Pub Date : 2025-03-14DOI: 10.1016/j.smim.2025.101944
Jane Andersen , Fabienne Brilot
MOG antibody-associated disease (MOGAD), an inflammatory demyelinating pathology, is typically associated with the clinical phenotypes acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), or transverse myelitis (TM). The mainstay of diagnosis is detection of antibodies targeting oligodendrocyte-expressed MOG (MOG-IgG). MOG-IgG-mediated demyelination occurs via complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), enhanced cognate T-cell CNS infiltration and activation, and oligodendrocyte cytoskeleton disruption, but the exact role of the immune system in MOGAD is still poorly understood. The disease course is either monophasic or relapsing, with relapsing course affecting approximately two-thirds of individuals. Neurological disability accumulates with relapse and may manifest as visual, motor, sensory, and cognitive deficits. Thus, accurate disease course prediction is of paramount importance. Prognostic biomarkers, implemented at a global scale, have the potential to guide timely therapeutic decisions to limit relapse-associated disability accrual while simultaneously avoiding unnecessary immunosuppression in monophasic individuals. This review explores recent insights in the understanding of MOGAD pathogenesis as well as advances in prognostic biomarkers of relapsing course and disease activity.
{"title":"Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Insights into pathogenesis and biomarkers of prognosis","authors":"Jane Andersen , Fabienne Brilot","doi":"10.1016/j.smim.2025.101944","DOIUrl":"10.1016/j.smim.2025.101944","url":null,"abstract":"<div><div>MOG antibody-associated disease (MOGAD), an inflammatory demyelinating pathology, is typically associated with the clinical phenotypes acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), or transverse myelitis (TM). The mainstay of diagnosis is detection of antibodies targeting oligodendrocyte-expressed MOG (MOG-IgG). MOG-IgG-mediated demyelination occurs via complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), enhanced cognate T-cell CNS infiltration and activation, and oligodendrocyte cytoskeleton disruption, but the exact role of the immune system in MOGAD is still poorly understood. The disease course is either monophasic or relapsing, with relapsing course affecting approximately two-thirds of individuals. Neurological disability accumulates with relapse and may manifest as visual, motor, sensory, and cognitive deficits. Thus, accurate disease course prediction is of paramount importance. Prognostic biomarkers, implemented at a global scale, have the potential to guide timely therapeutic decisions to limit relapse-associated disability accrual while simultaneously avoiding unnecessary immunosuppression in monophasic individuals. This review explores recent insights in the understanding of MOGAD pathogenesis as well as advances in prognostic biomarkers of relapsing course and disease activity.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101944"},"PeriodicalIF":7.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143621427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-13DOI: 10.1016/j.smim.2025.101941
Esko Kemppainen, Olga Albó, Helka Kaunisto, Emilia Siukola, Katri Lindfors
In celiac disease (CeD), dietary gluten serves as the driver for a comparatively well characterized small bowel mucosal immune response that generally results in small bowel mucosal villous atrophy and crypt hyperplasia along with a disease-specific transglutaminase 2 (TG2) targeting autoantibody response. Individuals with positive TG2 autoantibodies but normal small intestinal mucosal morphology are regarded at increased risk of developing CeD and represent patients with potential CeD. The removal of gluten from the diet leads to disappearance of the autoantibodies and normalization of the mucosal architecture in most cases. However, refractory CeD patients deviate from this dogma as they present with abnormal T cell compartment, persistent symptoms and villous atrophy despite a strict gluten-free diet. The heterogeneity of CeD presentation is further diversified by varying symptomatology. Gastrointestinal symptoms are the most canonical signs of CeD, and they include for instance diarrhea, vomiting, constipation and abdominal pain. Yet, a great portion of the patients manifest the disease at extraintestinal sites such as skin, musculoskeletal system or neuronal tissues. Beyond the involvement of various transglutaminase autoantibodies, the detailed immune mechanisms contributing to the development of these manifestations remains elusive, though. This review highlights the current understanding of the immunological differences in various manifestations of CeD. As the immunological basis of the different CeD phenotypes is at present insufficiently understood, more research on the subject is warranted before such data could be maximally applied to clinical practice.
