Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population.
Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.
{"title":"Allergic bronchopulmonary aspergillosis in a lung transplant recipient treated with mepolizumab","authors":"Foteini Ioakeim , Christophe Abellan , Alessio Casutt , Benoit Lechartier , Leslie Noirez , Catherine Beigelman-Aubry , John-David Aubert , Zisis Balmpouzis , Angela Koutsokera","doi":"10.1016/j.clim.2024.110265","DOIUrl":"10.1016/j.clim.2024.110265","url":null,"abstract":"<div><p>Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to <em>Aspergillus</em> spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population.</p><p>Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1016/j.clim.2024.110263
Salem Al-Tamemi , Abdulhakim Al-Rawas , Murtadha Al-Khabori , Khalil Al-Farsi , Mohammed Al-Huneini , Amr Abdalla , Salam Al-Kindi , David Dennison
Background
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity.
Methods
A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT.
Results
The median age at transplant was 11.0 months (4.6–61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40–100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2–13.6), 0.9 × 109/L 0.6–1.2), and 0.5 × 109/L (0.2–0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0–14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4–11.5). The 10-year overall probability of survival is 84.3%.
Conclusion
Monitoring IRC is important in ensuring adequate disease-free survival.
{"title":"Immune reconstitution and survival, following hematopoietic stem cell transplantation in Omani patients with inborn errors of immunity","authors":"Salem Al-Tamemi , Abdulhakim Al-Rawas , Murtadha Al-Khabori , Khalil Al-Farsi , Mohammed Al-Huneini , Amr Abdalla , Salam Al-Kindi , David Dennison","doi":"10.1016/j.clim.2024.110263","DOIUrl":"10.1016/j.clim.2024.110263","url":null,"abstract":"<div><h3>Background</h3><p>Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity.</p></div><div><h3>Methods</h3><p>A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT.</p></div><div><h3>Results</h3><p>The median age at transplant was 11.0 months (4.6–61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40–100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2–13.6), 0.9 × 10<sup>9</sup>/L 0.6–1.2), and 0.5 × 10<sup>9</sup>/L (0.2–0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0–14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4–11.5). The 10-year overall probability of survival is 84.3%.</p></div><div><h3>Conclusion</h3><p>Monitoring IRC is important in ensuring adequate disease-free survival.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141141525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1016/j.clim.2024.110262
Sahla El Mahdaoui , Marie Mathilde Hansen , Malene Bredahl Hansen , Victoria Hyslop Hvalkof , Helle Bach Søndergaard , Mie Reith Mahler , Jeppe Romme Christensen , Finn Sellebjerg , Marina Rode von Essen
Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25− Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25− Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1+ Tfh cells and CD25− Tfh cells, and the frequency of CSF CD25− Tfh cells. The study suggests that CD25− Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.
{"title":"Effects of anti-CD20 therapy on circulating and intrathecal follicular helper T cell subsets in multiple sclerosis","authors":"Sahla El Mahdaoui , Marie Mathilde Hansen , Malene Bredahl Hansen , Victoria Hyslop Hvalkof , Helle Bach Søndergaard , Mie Reith Mahler , Jeppe Romme Christensen , Finn Sellebjerg , Marina Rode von Essen","doi":"10.1016/j.clim.2024.110262","DOIUrl":"10.1016/j.clim.2024.110262","url":null,"abstract":"<div><p>Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25<sup>−</sup> Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25<sup>−</sup> Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1<sup>+</sup> Tfh cells and CD25<sup>−</sup> Tfh cells, and the frequency of CSF CD25<sup>−</sup> Tfh cells. The study suggests that CD25<sup>−</sup> Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003711/pdfft?md5=067c9241e5b14c9188b12b45b28eafd8&pid=1-s2.0-S1521661624003711-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-22DOI: 10.1016/j.clim.2024.110261
Ubaid Ullah Kalim , Rahul Biradar , Sini Junttila , Mohd Moin Khan , Subhash Tripathi , Meraj Hasan Khan , Johannes Smolander , Kartiek Kanduri , Tapio Envall , Asta Laiho , Alexander Marson , Omid Rasool , Laura L. Elo , Riitta Lahesmaa
Gene regulatory elements, such as enhancers, greatly influence cell identity by tuning the transcriptional activity of specific cell types. Dynamics of enhancer landscape during early human Th17 cell differentiation remains incompletely understood. Leveraging ATAC-seq-based profiling of chromatin accessibility and comprehensive analysis of key histone marks, we identified a repertoire of enhancers that potentially exert control over the fate specification of Th17 cells. We found 23 SNPs associated with autoimmune diseases within Th17-enhancers that precisely overlapped with the binding sites of transcription factors actively engaged in T-cell functions. Among the Th17-specific enhancers, we identified an enhancer in the intron of RORA and demonstrated that this enhancer positively regulates RORA transcription. Moreover, CRISPR-Cas9-mediated deletion of a transcription factor binding site-rich region within the identified RORA enhancer confirmed its role in regulating RORA transcription. These findings provide insights into the potential mechanism by which the RORA enhancer orchestrates Th17 differentiation.
