The frequencies of the Human leukocyte antigen (HLA) alleles in the Puyanawa indigenous reserve population and their association with the NDO-LID and ELISA PGL-1 rapid serological test was assessed. ...This was a cross-sectional study with an epidemiological clinical design conducted in two indigenous communities in the state of Acre, Brazil. Blood was collected in a tube with EDTA to identify HLA alleles and perform serological tests. DNA was obtained using the salting out procedure. The LabType™ technique (One-Lambda-USA) was used for HLA class I (loci A*, B* and C*) and II (loci DRB1*, DQA1* and DQB1*) typing. Allele frequency was obtained by direct count, and the chi-square test was used to assess the association with the NDO-LID and PGL-1 tests. The most frequent alleles in the two communities were: HLA-A*02:01, HLA-B*40:02, HLA-DRB1*16:02, HLA-DQA1*05:05 and HLA-DQB1*03:01. The allele HLA-C*04:01 was the most common in the Barão community, and the allele HLA-C*07:01 in Ipiranga. Among individuals who presented seropositivity to the NDO-LID test, the association with alleles HLA-A*02 (43.18% vs 24.8%, p=0.03, OR=2.35) and HLA-B*53 (6.83% vs 0.0%, p=0.03, OR=8.95) was observed in the Barão community. HLA-B*15 was associated with non-seroconversion to the NDO-LID test in Ipiranga. In both communities, HLA-B*40 and HLA-C*03 were associated with positive serological response to ELISA PGL-1. The HLA class I and II alleles most frequently found in this study have already been described among Terena indigenous groups, and HLA class I contributes to seroconversion to NDO-LID and PGL-1 tests in inhabitants of the Barão and Ipiranga communities.
The immunogenome is the part of the genome that underlies immune mechanisms and evolves under various selective pressures. Two complex regions of the immunogenome, major histocompatibility complex ...(MHC) and natural killer cell receptor (NKR) genes, play an important role in the response to selective pressures of pathogens. Their importance is expressed by their genetic polymorphism at the molecular level, and their diversity associated with different types of diseases at the population level. Findings of associations between specific combinations of MHC/NKR haplotypes with different diseases in model species suggest that these gene complexes did not evolve independently. No such associations have been described in horses so far. The aim of the study was to detect associations between MHC and NKR gene/microsatellite haplotypes in three horse breed groups (Camargue, African, and Romanian) by statistical methods; chi‐square test, Fisher's exact test, Pearson's goodness‐of‐fit test and logistic regression. Associations were detected for both MHC/NKR genes and microsatellites; the most significant associations were found between the most variable KLRA3 gene and the EQCA‐1 or EQCA‐2 genes. This finding supports the assumption that the KLRA3 is an important receptor for MHC I and that interactions of these molecules play important roles in the horse immunity and reproduction. Despite some limitations of the study such as low numbers of horses or lack of knowledge of the selected genes functions, the results were consistent across different statistical methods and remained significant even after overconservative Bonferroni corrections. We therefore consider them biologically plausible.
The Major Histocompatibility Complex (MHC) genes encode proteins that initiate the adaptive immune response by presenting pathogen‐derived antigenic peptides to T lymphocytes. Host–pathogen ...coevolution drives MHC polymorphism, introducing intraspecific variation in host life expectancy. This variation interacts with optimal growth strategy, as growth increases reproductive potential. While mortality rate and body size‐dependent fecundity are major factors shaping life histories, the effect of intraspecific variation in MHC‐based immunity on the evolution of growth strategies and host body size remains unknown.
Here, we model how host MHC–pathogen coevolution—and its concomitant impact on host mortality—can affect the evolution of host life histories, as represented by age at maturation and body size. Life histories were compared in scenarios with and without adaptive immune response under equal population‐level mortality rates.
We show that host–pathogen coevolutionary dynamics selects for postponed maturation and increased body size. Although MHC genes and genes that determine body size were physically unlinked, selection imposed by the Red Queen process generated linkage disequilibrium between immunocompetent MHC alleles and the maturation‐postponing alleles that prolong growth phase and increase body size. Particularly large body size was attained when pathogens mutated slowly, thus allowing the advantage of resistant MHC alleles to persist over multiple generations.