{"title":"Differential immune responses behind different celiac disease manifestations","authors":"Esko Kemppainen, Olga Albó, Helka Kaunisto, Emilia Siukola, Katri Lindfors","doi":"10.1016/j.smim.2025.101941","DOIUrl":"10.1016/j.smim.2025.101941","url":null,"abstract":"<div><div>In celiac disease (CeD), dietary gluten serves as the driver for a comparatively well characterized small bowel mucosal immune response that generally results in small bowel mucosal villous atrophy and crypt hyperplasia along with a disease-specific transglutaminase 2 (TG2) targeting autoantibody response. Individuals with positive TG2 autoantibodies but normal small intestinal mucosal morphology are regarded at increased risk of developing CeD and represent patients with potential CeD. The removal of gluten from the diet leads to disappearance of the autoantibodies and normalization of the mucosal architecture in most cases. However, refractory CeD patients deviate from this dogma as they present with abnormal T cell compartment, persistent symptoms and villous atrophy despite a strict gluten-free diet. The heterogeneity of CeD presentation is further diversified by varying symptomatology. Gastrointestinal symptoms are the most canonical signs of CeD, and they include for instance diarrhea, vomiting, constipation and abdominal pain. Yet, a great portion of the patients manifest the disease at extraintestinal sites such as skin, musculoskeletal system or neuronal tissues. Beyond the involvement of various transglutaminase autoantibodies, the detailed immune mechanisms contributing to the development of these manifestations remains elusive, though. This review highlights the current understanding of the immunological differences in various manifestations of CeD. As the immunological basis of the different CeD phenotypes is at present insufficiently understood, more research on the subject is warranted before such data could be maximally applied to clinical practice.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101941"},"PeriodicalIF":7.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143621426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-08DOI: 10.1016/j.smim.2025.101933
Sharan Kumar Balaji , Waris Muhammad Khuwaja , Md Liakat Hossain , Luchiano Giovanni Benjamin Fernando, Xintong Dong
Itch is an unpleasant sensation that is encoded by specific sensory neurons called pruriceptors. Itch is associated with almost all skin diseases. Recent studies revealed that many itchy skin diseases are associated with microbiome dysbiosis. Pathogenic microbes secrete proteases and toxins to invade skin cells. Some microbial products can directly activate sensory neurons, while others activate the mammalian immune system and indirectly cause itch. In this review, we summarize the current knowledge on microbe-immune-neuron crosstalks and discuss their relevance in itchy skin diseases.
{"title":"Neuroimmune interactions between itch neurons and skin microbes","authors":"Sharan Kumar Balaji , Waris Muhammad Khuwaja , Md Liakat Hossain , Luchiano Giovanni Benjamin Fernando, Xintong Dong","doi":"10.1016/j.smim.2025.101933","DOIUrl":"10.1016/j.smim.2025.101933","url":null,"abstract":"<div><div>Itch is an unpleasant sensation that is encoded by specific sensory neurons called pruriceptors. Itch is associated with almost all skin diseases. Recent studies revealed that many itchy skin diseases are associated with microbiome dysbiosis. Pathogenic microbes secrete proteases and toxins to invade skin cells. Some microbial products can directly activate sensory neurons, while others activate the mammalian immune system and indirectly cause itch. In this review, we summarize the current knowledge on microbe-immune-neuron crosstalks and discuss their relevance in itchy skin diseases.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101933"},"PeriodicalIF":7.4,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-18DOI: 10.1016/j.smim.2025.101931
Ruchi Saxena , Elizabeth B. Gottlin , Michael J. Campa , You-Wen He , Edward F. Patz Jr.