{"title":"A proximal enhancer regulates RORA expression during early human Th17 cell differentiation","authors":"Ubaid Ullah Kalim , Rahul Biradar , Sini Junttila , Mohd Moin Khan , Subhash Tripathi , Meraj Hasan Khan , Johannes Smolander , Kartiek Kanduri , Tapio Envall , Asta Laiho , Alexander Marson , Omid Rasool , Laura L. Elo , Riitta Lahesmaa","doi":"10.1016/j.clim.2024.110261","DOIUrl":"10.1016/j.clim.2024.110261","url":null,"abstract":"<div><p>Gene regulatory elements, such as enhancers, greatly influence cell identity by tuning the transcriptional activity of specific cell types. Dynamics of enhancer landscape during early human Th17 cell differentiation remains incompletely understood. Leveraging ATAC-seq-based profiling of chromatin accessibility and comprehensive analysis of key histone marks, we identified a repertoire of enhancers that potentially exert control over the fate specification of Th17 cells. We found 23 SNPs associated with autoimmune diseases within Th17-enhancers that precisely overlapped with the binding sites of transcription factors actively engaged in T-cell functions. Among the Th17-specific enhancers, we identified an enhancer in the intron of RORA and demonstrated that this enhancer positively regulates RORA transcription. Moreover, CRISPR-Cas9-mediated deletion of a transcription factor binding site-rich region within the identified RORA enhancer confirmed its role in regulating RORA transcription. These findings provide insights into the potential mechanism by which the RORA enhancer orchestrates Th17 differentiation.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S152166162400370X/pdfft?md5=ec84d01de2fe59f7a407e8d211a2b03c&pid=1-s2.0-S152166162400370X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-22DOI: 10.1016/j.clim.2024.110260
Ivy L. Debreceni , Jennifer Y. Barr , Ellen M. Upton , Yi-Guang Chen , Scott M. Lieberman
Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.
{"title":"IL-27 promotes pathogenic T cells in a mouse model of Sjögren's disease","authors":"Ivy L. Debreceni , Jennifer Y. Barr , Ellen M. Upton , Yi-Guang Chen , Scott M. Lieberman","doi":"10.1016/j.clim.2024.110260","DOIUrl":"https://doi.org/10.1016/j.clim.2024.110260","url":null,"abstract":"<div><p>Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39<sup>hi</sup> exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141090966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.
成纤维细胞样滑膜细胞(FLS)在类风湿性关节炎(RA)中起着至关重要的作用。伊塔康酸(ITA)是从三羧酸(TCA)循环中提取的一种内源性代谢物,因其抗炎、抗病毒和抗菌作用而备受关注。本研究评估了 ITA 对 FLS 的影响及其治疗 RA 的潜力。ITA在体外明显减少了FLS的增殖和迁移,并通过细胞外通量分析仪测量了线粒体氧化磷酸化和糖酵解。在 TCA 循环中,ITA 会积累包括琥珀酸盐和柠檬酸盐在内的代谢物。在Ⅱ型胶原诱导的关节炎(CIA)大鼠中,关节内注射ITA可减少关节炎和骨侵蚀。在胶原抗体诱导的关节炎中,缺乏产生ITA能力的Irg1缺陷小鼠的关节炎比对照小鼠更严重。ITA通过抑制FLS的增殖和迁移改善了CIA。因此,ITA可能是一种治疗RA的新型药物。
{"title":"Itaconate reduces proliferation and migration of fibroblast-like synoviocytes and ameliorates arthritis models","authors":"Maria Tada , Yuki Kudo , Michihito Kono , Masatoshi Kanda , Shuhei Takeyama , Kodai Sakiyama , Hotaka Ishizu , Tomohiro Shimizu , Tsutomu Endo , Ryo Hisada , Yuichiro Fujieda , Masaru Kato , Olga Amengual , Norimasa Iwasaki , Tatsuya Atsumi","doi":"10.1016/j.clim.2024.110255","DOIUrl":"10.1016/j.clim.2024.110255","url":null,"abstract":"<div><p>Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. <em>Irg1</em>-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-18DOI: 10.1016/j.clim.2024.110259
M.Y. Hardy , L.M. Henneken , A.K. Russell , Y. Okura , A. Mizoroki , Y. Ozono , S. Kobayashi , Y. Murakami , J.A. Tye-Din
The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52).
