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==Crystallographic structure of a rheumatoid arthritis MHC susceptibility allele, HLA-DR1 (DRB1*0101), complexed with the immunodominant determinant of human type II collagen==
==Crystallographic structure of a rheumatoid arthritis MHC susceptibility allele, HLA-DR1 (DRB1*0101), complexed with the immunodominant determinant of human type II collagen==
<table><tr><td colspan='2'>[[2fse]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FSE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2FSE FirstGlance]. <br>
<table><tr><td colspan='2'>[[2fse]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FSE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2FSE FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">COL2A1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
[[http://www.uniprot.org/uniprot/CO2A1_HUMAN CO2A1_HUMAN]] Defects in COL2A1 are the cause of spondyloepiphyseal dysplasia congenital type (SEDC) [MIM:[http://omim.org/entry/183900 183900]]. This disorder is characterized by disproportionate short stature and pleiotropic involvement of the skeletal and ocular systems.<ref>PMID:2543071</ref> <ref>PMID:2339128</ref> <ref>PMID:8325895</ref> <ref>PMID:8423604</ref> <ref>PMID:8019561</ref> <ref>PMID:7757086</ref> <ref>PMID:10678662</ref> <ref>PMID:11746045</ref> Defects in COL2A1 are the cause of spondyloepimetaphyseal dysplasia, Strudwick type (SEMDSTWK) [MIM:[http://omim.org/entry/184250 184250]]. A bone disease characterized by disproportionate short stature from birth, with a very short trunk and shortened limbs, and skeletal abnormalities including lordosis, scoliosis, flattened vertebrae, pectus carinatum, coxa vara, clubfoot, and abnormal epiphyses or metaphyses. A distinctive radiographic feature is irregular sclerotic changes, described as dappled in the metaphyses of the long bones.[:]<ref>PMID:7550321</ref> <ref>PMID:16088915</ref> Defects in COL2A1 are the cause of achondrogenesis type 2 (ACG2) [MIM:[http://omim.org/entry/200610 200610]]; also known as achondrogenesis-hypochondrogenesis type II. ACG2 is a disease characterized by the absence of ossification in the vertebral column, sacrum and pubic bones.<ref>PMID:7757086</ref> <ref>PMID:2572591</ref> <ref>PMID:7757081</ref> <ref>PMID:7829510</ref> <ref>PMID:10797431</ref> <ref>PMID:10745044</ref> <ref>PMID:17994563</ref> Defects in COL2A1 are the cause of Legg-Calve-Perthes disease (LCPD) [MIM:[http://omim.org/entry/150600 150600]]; also known as Legg-Perthes disease or Perthes disease. LCPD is characterized by loss of circulation to the femoral head, resulting in avascular necrosis in a growing child. Clinical pictures of the disease vary, depending on the phase of disease progression through ischemia, revascularization, fracture and collapse, and repair and remodeling of the bone.<ref>PMID:17394019</ref> Defects in COL2A1 are the cause of Kniest dysplasia (KD) [MIM:[http://omim.org/entry/156550 156550]]; also known as Kniest syndrome or metatropic dwarfism type II. KD is a moderately severe chondrodysplasia phenotype that results from mutations in the COL2A1 gene. Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss.<ref>PMID:7874117</ref> <ref>PMID:8863156</ref> Defects in COL2A1 are a cause of primary avascular necrosis of femoral head (ANFH) [MIM:[http://omim.org/entry/608805 608805]]; also known as ischemic necrosis of the femoral head or osteonecrosis of the femoral head. ANFH causes disability that often requires surgical intervention. Most cases are sporadic, but families in which there is an autosomal dominant inheritance of the disease have been identified. It has been estimated that 300,000 to 600,000 people in the United States have ANFH. Approximately 15,000 new cases of this common and disabling disorder are reported annually. The age at the onset is earlier than that for osteoarthritis. The diagnosis is typically made when patients are between the ages of 30 and 60 years. The clinical manifestations, such as pain on exertion, a limping gait, and a discrepancy in leg length, cause considerable disability. Moreover, nearly 10 percent of the 500,000 total-hip arthroplasties performed each year in the United States involve patients with ANFH. As a result, this disease creates a substantial socioeconomic cost as well as a burden for patients and their families.<ref>PMID:15930420</ref> Defects in COL2A1 are the cause of osteoarthritis with mild chondrodysplasia (OACD) [MIM:[http://omim.org/entry/604864 604864]]. Osteoarthritis is a common disease that produces joint pain and stiffness together with radiologic evidence of progressive degeneration of joint cartilage. Some forms of osteoarthritis are secondary to events such as trauma, infections, metabolic disorders, or congenital or heritable conditions that deform the epiphyses or related structures. In most patients, however, there is no readily identifiable cause of osteoarthritis. Inheritance in a Mendelian dominant manner has been demonstrated in some families with primary generalized osteoarthritis. Reports demonstrate coinheritance of primary generalized osteoarthritis with specific alleles of the gene COL2A1, the precursor of the major protein of cartilage.<ref>PMID:7757086</ref> <ref>PMID:1975693</ref> <ref>PMID:1985108</ref> <ref>PMID:8507190</ref> Defects in COL2A1 are the cause of platyspondylic lethal skeletal dysplasia Torrance type (PLSD-T) [MIM:[http://omim.org/entry/151210 151210]]. Platyspondylic lethal skeletal dysplasias (PLSDs) are a heterogeneous group of chondrodysplasias characterized by severe platyspondyly and limb shortening. PLSD-T is characterized by varying platyspondyly, short ribs with anterior cupping, hypoplasia of the lower ilia with broad ischial and pubic bones, and shortening of the tubular bones with splayed and cupped metaphyses. Histology of the growth plate typically shows focal hypercellularity with slightly enlarged chondrocytes in the resting cartilage and relatively well-preserved columnar formation and ossification at the chondro-osseous junction. PLSD-T is generally a perinatally lethal disease, but a few long-term survivors have been reported.