The emergence of adaptive immunity, which is pathogen‐specific and enables immunological memory, is considered a major evolutionary innovation of vertebrates. Our work suggests that the adaptive immune response, mediated by polymorphic MHC genes, may drive the evolution of host body size. This form of adaptive immunity may have thus predisposed vertebrates to evolve large body size and exhibit the macroevolutionary patterns of increasing body size over time that have been detected in comparative studies.
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Read the free Plain Language Summary for this article on the Journal blog.
Until around 1990, most multigene families were thought to be subject to concerted evolution, in which all member genes of a family evolve as a unit in concert. However, phylogenetic analysis of MHC ...and other immune system genes showed a quite different evolutionary pattern, and a new model called birth-and-death evolution was proposed. In this model, new genes are created by gene duplication and some duplicate genes stay in the genome for a long time, whereas others are inactivated or deleted from the genome. Later investigations have shown that most non-rRNA genes including highly conserved histone or ubiquitin genes are subject to this type of evolution. However, the controversy over the two models is still continuing because the distinction between the two models becomes difficult when sequence differences are small. Unlike concerted evolution, the model of birth-and-death evolution can give some insights into the origins of new genetic systems or new phenotypic characters.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To survive organisms must defend themselves against pathogens. Classical Major Histocompatibility Complex (MHC) genes play a key role in pathogen defense by encoding molecules involved in pathogen ...recognition. MHC gene diversity influences the variety of pathogens individuals can recognize and respond to and has consequently been a popular genetic marker for disease resistance in ecology and evolution. However, MHC diversity is predominantly estimated using genomic DNA (gDNA) with little knowledge of expressed diversity. This limits our ability to interpret the adaptive significance of variation in MHC diversity, especially in species with very many MHC genes such as songbirds. Here, we address this issue using phylogenetic comparative analyses of the number of MHC class I alleles (MHC-I diversity) in gDNA and complementary DNA (cDNA), that is, expressed alleles, across 13 songbird species. We propose three theoretical relationships that could be expected between genomic and expressed MHC-I diversity on a macroevolutionary scale and test which of these are best supported. In doing so, we show that significantly fewer MHC-I alleles than the number available are expressed, suggesting that optimal MHC-I diversity could be achieved by modulating gene expression. Understanding the relationship between genomic and expressed MHC diversity is essential for interpreting variation in MHC diversity in an evolutionary context.
In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of ...the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein-protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins.
Abstract
A key component of pathogen-specific adaptive immunity in vertebrates is the presentation of pathogen-derived antigenic peptides by major histocompatibility complex (MHC) molecules. The ...excessive polymorphism observed at MHC genes is widely presumed to result from the need to recognize diverse pathogens, a process called pathogen-driven balancing selection. This process assumes that pathogens differ in their peptidomes—the pool of short peptides derived from the pathogen’s proteome—so that different pathogens select for different MHC variants with distinct peptide-binding properties. Here, we tested this assumption in a comprehensive data set of 51.9 Mio peptides, derived from the peptidomes of 36 representative human pathogens. Strikingly, we found that 39.7% of the 630 pairwise comparisons among pathogens yielded not a single shared peptide and only 1.8% of pathogen pairs shared more than 1% of their peptides. Indeed, 98.8% of all peptides were unique to a single pathogen species. Using computational binding prediction to characterize the binding specificities of 321 common human MHC class-I variants, we investigated quantitative differences among MHC variants with regard to binding peptides from distinct pathogens. Our analysis showed signatures of specialization toward specific pathogens especially by MHC variants with narrow peptide-binding repertoires. This supports the hypothesis that such fastidious MHC variants might be maintained in the population because they provide an advantage against particular pathogens. Overall, our results establish a key selection factor for the excessive allelic diversity at MHC genes observed in natural populations and illuminate the evolution of variable peptide-binding repertoires among MHC variants.
