scholarly journals Genetic diversity, evolution and selection in the major histocompatibility complex DRB and DQB loci in the family Equidae

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Marie Klumplerova ◽  
Petra Splichalova ◽  
Jan Oppelt ◽  
Jan Futas ◽  
Aneta Kohutova ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Major Histocompatibility Complex ◽  
Positive Selection ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Depth Analysis ◽  
The Family ◽  
Antigen Presenting

Abstract Background The mammalian Major Histocompatibility Complex (MHC) is a genetic region containing highly polymorphic genes with immunological functions. MHC class I and class II genes encode antigen-presenting molecules expressed on the cell surface. The MHC class II sub-region contains genes expressed in antigen presenting cells. The antigen binding site is encoded by the second exon of genes encoding antigen presenting molecules. The exon 2 sequences of these MHC genes have evolved under the selective pressure of pathogens. Interspecific differences can be observed in the class II sub-region. The family Equidae includes a variety of domesticated, and free-ranging species inhabiting a range of habitats exposed to different pathogens and represents a model for studying this important part of the immunogenome. While equine MHC class II DRA and DQA loci have received attention, the genetic diversity and effects of selection on DRB and DQB loci have been largely overlooked. This study aimed to provide the first in-depth analysis of the MHC class II DRB and DQB loci in the Equidae family. Results Three DRB and two DQB genes were identified in the genomes of all equids. The genes DRB2, DRB3 and DQB3 showed high sequence conservation, while polymorphisms were more frequent at DRB1 and DQB1 across all species analyzed. DQB2 was not found in the genome of the Asiatic asses Equus hemionus kulan and E. h. onager. The bioinformatic analysis of non-zero-coverage-bases of DRB and DQB genes in 14 equine individual genomes revealed differences among individual genes. Evidence for recombination was found for DRB1, DRB2, DQB1 and DQB2 genes. Trans-species allele sharing was identified in all genes except DRB1. Site-specific selection analysis predicted genes evolving under positive selection both at DRB and DQB loci. No selected amino acid sites were identified in DQB3. Conclusions The organization of the MHC class II sub-region of equids is similar across all species of the family. Genomic sequences, along with phylogenetic trees suggesting effects of selection as well as trans-species polymorphism support the contention that pathogen-driven positive selection has shaped the MHC class II DRB/DQB sub-regions in the Equidae.

scholarly journals Degradation of Mouse Invariant Chain: Roles of Cathepsins S and D and the Influence of Major Histocompatibility Complex Polymorphism

1997 ◽  
Vol 186 (4) ◽  
pp. 549-560 ◽  
Author(s):  
José A. Villadangos ◽  
Richard J. Riese ◽  
Christoph Peters ◽  
Harold A. Chapman ◽  
Hidde L. Ploegh
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Cysteine Proteases ◽  
Class Ii ◽  
Invariant Chain ◽  
Antigenic Peptides ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Antigen Presenting ◽  
Endocytic Compartments

Antigen-presenting cells (APC) degrade endocytosed antigens into peptides that are bound and presented to T cells by major histocompatibility complex (MHC) class II molecules. Class II molecules are delivered to endocytic compartments by the class II accessory molecule invariant chain (Ii), which itself must be eliminated to allow peptide binding. The cellular location of Ii degradation, as well as the enzymology of this event, are important in determining the sets of antigenic peptides that will bind to class II molecules. Here, we show that the cysteine protease cathepsin S acts in a concerted fashion with other cysteine and noncysteine proteases to degrade mouse Ii in a stepwise fashion. Inactivation of cysteine proteases results in incomplete degradation of Ii, but the extent to which peptide loading is blocked by such treatment varies widely among MHC class II allelic products. These observations suggest that, first, class II molecules associated with larger Ii remnants can be converted efficiently to class II–peptide complexes and, second, that most class II–associated peptides can still be generated in cells treated with inhibitors of cysteine proteases. Surprisingly, maturation of MHC class II in mice deficient in cathepsin D is unaffected, showing that this major aspartyl protease is not involved in degradation of Ii or in generation of the bulk of antigenic peptides.

Genetic diversity at the Major Histocompatibility Complex class II DZB gene, and geographical distribution of alleles, in platypuses in a Tasmanian river catchment.

