scholarly journals Like wings of a bird: functional divergence and complementarity between HLA-A and HLA-B molecules

2020 ◽  
Author(s):  
Da Di ◽  
Jose Manuel Nunes ◽  
Wei Jiang ◽  
Alicia Sanchez-Mazas
Keyword(s):  
Balancing Selection ◽  
Functional Divergence ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Environmental Pressures ◽  
Protein Levels ◽  
Functional Complementarity ◽  
Vital Functions ◽  
Almost All ◽  
Immune Potential

Abstract Human leukocyte antigen (HLA) genes are among the most polymorphic of our genome, as a likely consequence of balancing selection related to their central role in adaptive immunity. HLA-A and HLA-B genes were recently suggested to evolve through a model of joint divergent asymmetric selection conferring all populations, including those with severe loss of diversity, an equivalent immune potential. However, the mechanisms by which these two genes might undergo joint evolution while displaying very distinct allelic profiles in populations worldwide are still unknown. To address this issue, we carried out extensive data analyses (among which factorial correspondence and linear modelling) on 2,909 common and rare HLA-A, HLA-B and HLA-C alleles and 200,000 simulated pathogenic peptides by taking into account sequence variation, predicted peptide-binding affinity and HLA allele frequencies in 123 populations worldwide. Our results show that HLA-A and HLA-B (but not HLA-C) molecules maintain considerable functional divergence in almost all populations, which likely plays an instrumental role in their immune defence. We also provide robust evidence of functional complementarity between HLA-A and HLA-B molecules, which display asymmetric relationships in terms of amino acid diversity at both inter- and intra-protein levels and in terms of promiscuous or fastidious peptide-binding specificities. Like two wings of a flying bird, the functional complementarity of HLA-A and HLA-B is a perfect example, in our genome, of duplicated genes sharing their capacity of assuming common vital functions while being submitted to complex and sometimes distinct environmental pressures.

scholarly journals The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function

2020 ◽  
Vol 117 (21) ◽  
pp. 11636-11647 ◽  
Author(s):  
Philippa M. Saunders ◽  
Bruce J. MacLachlan ◽  
Phillip Pymm ◽  
Patricia T. Illing ◽  
Yuanchen Deng ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Cell Recognition ◽  
Leukocyte Antigen ◽  
Binding Cleft

Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.

scholarly journals HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation

2019 ◽  
Vol 37 (3) ◽  
pp. 639-650 ◽  
Author(s):  
Jatin Arora ◽  
Federica Pierini ◽  
Paul J McLaren ◽  
Mary Carrington ◽  
Jacques Fellay ◽  
...  
Keyword(s):  
Balancing Selection ◽  
Human Leukocyte ◽  
Hla Class I ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Heterozygote Advantage ◽  
Hla Alleles ◽  
Relative Contribution ◽  
Peptide Presentation ◽  
Hiv 1

Abstract Pathogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity. A hallmark for balancing selection in humans is the heterozygote advantage at genes of the human leukocyte antigen (HLA), resulting in improved HIV-1 control. However, the actual mechanism of the observed heterozygote advantage is still elusive. HLA heterozygotes may present a broader array of antigenic viral peptides to immune cells, possibly resulting in a more efficient cytotoxic T-cell response. Alternatively, heterozygosity may simply increase the chance to carry the most protective HLA alleles, as individual HLA alleles are known to differ substantially in their association with HIV-1 control. Here, we used data from 6,311 HIV-1-infected individuals to explore the relative contribution of quantitative and qualitative aspects of peptide presentation in HLA heterozygote advantage against HIV. Screening the entire HIV-1 proteome, we observed that heterozygous individuals exhibited a broader array of HIV-1 peptides presented by their HLA class I alleles. In addition, viral load was negatively correlated with the breadth of the HIV-1 peptide repertoire bound by an individual’s HLA variants, particularly at HLA-B. This suggests that heterozygote advantage at HLA-B is at least in part mediated by quantitative peptide presentation. We also observed higher HIV-1 sequence diversity among HLA-B heterozygous individuals, suggesting stronger evolutionary pressure from HLA heterozygosity. However, HLA heterozygotes were also more likely to carry certain HLA alleles, including the highly protective HLA-B*57:01 variant, indicating that HLA heterozygote advantage ultimately results from a combination of quantitative and qualitative effects in antigen presentation.