Immunoglobulin A Deficiency (IgAD) is a polygenic primary immune deficiency, with a strong genetic association to the human leukocyte antigen (HLA) region. Previous genome-wide association studies ...(GWAS) have identified five non-HLA risk loci (
,
,
and
). In this study, we investigated the genetic interactions between different HLA susceptibility haplotypes and non-MHC genes in IgAD. To do this, we stratified IgAD subjects and healthy controls based on HLA haplotypes (
= 10,993), and then performed GWAS to identify novel genetic regions contributing to IgAD susceptibility. After replicating previously published HLA risk haplotypes, we compared individuals carrying at least one HLA risk allele (
or
or
) with individuals lacking an HLA risk allele. Subsequently, we stratified subjects based on the susceptibility alleles/haplotypes and performed gene-based association analysis using 572,856 SNPs and 24,125 genes. A significant genome-wide association in
(rs4097492;
= 7.63 × 10
) was observed in the cohort carrying at least one MHC risk allele. We also identified a significant gene-based association for
(
= 2.1 × 10
) in patients not carrying known HLA susceptibility alleles. Our findings indicate that the etiology of IgAD differs depending on the genetic background of HLA susceptibility haplotypes.
Birds are a wonderfully diverse and accessible clade with an exceptional range of ecologies and behaviors, making the study of the avian major histocompatibility complex (MHC) of great interest. In ...the last 20 years, particularly with the advent of high-throughput sequencing, the avian MHC has been explored in great depth in several dimensions: its ability to explain ecological patterns in nature, such as mating preferences; its correlation with parasite resistance; and its structural evolution across the avian tree of life. Here, we review the latest pulse of avian MHC studies spurred by high-throughput sequencing. Despite high-throughput approaches to MHC studies, substantial areas remain in need of improvement with regard to our understanding of MHC structure, diversity, and evolution. Recent studies of the avian MHC have nonetheless revealed intriguing connections between MHC structure and life history traits, and highlight the advantages of long-term ecological studies for understanding the patterns of MHC variation in the wild. Given the exceptional diversity of birds, their accessibility, and the ease of sequencing their genomes, studies of avian MHC promise to improve our understanding of the many dimensions and consequences of MHC variation in nature. However, significant improvements in assembling complete MHC regions with long-read sequencing will be required for truly transformative studies.
CD44 gene is a cell surface receptor which undergoes complex alternative splicing and extensive post-translational modifications. Although many studies have showed that CD44 is involved in the ...process of host defense, the function of piscine CD44 in antibacterial or antiviral defense response remains unclear. In the present study, we report the functional characterization of zebrafish CD44c, which is more similar to CD44b antigen isoforms rather than CD44a based on amino acid composition and phylogenetic analysis. The expression of zebrafish CD44c was inducible in response to bacterial and viral infections. During SVCV infection, the in vivo studies revealed that CD44c overexpression led to the increased virus loads and decreased survival rate. The attenuated response by zebrafish CD44c in response to SVCV infection were characterized by the impaired production of inflammatory cytokines and the impaired expressions of IFNs, IFN-stimulated genes, MHC class I and II genes. During Edwardsiella piscicida infection, the overexpression of zebrafish CD44c facilitated bacterial growth and dissemination, but did not impact on larvae survival. The detrimental role of CD44c in host defense against E. piscicida infection was supported by a decreased production of several antibacterial molecules including defbl2, defbl3, NK-lysin and RNase3. All together, these results firstly demonstrate the negative regulation of piscine CD44c in viral and bacterial infection.
•Zebrafish CD44c is more similar to CD44b antigen isoforms rather than CD44a.•CD44c overexpression led to the increased virus loads and decreased survival rate in response to SVCV infection.•CD44c overexpression facilitated bacterial growth and dissemination, but did not impact on larvae survival.•CD44c overexpression impaired the production of inflammatory cytokines, IFNs, IFN-stimulated genes and MHC genes.•CD44c overexpression inhibited the expression of several antibacterial molecules.
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