Objective
To assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes.
Methods
We employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 μg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody).
Results
In HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72–92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens.
Conclusion
DONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.
治疗乳糜泻(Ceeliac disease,CeD)的无麸质饮食是一种限制性饮食,往往不能诱导症状和/或粘膜疾病的完全缓解。麸质过敏症发病机制的核心是麸质特异性 CD4+ T 细胞,85% 以上的麸质过敏症患者的 CD4+ T 细胞受到 HLA-DQ2.5 的限制,这使得 HLA-DQ2.5 成为抑制麸质依赖性免疫的一个有吸引力的靶点。最近,一种新型抗HLA-DQ2.5抗体(DONQ52)被开发出来,它能特异性识别HLA-DQ2.5和多个麸质表位的复合物:目的:评估DONQ52抑制CeD患者T细胞对包含免疫优势T细胞表位的最具免疫原性的麸质多肽反应的能力:方法:我们在CeD患者中采用了体内麸质挑战模型,该模型可定量读出与疾病相关的麸质特异性T细胞反应。HLA-DQ2.5+ CeD 患者食用含有小麦、大麦或黑麦的食物 3 天,并在开始挑战前(D1)和挑战后 6 天(D6)采集血液。分离外周血单核细胞,并用干扰素(IFN)-γ 酶联免疫吸附点测定法(ELISpot)评估其对包含一系列免疫优势 T 细胞表位的麸质肽的反应。评估了 DONQ52(4 或 40 μg/mL)的抑制作用,并与泛 HLA-DQ 阻断(SPVL3 抗体)进行了比较:结果:在HLA-DQ2.5+ CeD患者中,DONQ52能降低T细胞对所有麦麸肽的反应,其效果等同于或高于泛HLA-DQ抗体阻断。它能将T细胞对最具有免疫优势的小麦表位的反应降低87.3%(IQR 72.4-92.4)。值得注意的是,DONQ52 还大大降低了 T 细胞对优势大麦角蛋白和黑麦鞘氨醇衍生肽的反应。DONQ52 对非麸质抗原的 T 细胞反应没有影响:结论:DONQ52 能显著阻断 HLA-DQ2.5 限制的 T 细胞对 CeD 中免疫原性最强的麸质多肽的反应。我们的研究结果支持体外数据,即 DONQ52 对多种谷蛋白肽:HLA-DQ2.5 复合物具有选择性和广泛的交叉反应性。这项工作提供了多特异性抗体阻断可能有效抑制 CeD 中致病性麸质特异性 T 细胞反应的概念证明,并为正在进行的治疗开发提供了支持。
{"title":"A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific T cells induced by gluten ingestion in patients with celiac disease","authors":"M.Y. Hardy , L.M. Henneken , A.K. Russell , Y. Okura , A. Mizoroki , Y. Ozono , S. Kobayashi , Y. Murakami , J.A. Tye-Din","doi":"10.1016/j.clim.2024.110259","DOIUrl":"10.1016/j.clim.2024.110259","url":null,"abstract":"<div><p>The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52).</p></div><div><h3>Objective</h3><p>To assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes.</p></div><div><h3>Methods</h3><p>We employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 μg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody).</p></div><div><h3>Results</h3><p>In HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72–92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens.</p></div><div><h3>Conclusion</h3><p>DONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003681/pdfft?md5=9fdf4526b65a872dc51c5c1e70e84367&pid=1-s2.0-S1521661624003681-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1016/j.clim.2024.110257
Jianfang Liao, Juan Cao
{"title":"Regarding the “Renal dysfunction in AQP4 NMOSD and MS; a potential predictor of relapse and prognosis”","authors":"Jianfang Liao, Juan Cao","doi":"10.1016/j.clim.2024.110257","DOIUrl":"10.1016/j.clim.2024.110257","url":null,"abstract":"","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141049939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lymphocytes such as CD4+ T cells and B cells mainly infiltrate the salivary glands; however, the precise roles and targets of autoreactive T cells and autoantibodies in the pathogenesis of Sjögren's Syndrome (SS) remain unclear. This study was designed to clarify the role of autoreactive T cells and autoantibodies at the single-cell level involved in the development of sialadenitis. Infiltrated CD4+ T and B cells in the salivary glands of a mouse model resembling SS were single-cell-sorted, and their T cell receptor (TCR) and B cell receptor (BCR) sequences were analyzed. The predominant TCR and BCR clonotypes were reconstituted