<ref>PMID:10745044</ref> <ref>PMID:14729840</ref> <ref>PMID:15643621</ref> Defects in COL2A1 are the cause of multiple epiphyseal dysplasia with myopia and conductive deafness (EDMMD) [MIM:[http://omim.org/entry/132450 132450]]. Multiple epiphyseal dysplasia is a generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. EDMMD is an autosomal dominant disorder characterized by epiphyseal dysplasia associated with progressive myopia, retinal thinning, crenated cataracts, conductive deafness.<ref>PMID:9800905</ref> Defects in COL2A1 are the cause of spondyloperipheral dysplasia (SPD) [MIM:[http://omim.org/entry/271700 271700]]. SPD patients manifest short stature, midface hypoplasia, sensorineural hearing loss, spondyloepiphyseal dysplasia, platyspondyly and brachydactyly. Defects in COL2A1 are the cause of Stickler syndrome type 1 (STL1) [MIM:[http://omim.org/entry/108300 108300]]; also known as vitreous type 1, or membranous vitreous type. STL1 is an autosomal dominant form of Stickler syndrome, an inherited disorder that associates ocular signs with more or less complete forms of Pierre Robin sequence, bone disorders and sensorineural deafness. Ocular disorders may include juvenile cataract, myopia, strabismus, vitreoretinal or chorioretinal degeneration, retinal detachment, and chronic uveitis. Robin sequence includes an opening in the roof of the mouth (a cleft palate), a large tongue (macroglossia), and a small lower jaw (micrognathia). Bones are affected by slight platyspondylisis and large, often defective epiphyses. Juvenile joint laxity is followed by early signs of arthrosis. The degree of hearing loss varies among affected individuals and may become more severe over time. Syndrome expressivity is variable.<ref>PMID:8317498</ref> <ref>PMID:7977371</ref> <ref>PMID:11007540</ref> <ref>PMID:16752401</ref> <ref>PMID:17721977</ref> <ref>PMID:20513134</ref> Defects in COL2A1 are the cause of Stickler syndrome type 1 non-syndromic ocular (STL1O) [MIM:[http://omim.org/entry/609508 609508]]. STL1O is an autosomal dominant form of Stickler syndrome characterized by the ocular signs typically seen in STL1 such as cataract, myopia, retinal detachment. STL1 systemic features of premature osteoarthritis, cleft palate, hearing impairment, and craniofacial abnormalities are either absent or very mild in STL1O patients. Defects in COL2A1 are a cause of rhegmatogenous retinal detachment autosomal dominant (DRRD) [MIM:[http://omim.org/entry/609508 609508]]. Rhegmatogenous retinal detachment most frequently results from a break or tear in the retina that allows fluid from the vitreous humor to enter the potential space beneath the retina. It is often associated with pathologic myopia and in most cases leads to visual impairment or blindness if untreated.<ref>PMID:11007540</ref> <ref>PMID:15671297</ref> Defects in COL2A1 are the cause of Czech dysplasia (CZECHD) [MIM:[http://omim.org/entry/609162 609162]]. A skeletal dysplasia characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes.<ref>PMID:7757086</ref> <ref>PMID:8244341</ref> <ref>PMID:18553548</ref> <ref>PMID:19764028</ref> [[http://www.uniprot.org/uniprot/2B11_HUMAN 2B11_HUMAN]] Genetic variation in HLA-DRB1 is a cause of susceptibility to sarcoidosis type 1 (SS1) [MIM:[http://omim.org/entry/181000 181000]]. Sarcoidosis is an idiopathic, systemic, inflammatory disease characterized by the formation of immune granulomas in involved organs. Granulomas predominantly invade the lungs and the lymphatic system, but also skin, liver, spleen, eyes and other organs may be involved.<ref>PMID:14508706</ref>
[https://www.uniprot.org/uniprot/DRB1_HUMAN DRB1_HUMAN] Giant cell arteritis;NON RARE IN EUROPE: Rheumatoid arthritis;Narcolepsy type 1;Pediatric multiple sclerosis;Sarcoidosis;Systemic lupus erythematosus;Systemic-onset juvenile idiopathic arthritis;Autoimmune pulmonary alveolar proteinosis;Limited systemic sclerosis;Limited cutaneous systemic sclerosis;Diffuse cutaneous systemic sclerosis;NON RARE IN EUROPE: Multiple sclerosis;Follicular lymphoma;Bullous pemphigoid;NON RARE IN EUROPE: Celiac disease;Narcolepsy type 2. In populations of European descent, allele DRB1*01:03 is associated with increased susceptibility to Crohn disease and colonic ulcerative colitis. Decreased heterozygosity in individuals with colonic ulcerative colitis suggests that it acts as a recessive risk allele.<ref>PMID:25559196</ref> Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB1*04:02, DRB1*11:01 and DRB1*12:01 are associated with sarcoidosis. Allele DRB1*04:02 is significantly associated with specific sarcodosis phenotypes such as eye, parotid and salivary gland involvement.<ref>PMID:14508706</ref> Disease susceptibility is associated with variants affecting the gene represented in this entry. In populations of European descent, allele DRB1*15:01 has the strongest association with multiple sclerosis among all HLA class II alleles. Additional risk is associated with the strongly linked alleles DRB1*03:01 and DQB1*02:01 as well as with allele DRB1*13:03 (PubMed:21833088). It is postulated that bacterial or viral infection triggers the autoimmune MS. Microbial peptides having low affinity crossreactivity to MBP autoantigen, may stimulate autoreactive T cells via molecular mimicry and initiate the autoimmune inflammation (PubMed:19303388).<ref>PMID:19303388</ref> <ref>PMID:21833088</ref> Allele DRB1*15:01 is associated with increased susceptibility to Goodpasture syndrome. Can present a self-peptide derived from COL4A3 (GWISLWKGFSF) on TCR (TRAV19 biased) in pathogenic CD4-positive T-helper 1 and T-helper 17 cells, triggering autoimmune inflammation.