Expression of XBP1s in B lymphocytes is critical for pristane-induced lupus nephritis in mice

2020 ◽  
Vol 318 (5) ◽  
pp. F1258-F1270 ◽  
Author(s):  
Li Xiang ◽  
An Liu ◽  
Guoshuang Xu
Keyword(s):  
B Cells ◽  
Lupus Nephritis ◽  
Mouse Model ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
B Lymphocyte ◽  
B Cell Activation ◽  
Protein Levels ◽  
Almost All

B lymphocyte hyperactivity plays a pathogenic role in systemic lupus erythematosus (SLE), and spliced X box-binding protein 1 (XBP1s) has been implicated in B cell maturation and differentiation. We hypothesized that blockade of the XBP1s pathway inhibits the B cell hyperactivity underlying SLE and lupus nephritis (LN) development. In the present study, we systematically evaluated the changes in B cell activation induced by the Xbp1 splicing inhibitor STF083010 in a pristane-induced lupus mouse model. The lupus mouse model was successfully established, as indicated by the presence of LN with markedly increased urine protein levels, renal deposition of Ig, and mesangial cell proliferation. In lupus mice, B cell hyperactivity was confirmed by increased CD40 and B cell-activating factor levels. B cell activation and plasma cell overproduction were determined by increases in CD40-positive and CD138-positive cells in the spleens of lupus mice by flow cytometry and further confirmed by CD45R and Ig light chain staining in the splenic tissues of lupus mice. mRNA and protein expression of XBP1s in B cells was assessed by real-time PCR, Western blot analysis, and immunofluorescence analysis and was increased in lupus mice. In addition, almost all changes were reversed by STF083010 treatment. However, the expression of XBP1s in the kidneys did not change when mice were exposed to pristane and STF083010. Taken together, these findings suggest that expression of XBP1s in B cells plays key roles in SLE and LN development. Blockade of the XBP1s pathway may be a potential strategy for SLE and LN treatment.

scholarly journals Human Leukocyte Antigens A*3001 and A*3002 Show Distinct Peptide-Binding Patterns of theMycobacterium tuberculosisProtein TB10.4: Consequences for Immune Recognition

2010 ◽  
Vol 18 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Rebecca Axelsson-Robertson ◽  
Raija K. Ahmed ◽  
Frank F. Weichold ◽  
Marthie M. Ehlers ◽  
Marleen M. Kock ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Recombinant Expression ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Sub Saharan Africa ◽  
Immune Recognition ◽  
Interleukin 7 ◽  
Binding Peptides ◽  
Sub Saharan

ABSTRACTHigh-tuberculosis (TB)-burden countries are located in sub-Saharan Africa. We examined the frequency of human leukocyte antigen (HLA) alleles, followed by recombinant expression of the most frequent HLA-A alleles, i.e., HLA-A*3001 and HLA-A*3002, to study differences in mycobacterial peptide presentation and CD8+T-cell recognition. We screened a peptide library (9-mer peptides with an 8-amino-acid overlap) for binding, affinity, and off-rate of theMycobacterium tuberculosis-associated antigen TB10.4 and identified only three TB10.4 peptides with considerable binding to HLA-A*3001. In contrast, 22 peptides bound to HLA-A*3002. This reflects a marked difference in the binding preference between the two alleles, with A*3002 tolerating a more promiscuous peptide-binding pattern and A*3001 accommodating only a very selective peptide repertoire. Subsequent analysis of the affinity and off-rate of the binding peptides revealed a strong affinity (8 nM to 7 μM) and moderate off-rate (20 min to 3 h) for both alleles. Construction of HLA-A*3001 and HLA-A*3002 tetramers containing selected binding peptides from TB10.4, including a peptide which was shared among both alleles, QIMYNYPAM (TB10.43-11), allowed us to enumerate epitope-specific T cells in HLA-A*3001- and HLA-A*3002-typed patients with active TB. HLA-A*3001 and HLA-A*3002 major histocompatibility complex-peptide complexes were recognized in individuals with active TB, irrespective of their homozygous HLA-A*3001 or HLA-A*3002 genetic background. The antigen-specific T cells exhibited the CD45RA+CCR7+precursor phenotype and the interleukin-7 receptor (CD127), which were different from the phenotype and receptor exhibited by the parental CD8+T-cell population.

scholarly journals Balancing selection and heterogeneity across the classical human leukocyte antigen loci: A meta-analytic review of 497 population studies

2008 ◽  
Vol 69 (7) ◽  
pp. 443-464 ◽  
Author(s):  
Owen D. Solberg ◽  
Steven J. Mack ◽  
Alex K. Lancaster ◽  
Richard M. Single ◽  
Yingssu Tsai ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Population Studies ◽  
Balancing Selection ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Analytic Review ◽  
Classical Human Leukocyte Antigen

scholarly journals HLA-Modeler: Automated Homology Modeling of Human Leukocyte Antigens

