HLA-DP, HLA-DQ, and HLA-DR Have Different Requirements for Invariant Chain and HLA-DM

Lith, Marcel van; McEwen-Smith, Rosanna M.; Benham, Adam M.

doi:10.1074/jbc.m110.148155

Cited by 63 publications

(56 citation statements)

References 52 publications

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“…The latter pathway is extremely rapid (Reid and Watts 1990) and potentially may provide opportunities for MHCII to also sample antigens that differ from those found in the late endosomal compartments, thereby contributing to the diversity in antigen presentation (Pinet et al 1995;Lindner and Unanue 1996;Griffin et al 1997;Pathak and Blum 2000). MHCII peptide loading at these alternate locations may differ for the requirements of DM or Ii (Vergelli et al 1997;Villadangos et al 2000) and is more prominent for some MHCII isotypes (van Lith et al 2010). The mechanism(s) for endocytosis of pMHCII are not well understood.…”

Section: Trafficking Of Pmhciimentioning

confidence: 99%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

139

102

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For the initiation of adaptive immune responses, dendritic cells present antigenic peptides in association with major histocompatibility complex class II (MHCII) to naïve CD4 þ T lymphocytes. In this review, we discuss how antigen presentation is regulated through intracellular processing and trafficking of MHCII. Newly synthesized MHCII is chaperoned by the invariant chain to endosomes, where peptides from endocytosed pathogens can bind. In nonactivated dendritic cells, peptide-loaded MHCII is ubiquitinated and consequently sorted by the ESCRT machinery to intraluminal vesicles of multivesicular bodies, ultimately leading to lysosomal degradation. Ubiquitination of newly synthesized MHCII is blocked when dendritic cells are activated, now allowing its transfer to the cell surface. This mode of regulation for MHCII is a prime example of how molecular processing and sorting at multivesicular bodies can determine the expression of signaling receptors at the plasma membrane.

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Section: Trafficking Of Pmhciimentioning

confidence: 99%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

139

102

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“…One of the most polymorphic genetic systems, the Human Leukocyte Antigen (HLA) system is divided into Class I (HLA-A, B and C) and Class II (HLA-DP, DQ and DR) molecules [1][2][3]. HLA-DP, DQ, and DR represent three differing isotypes, each being highly polymorphic [1][2][3]. Different HLA-DP variants can be protective, or alternatively, risk factors for infectious diseases, immune dysfunction, and autoimmunity [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HLA-DPDQDR is expressed in all lesional skin from patients with autoimmune skin diseases

Velez¹,

Calle-Isaza²,

Howard³

2014

Our Dermatol Online

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Introduction: Human genes responsible for human antigen presentation and transplant rejection functions are located on the short arm of Chromosome 6, and are called the Major Histocompatibility Complex (MHC). Moreover, the primary physiologic function of MHC molecules is to present peptides to T lymphocytes. MHC molecules are integral components of the ligands that most T cells recognize, since the T cell receptor (TCR) has specificity for complexes of foreign antigenic peptides, as well as self-MHC molecules. Aim: Our investigation attempts to investigate the presence of HLA-DPDQDR within lesional skin biopsies from patients affected by autoimmune skin blistering diseases (ABDs). Materials and Methods:We utilized immunohistochemistry (IHC) to evaluate the presence of HLA-DPDQDR in lesional skin biopsies of patients affected by ABDs. We tested 30 patients with endemic pemphigus foliaceus (EPF), 15 controls from the EPF endemic area, and 15 biopsies from healthy controls from the USA. We also tested archival biopsies from patients with selected ABDs, including 30 patients with bullous pemphigoid (BP), 20 with pemphigus vulgaris (PV), 8 with pemphigus foliaceus (PF), 14 with dermatitis herpetiformis (DH) and 2 with epidermolysis bullosa acquisita (EBA). Results: Most ABD biopsies stained positive for HLA-DPDQDR in the lesional blisters and/or inflamed neurovascular neuroplexus areas in the superficial dermis, and also at mesenchymal-endothelial like-cell junctions in the dermis. In BP, EBA and EPF, the HLA-DPDQDR staining was also seen in dermal eccrine sweat gland coils and ducts. Conclusion: We document that HLA-DPDQDR is expressed in several anatomic areas of lesional skin in patients with ABDs. Notably, HLA-DPDQDR positivity was also consistently present in areas of the classic immune response, including epidermal intercellular junctions in pemphigus, and at basement membrane sites in bullous pemphigoid and other subepidermal blistering diseases.

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“…Western blot analysis revealed similar expression levels for each individual chain (data not shown). The presence of SDS-resistant MHCII heterodimers relies on efficient DM-mediated selection of kinetically stable complexes and indirectly demonstrates effective DM/DR interaction (25). We observed the formation of HLA-DR1 SDS-stable dimers in the presence of either DMA*0101 or DMA*0103, DMB*0101, clearly indicating that the latter variant acts as an exchange catalyst under cellular conditions (Fig 2D).…”

Section: Hla-dma Polymorphisms Affect Dm Stability and Peptide Exchanmentioning

confidence: 55%

“…To verify both the expression of functional HLA-DR molecules and the functionality of HLA-DM molecules, we assessed the presence of SDS stable dimers as previously described (25). Cell pellets were lysed, divided into two aliquots, and mixed with 23 SDS-PAGE loading buffer.…”

Section: Hla-dm Reconstitution In Hela Cellsmentioning

confidence: 99%

HLA-DMA Polymorphisms Differentially Affect MHC Class II Peptide Loading

Álvaro-Benito

Wieczorek

Sticht

et al. 2015

The Journal of Immunology

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During the adaptive immune response, MHCII proteins display antigenic peptides on the cell surface of APCs for CD4+ T cell surveillance. HLA-DM, a nonclassical MHCII protein, acts as a peptide exchange catalyst for MHCII, editing the peptide repertoire. Although they map to the same gene locus, MHCII proteins exhibit a high degree of polymorphism, whereas only low variability has been observed for HLA-DM. As HLA-DM activity directly favors immunodominant peptide presentation, polymorphisms in HLA-DM (DMA or DMB chain) might well be a contributing risk factor for autoimmunity and immune disorders. Our systematic comparison of DMA*0103/DMB*0101 (DMA-G155A and DMA-R184H) with DMA*0101/DMB*0101 in terms of catalyzed peptide exchange and dissociation, as well as direct interaction with several HLA-DR/peptide complexes, reveals an attenuated catalytic activity of DMA*0103/DMB*0101. The G155A substitution dominates the catalytic behavior of DMA*0103/DMB*0101 by decreasing peptide release velocity. Preloaded peptide–MHCII complexes exhibit ∼2-fold increase in half-life in the presence of DMA*0103/DMB*0101 when compared with DMA*0101/DMB*0101. We show that this effect leads to a greater persistence of autoimmunity-related Ags in the presence of high-affinity competitor peptide. Our study therefore reveals that HLA-DM polymorphic residues have a considerable impact on HLA-DM catalytic activity.

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HLA-DP, HLA-DQ, and HLA-DR Have Different Requirements for Invariant Chain and HLA-DM

Cited by 63 publications

References 52 publications

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

HLA-DPDQDR is expressed in all lesional skin from patients with autoimmune skin diseases

HLA-DMA Polymorphisms Differentially Affect MHC Class II Peptide Loading

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