<ref>PMID:28467828</ref> Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB1*04:01; DRB1*04:04; DRB1*04:05; DRB1*04:08; DRB1*10:01; DRB1*01:01 and DRB1*01:02 are associated with increased susceptibility to rheumatoid arthritis, where affected individuals have antibodies to cyclic citrullinated peptide (anti-CCP-positive rheumatoid arthritis). Variations at position 40 in the peptide-binding cleft of these alleles explain most of the association to rheumatoid arthritis risk.<ref>PMID:22286218</ref>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/2DRA_HUMAN 2DRA_HUMAN]] Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal miroenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading. [[http://www.uniprot.org/uniprot/CO2A1_HUMAN CO2A1_HUMAN]] Type II collagen is specific for cartilaginous tissues. It is essential for the normal embryonic development of the skeleton, for linear growth and for the ability of cartilage to resist compressive forces. [[http://www.uniprot.org/uniprot/2B11_HUMAN 2B11_HUMAN]] Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route; where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules; and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments; exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides; autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs; other cells of the gastrointestinal tract; such as epithelial cells; express MHC class II molecules and CD74 and act as APCs; which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen; three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs; CD74 undergoes a sequential degradation by various proteases; including CTSS and CTSL; leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells; the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal miroenvironment has been implicated in the regulation of antigen loading into MHC II molecules; increased acidification produces increased proteolysis and efficient peptide loading.
[https://www.uniprot.org/uniprot/DRB1_HUMAN DRB1_HUMAN] A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA-DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB1-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:15265931, PubMed:16148104, PubMed:22327072, PubMed:27591323, PubMed:29884618, PubMed:31495665, PubMed:8642306). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819).<ref>PMID:15265931</ref> <ref>PMID:17182262</ref> <ref>PMID:22327072</ref> <ref>PMID:23783831</ref> <ref>PMID:25413013</ref> <ref>PMID:27591323</ref> <ref>PMID:29884618</ref> <ref>PMID:31495665</ref> <ref>PMID:8145819</ref> <ref>PMID:8642306</ref> Allele DRB1*01:01: Displays an immunodominant epitope derived from Bacillus anthracis pagA/protective antigen, PA (KLPLYISNPNYKVNVYAVT), to both naive and PA-specific memory CD4-positive T cells (PubMed:22327072). Presents immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (PHQFINLRSNNSATLIVPYV), contributing to viral clearance (PubMed:27591323). Displays commonly recognized peptides derived from IAV external protein HA (PKYVKQNTLKLAT and SNGNFIAPEYAYKIVK) and from internal proteins M, NP and PB1, with M-derived epitope (GLIYNRMGAVTTEV) being the most immunogenic (PubMed:25413013, PubMed:32668259, PubMed:8145819, PubMed:9075930). Presents a self-peptide derived from COL4A3 (GWISLWKGFSF) to TCR (TRAV14 biased) on CD4-positive, FOXP3-positive regulatory T cells and mediates immune tolerance to self (PubMed:28467828). May present peptides derived from oncofetal trophoblast glycoprotein TPBG 5T4, known to be recognized by both T-helper 1 and regulatory T cells (PubMed:31619516). Displays with low affinity a self-peptide derived from MBP (VHFFKNIVTPRTP) (PubMed:9075930).<ref>PMID:22327072</ref> <ref>PMID:25413013</ref> <ref>PMID:27591323</ref> <ref>PMID:28467828</ref> <ref>PMID:29884618</ref> <ref>PMID:31619516</ref> <ref>PMID:32668259</ref> <ref>PMID:8145819</ref> <ref>PMID:9075930</ref> Allele DRB1*03:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Displays self-peptides derived from retinal SAG (NRERRGIALDGKIKHE) and thyroid TG (LSSVVVDPSIRHFDV) (PubMed:25413013). Presents viral epitopes derived from HHV-6B gH/U48 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection (PubMed:31020640). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and long-term protection (PubMed:19830726).<ref>PMID:19830726</ref> <ref>PMID:25413013</ref> <ref>PMID:27591323</ref> <ref>PMID:31020640</ref> Allele DRB1*04:01: Presents an immunodominant bacterial epitope derived from M. tuberculosis esxB/culture filtrate antigen CFP-10 (EISTNIRQAGVQYSR), eliciting CD4-positive T cell effector functions such as IFNG production and cytotoxic activity (PubMed:15265931). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Presents tumor epitopes derived from melanoma-associated TYR antigen (QNILLSNAPLGPQFP and DYSYLQDSDPDSFQD), triggering CD4-positive T cell effector functions such as GMCSF production (PubMed:8642306). Displays preferentially citrullinated self-peptides derived from VIM (GVYATR/citSSAVR and SAVRAR/citSSVPGVR) and ACAN (VVLLVATEGR/ CitVRVNSAYQDK) (PubMed:24190431). Displays self-peptides derived from COL2A1 (PubMed:9354468).<ref>PMID:15265931</ref> <ref>PMID:24190431</ref> <ref>PMID:27591323</ref> <ref>PMID:8642306</ref> <ref>PMID:9354468</ref> Allele DRB1*04:02: Displays native or citrullinated self-peptides derived from VIM.<ref>PMID:24190431</ref> Allele DRB1*04:04: May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (HIVMQYMYVPPGAPIPTTRN) and VP2 (RGDSTITSQDVANAVVGYGV), contributing to viral clearance (PubMed:27591323). Displays preferentially citrullinated self-peptides derived from VIM (SAVRAR/citSSVPGVR) (PubMed:24190431).<ref>PMID:24190431</ref> <ref>PMID:27591323</ref> Allele DRB1*04:05: May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies.<ref>PMID:19120973</ref> Allele DRB1*05:01: Presents an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load.