Cancer remains a formidable global health challenge requiring the continued exploration of innovative therapeutic approaches. While traditional treatment strategies including surgery, chemotherapy, and radiation therapy have had some success, primarily in early-stage disease, the quest for more targeted, personalized, safer, and effective therapies remains an ongoing pursuit. Over the past decade, significant advances in the field of tumor immunology have dramatically shifted a focus towards immunotherapy, although the ability to harness and coopt the immune system to treat cancer is still just beginning to be realized. One important area that has yet to be fully explored is the complement system, an integral part of innate immunity that has gathered attention recently as a source of potential targets for anti-cancer therapy. The complement system has a complex and context dependent role in cancer biology in that it not only contributes to immune surveillance but also may promote tumor progression. Complement regulators, including CD46, CD55, CD59, and complement factor H, exercise defined control over complement activation, and have also been acknowledged for their role in the tumor microenvironment. This review explores the intricate role of complement regulators in cancer development and progression, examining their potential as therapeutic targets, current strategies, challenges, and the evolving landscape of clinical research.
{"title":"Complement regulators as novel targets for anti-cancer therapy: A comprehensive review","authors":"Ruchi Saxena , Elizabeth B. Gottlin , Michael J. Campa , You-Wen He , Edward F. Patz Jr.","doi":"10.1016/j.smim.2025.101931","DOIUrl":"10.1016/j.smim.2025.101931","url":null,"abstract":"<div><div>Cancer remains a formidable global health challenge requiring the continued exploration of innovative therapeutic approaches. While traditional treatment strategies including surgery, chemotherapy, and radiation therapy have had some success, primarily in early-stage disease, the quest for more targeted, personalized, safer, and effective therapies remains an ongoing pursuit. Over the past decade, significant advances in the field of tumor immunology have dramatically shifted a focus towards immunotherapy, although the ability to harness and coopt the immune system to treat cancer is still just beginning to be realized. One important area that has yet to be fully explored is the complement system, an integral part of innate immunity that has gathered attention recently as a source of potential targets for anti-cancer therapy. The complement system has a complex and context dependent role in cancer biology in that it not only contributes to immune surveillance but also may promote tumor progression. Complement regulators, including CD46, CD55, CD59, and complement factor H, exercise defined control over complement activation, and have also been acknowledged for their role in the tumor microenvironment. This review explores the intricate role of complement regulators in cancer development and progression, examining their potential as therapeutic targets, current strategies, challenges, and the evolving landscape of clinical research.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101931"},"PeriodicalIF":7.4,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-11DOI: 10.1016/j.smim.2025.101932
Mohamed-Ridha Barbouche, Luigi D. Notarangelo
{"title":"Learning from Inborn Errors of Immunity: From mechanisms to translation","authors":"Mohamed-Ridha Barbouche, Luigi D. Notarangelo","doi":"10.1016/j.smim.2025.101932","DOIUrl":"10.1016/j.smim.2025.101932","url":null,"abstract":"","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101932"},"PeriodicalIF":7.4,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-10DOI: 10.1016/j.smim.2024.101928
Rebecca Liu , Dean R. Buttaci , Caroline L. Sokol
Once regarded as distinct systems, the nervous system and the immune system are now recognized for their complex interactions within the barrier tissues. The neuroimmune circuitry comprises a dual-network system that detects external and internal disturbances, providing critical information to tailor a context-specific response to various threats to tissue integrity, such as wounding or exposure to noxious and harmful stimuli like pathogens, toxins, or allergens. Using the skin as an example of a barrier tissue with the polarized sensory neuronal responses of itch and pain, we explore the molecular pathways driving neuronal activation and the effects of this activation on the immune response. We then apply these findings to other barrier tissues, to find common pathways controlling neuroimmune responses in the barriers.