in vitro, and their pathogenicity was evaluated by transferring reconstituted TCR-expressing CD4+ T cells into Rag2−/− mice and administering recombinant IgG in vivo. The reconstitution of Th17 cells expressing TCR (#G) in Rag2−/− mice resulted in the infiltration of T cells into the salivary glands and development of sialadenitis, while an autoantibody (IgGr22) was observed to promote the proliferation of pathogenic T cells. IgGr22 specifically recognizes double-stranded RNA (dsRNA) and induces the activation of dendritic cells, thereby enhancing the expression of IFN signature and inflammatory genes. TCR#G recognizes antigens related to the gut microbiota. Antibiotic treatment severely reduces the activation of TCR#G-expressing Th17 cells and suppresses sialadenitis development. These data suggest that the anti-dsRNA antibodies and, TCR recognizing the gut microbiota involved in the development of sialadenitis like SS. Thus, our model provides a novel strategy for defining the roles of autoreactive TCR and autoantibodies in the development and pathogenesis of SS.
CD4+ T细胞和B细胞等淋巴细胞主要浸润唾液腺;然而,自反应性T细胞和自身抗体在斯约格伦综合征(SS)发病机制中的确切作用和靶点仍不清楚。本研究旨在阐明自反应 T 细胞和自身抗体在单细胞水平上参与唾液腺炎发病的作用。对类似 SS 的小鼠模型唾液腺中浸润的 CD4+ T 细胞和 B 细胞进行了单细胞分选,并分析了它们的 T 细胞受体(TCR)和 B 细胞受体(BCR)序列。体外重组了主要的TCR和BCR克隆型,并通过将重组的TCR表达CD4+ T细胞转移到Rag2-/-小鼠体内和体内注射重组IgG来评估它们的致病性。在Rag2-/-小鼠体内重组表达TCR(#G)的Th17细胞会导致T细胞浸润唾液腺并引发唾液腺炎,同时观察到一种自身抗体(IgGr22)会促进致病性T细胞的增殖。IgGr22 能特异性识别双链 RNA(dsRNA)并诱导树突状细胞活化,从而增强 IFN 标志和炎症基因的表达。TCR#G 可识别与肠道微生物群相关的抗原。抗生素治疗严重降低了表达 TCR#G 的 Th17 细胞的活化,抑制了唾液腺炎的发展。这些数据表明,抗dsRNA抗体和识别肠道微生物群的TCR参与了类似SS的唾液腺炎的发生。因此,我们的模型为确定自反应性 TCR 和自身抗体在 SS 的发展和发病机制中的作用提供了一种新策略。
{"title":"Reconstruction of Sjögren's syndrome-like sialadenitis by a defined disease specific gut-reactive single TCR and an autoantibody","authors":"Mana Iizuka-Koga , Minako Ito , Noriko Yumoto , Setsuko Mise-Omata , Taeko Hayakawa , Kyoko Komai , Shunsuke Chikuma , Satoru Takahashi , Isao Matsumoto , Takayuki Sumida , Akihiko Yoshimura","doi":"10.1016/j.clim.2024.110258","DOIUrl":"10.1016/j.clim.2024.110258","url":null,"abstract":"<div><p>Lymphocytes such as CD4<sup>+</sup> T cells and B cells mainly infiltrate the salivary glands; however, the precise roles and targets of autoreactive T cells and autoantibodies in the pathogenesis of Sjögren's Syndrome (SS) remain unclear. This study was designed to clarify the role of autoreactive T cells and autoantibodies at the single-cell level involved in the development of sialadenitis. Infiltrated CD4<sup>+</sup> T and B cells in the salivary glands of a mouse model resembling SS were single-cell-sorted, and their T cell receptor (TCR) and B cell receptor (BCR) sequences were analyzed. The predominant TCR and BCR clonotypes were reconstituted in vitro, and their pathogenicity was evaluated by transferring reconstituted TCR-expressing CD4<sup>+</sup> T cells into Rag2<sup>−/−</sup> mice and administering recombinant IgG in vivo. The reconstitution of Th17 cells expressing TCR (#G) in Rag2<sup>−/−</sup> mice resulted in the infiltration of T cells into the salivary glands and development of sialadenitis, while an autoantibody (IgGr22) was observed to promote the proliferation of pathogenic T cells. IgGr22 specifically recognizes double-stranded RNA (dsRNA) and induces the activation of dendritic cells, thereby enhancing the expression of IFN signature and inflammatory genes. TCR#G recognizes antigens related to the gut microbiota. Antibiotic treatment severely reduces the activation of TCR#G-expressing Th17 cells and suppresses sialadenitis development. These data suggest that the anti-dsRNA antibodies and, TCR recognizing the gut microbiota involved in the development of sialadenitis like SS. Thus, our model provides a novel strategy for defining the roles of autoreactive TCR and autoantibodies in the development and pathogenesis of SS.