<ref>PMID:29884618</ref> Allele DRB1*07:01: Upon EBV infection, presents latent antigen EBNA2 peptide (PRSPTVFYNIPPMPLPPSQL) to CD4-positive T cells, driving oligoclonal expansion and selection of a dominant virus-specific memory T cell subset with cytotoxic potential to directly eliminate virus-infected B cells (PubMed:31308093). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (VPYVNAVPMDSMVRHNNWSL), contributing to viral clearance (PubMed:27591323). In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (MTEYKLVVVGAVGVGKSALTIQLI), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:22929521). In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a KRAS neoantigen (MTEYKLVVVGAVGVGKSALTIQLI) carrying G12V hotspot driver mutation and may mediate tumor regression (PubMed:30282837).<ref>PMID:22929521</ref> <ref>PMID:27591323</ref> <ref>PMID:30282837</ref> <ref>PMID:31308093</ref> Allele DRB1*11:01: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SDRIIQITRGDSTITSQDVA), contributing to viral clearance (PubMed:27591323). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and longterm protection (PubMed:19830726). In the context of tumor immunesurveillance, may present tumor-derived neoantigens to CD4-positive T cells and trigger anti-tumor helper functions (PubMed:31495665).<ref>PMID:19830726</ref> <ref>PMID:27591323</ref> <ref>PMID:29884618</ref> <ref>PMID:31495665</ref> Allele DRB1*13:01: Presents viral epitopes derived from HHV-6B antigens to polyfunctional CD4-positive T cells implicated in control of HHV-6B infection.<ref>PMID:31020640</ref> Allele DRB1*15:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SNNSATLIVPYVNAVPMDSM), contributing to viral clearance (PubMed:27591323). Displays a self-peptide derived from MBP (ENPVVHFFKNIVTPR) (PubMed:25413013, PubMed:9782128). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies.<ref>PMID:19120973</ref> <ref>PMID:27591323</ref> <ref>PMID:9782128</ref> Allele DRB1*15:02: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:19120973).<ref>PMID:19120973</ref> <ref>PMID:29884618</ref> (Microbial infection) Acts as a receptor for Epstein-Barr virus on lymphocytes.<ref>PMID:11864610</ref> <ref>PMID:9151859</ref>
<text>to colour the structure by Evolutionary Conservation</text>
<text>to colour the structure by Evolutionary Conservation</text>
</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2fse ConSurf].
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
Crystallographic structure of a rheumatoid arthritis MHC susceptibility allele, HLA-DR1 (DRB1*0101), complexed with the immunodominant determinant of human type II collagen
2fse is a 6 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
DRB1_HUMAN Giant cell arteritis;NON RARE IN EUROPE: Rheumatoid arthritis;Narcolepsy type 1;Pediatric multiple sclerosis;Sarcoidosis;Systemic lupus erythematosus;Systemic-onset juvenile idiopathic arthritis;Autoimmune pulmonary alveolar proteinosis;Limited systemic sclerosis;Limited cutaneous systemic sclerosis;Diffuse cutaneous systemic sclerosis;NON RARE IN EUROPE: Multiple sclerosis;Follicular lymphoma;Bullous pemphigoid;NON RARE IN EUROPE: Celiac disease;Narcolepsy type 2. In populations of European descent, allele DRB1*01:03 is associated with increased susceptibility to Crohn disease and colonic ulcerative colitis. Decreased heterozygosity in individuals with colonic ulcerative colitis suggests that it acts as a recessive risk allele.[1] Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB1*04:02, DRB1*11:01 and DRB1*12:01 are associated with sarcoidosis. Allele DRB1*04:02 is significantly associated with specific sarcodosis phenotypes such as eye, parotid and salivary gland involvement.[2] Disease susceptibility is associated with variants affecting the gene represented in this entry. In populations of European descent, allele DRB1*15:01 has the strongest association with multiple sclerosis among all HLA class II alleles. Additional risk is associated with the strongly linked alleles DRB1*03:01 and DQB1*02:01 as well as with allele DRB1*13:03 (PubMed:21833088). It is postulated that bacterial or viral infection triggers the autoimmune MS. Microbial peptides having low affinity crossreactivity to MBP autoantigen, may stimulate autoreactive T cells via molecular mimicry and initiate the autoimmune inflammation (PubMed:19303388).[3][4] Allele DRB1*15:01 is associated with increased susceptibility to Goodpasture syndrome. Can present a self-peptide derived from COL4A3 (GWISLWKGFSF) on TCR (TRAV19 biased) in pathogenic CD4-positive T-helper 1 and T-helper 17 cells, triggering autoimmune inflammation.[5] Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB1*04:01; DRB1*04:04; DRB1*04:05; DRB1*04:08; DRB1*10:01; DRB1*01:01 and DRB1*01:02 are associated with increased susceptibility to rheumatoid arthritis, where affected individuals have antibodies to cyclic citrullinated peptide (anti-CCP-positive rheumatoid arthritis). Variations at position 40 in the peptide-binding cleft of these alleles explain most of the association to rheumatoid arthritis risk.[6]
Function
