of newborns born to mothers with respect to IgG subclass. Methodology: This was a descriptive study done on 75 antenatal Rh (D) alloimmunized women who fulfilled the inclusion criteria. Blood samples from study participants were subjected to IgG subtyping using the “DAT IgG1/IgG3 ID card” (Bio-Rad, Switzerland), and the outcome of pregnancy was assessed by categorizing the newborns into mild, moderate, and severe HDFN. The data obtained were analyzed using SPSS version 16. Prevalence was calculated and severity of HDFN was correlated with subclass. Results: Among the study population, 23% of mothers had IgG1 alone. Majority (72%) had both IgG1 + IgG3 subclasses and a few (5%) had IgG2 + IgG4. When the mother had both IgG1 + IgG3 subclasses in their body most newborns had only mild HDFN. Few cases of moderate-to-severe cases of HDFN were seen. Most newborns had only mild HDFN even though there were few moderate-to-severe cases of HDFN. No significant association could be demonstrated between severity of HDFN and type of IgG subclasses. Conclusion: Majority of maternal IgG found in HDFN was a combination of IgG1+IgG3.Such cases exhibited stronger grades of reaction in Indirect Coombs Test. A significant association could not be demonstrated between severity of HDFN and type of IgG subclasses.

Identification of IgG1 and IgG3 Allotypes by PCR and Sanger Sequencing.

The immunoglobulin heavy constant gamma (IGHG) gene cluster encoding immunoglobulin G (IgG) subclasses is highly polymorphic, resulting in amino acid variation along the antibody constant heavy chain referred to as allotypes. IGHG1 and IGHG3 are the two most polymorphic IgG subclasses in humans, with 4 classical IgG1 allotypes and 13 allotypes described for IgG3, though recent studies suggest greater allelic diversity, especially in underrepresented ethnic populations. Polymerase chain reaction (PCR) and Sanger sequencing of IGHG amplicons allow for the identification of the single nucleotide polymorphisms (SNPs) responsible for the observed amino acid substitutions. Here, we provide a detailed protocol for the amplification of IGHG1 and IGHG3 segments by PCR, sample preparation for Sanger sequencing, and analysis of sequencing data to identify SNPs associated with different IgG1 and IgG3 allotypes.

Serological characteristics and clinical implications of IgG subclasses in visceral leishmaniasis.

Visceral leishmaniasis (VL) represents the most severe form of Leishmaniasis infection, often resulting in fatality without timely treatment. Previous studies have found that immunosuppression increases the risk of VL disease progression and mortality, and the total immunoglobulin G (IgG) levels in peripheral blood vary before and after treatment. However, the distinct levels and roles of IgG subclasses in VL have not been documented yet. This study aims to elucidate the characteristics and clinical significance of IgG subclasses in VL. A total of 43 cases newly-diagnosed with VL were enrolled in the cohort. We measured the levels of IgG subclasses before and after standard treatment and conducted assessments of bone marrow features. In addition, we analysed other haematological indices and examined the variations in IgG subclasses, as well as their correlation with clinical and laboratory factors. The levels of total IgG, IgG1, and the ratios of both IgG1/IgG and IgG1/IgG2 decreased significantly after treatment, whereas the ratios of IgG2/ IgG showed an obvious increase. The VL patients without hyperglobulinemia displayed significant lower IgG1/IgG2 ratios, but higher IgG2/IgG ratios compared with those with hyperglobulinemia. In addition, VL patients with positive bone marrow amastigotes had significant higher IgG1/IgG and IgG1/IgG2 ratios, but lower IgG2/IgG ratios. IgG subclasses were correlated with abnormal blood test results, particularly immunological elements including IgM and Complement 4 (C4). IgG1 and IgG2 exhibited contrasting changes after treatment in VL patients. The features of bone marrow and laboratory tests indicated that IgG1 and IgG2 serve different roles in the progression of VL. The ratios of IgG subclasses may be more precise indicators to evaluate immune reaction in VL than traditional total IgG.