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S152166162400367X/pdfft?md5=a89c51a62bd2d391439f22d442f68c69&pid=1-s2.0-S152166162400367X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In metastatic renal cell carcinoma (mRCC), existing treatments including checkpoint inhibitors are failed to cure and/or prevent recurrence of the disease. Therefore, in-depth understanding of tumor tissue resident memory T cells (TRMs) dysfunction are necessitated to enrich efficacy of immunotherapies and increasing disease free survival in treated patients. In patients, we observed dysregulation of K+, Ca2+, Na2+ and Zn2+ ion channels leads to excess infiltration of their respective ions in tumor TRMs, thus ionic gradients are disturbed and cells became hyperpolarized. Moreover, overloaded intramitochondrial calcium caused mitochondrial depolarization and trigger apoptosis of tumor TRMs. Decreased prevalence of activated tumor TRMs reflected our observations. Furthermore, disruptions in ionic concentrations impaired the functional activities and/or suppressed anti-tumor action of circulating and tumor TRMs in RCC. Collectively, these findings revealed novel mechanism behind dysfunctionality of tumor TRMs. Implicating enrichment of activated TRMs within tumor would be beneficial for better management of RCC patients.
{"title":"Ionic reverberation modulates the cellular fate of CD8+tissue resident memory T cells (TRMs) in patients with renal cell carcinoma: A novel mechanism","authors":"Ashu Singh , Saumitra Dey Choudhury , Prabhjot Singh , Vishwendra Vikram Singh , Som Nath Singh , Alpana Sharma","doi":"10.1016/j.clim.2024.110256","DOIUrl":"10.1016/j.clim.2024.110256","url":null,"abstract":"<div><p>In metastatic renal cell carcinoma (mRCC), existing treatments including checkpoint inhibitors are failed to cure and/or prevent recurrence of the disease. Therefore, in-depth understanding of tumor tissue resident memory T cells (TRMs) dysfunction are necessitated to enrich efficacy of immunotherapies and increasing disease free survival in treated patients. In patients, we observed dysregulation of K<sup>+</sup>, Ca<sup>2+</sup>, Na<sup>2+</sup> and Zn<sup>2+</sup> ion channels leads to excess infiltration of their respective ions in tumor TRMs, thus ionic gradients are disturbed and cells became hyperpolarized. Moreover, overloaded intramitochondrial calcium caused mitochondrial depolarization and trigger apoptosis of tumor TRMs. Decreased prevalence of activated tumor TRMs reflected our observations. Furthermore, disruptions in ionic concentrations impaired the functional activities and/or suppressed anti-tumor action of circulating and tumor TRMs in RCC. Collectively, these findings revealed novel mechanism behind dysfunctionality of tumor TRMs. Implicating enrichment of activated TRMs within tumor would be beneficial for better management of RCC patients.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}