DRB1_HUMAN A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA-DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB1-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:15265931, PubMed:16148104, PubMed:22327072, PubMed:27591323, PubMed:29884618, PubMed:31495665, PubMed:8642306). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819).[7][8][9][10][11][12][13][14][15][16] Allele DRB1*01:01: Displays an immunodominant epitope derived from Bacillus anthracis pagA/protective antigen, PA (KLPLYISNPNYKVNVYAVT), to both naive and PA-specific memory CD4-positive T cells (PubMed:22327072). Presents immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (PHQFINLRSNNSATLIVPYV), contributing to viral clearance (PubMed:27591323). Displays commonly recognized peptides derived from IAV external protein HA (PKYVKQNTLKLAT and SNGNFIAPEYAYKIVK) and from internal proteins M, NP and PB1, with M-derived epitope (GLIYNRMGAVTTEV) being the most immunogenic (PubMed:25413013, PubMed:32668259, PubMed:8145819, PubMed:9075930). Presents a self-peptide derived from COL4A3 (GWISLWKGFSF) to TCR (TRAV14 biased) on CD4-positive, FOXP3-positive regulatory T cells and mediates immune tolerance to self (PubMed:28467828). May present peptides derived from oncofetal trophoblast glycoprotein TPBG 5T4, known to be recognized by both T-helper 1 and regulatory T cells (PubMed:31619516). Displays with low affinity a self-peptide derived from MBP (VHFFKNIVTPRTP) (PubMed:9075930).[17][18][19][20][21][22][23][24][25] Allele DRB1*03:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Displays self-peptides derived from retinal SAG (NRERRGIALDGKIKHE) and thyroid TG (LSSVVVDPSIRHFDV) (PubMed:25413013). Presents viral epitopes derived from HHV-6B gH/U48 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection (PubMed:31020640). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and long-term protection (PubMed:19830726).[26][27][28][29] Allele DRB1*04:01: Presents an immunodominant bacterial epitope derived from M. tuberculosis esxB/culture filtrate antigen CFP-10 (EISTNIRQAGVQYSR), eliciting CD4-positive T cell effector functions such as IFNG production and cytotoxic activity (PubMed:15265931). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Presents tumor epitopes derived from melanoma-associated TYR antigen (QNILLSNAPLGPQFP and DYSYLQDSDPDSFQD), triggering CD4-positive T cell effector functions such as GMCSF production (PubMed:8642306). Displays preferentially citrullinated self-peptides derived from VIM (GVYATR/citSSAVR and SAVRAR/citSSVPGVR) and ACAN (VVLLVATEGR/ CitVRVNSAYQDK) (PubMed:24190431). Displays self-peptides derived from COL2A1 (PubMed:9354468).[30][31][32][33][34] Allele DRB1*04:02: Displays native or citrullinated self-peptides derived from VIM.[35] Allele DRB1*04:04: May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (HIVMQYMYVPPGAPIPTTRN) and VP2 (RGDSTITSQDVANAVVGYGV), contributing to viral clearance (PubMed:27591323). Displays preferentially citrullinated self-peptides derived from VIM (SAVRAR/citSSVPGVR) (PubMed:24190431).[36][37] Allele DRB1*04:05: May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies.[38] Allele DRB1*05:01: Presents an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load.[39] Allele DRB1*07:01: Upon EBV infection, presents latent antigen EBNA2 peptide (PRSPTVFYNIPPMPLPPSQL) to CD4-positive T cells, driving oligoclonal expansion and selection of a dominant virus-specific memory T cell subset with cytotoxic potential to directly eliminate virus-infected B cells (PubMed:31308093). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (VPYVNAVPMDSMVRHNNWSL), contributing to viral clearance (PubMed:27591323). In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (MTEYKLVVVGAVGVGKSALTIQLI), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:22929521). In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a KRAS neoantigen (MTEYKLVVVGAVGVGKSALTIQLI) carrying G12V hotspot driver mutation and may mediate tumor regression (PubMed:30282837).[40][41][42][43] Allele DRB1*11:01: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SDRIIQITRGDSTITSQDVA), contributing to viral clearance (PubMed:27591323). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and longterm protection (PubMed:19830726). In the context of tumor immunesurveillance, may present tumor-derived neoantigens to CD4-positive T cells and trigger anti-tumor helper functions (PubMed:31495665).[44][45][46][47] Allele DRB1*13:01: Presents viral epitopes derived from HHV-6B antigens to polyfunctional CD4-positive T cells implicated in control of HHV-6B infection.[48] Allele DRB1*15:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SNNSATLIVPYVNAVPMDSM), contributing to viral clearance (PubMed:27591323). Displays a self-peptide derived from MBP (ENPVVHFFKNIVTPR) (PubMed:25413013, PubMed:9782128). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies.[49][50][51] Allele DRB1*15:02: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:19120973).[52][53] (Microbial infection) Acts as a receptor for Epstein-Barr virus on lymphocytes.[54][55]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The expression of HLA-DR1 (DRB1*0101) is associated with an enhanced risk for developing rheumatoid arthritis (RA). To study its function, we have solved the three-dimensional structure of HLA-DR1 complexed with a candidate RA autoantigen, the human type II collagen peptide CII (259-273). Based on these structural data, the CII peptide is anchored by Phe263 at the P1 position and Glu266 at P4. Surprisingly, the Lys at the P2 position appears to play a dual role by participating in peptide binding via interactions with DRB1-His81 and Asn82, and TCR interaction, based on functional assays. The CII peptide is also anchored by the P4 Glu266 residue through an ionic interaction with DRB1-Arg71 and Glu28. Participation of DRB1-Arg71 is significant because it is part of the shared epitope expressed by DR alleles associated with RA susceptibility. Potential anchor residues at P6 and P9 of the CII peptide are both Gly, and the lack of side chains at these positions appears to result in both a narrower binding groove with the peptide protruding out of the groove at this end of the DR1 molecule. From the TCR perspective, the P2-Lys264, P5-Arg267, and P8-Lys270 residues are all oriented away from the binding groove and collectively represent a positive charged interface for CII-specific TCR binding. Comparison of the DR1-CII structure to a DR1-hemagglutinin peptide structure revealed that the binding of these two peptides generates significantly different interfaces for the interaction with their respective Ag-specific TCRs.
