Autoimmune diseases involve multiple genes. While functions of these genes are largely unknown, some may be related to an intrinsic hyperresponsiveness of B cells. B-cell responses are controlled by signaling thresholds through the B-cell antigen receptor (BCR) complex. The B1 isoform of type II IgG Fc receptors (FcgammaRIIB1) is exclusively expressed on B cells and serves as a negative regulator for inhibiting BCR-elicited activation. Thus, its allelic variants associated with functional deficits could be examined for possible associations with susceptibility to autoimmune diseases. We found that there are three types of polymorphisms in the reported FcgammaRIIB transcription regulatory regions in mouse strains. Compared to normal healthy mouse strains (group III), autoimmune disease-prone strains (group I) share three deletion sites: two in the promoter region and one in the third intron. Strains (group II) that per se are not autoimmune-prone, but have potentials to accelerate autoimmune diseases share two deletion sites in the third intron: one identical to that in group I and the other unique to group II. These polymorphisms correlated well with extents of down-regulation of FcgammaRIIB1 expression in germinal-center B cells upon stimulation with antigens and up-regulation of IgG antibody responses. Our data imply that these FcgammaRIIB polymorphisms are selected evolutionarily for natural defense against pathogens, and that such polymorphisms may, in turn, form the basis of one aspect of autoimmune susceptibility.

Although aflatoxins (AFs) have been shown to be immune-suppressive agents in animals, the potential role of AFs in modifying the distribution and function of leukocyte subsets in humans has never been assessed. We examined the cellular immune status of 64 Ghanaians in relation to levels of aflatoxin B1 (AFB1)-albumin adducts in plasma. The percentages of leukocyte immunophenotypes in peripheral blood, CD4+ T cell proliferative response, CD4+ T(h) and CD8+ T cell cytokine profiles and monocyte phagocytic activity were measured using flow cytometry. NK cell cytotoxic function was determined by perforin and tumor necrosis factor-alpha expression in CD3-CD56+ NK cells. AFB1-albumin adducts levels ranged from 0.3325 to 2.2703 (mean = 0.9972 +/- 0.40, median = 0.9068) pmol mg(-1) albumin. Study participants with high AFB1 levels had significantly lower percentages of CD3+ and CD19+ cells that showed the CD69+ activation marker (CD3+CD69+ and CD19+CD69+) than participants with low AFB1 levels (P = 0.002 for both). Also, the percentages of CD8+ T cells that contained perforin or both perforin and granzyme A were significantly lower in participants with high AFB1 levels compared with those with low AFB1 (P = 0.012 for both). Low levels of CD3+CD69+ (r = -0.32, P = 0.016) and CD19+CD69+ (r = -0.334, P = 0.010) cells were significantly associated with high AFB1 levels using correlation analysis. By multivariate analysis, there were strong negative correlations between the percentages of these cells (CD3+CD69+: b = -0.574, P = 0.001, and CD19+CD69+: b = -0.330, P = 0.032) and AFB1 levels. These alterations in immunological parameters in participants with high AFB1 levels could result in impairments in cellular immunity that could decrease host resistance to infections.

FcγRIIB1 molecules serve as negative feedback regulator for B cell Ag receptor-elicited activation of B cells; thus, any impaired FcγRIIB1 function may possibly be related to aberrant B cell activation. We earlier found deletion polymorphism in the Fcgr2b promoter region among mouse strains in which systemic autoimmune disease-prone NZB, BXSB, MRL, and autoimmune diabetes-prone nonobese diabetic, but not NZW, BALB/c, and C57BL/6 mice have two identical deletion sites, consisting of 13 and 3 nucleotides. In this study, we established congenic C57BL/6 mice for NZB-type Fcgr2b allele and found that NZB-type allele down-regulates FcγRIIB1 expression levels in germinal center B cells and up-regulates IgG Ab responses. We did luciferase reporter assays to determine whether NZB-type deletion polymorphism affects transcriptional regulation of Fcgr2b gene. Although NZW- and BALB/c-derived segments from position −302 to +585 of Fcgr2b upstream region produced significant levels of luciferase activities, only a limited activity was detected in the NZB-derived sequence. EMSA and Southwestern analysis revealed that defect in transcription activity in the NZB-derived segment is likely due to absence of transactivation by AP-4, which binds to the polymorphic 13 nucleotide deletion site. Our data imply that because of the deficient AP-4 binding, the NZB-type Fcgr2b allele polymorphism results in up-regulation of IgG Ab responses through down-regulation of FcγRIIB1 expression levels in germinal center B cells, and that such polymorphism may possibly form the basis of autoimmune susceptibility in combination with other background contributing genes.

