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Hypersensitivity pneumonitis
Published in Muhunthan Thillai, David R Moller, Keith C Meyer, Clinical Handbook of Interstitial Lung Disease, 2017
Christine Fiddler, Helen Parfrey
Studies evaluating gene polymorphisms have been undertaken in small cohorts but to date no genetic factors have consistently been associated with HP. One case of familial HP was reported from Japan where summer-type HP occurred in families living in the same house and the affected individuals had HLA-DR9 phenotype (12). Other MHC class II polymorphisms, HLA-DR and DQw3, have been described in HP from populations with diverse genetic backgrounds (13,14). MHC class I has also been implicated in the disease pathogenesis. Polymorphisms in HLA-A2, the immunoproteasome catalytic subunit β type 8 (PSMB8) that degrades ubiquitinated proteins to generate antigenic peptides for presentation to cytotoxic T cells (15), and the transporters associated with antigen-processing (TAP) genes responsible for loading peptides onto MHC class I (16) have been identified. These findings highlight the importance of antigen presentation in the pathogenesis of HP.
Palmoplantar psoriasis
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
Dario Kivelevitch, Bobbak Mansouri, M. Alan Menter
The etiology of PPP is not completely understood. Its genetic background does differ from that of chronic plaque psoriasis. Human leukocyte antigen (HLA) association studies have found an increased frequency of HLA-B8 and HLA-Bw35 alleles among Caucasian PPP patients.8,9 PPP has also been associated with the absence of HLA-Cw*0602 with a Japanese study suggesting that HLA-DR molecules (specifically HLA-DR9) are likely to be involved in PPP pathogenesis.10,11 Interestingly, none of these studies found an increased frequency of the known psoriasis-associated HLA antigens in PPP. Furthermore, allelic variation in three genes located in the PSORS1 region (HLA-Cw*6, HCR*WWCC, and CDSN*5) was associated with guttate psoriasis but not PPP.12
Immunopathology of Myasthenia Gravis
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
Although the genetic influences on autoimmune disease are multifactorial, histocompatibility antigens may be one of these genetic factors. Patients with MG show an increased frequency of HLA-A1-B8. This association appears strongest in young women with thymic hyperplasia75,94,349,350 and with HLA-DR9 and DRW 13 in childhood MG in Japanese351 and HLA-BW46 in childhood Chinese.352 The HLA-DR3 haplotype, which is in linkage disequilibrium with A1-B8, is associated with an increased risk for MG,353,354 but also with other autoimmune diseases, including diabetes mellitus.355 The presence of HLA-B8 was related to higher mean anti-AChR titers,85,94 reflecting a state of immunologic hyper-reactivity. Further analysis of the HLA-DQ subregion revealed a close association with the presence of a 15-kb restriction fragment in MG patients, which was not the case in other patients with other autoimmune diseases, including HLA-DR3 positive diabetes mellitus or premature ovarian failure.356 The relative risk for a HLA-DR3 individual expressing the 15-kb restriction fragment to contract MG is 35 compared to a relative risk factor of 6 for HLA-B8.356 Therefore HLA-DQ polymorphism may be closely linked to the immune response genes to AChR and susceptibility for MG. Analysis of the DNA sequences of MG-associated HLA-DQ beta haplotypes may perhaps lead to therapy by blocking the sites by peptides or the HLA-DQ molecule interacting with AChR on the antigen-presenting cell. Similar peptide therapy has been successfully applied to treat experimental allergic encephalomyelitis in rats.357
The small molecule antibody mimic SH7139 targets a family of HLA-DRs expressed by B-cell lymphomas and other solid cancers
Published in Journal of Drug Targeting, 2020
Rod Balhorn, Monique Cosman Balhorn, Karuppiah Balakrishnan, Robert B. Rebhun
In the IHC assays conducted in this study, SH7129 exhibited very strong binding to its target as evidenced by its detection on the surface of the PBMCs expressing certain HLA-DRs even after thirteen buffer washes and two incubations (Table 2 and Figures 2 and 4). These results are consistent with the affinity of SH7129 reported previously for HLA-DR10 expressing Raji lymphoma cells (Kd ∼ 23pM) [22]. Although SH7129 is only 1/60th the size of an antibody, its affinity for HLA-DR7, HLA-DR9, HLA-DR10, HLA-DR11, HLA-DR12, HLA-DR13, HLA-DR15 and HLA-DR16 is similar to the best therapeutic monoclonal antibodies, which typically bind to their antigens with nM to pM affinities [97]. The observed lack of staining of PBMCs expressing HLA-DR1, HLA-DR3, HLA-DR4, HLA-DR8 and HLA-DR14 is most likely due to sequence differences predominantly in Site 2 that prevent Dv binding and to changes in Site 3 that block Cb binding. SH7129 may still bind to these HLA-DRs, but its affinity may not be high enough to remain bound under the stringent washing conditions used in our IHC assay. A one thousand-fold reduction in SHAL affinity would be expected if the sequence or structural changes eliminated the ability of one ligand to bind to HLA-DR. Bidentate SHALs containing only two ligands typically bind to their target protein with affinities in the nanomolar range. Picomolar affinities have only been observed with tridentate SHALs containing three ligands or with bis-bidentate SHALs that bind bivalently to two neighbouring HLA-DRs [22].