{"title":"Neurogenic inflammation and itch in barrier tissues","authors":"Rebecca Liu , Dean R. Buttaci , Caroline L. Sokol","doi":"10.1016/j.smim.2024.101928","DOIUrl":"10.1016/j.smim.2024.101928","url":null,"abstract":"<div><div>Once regarded as distinct systems, the nervous system and the immune system are now recognized for their complex interactions within the barrier tissues. The neuroimmune circuitry comprises a dual-network system that detects external and internal disturbances, providing critical information to tailor a context-specific response to various threats to tissue integrity, such as wounding or exposure to noxious and harmful stimuli like pathogens, toxins, or allergens. Using the skin as an example of a barrier tissue with the polarized sensory neuronal responses of itch and pain, we explore the molecular pathways driving neuronal activation and the effects of this activation on the immune response. We then apply these findings to other barrier tissues, to find common pathways controlling neuroimmune responses in the barriers.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101928"},"PeriodicalIF":7.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-09DOI: 10.1016/j.smim.2025.101930
Ketil Størdal , Kalle Kurppa
In recent years, wheat- and gluten-free diets have increased in demand due to reported increases in various conditions reported to be driven by ingredients of these food products. Celiac disease, wheat allergy and non-celiac wheat sensitivity constitute the three main categories of wheat-related disorders. Celiac disease is a well-characterized immune-mediated disease caused by immune reaction against specific gliadin epitopes, the main protein in wheat. Screening studies of samples collected over time bring evidence that there is a true increase in prevalence not only driven by increased testing activity. Clinical presentation of CeD is diverse and there is an increased risk of autoimmune co-morbidities. Wheat allergy consists of IgE- and non-IgE-mediated reactions, driven by Th2-cells directing eosinophil and basophil responses. Rapid IgE-mediated reactions are characterized by specific IgE antibodies in conjunction with symptoms originating especially from the respiratory and gastrointestinal tract. There is an increased risk of other allergies and the majority recover during adolescence. Non-IgE-mediated wheat allergy is a less-well defined condition, which is often diagnostically challenging due to a longer interval between exposure and symptoms and lack of non-invasive biomarkers. In this condition, wheat as a trigger needs to be established by exclusion followed by dietary challenge. Non-celiac wheat sensitivity, despite being the most recently recognized, has the highest reported prevalence among the three wheat-related entities. It remains, however, particularly poorly characterized due to unclear pathophysiology and lack of diagnostic markers. This narrative review will scrutinize the shared and distinct clinical features of the three wheat-related conditions, focusing on epidemiology, clinical presentation, co-morbidities, diagnosis, treatment and prognosis.
{"title":"Celiac disease, non-celiac wheat sensitivity, wheat allergy – clinical and diagnostic aspects","authors":"Ketil Størdal , Kalle Kurppa","doi":"10.1016/j.smim.2025.101930","DOIUrl":"10.1016/j.smim.2025.101930","url":null,"abstract":"<div><div>In recent years, wheat- and gluten-free diets have increased in demand due to reported increases in various conditions reported to be driven by ingredients of these food products. Celiac disease, wheat allergy and non-celiac wheat sensitivity constitute the three main categories of wheat-related disorders. Celiac disease is a well-characterized immune-mediated disease caused by immune reaction against specific gliadin epitopes, the main protein in wheat. Screening studies of samples collected over time bring evidence that there is a true increase in prevalence not only driven by increased testing activity. Clinical presentation of CeD is diverse and there is an increased risk of autoimmune co-morbidities. Wheat allergy consists of IgE- and non-IgE-mediated reactions, driven by Th2-cells directing eosinophil and basophil responses. Rapid IgE-mediated reactions are characterized by specific IgE antibodies in conjunction with symptoms originating especially from the respiratory and gastrointestinal tract. There is an increased risk of other allergies and the majority recover during adolescence. Non-IgE-mediated wheat allergy is a less-well defined condition, which is often diagnostically challenging due to a longer interval between exposure and symptoms and lack of non-invasive biomarkers. In this condition, wheat as a trigger needs to be established by exclusion followed by dietary challenge. Non-celiac wheat sensitivity, despite being the most recently recognized, has the highest reported prevalence among the three wheat-related entities. It remains, however, particularly poorly characterized due to unclear pathophysiology and lack of diagnostic markers. This narrative review will scrutinize the shared and distinct clinical features of the three wheat-related conditions, focusing on epidemiology, clinical presentation, co-morbidities, diagnosis, treatment and prognosis.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101930"},"PeriodicalIF":7.4,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-09DOI: 10.1016/j.smim.2025.101929
Andrea Balduit , Chiara Agostinis , Roberta Bulla
Ground-breaking awareness has been reached about the intricate and dynamic connection between developing tumors and the host immune system. Being a powerful arm of innate immunity and a functional bridge with adaptive immunity, the complement system (C) has also emerged as a pivotal player in the tumor microenvironment (TME). Its “double-edged sword” role in cancer can find an explanation in the controversial relationship between C capability to mediate tumor cell cytolysis or, conversely, to sustain chronic inflammation and tumor progression by enhancing cell invasion, angiogenesis, and metastasis to distant organs. However, comprehensive knowledge about the actual role of C in cancer progression is impaired by several limitations of the currently available studies.