2019 ◽  
Vol 40 (2) ◽  
pp. 241-250
Author(s):  
J.W. Macgregor ◽  
C. Holyoake ◽  
S. Munks ◽  
J.H. Connolly ◽  
I.D. Robertson ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Island Populations ◽  
Low Genetic Diversity ◽  
Histocompatibility Complex ◽  
Wildlife Populations ◽  
River Catchments

Genetic diversity at loci concerned with fitness is an important part of the ability of a wild population to adapt to changes in its environment, including climatic events, disease and pollution. Research into the effects of genetic diversity on the impacts of disease on wildlife populations has focussed on genes of the major histocompatibility complex (MHC). This study investigated the genetic diversity at the MHC class II DZB gene, as well as the distribution of alleles of the same gene, for platypuses Ornithorhynchus anatinus in the Seabrook Creek Catchment in northwest Tasmania. This study detected 10 previously identified alleles and two previously unreported alleles at the MHC Class II DZB locus in 18 platypuses from the Seabrook Creek Catchment. An additional sequence isolated from two individuals was consistent with a pseudogene. Alleles were reasonably well distributed geographically through the catchment, but there was evidence of a degree of isolation at one site. Consistent with evidence that smaller wildlife populations have relatively low genetic diversity, and that there is relatively slow gene flow between river catchments, the observed genetic diversity at the MHC Class II locus was lower than those in larger previously studied river catchments but higher than those in two island populations. Consequently, this population of platypuses may have a limited capacity to respond to new infectious challenges, such as the fungal disease mucormycosis.

scholarly journals A novel antigen-processing-defective phenotype in major histocompatibility complex class II-positive CIITA transfectants is corrected by interferon-gamma.

1995 ◽  
Vol 182 (6) ◽  
pp. 1793-1799 ◽  
Author(s):  
C A Siegrist ◽  
E Martinez-Soria ◽  
I Kern ◽  
B Mach
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Interferon Gamma ◽  
Antigen Processing ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Invariant Chain ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Antigen Presenting

Presentation of exogenous protein antigens to T lymphocytes is based on the intersection of two complex pathways: (a) synthesis, assembly, and transport of major histocompatibility complex (MHC) class II-invariant chain complexes from the endoplasmic reticulum to a specialized endosomal compartment, and (b) endocytosis, denaturation, and proteolysis of antigens followed by loading of antigenic peptides onto newly synthesized MHC class II molecules. It is believed that expression of MHC class II heterodimers, invariant chain and human leukocyte antigen-DM is both necessary and sufficient to reconstitute a functional MHC class II loading compartment in antigen-presenting cells. Expression of each of these essential molecules is under the control of the MHC class II transactivator CIITA. Unexpectedly, however, whereas interferon gamma stimulation does confer effective antigen-processing function to nonprofessional antigen presenting cells, such as melanoma cells, expression of the CIITA transactivator alone is not sufficient. Activation of antigen-specific T cells thus requires additional CIITA-independent factor(s), and such factor(s) can be induced by interferon gamma.

scholarly journals Targeted Expression of Major Histocompatibility Complex (MHC) Class II Molecules Demonstrates that Dendritic Cells Can Induce Negative but Not Positive Selection of Thymocytes In Vivo

1997 ◽  
Vol 185 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Thomas Brocker ◽  
Mireille Riedinger ◽  
Klaus Karjalainen
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
Positive Selection ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Selection Of

It is well established that lymphoid dendritic cells (DC) play an important role in the immune system. Beside their role as potent inducers of primary T cell responses, DC seem to play a crucial part as major histocompatibility complex (MHC) class II+ “interdigitating cells” in the thymus during thymocyte development. Thymic DC have been implicated in tolerance induction and also by some authors in inducing major histocompatibility complex restriction of thymocytes. Most of our knowledge about thymic DC was obtained using highly invasive and manipulatory experimental protocols such as thymus reaggregation cultures, suspension cultures, thymus grafting, and bone marrow reconstitution experiments. The DC used in those studies had to go through extensive isolation procedures or were cultured with recombinant growth factors. Since the functions of DC after these in vitro manipulations have been reported to be not identical to those of DC in vivo, we intended to establish a system that would allow us to investigate DC function avoiding artificial interferences due to handling. Here we present a transgenic mouse model in which we targeted gene expression specifically to DC. Using the CD11c promoter we expressed MHC class II I-E molecules specifically on DC of all tissues, but not on other cell types. We report that I-E expression on thymic DC is sufficient to negatively select I-E reactive CD4+ T cells, and to a less complete extent, CD8+ T cells. In contrast, if only DC expressed I-E in a class II–deficient background, positive selection of CD4+ T cells could not be observed. Thus negative, but not positive, selection events can be induced by DC in vivo.

scholarly journals Relationship between invariant chain expression and major histocompatibility complex class II transport into early and late endocytic compartments.

