B cell selection and susceptibility to autoimmunity

Autoreactive B cells arise routinely as part of the naive B cell repertoire. The immune system employs several mechanisms in an attempt to silence these autoreactive cells before they achieve immunocompetence. The BCR plays a central role in B cell development, activation, survival, and apoptosis, and thus is a critical component of the regulation of both protective and autoreactive B cells. The strength of signal mediated by the BCR is determined by numerous factors, both B cell intrinsic and B cell extrinsic. Perturbations in the molecules that regulate the BCR signal strength or that activate pathways that engage in cross talk with the BCR-mediated signaling pathways can lead to the aberrant survival and activation of autoreactive B cells. In this review, we will discuss the some newly identified genetic loci and factors that modulate the BCR signal transduction pathway and, therefore, the regulation of autoreactive B cells. We will also provide evidence for a model of autoreactivity in which a reduction in the strength of the BCR signal allows the survival and the modulation of a naive B cell repertoire replete with autoreactivity.     

Different response to Plasmodium falciparum in west African sympatric ethnic groups: possible implications for malaria control strategies

The comparison of malaria indicators among populations with different genetic backgrounds and uniformly exposed to the same parasite strains, is one of the approaches to the study of human heterogeneities in the response to the infection. The results of our comparative studies conducted in Burkina Faso, West Africa, showed consistent interethnic differences in Plasmodium falciparum infection rates, malaria morbidity, prevalence and levels of antibodies to various P. falciparum antigens, and genetic background. The differences in the immune response were not explained by the entomological observations which indicated substantially uniform exposure to infective bites. The presence in the same epidemiological context of individuals characterized by different immune reactivity to malaria represents an ideal opportunity to study the possible relationships between the baseline level of anti-malaria immunity of a population and the protective efficacy of control measures based on the reduction of transmission. In spite of similar reduction of entomological inoculation rates obtained by permethrin-impregnated curtains, ethnic- and age-dependent efficacy was observed. These studies demonstrate the existence of marked interethnic differences in the susceptibility to P. falciparum malaria, probably involving the genetic regulation of humoral immune responses. These differences should be considered in the development of anti-malaria vaccines and in the evaluation and application of malaria control strategies.     

Genetic susceptibility to malaria getting complex

The evolution of sickle cell disease illustrates the powerful selective pressure of malaria in Africa, and candidate gene association studies have identified more than ten putative susceptibility determinants involving erythrocytes or the immune system. Efforts at present are aimed at understanding the functional basis of known associations, and at developing both linkage- and association-based approaches of genome-wide screening for novel susceptibility factors.     

Distribution of natural killer cell immunoglobulin-like receptor sequences in three ethnic groups

Killer cell immunoglobulin-like receptors (KIRs) are members of a group of molecules that specifically recognize HLA class I ligands and are found on subsets of human lymphopoetic cells. The number of KIR loci can vary between individuals, resulting in a heterogeneous array of possible KIR genes. The range of observed profiles has been explained by the occurrence of two haplotype families termed A and B which can be distinguished on the basis of certain KIR sequences. Here we attempted to determine whether the frequencies of putative KIR loci and the two haplotype groups vary in three ethnically defined, healthy, and unrelated control populations, namely UK Caucasoid (n=136), Palestinian (n=105) and Thai (n=119). We molecularly typed genomic DNA for the presence of 12 putative KIR loci, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, and KIR3DS1, using modified PCR sequence-specific primers. The patterns of KIR locus frequencies combined with the similar linkage disequilibrium values suggest that there was a distinction in the distribution of the two broad haplotype groups between the populations studied. The A haplotype was always the most prevalent, but the ratio of A to B varied between populations. The frequency of B haplotype was highest in the Palestinians and lowest in the Thais (Pc<0.0001).     