ADAMTS-13 conformation influences autoimmune recognition in immune thrombotic thrombocytopenic purpura

BackgroundPatients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) have anti–ADAMTS-13 immunoglobulin G (IgG) autoantibodies that enhance ADAMTS-13 clearance and/or inhibit its function. ADAMTS-13 normally circulates in a closed conformation, which is manifested by the interaction of the CUB domains with the central spacer domain. Disruption of the spacer–CUB interaction opens ADAMTS-13, which augments its proteolytic function but may also expose cryptic autoimmune epitopes that promote further autoantibody recognition. ObjectivesTo explore differences in autoantibody binding to ADAMTS-13 in its closed or open conformations in patients with iTTP and to correlate these differences with disease-related parameters. MethodsWe developed a novel assay to measure autoantibodies binding to closed and open ADAMTS-13. Autoantibody titer and IgG subclass binding to open or closed ADAMTS-13 were measured in 70 iTTP first presentation samples and correlated with clinical data, remission, and relapse. ResultsIn 70 patients with iTTP, the mean autoantibody titer against open ADAMTS-13 was, on average, approximately 2-fold greater than that against closed ADAMTS-13, suggesting that ADAMTS-13 opening increases epitope exposure and immune complex formation. Autoantibody titer against closed/open ADAMTS-13 and IgG subclass did not correlate with ADAMTS-13 antigen at presentation. Two patients with iTTP and persistent autoantibodies lost specificity for closed ADAMTS-13 in remission. Recognition of closed/open ADAMTS-13 and autoantibody IgG subclass between the first and second iTTP episodes were very similar. ConclusionADAMTS-13 autoantibody binding is highly influenced by ADAMTS-13 conformation. Although this does not appear to modify the pathogenicity of autoantibodies, the autoantibody signature at relapse suggests that relapse represents re-emergence of the original autoimmune response rather than de novo presentation.

Educational technology for the use of palivizumab in preventing respiratory syncytial virus infection

The only medication available for preventing severe lower respiratory tract disease caused by respiratory syncytial virus in pediatric patients at high risk is Palivizumab, a humanized monoclonal antibody of immunoglobulin G subclass 1 (IgG1). The objective of this work was to validate an educational technology for the use of Palivizumab in preventing respiratory syncytial virus infections. This is methodological research that includes four stages: literature review, construction of a flowchart for healthcare professionals, preparation of an educational booklet for parents and/or caregivers, and validation of the educational booklet by judges of content and appearance. For the construction of the booklet, an integrative literature review was initially conducted to identify and understand all aspects related to the topic. This review aimed to identify and incorporate important studies that provide a relevant contribution to building a solid theoretical foundation to guide the research. A total of 57 studies were included. The educational booklet, "For those who will take care of me with Palivizumab," was constructed and validated for content and appearance by nurses (teachers and assistance). The validation process was based on the responses from the judges of content and appearance. A global Content Validation Index of 0.92 was obtained. As for appearance, the Suitability Assessment of Materials instrument was used, resulting in an overall average score of 7.91. After incorporating the judges' suggestions, the educational material was adjusted to meet the needs and expectations it aims to fulfill. Subsequently, the educational material was sent for proofreading and printing, and once ready, it will be made available to the hospital. The booklet empowers parents and/or caregivers in the prevention and health promotion of children who will use Palivizumab, while the flowchart guides healthcare professionals attending to this population.

Immunomodulation of Antibody Glycosylation through the Placental Transfer

Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental transfer of antibodies, mainly immunoglobulin G (IgG), is critical in protecting the developing fetus from infections. This review looks at how immunomodulation of antibody glycosylation occurs during placental transfer and how it affects fetal health. The passage of maternal IgG antibodies through the placental layers, including the syncytiotrophoblast, stroma, and fetal endothelium, is discussed. The effect of IgG subclass, glycosylation, concentration, maternal infections, and antigen specificity on antibody transfer efficiency is investigated. FcRn-mediated IgG transport, influenced by pH-dependent binding, is essential for placental transfer. Additionally, this review delves into the impact of glycosylation patterns on antibody functionality, considering both protective and pathological effects. Factors affecting the transfer of protective antibodies, such as maternal vaccination, are discussed along with reducing harmful antibodies. This in-depth examination of placental antibody transfer and glycosylation provides insights into improving neonatal immunity and mitigating the effects of maternal autoimmune and alloimmune conditions.

Non-enzymatic glycation and aggregation of camel immunoglobulins induce breast cancer cell proliferation.

