Supplementary Figure 1.Optimization IHC on pilot series of cHL cases. from Classical Hodgkin Lymphoma with Reduced β<sub>2</sub>M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status
Margaretha G.M. RoemerRanjana H. AdvaniRobert ReddGeraldine S. PinkusYasodha NatkunamAzra H. LigonCourtney ConnellyChristine J. PakChristopher D. CareySarah E. DaadiBjoern ChapuyDaphne de JongRichard T. HoppeDonna NeubergMargaret A. ShippScott J. Rodig
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<p>Three distinct patterns of staining of HRS cell membranes were observed relative to the staining of reactive inflammatory cells: "positive" (Pos), "decreased" (Dec) and "negative" (Neg) for β2M, MHC class I and MHC class II. CHL #1: β2M and MHC class I positive, MHC class II negative; cHL #2: beta2M and MHC class I decreased, MHC class II positive; cHL #3: beta2M and MHC class I negative, MHC class II decreased. Black arrows highlight individual HRS cells or two adjacent HRS cells with distinct patterns of membrane staining, as indicated.</p>Keywords:
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Abstract Recent studies demonstrate that MHC class II molecules can signal via associated Ig-αβ dimers, signal transducers previously thought to function only in B cell Ag receptor (BCR) signaling. Surprisingly, the biologic outputs of MHC class II and BCR ligation (by thymus-dependent Ags) differ, e.g., MHC class II signaling leads to robust proliferation and extension of pseudopods. It seemed possible that these differences might be due, at least in part, to differential use of inhibitory coreceptors thought to modulate membrane Ig signals. In this study, we demonstrate that CD22, an inhibitory BCR coreceptor, neither associates with nor functions in MHC class II/Ig-αβ signaling. Interestingly, CD22 is actively excluded from cell surface MHC class II aggregates.
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In the past years we performed studies to gain more insight into the processing of major histocompatibility class II (MHC class II) in dendritic cells. We focused on the sorting mechanisms of MHC class II, the degradation of its associated Ii and peptide loading at the endosomal system. In addition, we investigated the regulatory function of these intracellular processes on MHC class II surface expression and antigen presentation. In chapter 2 of this thesis we report that MHC class II can be post-translationally modified by the addition of ubiquitin moieties at a unique lysine residue in the cytosolic domain of the b-chain. Furthermore, it is demonstrated that ubiquitination of MHC class II regulates its cell surface expression by providing a signal for efficient sorting towards degradation in the lysosome. The third chapter describes the effect on MHC class II homeostasis when the formation of ILV is hampered by over-expressing a dominant negative mutant of VPS4. We observed that interference with ILV formation did not affect MHC class II peptide loading but increased MHC class II expression by immature DCs, underlining the role of MVB sorting in MHC class II degradation. The long standing issue on whether the large amount of ILV-localized MHC class II present in immature DCs can be recruited by maturing DCs for antigen presentation is covered in chapter 4. Here we show that upon DC activation, antigens are presented mainly by newly synthesized MHC class II. In chapter 5 we report that, in contrast to claims in existing literature, the degradation of the MHC class II associated invariant chain is a constitutive process and not up-regulated during DC maturation. We also pinpointed a possible artifact that can explain these discrepancies in the literature. In chapter 6 an experimental procedure is presented that improves antigen presentation by immature dendritic cells. We were able to show that an artificially intracellularly accumulated cohort of MHC class II molecules could be synchronously released to enhance cell surface expression of MHC class II and antigen presentation towards T cells. The strategy described in this chapter might be helpful to design immuno-tolerizing vaccines.
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연구배경: 갑상선 유두암은 비교적 예후가 좋은 것으로 알려져 있으나 재발을 하거나 원격전이 및 주위조직 침습을 동반하는 경우 예후가 나쁜 것으로 알려져 있다. 그러나 현재 갑상선 유두암의 예후를 예상할 수 있는 적당한 분자표지자가 없는 상태이다. MHC 항원은 갑상선암의 발생 및 진행에 대한 면역반응에 필수적인 분자로 알려져 있다. 또한 최근 진행된 연구에 의해 MHC class II 항원이 갑상선 유두암의 발암 유전자 돌연변이에 의해 발현이 증가된다는 사실이 알려졌다. 이에 저자들은 MHC class II 항원의 발현 유무와 갑상선 유두암의 임상양상의 관련성을 평가하기 위하여 본 연구를 수행하였다. 방법: 1987년부터 2003년까지 갑상선 절제술을 시행한 215명의 환자를 대상으로 의무기록 검토를 통한 임상양상 및 다양한 예후 인자들에 대한 후향적 분석을 시행하였으며 이들의 갑상선 조직에 대한 면역조직화학적 염색을 통해 MHC class II 항원의 발현 유무를 조사하였다. 추적관찰을 통해 재발 여부를 분명하게 판정할 수 있는 43명의 갑상선 유두암 환자를 선별하여 재발군과 비재발군으로 분류하였으며 두 군 간의 MHC 항원의 발현 양상에 따른 차이를 비교하였다. 결과: MHC class II 항원은 양성 질환에 비해 갑상선암에서 발현이 증가되어 있었으며 특히 갑상선 유두암에서 통계학적으로 의미 있게 발현이 증가되어 있었다. 갑상선 유두암에서 나이를 제외한 대부분의 임상적 인자 및 병리학적 인자들이 MHC class II 항원의 발현 유무에 따른 차이를 보이지 않았다. MHC class I 항원은 재발군과 비재발군 사이에서 발현 양상에 차이가 나지 않았으나 MHC class II 항원의 경우 재발군에서 발현이 억제되어 있어 비재발군과 통계학적으로 의미 있는 차이를 보였다. 결론: MHC class II 항원은 갑상선 유두암이 재발한 환자에서 발현이 저하되어 있는 것으로 확인되어 임상양상을 예측할 수 있는 분자표지자로서의 활용 가능성이 높다고 하겠다.