1993 ◽  
Vol 177 (3) ◽  
pp. 583-596 ◽  
Author(s):  
P Romagnoli ◽  
C Layet ◽  
J Yewdell ◽  
O Bakke ◽  
R N Germain
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Endocytic Pathway ◽  
Invariant Chain ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Late Endosomes ◽  
Early Endosomes ◽  
Endocytic Compartments

Invariant chain (Ii), which associates with major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum, contains a targeting signal for transport to intracellular vesicles in the endocytic pathway. The characteristics of the target vesicles and the relationship between Ii structure and class II localization in distinct endosomal subcompartments have not been well defined. We demonstrate here that in transiently transfected COS cells expressing high levels of the p31 or p41 forms of Ii, uncleaved Ii is transported to and accumulates in transferrin-accessible (early) endosomes. Coexpressed MHC class II is also found in this same compartment. These early endosomes show altered morphology and a slower rate of content movement to later parts of the endocytic pathway. At more moderate levels of Ii expression, or after removal of a highly conserved region in the cytoplasmic tail of Ii, coexpressed class II molecules are found primarily in vesicles with the characteristics of late endosomes/prelysosomes. The Ii chains in these late endocytic vesicles have undergone proteolytic cleavage in the lumenal region postulated to control MHC class II peptide binding. These data indicate that the association of class II with Ii results in initial movement to early endosomes. At high levels of Ii expression, egress to later endocytic compartments is delayed and class II-Ii complexes accumulate together with endocytosed material. At lower levels of Ii expression, class II-Ii complexes are found primarily in late endosomes/prelysosomes. These data provide evidence that the route of class II transport to the site of antigen processing and loading involves movement through early endosomes to late endosomes/prelysosomes. Our results also reveal an unexpected ability of intact Ii to modify the structure and function of the early endosomal compartment, which may play a role in regulating this processing pathway.

scholarly journals CD1 and Major Histocompatibility Complex II Molecules Follow a Different Course during Dendritic Cell Maturation

2003 ◽  
Vol 14 (8) ◽  
pp. 3378-3388 ◽  
Author(s):  
Nicole N. van der Wel ◽  
Masahiko Sugita ◽  
Donna M. Fluitsma ◽  
Xaiochun Cao ◽  
Gerty Schreibelt ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
Dendritic Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex

The maturation of dendritic cells is accompanied by the redistribution of major histocompatibility complex (MHC) class II molecules from the lysosomal MHC class II compartment to the plasma membrane to mediate presentation of peptide antigens. Besides MHC molecules, dendritic cells also express CD1 molecules that mediate presentation of lipid antigens. Herein, we show that in human monocyte-derived dendritic cells, unlike MHC class II, the steady-state distribution of lysosomal CD1b and CD1c isoforms was unperturbed in response to lipopolysaccharide-induced maturation. However, the lysosomes in these cells underwent a dramatic reorganization into electron dense tubules with altered lysosomal protein composition. These structures matured into novel and morphologically unique compartments, here termed mature dendritic cell lysosomes (MDL). Furthermore, we show that upon activation mature dendritic cells do not lose their ability of efficient clathrin-mediated endocytosis as demonstrated for CD1b and transferrin receptor molecules. Thus, the constitutive endocytosis of CD1b molecules and the differential sorting of MHC class II from lysosomes separate peptide- and lipid antigen-presenting molecules during dendritic cell maturation.

scholarly journals MPYS, a Novel Membrane Tetraspanner, Is Associated with Major Histocompatibility Complex Class II and Mediates Transduction of Apoptotic Signals

2008 ◽  
Vol 28 (16) ◽  
pp. 5014-5026 ◽  
Author(s):  
Lei Jin ◽  
Paul M. Waterman ◽  
Karen R. Jonscher ◽  
Cindy M. Short ◽  
Nichole A. Reisdorph ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Cell Activation ◽  
Cytoplasmic Tail ◽  
Class Ii ◽  
Antigenic Peptides ◽  
Major Histocompatibility ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Death Signals

