MHC Class I Family Proteins Retard Systemic Lupus Erythematosus Autoimmunity and B Cell Lymphomagenesis

McPhee, Caroline G.; Sproule, Thomas J.; Shin, Dong‐Mi; Bubier, Jason A.; Schott, William H.; Steinbuck, Martin P.; Avenesyan, Lia; Morse, Herbert C.; Roopenian, Derry C.

doi:10.4049/jimmunol.1101776

Cited by 40 publications

(55 citation statements)

References 56 publications

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“…39 Moreover, MIPs are the targets of several immune processes, including autoimmunity, graft rejection, GVHD, and the GVL effect. 5,6,35 Estimates suggest that the immunopeptidome comprises approximately 0.1% of the nonapeptide sequences (the typical length of MIPs) found in the proteome. 5 Despite the important role of MIPs in health and disease, we know little about their biogenesis except for the fact that they derive from DRiPs, the physical nature of which remains ill-defined.…”

Section: Discussionmentioning

confidence: 99%

“…MHC I-associated peptides (MIPs) play crucial roles in many processes, including the development and homeostasis of CD8 T cells, self/nonself discrimination, tumor immunosurveillance, tissue rejection, GVHD, and odorant-based mate selection. [1][2][3][4][5][6] Classic MHC I molecules are encoded by 3 genes in humans, HLA-A, HLA-B, and HLA-C, which have an astounding allelic diversity. 7 Genetic polymorphisms that distinguish HLA allomorphs affect mainly their peptide-binding groove.…”

Section: Introductionmentioning

confidence: 99%

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MHC I–associated peptides preferentially derive from transcripts bearing miRNA response elements

Granados

Yahyaoui

Laumont

et al. 2012

Blood

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MHC I-associated peptides (MIPs) play an essential role in normal homeostasis and diverse pathologic conditions. MIPs derive mainly from defective ribosomal products (DRiPs), a subset of nascent proteins that fail to achieve a proper conformation and the physical nature of which remains elusive. In the present study, we used high-throughput proteomic and transcriptomic methods to unravel the structure and biogenesis of MIPs presented by HLA-A and HLA-B molecules on human EBV-infected B lymphocytes from 4 patients. We found that although HLA-different subjects present distinctive MIPs derived from different proteins, these MIPs originate from proteins that are functionally interconnected and implicated in similar biologic pathways. Secondly, the MIP repertoire of human B cells showed no bias toward conserved versus polymorphic genomic sequences, were derived preferentially from abundant transcripts, and conveyed to the cell surface a cell-type-specific signature. Finally, we discovered that MIPs derive preferentially from transcripts bearing miRNA response elements. Furthermore, whereas MIPs of HLA-disparate subjects are coded by different sets of transcripts, these transcripts are regulated by mostly similar miRNAs. Our data support an emerging model in which the generation of MIPs by a transcript depends on its abundance and DRiP rate, which is regulated to a large extent by miRNAs. (Blood. 2012;119(26):e181-e191)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MHC I–associated peptides preferentially derive from transcripts bearing miRNA response elements

Granados

Yahyaoui

Laumont

et al. 2012

Blood

View full text Add to dashboard Cite

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“…In general, CD8 T cells are critical in limiting tolerance breaks in normal mice and they fail in lupus prone mice (55). Defects in CD8 mediated lupus down regulation have been reported in NZB/W (56–58), MRL/lpr (59, 60) and BxSB lupus mice (61, 62). Also, Qa-1 restricted CD8 T cells have been reported to down regulate Qa-1 expressing Tfh cells and prevent lupus (63).…”

Section: Discussionmentioning

confidence: 97%

Intrinsic Differences in Donor CD4 T Cell IL-2 Production Influence Severity of Parent-into-F1 Murine Lupus by Skewing the Immune Response Either toward Help for B Cells and a Sustained Autoantibody Response or toward Help for CD8 T Cells and a Downregulatory Th1 Response