Glycation of biomolecules results in the formation of advanced glycation end products (AGEs). Immunoglobulin G (IgG) has been implicated in the progression of various diseases, including diabetes and cancer. This study purified three IgG subclasses (IgG1, IgG2, and IgG3) from Camelus dromedarius colostrum using ammonium sulfate fractionation and chromatographic procedures. SDS-PAGE was performed to confirm the purity and molecular weight of the IgG subclasses. Several biochemical and biophysical techniques were employed to study the effect of glycation on camel IgG using methylglyoxal (MGO), a dicarbonyl sugar. Early glycation measurement showed an increase in the fructosamine content by ~four-fold in IgG2, ~two-fold in IgG3, and a slight rise in IgG1. AGEs were observed in all classes of IgGs with maximum hyperchromicity (96.6%) in IgG2. Furthermore, glycation-induced oxidation of IgGs led to an increase in carbonyl content and loss of -SH groups. Among subclass, IgG2 showed the highest (39.7%) increase in carbonyl content accompanied by 82.5% decrease in -SH groups. Far UV-CD analysis illustrated perturbation of β-sheet structure during glycation reaction with MGO. Moreover, glycation of IgG proceeds to various conformational states like aggregation and increased hydrophobicity. In addition, the cytotoxicity assay (MTT) illustrated the proliferation of breast cancer cells (MCF-7) with IgG2 treatment.

Discordance of light chain isotypes between serum and glomerular deposits in proliferative glomerulonephritis with monoclonal IgG deposits: a case report and review of the literature

BackgroundProliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a disease entity with nonorganized granular glomerular deposition with monoclonal proteins of both heavy and light chains. Dysproteinemia was observed in only 30% of the patients with PGNMID. We herein report a case of PGNMID with discrepancy between serum and glomerular deposits.Case presentationThe patient was a 50-year-old man who had been followed at a local clinic due to hypertension, type 2 diabetes, hyperlipidemia, hyperuricemia, fatty liver, and obesity. Proteinuria had been noted five years previously, and he had been referred to a hematology department due to hyperproteinemia, high gamma globulin, and κ Bence-Jones protein (BJP) positivity one year previously. Bone marrow aspiration showed 5% plasma cells, and he was referred to the nephrology department to evaluate persistent proteinuria. He was hypertensive, and his estimated glomerular filtration rate was 54.2 ml/min/1.73 m2. His urinary protein level was 0.84 g/g⋅Cr. Urine and serum immunofixation showed BJP-κ type and IgG-κ type, respectively. Kidney biopsy showed an increase in mesangial cells and matrix without nodular lesions under a light microscope. Immunofluorescence microscopy showed granular deposits of IgG and C3 on the capillary wall and weak positivity for C1q. IgG3 was predominant among the IgG subclasses, and intraglomerular κ and λ staining was negative for κ and positive for λ. Direct fast scarlet staining was negative. Electron microscopy showed lumpy deposits without a fibrillar structure in the subepithelial area. Based on the above findings, a diagnosis of membranous nephropathy-type PGNMID was made. Since proteinuria increased gradually after three years of treatment with valsartan (40 mg, daily), oral prednisolone (30 mg, daily) was initiated, which led to decreased proteinuria. The dose of oral prednisolone was gradually tapered to 10 mg per day. At that time, proteinuria was 0.88 g/g⋅Cr. We found 204 cases in 81 articles in the PubMed database, among which 8 showed discrepancy in the heavy and/or light chains between serum and kidney.ConclusionsWe experienced a case of membranous nephropathy-type PGNMID with discrepancy in light chains between serum and kidney that was successfully treated with oral prednisolone.

Prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures during FVIII inhibitor eradication.

Factor VIII (FVIII) inhibitor formation is a major clinical concern during replacement therapy in patients with hemophilia A. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. Hemophilia Inhibitor Previously Untreated Patient (PUP) Study (HIPS) was a prospective clinical trial to investigate changes in the immune system of PUPs with severe hemophilia A. Five patients who developed persistent FVIII inhibitors during HIPS entered an ITI extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure, or a maximum of 2 years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities, and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in 2 patients and failed in 3. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors, which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the immunoglobulin G1 (IgG1) and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, 1 patient with partial ITI success and 1 patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies. This trial was registered at www.clinicaltrials.gov as #NCT01652027.