In the current review, we aim to bring a fresh eye to the controversial role of C in cancer by analyzing the interplay between C and extracellular matrix (ECM) components as potential orchestrators of the TME. The interaction of C components with specific ECM components can determine C activation or inhibition and promote specific non-canonical functions, which can, in the tumor context, favor or limit progression based on the cancer setting. An in-depth and tumor-specific characterization of TME composition in terms of C components and ECM proteins could be essential to determine their potential interactions and become a key element for improving drug development, prognosis, and therapy response prediction in solid tumors.
{"title":"Beyond the Norm: The emerging interplay of complement system and extracellular matrix in the tumor microenvironment","authors":"Andrea Balduit , Chiara Agostinis , Roberta Bulla","doi":"10.1016/j.smim.2025.101929","DOIUrl":"10.1016/j.smim.2025.101929","url":null,"abstract":"<div><div>Ground-breaking awareness has been reached about the intricate and dynamic connection between developing tumors and the host immune system. Being a powerful arm of innate immunity and a functional bridge with adaptive immunity, the complement system (C) has also emerged as a pivotal player in the tumor microenvironment (TME). Its “double-edged sword” role in cancer can find an explanation in the controversial relationship between C capability to mediate tumor cell cytolysis or, conversely, to sustain chronic inflammation and tumor progression by enhancing cell invasion, angiogenesis, and metastasis to distant organs. However, comprehensive knowledge about the actual role of C in cancer progression is impaired by several limitations of the currently available studies.</div><div>In the current review, we aim to bring a fresh eye to the controversial role of C in cancer by analyzing the interplay between C and extracellular matrix (ECM) components as potential orchestrators of the TME. The interaction of C components with specific ECM components can determine C activation or inhibition and promote specific non-canonical functions, which can, in the tumor context, favor or limit progression based on the cancer setting. An in-depth and tumor-specific characterization of TME composition in terms of C components and ECM proteins could be essential to determine their potential interactions and become a key element for improving drug development, prognosis, and therapy response prediction in solid tumors.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101929"},"PeriodicalIF":7.4,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-06DOI: 10.1016/j.smim.2024.101927
Kelly S.W. Lee , Qingyang Zhang , Tatsuya Suwa, Heather Clark, Monica M. Olcina
The complement system is increasingly recognised as a key player in tumour progression and response to cancer treatment. Cytotoxic therapies, including chemo- and radiotherapy are standard-of-care for the majority of cancer patients. Cytotoxics have been found to alter the expression of complement system proteins and activation of components. Many recent reports highlight the role of local dysregulation of complement proteins in the tumour microenvironment and how targeting such dysregulation can have either anti- or pro-tumoricidal effects depending on several factors including treatment scheduling, the tumour type and its microenvironment characteristics. This review will explore the complex effects of cytotoxic therapy on complement regulation and what lessons can be learnt to identify the most effective way to therapeutically modulate complement system proteins for cancer therapy.