Crystallographic structure of a rheumatoid arthritis MHC susceptibility allele, HLA-DR1 (DRB1*0101), complexed with the immunodominant determinant of human type II collagen.,Rosloniec EF, Ivey RA 3rd, Whittington KB, Kang AH, Park HW J Immunol. 2006 Sep 15;177(6):3884-92. PMID:16951351[56]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins L, Huang H, Ripke S, Gusareva ES, Annese V, Hauser SL, Oksenberg JR, Thomsen I, Leslie S, Daly MJ, Van Steen K, Duerr RH, Barrett JC, McGovern DP, Schumm LP, Traherne JA, Carrington MN, Kosmoliaptsis V, Karlsen TH, Franke A, Rioux JD. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet. 2015 Feb;47(2):172-9. PMID:25559196 doi:10.1038/ng.3176
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↑Schmid D, Pypaert M, Münz C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity. 2007 Jan;26(1):79-92. PMID:17182262 doi:10.1016/j.immuni.2006.10.018
↑Kwok WW, Tan V, Gillette L, Littell CT, Soltis MA, LaFond RB, Yang J, James EA, DeLong JH. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire. J Immunol. 2012 Mar 15;188(6):2537-44. PMID:22327072 doi:10.4049/jimmunol.1102190
↑Adamopoulou E, Tenzer S, Hillen N, Klug P, Rota IA, Tietz S, Gebhardt M, Stevanovic S, Schild H, Tolosa E, Melms A, Stoeckle C. Exploring the MHC-peptide matrix of central tolerance in the human thymus. Nat Commun. 2013;4:2039. PMID:23783831 doi:10.1038/ncomms3039
↑Kim A, Hartman IZ, Poore B, Boronina T, Cole RN, Song N, Ciudad MT, Caspi RR, Jaraquemada D, Sadegh-Nasseri S. Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources. Nat Commun. 2014 Nov 21;5:5369. PMID:25413013 doi:10.1038/ncomms6369
↑Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
↑Galperin M, Farenc C, Mukhopadhyay M, Jayasinghe D, Decroos A, Benati D, Tan LL, Ciacchi L, Reid HH, Rossjohn J, Chakrabarti LA, Gras S. CD4(+) T cell-mediated HLA class II cross-restriction in HIV controllers. Sci Immunol. 2018 Jun 8;3(24). pii: 3/24/eaat0687. doi:, 10.1126/sciimmunol.aat0687. PMID:29884618 doi:https://dx.doi.org/10.1126/sciimmunol.aat0687
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↑Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994 Mar 17;368(6468):215-21. PMID:8145819 doi:https://dx.doi.org/10.1038/368215a0
↑Topalian SL, Gonzales MI, Parkhurst M, Li YF, Southwood S, Sette A, Rosenberg SA, Robbins PF. Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes. J Exp Med. 1996 May 1;183(5):1965-71. PMID:8642306 doi:10.1084/jem.183.5.1965
↑Kwok WW, Tan V, Gillette L, Littell CT, Soltis MA, LaFond RB, Yang J, James EA, DeLong JH. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire. J Immunol. 2012 Mar 15;188(6):2537-44. PMID:22327072 doi:10.4049/jimmunol.1102190
↑Kim A, Hartman IZ, Poore B, Boronina T, Cole RN, Song N, Ciudad MT, Caspi RR, Jaraquemada D, Sadegh-Nasseri S. Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources. Nat Commun. 2014 Nov 21;5:5369. PMID:25413013 doi:10.1038/ncomms6369
↑Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
↑Ooi JD, Petersen J, Tan YH, Huynh M, Willett ZJ, Ramarathinam SH, Eggenhuizen PJ, Loh KL, Watson KA, Gan PY, Alikhan MA, Dudek NL, Handel A, Hudson BG, Fugger L, Power DA, Holt SG, Coates PT, Gregersen JW, Purcell AW, Holdsworth SR, La Gruta NL, Reid HH, Rossjohn J, Kitching AR. Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature. 2017 May 11;545(7653):243-247. doi: 10.1038/nature22329. Epub 2017 May 3. PMID:28467828 doi:https://dx.doi.org/10.1038/nature22329
↑Galperin M, Farenc C, Mukhopadhyay M, Jayasinghe D, Decroos A, Benati D, Tan LL, Ciacchi L, Reid HH, Rossjohn J, Chakrabarti LA, Gras S. CD4(+) T cell-mediated HLA class II cross-restriction in HIV controllers. Sci Immunol. 2018 Jun 8;3(24). pii: 3/24/eaat0687. doi:, 10.1126/sciimmunol.aat0687. PMID:29884618 doi:https://dx.doi.org/10.1126/sciimmunol.aat0687
↑MacLachlan BJ, Dolton G, Papakyriakou A, Greenshields-Watson A, Mason GH, Schauenburg A, Besneux M, Szomolay B, Elliott T, Sewell AK, Gallimore A, Rizkallah P, Cole DK, Godkin A. Human leukocyte antigen (HLA) class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope. J Biol Chem. 2019 Oct 16. pii: RA119.009437. doi: 10.1074/jbc.RA119.009437. PMID:31619516 doi:https://dx.doi.org/10.1074/jbc.RA119.009437