ABSTRACT Although the best-defined function of type II major histocompatibility complex (MHC-II) is presentation of antigenic peptides to T lymphocytes, these molecules can also transduce signals leading alternatively to cell activation or apoptotic death. MHC-II is a heterodimer of two transmembrane proteins, each containing a short cytoplasmic tail that is dispensable for transduction of death signals. This suggests the function of an undefined MHC-II-associated transducer in signaling the death response. Here we describe a novel plasma membrane tetraspanner (MPYS) that is associated with MHC-II and mediates its transduction of death signals. MPYS is unusual among tetraspanners in containing an extended C-terminal cytoplasmic tail (∼140 amino acids) with multiple embedded signaling motifs. MPYS is tyrosine phosphorylated upon MHC-II aggregation and associates with inositol lipid and tyrosine phosphatases. Finally, MHC class II-mediated cell death signaling requires MPYS-dependent activation of the extracellular signal-regulated kinase signaling pathway.

scholarly journals Engagement of major histocompatibility complex class II molecules by superantigen induces inflammatory cytokine gene expression in human rheumatoid fibroblast-like synoviocytes.

1992 ◽  
Vol 175 (2) ◽  
pp. 613-616 ◽  
Author(s):  
W Mourad ◽  
K Mehindate ◽  
T J Schall ◽  
S R McColl
Keyword(s):  
Gene Expression ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Inflammatory Cytokine ◽  
Class Ii ◽  
Type B ◽  
Major Histocompatibility ◽  
Ifn Gamma ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Molecules

Cells in the rheumatoid synovium express high levels of major histocompatibility complex (MHC) class II molecules in vivo. We have therefore examined the ability of engagement of MHC class II molecules by the superantigen Staphylococcal enterotoxin A (SEA) to activate interleukin 6 (IL-6) and IL-8 gene expression in type B synoviocytes isolated from patients with rheumatoid arthritis. SEA had a minimal or undetectable effect on the expression of either gene in resting synoviocytes, as determined by Northern blot and specific enzyme-linked immunosorbent assay. However, induction of MHC class II molecule expression after treatment of synoviocytes with interferon gamma (IFN-gamma) enabled the cells to respond to SEA in a dose-dependent manner, resulting in an increase in both the level of steady-state mRNA for IL-6 and IL-8, and the release of these cytokines into the supernatant. IFN-gamma by itself had no effect on the expression of either cytokine. Pretreatment of the cells with the transcription inhibitor actinomycin D prevented the increase in cytokine mRNA induced by SEA, whereas cycloheximide superinduced mRNA for both cytokines after stimulation by SEA. Taken together, these results indicate that signaling through MHC class II molecules may represent a novel mechanism by which inflammatory cytokine production is regulated in type B rheumatoid synoviocytes, and potentially provides insight into the manner by which superantigens may initiate and/or propagate autoimmune diseases.

scholarly journals Major histocompatibility complex-restricted recognition of retroviral superantigens by V beta 17+ T cells.

1992 ◽  
Vol 176 (1) ◽  
pp. 275-280 ◽  
Author(s):  
M A Blackman ◽  
F E Lund ◽  
S Surman ◽  
R B Corley ◽  
D L Woodland
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Direct Role ◽  
Histocompatibility Complex ◽  
Class Ii Mhc ◽  
Mhc Class Ii Molecules

It has been established that at least some V beta 17+ T cells interact with an endogenous superantigen encoded by the murine retrovirus, Mtv-9. To analyze the role of major histocompatibility complex (MHC) class II molecules in presenting the Mtv-9 encoded superantigen, vSAG-9 to V beta 17+ hybridomas, a panel of nine hybridomas was tested for their ability to respond to A20/2J (H-2d) and LBK (H-2a) cells which had been transfected with the vSAG-9 gene. Whereas some of the hybridomas recognized vSAG-9 exclusively in the context of H-2a, other hybridomas recognized vSAG-9 exclusively in the context of H-2d or in the context of both H-2d and H-2a. These results suggest that: (a) the class II MHC molecule plays a direct role in the recognition of retroviral superantigen by T cells, rather than serving simply as a platform for presentation; and, (b) it is likely that components of the TCR other than V beta are involved in the vSAG-9/TCR/class II interaction.

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