Both malaria and intestinal helminths are endemic in sub-Saharan Africa, and their co-infection occurs commonly. This cross-sectional study assessed the prevalence of malaria and intestinal helminth co-infection in a sample of > 700 pregnant women in Ghana and identified risk factors for co-infection. The prevalence of malaria infection, intestinal helminth infection(s), and co-infection was 36.3%, 25.7%, and 16.6%, respectively. Women with intestinal helminth infection(s) were 4.8 times more likely to have malaria infection. Young age, low income, being single, and being primigravid were each associated with increased odds of co-infection. These associations were present when assessed separately for primi- and multigravid women, but the strength of associations varied considerably for the two groups of women. Young age had the strongest association among both primigravid (odds ratio = 5.2) and multigravid (odds ratio = 3.2) women. This study shows relatively high prevalence rates of malaria, intestinal helminths, and co-infection in pregnant women in Ghana.

Systemic lupus erythematosus (SLE) is a multigenic disease associated with IgG hypergammaglobulinemia, IgG anti-nuclear antibodies and immune complex (IC)-type glomerulonephritis. In both human and murine SLE, one susceptibility allele has been mapped to the interval linked to the IgG Fc receptor II (FcgammaRII) gene on chromosome 1. In spontaneous SLE models of NZB and (NZB x NZW) F(1) mice, expression of FcgammaRIIB1, which acts as a negative regulator for B cells, was abnormally down-regulated in follicular germinal center B cells from aged mice, compared to findings in non-SLE NZW, while levels in non-germinal center B cells were practically identical. Such strain differences were also evident in young mice upon in vivo stimulation with foreign antigens. In the FcgammaRIIB promoter region, the NZB allele has two deletion sites, including transcription factor-binding sites. Analyses using (NZB x NZW) F(1) x NZW backcross mice showed that this NZB allele was significantly linked to hyper-IgG, irrespective of the MHC haplotype, while high levels of IgG antibodies specific for DNA were regulated by a combinatorial effect of the F(1)-unique MHC haplotype and the NZB FcgammaRIIB allele. Therefore, the FcgammaRIIB promoter polymorphism may possibly predispose to SLE through germinal center B cells abnormally down-regulating FcgammaRIIB1 expression upon autoantigen stimulations and thus escaping negative signals for IgG production.

Both aflatoxin and the human immunodeficiency virus (HIV) cause immune suppression and millions of HIV-infected people in developing countries are chronically exposed to aflatoxin in their diets. We investigated the possible interaction of aflatoxin and HIV on immune suppression by comparing immune parameters in 116 HIV positive and 80 aged-matched HIV negative Ghanaians with high (≥0.91 pmol/mg albumin) and low (<0.91 pmol/mg albumin) aflatoxin B1 albumin adduct (AF-ALB) levels. AF-ALB levels and HIV viral load were measured in plasma and the percentages of leukocyte immunophenotypes and cytokine expression were determined using flow cytometry. The cross-sectional comparisons found that (1) among both HIV positive and negative participants, high AF-ALB was associated with lower perforin expression on CD8+ T-cells (P = .012); (2) HIV positive participants with high AF-ALB had significantly lower percentages of CD4+ T regulatory cells (Tregs; P = .009) and naive CD4+ T cells (P = .029) compared to HIV positive participants with low AF-ALB; and (3) HIV positive participants with high AF-ALB had a significantly reduced percentage of B-cells (P = .03) compared to those with low AF-ALB. High AF-ALB appeared to accentuate some HIV associated changes in T-cell phenotypes and in B-cells in HIV positive participants.

No abstract

Summaryobjective To investigate the association between birth outcomes and blood levels of aflatoxin B 1 (AFB1)-lysine adduct in pregnant women in Kumasi, Ghana.method A cross-sectional study of 785 pregnant women attending antenatal clinic was conducted. Aflatoxin B 1 (AFB 1 )-lysine adduct levels were determined by high performance liquid chromatography (HPLC) on blood taken after delivery. The birth outcomes considered were small for gestation age, low birthweight, preterm delivery and stillbirth. Participants were divided into quartiles based on the distribution of aflatoxin B 1 -lysine adducts in pg ⁄ mg albumin ('low': £2.67, 'moderate': >2.67 to £4.97, 'high': >4.97 to £11.34, 'very high': >11.34). Statistical analysis involved models that included sociodemographic variables and other potential confounders.results The average AFB 1 -lysine adduct level in maternal serum was 10.9 ± 19.00 pg ⁄ mg albumin (range = 0.44-268.73 pg ⁄ mg). After adjusting for socio-demographic variables and potential confounding factors, participants in the highest AFB 1 -lysine quartile with 'very high' AFB 1 -lysine level (>11.34 pg ⁄ mg) were more likely to have low birthweight babies (OR, 2.09; 95% CI, 1.19-3.68), and showed a trend of increasing risk for low birthweight (P trend = 0.007) compared to participants in the lowest quartile.conclusion This study adds to the growing body of evidence that aflatoxins may increase the risk of adverse birth outcomes. The findings have implications for targeted nutritional education of pregnant women in areas with high levels of aflatoxin contamination of foods.