↑Greenshields-Watson A, Attaf M, MacLachlan BJ, Whalley T, Rius C, Wall A, Lloyd A, Hughes H, Strange KE, Mason GH, Schauenburg AJ, Hulin-Curtis SL, Geary J, Chen Y, Lauder SN, Smart K, Vijaykrishna D, Grau ML, Shugay M, Andrews R, Dolton G, Rizkallah PJ, Gallimore AM, Sewell AK, Godkin AJ, Cole DK. CD4(+) T Cells Recognize Conserved Influenza A Epitopes through Shared Patterns of V-Gene Usage and Complementary Biochemical Features. Cell Rep. 2020 Jul 14;32(2):107885. PMID:32668259 doi:10.1016/j.celrep.2020.107885
↑Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994 Mar 17;368(6468):215-21. PMID:8145819 doi:https://dx.doi.org/10.1038/368215a0
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↑Faner R, James E, Huston L, Pujol-Borrel R, Kwok WW, Juan M. Reassessing the role of HLA-DRB3 T-cell responses: evidence for significant expression and complementary antigen presentation. Eur J Immunol. 2010 Jan;40(1):91-102. PMID:19830726 doi:10.1002/eji.200939225
↑Kim A, Hartman IZ, Poore B, Boronina T, Cole RN, Song N, Ciudad MT, Caspi RR, Jaraquemada D, Sadegh-Nasseri S. Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources. Nat Commun. 2014 Nov 21;5:5369. PMID:25413013 doi:10.1038/ncomms6369
↑Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
↑Becerra-Artiles A, Cruz J, Leszyk JD, Sidney J, Sette A, Shaffer SA, Stern LJ. Naturally processed HLA-DR3-restricted HHV-6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T-cell responses. Eur J Immunol. 2019 Aug;49(8):1167-1185. PMID:31020640 doi:10.1002/eji.201948126
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↑Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
↑Topalian SL, Gonzales MI, Parkhurst M, Li YF, Southwood S, Sette A, Rosenberg SA, Robbins PF. Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes. J Exp Med. 1996 May 1;183(5):1965-71. PMID:8642306 doi:10.1084/jem.183.5.1965
↑Dessen A, Lawrence CM, Cupo S, Zaller DM, Wiley DC. X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II. Immunity. 1997 Oct;7(4):473-81. PMID:9354468
↑Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, Wijeyewickrema LC, Eckle SB, van Heemst J, Pike RN, McCluskey J, Toes RE, La Gruta NL, Purcell AW, Reid HH, Thomas R, Rossjohn J. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 2013 Nov 18;210(12):2569-82. doi: 10.1084/jem.20131241. Epub 2013 Nov , 4. PMID:24190431 doi:https://dx.doi.org/10.1084/jem.20131241
↑Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, Wijeyewickrema LC, Eckle SB, van Heemst J, Pike RN, McCluskey J, Toes RE, La Gruta NL, Purcell AW, Reid HH, Thomas R, Rossjohn J. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 2013 Nov 18;210(12):2569-82. doi: 10.1084/jem.20131241. Epub 2013 Nov , 4. PMID:24190431 doi:https://dx.doi.org/10.1084/jem.20131241
↑Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
↑Fujiki F, Oka Y, Kawakatsu M, Tsuboi A, Nakajima H, Elisseeva OA, Harada Y, Li Z, Tatsumi N, Kamino E, Shirakata T, Nishida S, Taniguchi Y, Kawase I, Oji Y, Sugiyama H. A WT1 protein-derived, naturally processed 16-mer peptide, WT1(332), is a promiscuous helper peptide for induction of WT1-specific Th1-type CD4(+) T cells. Microbiol Immunol. 2008 Dec;52(12):591-600. PMID:19120973 doi:10.1111/j.1348-0421.2008.00080.x
↑Galperin M, Farenc C, Mukhopadhyay M, Jayasinghe D, Decroos A, Benati D, Tan LL, Ciacchi L, Reid HH, Rossjohn J, Chakrabarti LA, Gras S. CD4(+) T cell-mediated HLA class II cross-restriction in HIV controllers. Sci Immunol. 2018 Jun 8;3(24). pii: 3/24/eaat0687. doi:, 10.1126/sciimmunol.aat0687. PMID:29884618 doi:https://dx.doi.org/10.1126/sciimmunol.aat0687
↑Anguille S, Fujiki F, Smits EL, Oji Y, Lion E, Oka Y, Berneman ZN, Sugiyama H. Identification of a Wilms' tumor 1-derived immunogenic CD4(+) T-cell epitope that is recognized in the context of common Caucasian HLA-DR haplotypes. Leukemia. 2013 Mar;27(3):748-50. PMID:22929521 doi:10.1038/leu.2012.248