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Shinji Amari ◽  
Ryoichi Kataoka ◽  
Takashi Ikegami ◽  
Noriaki Hirayama
Keyword(s):  
Homology Modeling ◽  
Crystal Structures ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Antigenic Peptide ◽  
Structural Motif ◽  
3D Structures ◽  
Solvent Model ◽  
Hla Molecules ◽  
Homology Models

The three-dimensional (3D) structures of human leukocyte antigen (HLA) molecules are indispensable for the studies on the functions at molecular level. We have developed a homology modeling system named HLA-modeler specialized in the HLA molecules. Segment matching algorithm is employed for modeling and the optimization of the model is carried out by use of the PFROSST force field considering the implicit solvent model. In order to efficiently construct the homology models, HLA-modeler uses a local database of the 3D structures of HLA molecules. The structure of the antigenic peptide-binding site is important for the function and the 3D structure is highly conserved between various alleles. HLA-modeler optimizes the use of this structural motif. The leave-one-out cross-validation using the crystal structures of class I and class II HLA molecules has demonstrated that the rmsds of nonhydrogen atoms of the sites between homology models and crystal structures are less than 1.0 Å in most cases. The results have indicated that the 3D structures of the antigenic peptide-binding sites can be reproduced by HLA-modeler at the level almost corresponding to the crystal structures.

Variation in the composition of selected milk fraction samples from healthy and mastitic quarters, and its significance for mastitis diagnosis

2005 ◽  
Vol 72 (2) ◽  
pp. 144-152 ◽  
Author(s):  
Baljinder K Bansal ◽  
Joern Hamann ◽  
Nils Th Grabowski ◽  
Krishan B Singh
Keyword(s):  
Correct Identification ◽  
Udder Health ◽  
Protein Levels ◽  
Milk Samples ◽  
Lactating Cows ◽  
Animal Physiology ◽  
The Status ◽  
The Difference ◽  
D Values ◽  
Almost All

Seven variables – electrical conductivity (EC), somatic cell count (SCC), N-acetyl-β-D-glucosaminidase (NAGase), lactose, protein, fat and pH – were compared in four quarter milk fractions (MF1: strict foremilk; MF2: first 12–15 ml foremilk; MF3: subsequent 40–45 ml milk; MF4: strippings) and in one cow composite milk sample (CC) per cow. The study used 142 quarters from 37 lactating cows of the German Black Pied breed. To rule out any possible effect due to management, animal physiology and analytical procedures, the collection and processing of milk samples from each cow was repeated for three consecutive days, and the means of 3-d values were used. All variables were affected significantly by milk fraction and udder health. Compared with foremilk, EC, lactose and protein levels in strippings decreased, while SCC, NAGase and fat increased. The pH of foremilk and strippings did not differ significantly in healthy or in mastitic quarters. The difference between MF1 and MF2 was significant for EC in mastitic quarters, and for SCC in healthy quarters only. In general, mastitis resulted in a significant increase in EC, SCC, NAGase and protein but in a decrease in lactose and fat contents of milk in one or more of the milk fractions studied. Comparison of cow composite milk samples from healthy and mastitic cows revealed the significance (P<0·01) of udder health for EC, SCC and lactose. Of the different parameters that can distinguish between healthy and mastitic quarters or cows, EC could be used to classify 76% of quarters and 73% of cows correctly, while the lactose content permitted correct identification of 81% of quarters and 76% of cows. NAGase and pH could be used to determine the status of 73% and 61% of quarters, respectively. In general, the correlation observed in strippings was higher than in foremilk for almost all the variables studied. Surprisingly, EC, SCC, NAGase and lactose in milk from healthy quarters of mastitic cows (with at least one mastitic quarter) differed significantly (P<0·05) from those from healthy quarters of cows with all four healthy quarters, indicating an inconsistent effect of mastitic quarters on neighbouring healthy quarters (quarter interdependence).

Evidence for an effect of human leukocyte antigens on susceptibility to Kaposiʼs sarcoma related to charge and peptide-binding properties of class I molecules

AIDS ◽  
1995 ◽  
Vol 9 (10) ◽  
pp. 1194 ◽  
Author(s):  
M. Marmor ◽  
R. Winchester ◽  
A. Zeleniuch-Jacquotte ◽  
S. H. Weiss ◽  
K. Krasmski ◽  
...  
Keyword(s):  
Peptide Binding ◽  
Human Leukocyte ◽  
Class I ◽  
Human Leukocyte Antigens ◽  
Binding Properties ◽  
Leukocyte Antigens
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