Soloviova

Puliaiev

Haas

et al. 2015

The Journal of Immunology

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Using the parent-into-F1 model of induced lupus and (C57Bl/6xDBA2) F1 mice as hosts, we compared the inherent lupus-inducing properties of the two parental strain CD4 T cells. To control for donor CD4 recognition of alloantigen, we used H-2d identical DBA/2 and B10.D2 donor T cells. We demonstrate that these two normal, non-lupus prone parental strains exhibit two different T cell activation pathways in vivo. B10.D2 CD4 T cells induce a strong Th1/CMI pathway characterized by IL-2/IFN-g expression, help for CD8 CTL, skewing of DC subsets towards CD8a DC, coupled with reduced CD4Tfh cells and transient B cell help. By contrast, DBA/2 CD4 T cells exhibit a reciprocal, lupus-inducing pathway characterized by poor IL-2/IFN-g expression, poor help for CD8 CTL, skewing of DC subsets towards pDC coupled with greater CD4 Tfh cells, prolonged B cell activation, autoantibody formation, and lupus-like renal disease. Additionally, two distinct in vivo splenic gene expression signatures were induced. In vitro analysis of TCR signaling revealed defective DBA CD4 T cell induction of NF-κB, reduced degradation of IκBα and increased expression of the NF-κB regulator A20. Thus, attenuated NF-κB signaling may lead to diminished IL-2 production by DBA CD4 T cells. These results indicate that intrinsic differences in donor CD4 IL-2 production and subsequent immune skewing could contribute to lupus susceptibility in humans. Therapeutic efforts to skew immune function away from excessive help for B cells and towards help for CTL may be beneficial.

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“…For example, Jiang et al have demonstrated that MHC class Ib molecules activate a key population of CD8 + T-regulatory cells (Jiang et al 1995; Jiang et al 2005). When lacking functional CD8 + T-regulatory cells, mice develop a systemic lupus erythematosus-like syndrome, suggesting a role for these class Ib molecules in the suppression of autoimmunity (Kim et al 2011; McPhee et al 2011). While our study does not offer mechanistic insights, the demonstrated association between DLA-79 and immune-mediated disease supports further investigations regarding the role of class Ib molecules in these conditions.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs

et al. 2015

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Immune-mediated diseases are common and life-threatening disorders in dogs. Many canine immune-mediated diseases have strong breed predispositions and are believed to be inherited. However, the genetic mutations that cause these diseases are mostly unknown. As many immune-mediated diseases in humans share polymorphisms among a common set of genes, we conducted a candidate gene study of 15 of these genes across four immune-mediated diseases (immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, immune-mediated polyarthritis (IMPA), and atopic dermatitis) in 195 affected and 206 unaffected dogs to assess whether causative or predictive polymorphisms might exist in similar genes in dogs. We demonstrate a strong association (Fisher’s exact p = 0.0004 for allelic association, p = 0.0035 for genotypic association) between two polymorphic positions (10 bp apart) in exon 2 of one allele in DLA-79, DLA-79*001:02, and multiple immune-mediated diseases. The frequency of this allele was significantly higher in dogs with immune-mediated disease than in control dogs (0.21 vs. 0.12), and ranged from 0.28 in dogs with IMPA to 0.15 in dogs with atopic dermatitis. This allele has two non-synonymous substitutions (compared to the reference allele, DLA-79*001:01) resulting in F33L and N37D amino acid changes. These mutations occur in the peptide binding pocket of the protein, and based upon our computational modeling studies are likely to affect critical interactions with the peptide N-terminus. Further studies are warranted to confirm these findings more broadly, and to determine the specific mechanism by which the identified variants alter canine immune system function.

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MHC Class I Family Proteins Retard Systemic Lupus Erythematosus Autoimmunity and B Cell Lymphomagenesis

Cited by 40 publications

References 56 publications

MHC I–associated peptides preferentially derive from transcripts bearing miRNA response elements

MHC I–associated peptides preferentially derive from transcripts bearing miRNA response elements

Intrinsic Differences in Donor CD4 T Cell IL-2 Production Influence Severity of Parent-into-F1 Murine Lupus by Skewing the Immune Response Either toward Help for B Cells and a Sustained Autoantibody Response or toward Help for CD8 T Cells and a Downregulatory Th1 Response

Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs

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