↑Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
↑Yossef R, Tran E, Deniger DC, Gros A, Pasetto A, Parkhurst MR, Gartner JJ, Prickett TD, Cafri G, Robbins PF, Rosenberg SA. Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy. JCI Insight. 2018 Oct 4;3(19):e122467. PMID:30282837 doi:10.1172/jci.insight.122467
↑Meckiff BJ, Ladell K, McLaren JE, Ryan GB, Leese AM, James EA, Price DA, Long HM. Primary EBV Infection Induces an Acute Wave of Activated Antigen-Specific Cytotoxic CD4(+) T Cells. J Immunol. 2019 Sep 1;203(5):1276-1287. PMID:31308093 doi:10.4049/jimmunol.1900377
↑Faner R, James E, Huston L, Pujol-Borrel R, Kwok WW, Juan M. Reassessing the role of HLA-DRB3 T-cell responses: evidence for significant expression and complementary antigen presentation. Eur J Immunol. 2010 Jan;40(1):91-102. PMID:19830726 doi:10.1002/eji.200939225
↑Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
↑Galperin M, Farenc C, Mukhopadhyay M, Jayasinghe D, Decroos A, Benati D, Tan LL, Ciacchi L, Reid HH, Rossjohn J, Chakrabarti LA, Gras S. CD4(+) T cell-mediated HLA class II cross-restriction in HIV controllers. Sci Immunol. 2018 Jun 8;3(24). pii: 3/24/eaat0687. doi:, 10.1126/sciimmunol.aat0687. PMID:29884618 doi:https://dx.doi.org/10.1126/sciimmunol.aat0687
↑Abelin JG, Harjanto D, Malloy M, Suri P, Colson T, Goulding SP, Creech AL, Serrano LR, Nasir G, Nasrullah Y, McGann CD, Velez D, Ting YS, Poran A, Rothenberg DA, Chhangawala S, Rubinsteyn A, Hammerbacher J, Gaynor RB, Fritsch EF, Greshock J, Oslund RC, Barthelme D, Addona TA, Arieta CM, Rooney MS. Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction. Immunity. 2019 Oct 15;51(4):766-779.e17. PMID:31495665 doi:10.1016/j.immuni.2019.08.012
↑Becerra-Artiles A, Cruz J, Leszyk JD, Sidney J, Sette A, Shaffer SA, Stern LJ. Naturally processed HLA-DR3-restricted HHV-6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T-cell responses. Eur J Immunol. 2019 Aug;49(8):1167-1185. PMID:31020640 doi:10.1002/eji.201948126
↑Fujiki F, Oka Y, Kawakatsu M, Tsuboi A, Nakajima H, Elisseeva OA, Harada Y, Li Z, Tatsumi N, Kamino E, Shirakata T, Nishida S, Taniguchi Y, Kawase I, Oji Y, Sugiyama H. A WT1 protein-derived, naturally processed 16-mer peptide, WT1(332), is a promiscuous helper peptide for induction of WT1-specific Th1-type CD4(+) T cells. Microbiol Immunol. 2008 Dec;52(12):591-600. PMID:19120973 doi:10.1111/j.1348-0421.2008.00080.x
↑Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
↑Smith KJ, Pyrdol J, Gauthier L, Wiley DC, Wucherpfennig KW. Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein. J Exp Med. 1998 Oct 19;188(8):1511-20. PMID:9782128
↑Fujiki F, Oka Y, Kawakatsu M, Tsuboi A, Nakajima H, Elisseeva OA, Harada Y, Li Z, Tatsumi N, Kamino E, Shirakata T, Nishida S, Taniguchi Y, Kawase I, Oji Y, Sugiyama H. A WT1 protein-derived, naturally processed 16-mer peptide, WT1(332), is a promiscuous helper peptide for induction of WT1-specific Th1-type CD4(+) T cells. Microbiol Immunol. 2008 Dec;52(12):591-600. PMID:19120973 doi:10.1111/j.1348-0421.2008.00080.x
↑Galperin M, Farenc C, Mukhopadhyay M, Jayasinghe D, Decroos A, Benati D, Tan LL, Ciacchi L, Reid HH, Rossjohn J, Chakrabarti LA, Gras S. CD4(+) T cell-mediated HLA class II cross-restriction in HIV controllers. Sci Immunol. 2018 Jun 8;3(24). pii: 3/24/eaat0687. doi:, 10.1126/sciimmunol.aat0687. PMID:29884618 doi:https://dx.doi.org/10.1126/sciimmunol.aat0687
↑Mullen MM, Haan KM, Longnecker R, Jardetzky TS. Structure of the Epstein-Barr virus gp42 protein bound to the MHC class II receptor HLA-DR1. Mol Cell. 2002 Feb;9(2):375-85. PMID:11864610
↑Li Q, Spriggs MK, Kovats S, Turk SM, Comeau MR, Nepom B, Hutt-Fletcher LM. Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes. J Virol. 1997 Jun;71(6):4657-62. PMID:9151859 doi:10.1128/JVI.71.6.4657-4662.1997
↑Rosloniec EF, Ivey RA 3rd, Whittington KB, Kang AH, Park HW. Crystallographic structure of a rheumatoid arthritis MHC susceptibility allele, HLA-DR1 (DRB1*0101), complexed with the immunodominant determinant of human type II collagen. J Immunol. 2006 Sep 15;177(6):3884-92. PMID:16951351