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Abstract CD8+ and CD4+ T lymphocytes are important in controlling human CMV (HCMV) infection, but the virus has evolved protean mechanisms to inhibit MHC-based Ag presentation and escape T lymphocyte immunosurveillance. Herein, the interaction of HCMV with the MHC class II Ag presentation pathway was investigated in cells stably transfected with class II transactivator. Flow cytometry experiments demonstrate that HCMV infection decreases cell-surface MHC class II expression. HCMV down-regulates MHC class II surface expression without a significant effect on class II RNA or steady-state protein levels. SDS-stability and confocal microscopy experiments demonstrate normal levels of steady-state peptide-loaded class II molecules in infected cells and that class II molecules reach late endosomal and HLA-DM positive peptide-loading compartments. However, MHC class II positive vesicles are retained in an abnormal perinuclear distribution. Finally, experiments with a mutant HCMV strain demonstrate that this novel mechanism of decreased MHC class II expression is not mediated by one of the known HCMV immunomodulatory genes. These defects in MHC class II expression combined with previously identified CMV strategies for decreasing MHC class I expression enables infected cells to evade T lymphocyte immunosurveillance.
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The endosomal compartment, which contains all the components required for loading peptides onto MHC class II molecules, is classically considered to be dedicated to the loading of MHC class II but not MHC class I molecules. However, a report in this issue of the European Journal of Immunology [Eur. J. Immunol. 2014. 44: 774-784], together with other recent studies, shows that the endosomal compartment also supports efficient loading of MHC class I molecules. These results bring a new perspective on the crosstalk between the MHC class II and MHC class I antigen-processing pathways, and may inspire new ideas for the design of vaccines against viruses and tumors.
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Abstract CD4+ T lymphocytes play an important role in CD8+ T cell–mediated responses against tumors. Considering that ∼20% of melanomas express MHC class II, it is plausible that concomitant presentation by MHC class I and class II shapes positive (helper T cells) or negative (regulatory T cells) antitumor responses. Interestingly, gp100, a melanoma antigen, can be presented by both MHC class I and class II when expressed endogenously, suggesting that it can reach endosomal/MHC class II compartments (MIIC). Here, we showed that gp100 putative NH2-terminal signal sequence and the last 70 residues in COOH terminus are essential for MIIC localization and MHC class II presentation. Confocal microscopy analyses confirmed that gp100 was localized in LAMP-1+/HLA-DR+ endosomal/MIIC. Gp100 targeting sequences were characterized by deleting different sections in the COOH terminus (last 70 residues). Transfection in 293T cells, expressing MHC class I and class II molecules, revealed that specific deletions in COOH terminus resulted in decreased MHC class II presentation, without effects on class I presentation, suggesting a role in MIIC trafficking for these deleted sections. Then, we used these gp100 targeting sequences to mobilize green fluorescent protein to endosomal compartments and to allow MHC class II and class I presentation of minimal endogenous epitopes. We conclude that these specific sequences are MIIC-targeting motifs, which could be included in expression cassettes for endogenously expressed tumor or viral antigens for MHC class II and class I presentation and optimize in vivo T-cell responses or as an in vitro tool for characterization of new MHC class II epitopes. (Cancer Res 2006; 66(4): 2423-32)
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The major histocompatibility class I (MHC-I) genes are highly polymorphic and the proteins that they encode play a crucial role in both the innate and the adaptive immune response. A MHC-I molecule consists of three parts, one polymorphic heavy chain, one invariant light chain, β2-microglobulin and a peptide of usually between 8-11 amino acids in length. The maturation and quality control of MHC-I takes place in the endoplasmic reticulum and involves several different proteins including the MHC-I dedicated protein tapasin. In this thesis we have studied different parameters important for MHC-I formation and stability in humans and birds. We have used various approaches including in silico prediction methods, biochemical assays and cellular assays to elucidate the MHC-I maturation. We show that the functional relationships between MHC-I molecules in passerine birds of different species are based on the MHC-I characteristics such as peptide-binding specificity rather than species characteristics. In addition, passerine MHC-I molecules similar to human MHC-I molecules, have a complex dissociation. This suggests that just as in humans, passerine MHC-I molecules go through different maturation stages that most likely include interaction with quality control proteins such as tapasin. The cell surface expression of stable MHC-I molecules is crucial for the function of the adaptive immune response and for this reason MHC-I and its related proteins are often a target for viral and tumour evasion strategies. In human cells we show that tapasin promotes the formation of stable cell surface expressed MHC-I molecules and that the dependency on tapasin for a stable cell surface expression varies between different allomorphs (allele specific protein products). The dysregulation of tapasin results in alterations in the peptide repertoire that is presented by MHC-I at the cell surface and most often this induces a decreased stability of the expressed molecules. We here show that by adding certain peptides exogenously to cells deficient in tapasin we were able to increase MHC-I cell surface stability significantly suggesting that exogenous modulations of tapasin deficient cells might be a possible approach in immunotherapy. The formation of aberrant conformations of HLA-B*27:05 has been suggested to play a role in the pathogenesis of ankylosing spondylitis and here we showed that tapasin has a preventive effect on the formation and presentation of aberrant conformations of HLA-B*27:05 at the cell surface. In conclusion we show that the complex kinetics of MHC-I maturation and stability is a trait shared between birds and humans and we suggest that by studying MHC-I in other species than human we can gain valuable insight into the complex world of MHC-I. (Less)
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