Cortisol and susceptibility to malaria during pregnancy

We measured cortisol and prolactin concentrations in the peripheral venous blood of 23 non-pregnant and 59 pregnant Gabonese women from the second trimester of pregnancy until delivery. Cortisol concentrations were significantly higher in primigravidae women than in multigravidae women between 20 and 25 weeks' gestational age (166 vs. 132 ng/ml, respectively), between 28 and 37 weeks (226 vs. 161 ng/ml) and at delivery (287 vs. 188 ng/ml). Conversely, plasma prolactin levels were highest in multigravidae women. Cortisol and prolactin concentrations both increased with the period of pregnancy (P = 0.01 and P < 0.01, respectively), suggesting that a sustained increase in cortisol level underlies the increased susceptibility of pregnant women, particularly primigravidae women, to malaria. In support of this hypothesis, we found a significant association between cortisol concentration and Plasmodium falciparum infection, on the one hand, and strong correlations with parasite load in P. falciparum-infected primigravidae women, on the other hand (rho between 0.35 and 0.45 with P < 0.01).     

Diversity of killer cell immunoglobulin-like receptor genes in four ethnic groups in China

Killer cell immunoglobulin-like receptors (KIRs) show extensive variation in terms of gene content and allelic polymorphisms among different populations. The aim of this study was to analyze the distribution of KIR genes in the Bulang, Nu, Yugu, and Zhuang ethnic groups, which belong to four different language families in China, and thus to provide basic KIR gene and genotype data for these Chinese ethnic groups. Genotyping of 16 KIR genes was performed in 425 unrelated individuals using the polymerase chain reaction-sequence-specific oligonucleotide probe method with the Luminex MultiAnalyte Profiling System. The four framework KIR genes were detected in all four ethnic groups. The activating KIR genes as well as the inhibitory KIR genes showed extreme diversity among these four populations. A total of 35 distinct KIR genotypes were identified, one of which was previously unknown. The four most common genotypes were identified in all four populations and comprised 66.1~91.1% of all the genotypes. The group A haplotype occurred more frequently than the group B haplotype in the Nu, Yugu, and Zhuang populations, as in other East Asian populations. In contrast, the group A and group B haplotypes occurred equally in the Bulang population. The results of the present study suggested that the KIR genes and genotypes are diverse in these four ethnic groups, and each ethnic group has its own characteristic KIR distribution. The findings with respect to KIR gene diversity in these four populations should provide relevant genomic diversity data for the future study of viral infections, autoimmune diseases, and reproductive fitness.     

Polymorphism of human red cell glyoxalase I in six ethnic groups of China

Summary A total of 1242 individuals from six Chinese ethnic groups were studied with respect to the glyoxalase I polymorphism using agarose gel electrophoresis. The GLO1^*1 gene frequency and the number of subjects tested in each population are as follows: Uygur 0.2466 (219), Hui 0.1621 (219), Dong 0.1866 (201), Bai 0.1921 (203), Tujia 0.1075 (200), and Maio 0.1600 (200). The differences in the GLO1 gene frequencies between some of these populations are significant.     

A mathematical model for malaria involving differential susceptibility,exposedness and infectivity of human host

The main purpose of this article is to formulate a deterministic mathematical model for the transmission of malaria that considers two host types in the human population. The first type is called “non-immune” comprising all humans who have never acquired immunity against malaria and the second type is called “semi-immune”. Non-immune are divided into susceptible, exposed and infectious and semi-immune are divided into susceptible, exposed, infectious and immune. We obtain an explicit formula for the reproductive number, R ₀ which is a function of the weight of the transmission semi-immune-mosquito-semi-immune, R _0a , and the weight of the transmission non-immune-mosquito-non-immune, R _0e . Then, we study the existence of endemic equilibria by using bifurcation analysis. We give a simple criterion when R ₀ crosses one for forward and backward bifurcation. We explore the possibility of a control for malaria through a specific sub-group such as non-immune or semi-immune or mosquitoes.     

A mathematical model for malaria involving differential susceptibility, exposedness and infectivity of human host

The main purpose of this article is to formulate a deterministic mathematical model for the transmission of malaria that considers two host types in the human population. The first type is called "non-immune" comprising all humans who have never acquired immunity against malaria and the second type is called "semi-immune". Non-immune are divided into susceptible, exposed and infectious and semi-immune are divided into susceptible, exposed, infectious and immune. We obtain an explicit formula for the reproductive number, R(0) which is a function of the weight of the transmission semi-immune-mosquito-semi-immune, R(0a), and the weight of the transmission non-immune-mosquito-non-immune, R(0e). Then, we study the existence of endemic equilibria by using bifurcation analysis. We give a simple criterion when R(0) crosses one for forward and backward bifurcation. We explore the possibility of a control for malaria through a specific sub-group such as non-immune or semi-immune or mosquitoes.     