Targeting phosphorylated p53 to elicit tumor-reactive T helper responses against head and neck squamous cell carcinoma
Published in OncoImmunology, 2018
Kenzo Ohara, Takayuki Ohkuri, Takumi Kumai, Toshihiro Nagato, Yui Nozaki, Kei Ishibashi, Akemi Kosaka, Marino Nagata, Shohei Harabuchi, Mizuho Ohara, Kensuke Oikawa, Naoko Aoki, Yasuaki Harabuchi, Esteban Celis, Hiroya Kobayashi
As shown in Fig. 2, the dual-phosphorylated peptide p5322-41/Phospho-S33 and S37 (referred to as p-p53S33 and S37) could induce phosphorylated peptide-specific HTL responses from two individuals. These HTLs only responded to p-p53S33 and S37 and p-p53S33 in a concentration-dependent manner but not to p-p53S37 and non-phosphorylated wt p5322-41, suggesting that the TCR of these HTLs is specific to phosphorylated Ser33. These responses were restricted to HLA-DR molecules (Fig. 2B), indicating that the phosphorylated peptide was sufficient to allow binding to MHC class II molecules. To determine which HLA class II molecules presented the phosphorylated p53 peptides to the HTLs, a panel of mouse fibroblasts expressing single HLA-DR molecules was used as antigen presenting cells (APCs). As shown in Fig. 2C, HTLs J5 and J16 recognized the phosphorylated p53 peptide in the context of HLA-DR1, whereas the response of T20 was restricted by HLA-DR9. These findings demonstrate that the phosphorylated p53 peptides can bind to multiple HLA-DR molecules that cover a broad population of cancer patients. Taken together, these results revealed that HTL precursors that react to p-p53S33 and S37 exist in human PBMCs, and phosphorylated Ser33 might be more immunogenic than phosphorylated Ser37.
Bladder cancer-associated cancer-testis antigen-derived long peptides encompassing both CTL and promiscuous HLA class II-restricted Th cell epitopes induced CD4+ T cells expressing converged T-cell receptor genes in vitro
Published in OncoImmunology, 2018
Miki Tsuruta, Shohei Ueda, Poh Yin Yew, Isao Fukuda, Sachiko Yoshimura, Hiroyuki Kishi, Hiroshi Hamana, Masatoshi Hirayama, Junji Yatsuda, Atsushi Irie, Satoru Senju, Eiji Yuba, Tomomi Kamba, Masatoshi Eto, Hideki Nakayama, Yasuharu Nishimura
Using similar experiments, we could generate IFN-γ-producing Th cells specific to DEPDC1-LP2 (Fig. 2C), DEPDC1-LP3 (Fig. 2D and E), DEPDC1-LP4 (Fig. 2F–H), MPHOSPH1-LP1 (Fig. 2I–K), and MPHOSPH1-LP2 (Fig. 2L–N). In summary, DEPDC1-LPs induced HLA-DR4 (HD1 and HD4)-, HLA-DR53 (HD1), HLA-DR15 (HD5)- and HLA-DP5 (HD1, HD3 and HD7)-restricted Th cells, and MPHOSPH1-LPs induced HLA-DR4 (HD1 and HD4)-, HLA-DR9 (HD1)-, HLA-DP2 (HD2)- and HLA-DP5 (HD3)-restricted Th cells. The data indicated that these LPs were promiscuous Th-cell epitopes presented by frequently observed HLA class II molecules in the Japanese population (Table S4) as expeted,27,28 and combination of these peptides would induce DEPDC1- or MPHOSPH1-specific Th-cell responses in PBMCs of many Japanese donors.