{"title":"The role of the complement system in the response to cytotoxic therapy","authors":"Kelly S.W. Lee , Qingyang Zhang , Tatsuya Suwa, Heather Clark, Monica M. Olcina","doi":"10.1016/j.smim.2024.101927","DOIUrl":"10.1016/j.smim.2024.101927","url":null,"abstract":"<div><div>The complement system is increasingly recognised as a key player in tumour progression and response to cancer treatment. Cytotoxic therapies, including chemo- and radiotherapy are standard-of-care for the majority of cancer patients. Cytotoxics have been found to alter the expression of complement system proteins and activation of components<strong>.</strong> Many recent reports highlight the role of local dysregulation of complement proteins in the tumour microenvironment and how targeting such dysregulation can have either anti- or pro-tumoricidal effects depending on several factors including treatment scheduling, the tumour type and its microenvironment characteristics. This review will explore the complex effects of cytotoxic therapy on complement regulation and what lessons can be learnt to identify the most effective way to therapeutically modulate complement system proteins for cancer therapy.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101927"},"PeriodicalIF":7.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143135885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-31DOI: 10.1016/j.smim.2024.101922
Vitalijs Ovcinnikovs , Karin Dijkman , Gijs G. Zom , Frank J. Beurskens , Leendert A. Trouw
The complement system plays an integral role in both innate and adaptive immune responses. Beyond its protective function against infections, complement is also known to influence tumor immunity, where its activation can either promote tumor progression or mediate tumor cell destruction, depending on the context. One such context can be provided by antibodies, with their inherent capacity to activate the classical complement pathway. In recent years, our understanding of the mechanisms governing complement activation by IgG and IgM antibodies has expanded significantly. At the same time, preclinical and clinical studies on antibodies such as rituximab, ofatumumab, and daratumumab have provided evidence for the role of complement in therapeutic success, encouraging strategies to further enhance its activity. In this review we examine the main determinants of antibody-mediated complement activation, highlighting the importance of antibody subclass, affinity, valency, and geometry of antigen engagement. We summarize the evidence for complement involvement in anti-tumor activity and challenges of accurately estimating the extent of its contribution to therapeutic efficacy. Furthermore, we explore several engineering approaches designed to enhance complement activation, including increased Fc oligomerization and C1q affinity, bispecific C1q-recruiting antibodies, IgG subclass chimeras, as well as antibody and paratope combinations. Strategies targeting membrane-bound complement regulatory proteins to overcome tumor-associated complement inhibition are also discussed as a method to boost therapeutic efficacy. Finally, we highlight the potential of complement-dependent cellular cytotoxicity (CDCC) and complement-dependent cellular phagocytosis (CDCP) as effector mechanisms that warrant deeper investigation.
By integrating advances in antibody and complement biology with insights from efforts to enhance complement activation in therapeutic antibodies, this review aims to provide a comprehensive framework of antibody design and engineering strategies that optimize complement activity for improved anti-tumor efficacy.
{"title":"Enhancing complement activation by therapeutic anti-tumor antibodies: Mechanisms, strategies, and engineering approaches","authors":"Vitalijs Ovcinnikovs , Karin Dijkman , Gijs G. Zom , Frank J. Beurskens , Leendert A. Trouw","doi":"10.1016/j.smim.2024.101922","DOIUrl":"10.1016/j.smim.2024.101922","url":null,"abstract":"<div><div>The complement system plays an integral role in both innate and adaptive immune responses. Beyond its protective function against infections, complement is also known to influence tumor immunity, where its activation can either promote tumor progression or mediate tumor cell destruction, depending on the context. One such context can be provided by antibodies, with their inherent capacity to activate the classical complement pathway. In recent years, our understanding of the mechanisms governing complement activation by IgG and IgM antibodies has expanded significantly. At the same time, preclinical and clinical studies on antibodies such as rituximab, ofatumumab, and daratumumab have provided evidence for the role of complement in therapeutic success, encouraging strategies to further enhance its activity. In this review we examine the main determinants of antibody-mediated complement activation, highlighting the importance of antibody subclass, affinity, valency, and geometry of antigen engagement. We summarize the evidence for complement involvement in anti-tumor activity and challenges of accurately estimating the extent of its contribution to therapeutic efficacy. Furthermore, we explore several engineering approaches designed to enhance complement activation, including increased Fc oligomerization and C1q affinity, bispecific C1q-recruiting antibodies, IgG subclass chimeras, as well as antibody and paratope combinations. Strategies targeting membrane-bound complement regulatory proteins to overcome tumor-associated complement inhibition are also discussed as a method to boost therapeutic efficacy. Finally, we highlight the potential of complement-dependent cellular cytotoxicity (CDCC) and complement-dependent cellular phagocytosis (CDCP) as effector mechanisms that warrant deeper investigation.</div><div>By integrating advances in antibody and complement biology with insights from efforts to enhance complement activation in therapeutic antibodies, this review aims to provide a comprehensive framework of antibody design and engineering strategies that optimize complement activity for improved anti-tumor efficacy.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101922"},"PeriodicalIF":7.4,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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