Different antibody- and cytokine-mediated responses to Plasmodium falciparum parasite in two sympatric ethnic tribes living in Mali

The Fulani are known to be less susceptible to Plasmodium falciparum malaria infections and to have lower parasitaemia despite living under similar malaria transmission intensity compared with other ethnic tribes. The aim of the present study was to examine whether the Fulani were more polarised towards Th2 as reflected by higher numbers of malaria-specific IL-4- and IL-10-producing cells and lower numbers of IFN-gamma- and IL-12-producing cells as compared to their neighbour ethnic tribe, the Dogon of Mali. Total IgE and both anti-malaria IgE and IgG antibodies were measured by ELISA and the numbers of IL-4-, IFN-gamma-, IL-10- and IL-12-producing cells were enumerated using enzyme-linked ImmunoSpot assay (ELISPOT). Numbers of parasite clones were detected by polymerase chain reaction (PCR). The study was performed outside the transmission period and all individuals included were asymptomatic. The results revealed that the Fulani were less parasitised, had fewer circulating parasite clones in their blood, had significantly higher anti-malaria IgG and IgE antibodies and higher proportions of malaria-specific IL-4- and IFN-gamma-producing cells compared to the Dogon. The higher antigen-specific production of IL-4 among the Fulani was statistically significant both before and after adjustment for level of spontaneous cytokine production, while greater IFN-gamma production only attained statistical significance after adjustment for spontaneous levels. Taken together, the association of higher anti-malarial IgE and IgG antibodies and increased numbers of specific IL-4- and IFN-gamma-producing cells compared to the ethnic sympatric tribe, the Dogon, may assist in explaining the lower susceptibility to malaria observed in the Fulani.     

Glutamate-pyruvate transaminase subtypes in Singapore ethnic groups

Autopsy liver samples from 244 Chinese, 119 Malays and 136 Indians were screened for glutamate-pyruvate transaminase (GPT) subtypes by starch-gel electrophoresis and isoelectric focusing at pH 5-7. Altogether, ten phenotypes controlled by four alleles (GPT1, GPT2A, GPT2B and GPT3) were identified. There was no significant difference in the frequency of GPT alleles between the ethnic groups. The distribution of GPT types was in agreement with the Hardy-Weinberg equilibrium in all the ethnic groups.     

Apolipoprotein A-IV polymorphism in Singapore ethnic groups

A total of 627 subjects comprising 455 Chinese, 127 Dravidian Indians and 45 Malays were investigated for serum Apo A-IV polymorphism. The frequency of Apo A-IV*2 was found to be significantly higher (p less than 0.001) in Indians (0.043) compared to that in the Chinese (0.010) and Malays (0.011). The frequency of A-IV*3 was found to be around 0.02 in all the ethnic groups. A low frequency of A-IV*4 (less than 0.01) was observed in the Chinese and Indians. The phenotypic distribution of Apo A-IV was at Hardy-Weinberg equilibrium in the three ethnic groups.     

N-acetylglucosaminyltransferase V-deficiency increases susceptibility to murine malaria

It is considered that several glycoproteins on erythrocytes in mammalian species are involved in malaria parasite infection. To elucidate the role of N-glycans on malaria parasite infection, we induced experimental murine malaria infection (using Plasmodium berghei ANKA) in mice deficient in N-acetylglucosaminyltransferase V (Mgat5), which is one of the enzymes involved in β1,6-GlcNAc N-glycan biosynthesis. After infection, Mgat5^-/- mice showed severe body weight loss and parasitemia compared with wild-type mice. The Mgat5^-/- mice, but not wild-type mice, also showed severe pathology accompanied by marked infiltration of plasma cells into the lungs and liver. These results suggest that β1,6-GlcNAc N-glycans on/in host erythrocytes may interfere with invasion of the parasites and progression to severe malaria.