BACKGROUND: FNAIT occurs in 1 : 1-2000 live births, whereas maternal immunisation against human leukocyte antigen (HLA) class I is common. Whether HLA class I antibodies alone can cause FNAIT is debatable.
MATERIAL AND METHODS: A total of 260 patient samples were referred between 2007 and 2012. Referrals with maternal HLA class I antibodies and no other cause for the neonatal thrombocytopenia were included for analysis (cases, n = 23). HPA-1a negative mothers were excluded. Control groups were screened positive mothers of healthy neonates (controls, n = 33) and female blood donors (blood donors, n = 19). LABScreen single antigen HLA class I beads was used for antibody analysis. Clinical records were reviewed for cases.
RESULTS: All groups had broad antibody reactivity. Cases had more antibodies with high SFI levels compared with the controls (SFI>9999; medians 26, 6 and 0; P class I antibodies compared with control groups of women with healthy children and female blood donors. However, clinical outcome and antibody response correlated poorly in the heterogeneous case group, indicating a multifactorial cause to the thrombocytopenia in the majority of cases.
METHODS: Patients were recruited from 4 hospitals in Malaysia. Clinical data were recorded, and blood samples were taken for pharmacokinetic and genetic studies. Population pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling in Monolix. Age, weight, baseline immunoglobulin G concentration, ethnicity, sex, genotype, disease type, and comorbidity were investigated as potential covariates. Models were evaluated using the difference in objective function value, goodness-of-fit plots, visual predictive checks, and bootstrap analysis.
FINDINGS: A total of 292 blood samples were analyzed from 79 patients. The IVIG concentrations were best described by a 2-compartment model with linear elimination. Weight was found to be an important covariate for volume of distribution in the central compartment (Vc), volume of distribution in the peripheral compartment (Vp), and clearance in the central compartment, whereas disease type was found to be an important covariate for Vp. Goodness-of-fit plots indicated that the model fit the data adequately. Genetic polymorphism of the FCGRT gene encoding the neonatal Fc receptor did not affect the pharmacokinetic properties of IVIG.
IMPLICATIONS: This study supports the use of dosage based on weight as per current practice. The study findings highlight that Vp is significantly influenced by the type of disease being treated with IVIG. This relationship suggests that different disease types, particularly inflammatory and autoimmune conditions, may alter tissue permeability and fluid distribution due to varying degrees of inflammation. Increased inflammation can lead to enhanced permeability and retention of IVIG in peripheral tissues, reflecting higher Vp values.
METHODS: Consecutive biopsy-proven NAFLD patients (n = 191) and healthy controls (n = 188) were enrolled and genotyped for HLA-DQA1 and HLA-DQB1 alleles using the sequence-specific oligonucleotide-polymerase chain reaction method.
RESULTS: No association was found between the HLA alleles and NAFLD or NASH in a case-control setting. Nevertheless, among NAFLD patients, the frequency of HLA-DQB1*06 allele was significantly the lowest in NASH with significant fibrosis (10.4%) and approximately similar for NASH without significant fibrosis (22.9%) and NAFL (22.5%) (P = 0.004). It is noteworthy that the association remains significant after correction for multiple comparisons (Pc = 0.04). Multivariate analysis revealed that HLA-DQB1*06 allele is also associated with fibrosis score (P = 0.001); the result remains significant after correction for multiple comparisons.
CONCLUSION: These findings suggest that HLA-DQB1*06 is associated with lower fibrosis score in NAFLD patients.