Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway
Humoral immunity to factor VIII (FVIII) represents a significant challenge for the treatment of patients with hemophilia A. Current paradigms indicate that neutralizing antibodies against FVIII (inhibitors) occur through a classical CD4 T cell, germinal center (GC) dependent process. However, clinic...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.880829/full |
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| author | Seema R. Patel Taran S. Lundgren Taran S. Lundgren Wallace Hunter Baldwin Courtney Cox Ernest T. Parker John F. Healey Ryan P. Jajosky Patricia E. Zerra Patricia E. Zerra Cassandra D. Josephson Christopher B. Doering Sean R. Stowell Shannon L. Meeks |
| author_facet | Seema R. Patel Taran S. Lundgren Taran S. Lundgren Wallace Hunter Baldwin Courtney Cox Ernest T. Parker John F. Healey Ryan P. Jajosky Patricia E. Zerra Patricia E. Zerra Cassandra D. Josephson Christopher B. Doering Sean R. Stowell Shannon L. Meeks |
| author_sort | Seema R. Patel |
| collection | DOAJ |
| description | Humoral immunity to factor VIII (FVIII) represents a significant challenge for the treatment of patients with hemophilia A. Current paradigms indicate that neutralizing antibodies against FVIII (inhibitors) occur through a classical CD4 T cell, germinal center (GC) dependent process. However, clinical observations suggest that the nature of the immune response to FVIII may differ between patients. While some patients produce persistent low or high inhibitor titers, others generate a transient response. Moreover, FVIII reactive memory B cells are only detectable in some patients with sustained inhibitor titers. The determinants regulating the type of immune response a patient develops, let alone how the immune response differs in these patients remains incompletely understood. One hypothesis is that polymorphisms within immunoregulatory genes alter the underlying immune response to FVIII, and thereby the inhibitor response. Consistent with this, studies report that inhibitor titers to FVIII differ in animals with the same F8 pathogenic variant but completely distinct backgrounds; though, how these genetic disparities affect the immune response to FVIII remains to be investigated. Given this, we sought to mechanistically dissect how genetics impact the underlying immune response to FVIII. In particular, as the risk of producing inhibitors is weakly associated with differences in HLA, we hypothesized that genetic factors other than HLA influence the immune response to FVIII and downstream inhibitor formation. Our data demonstrate that FVIII deficient mice encoding the same MHC and F8 variant produce disparate inhibitor titers, and that the type of inhibitor response formed associates with the ability to generate GCs. Interestingly, the formation of antibodies through a GC or non-GC pathway does not appear to be due to differences in CD4 T cell immunity, as the CD4 T cell response to an immunodominant epitope in FVIII was similar in these mice. These results indicate that genetics can impact the process by which inhibitors develop and may in part explain the apparent propensity of patients to form distinct inhibitor responses. Moreover, these data highlight an underappreciated immunological pathway of humoral immunity to FVIII and lay the groundwork for identification of biomarkers for the development of approaches to tolerize against FVIII. |
| first_indexed | 2024-04-13T08:29:54Z |
| format | Article |
| id | doaj.art-470104dc411c45558fc574d5808a9c73 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T08:29:54Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-470104dc411c45558fc574d5808a9c732022-12-22T02:54:18ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-05-011310.3389/fimmu.2022.880829880829Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center PathwaySeema R. Patel0Taran S. Lundgren1Taran S. Lundgren2Wallace Hunter Baldwin3Courtney Cox4Ernest T. Parker5John F. Healey6Ryan P. Jajosky7Patricia E. Zerra8Patricia E. Zerra9Cassandra D. Josephson10Christopher B. Doering11Sean R. Stowell12Shannon L. Meeks13Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United StatesAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United StatesGraduate Program in Molecular and Systems Pharmacology, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, United StatesAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United StatesAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United StatesAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United StatesAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United StatesBrigham and Women’s Hospital, Harvard Medical School, Boston, MA, United StatesAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United StatesCenter for Transfusion Medicine and Cellular Therapies, Department of Laboratory Medicine and Pathology, Emory University School of Medicine, Atlanta, GA, United StatesAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United StatesAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United StatesBrigham and Women’s Hospital, Harvard Medical School, Boston, MA, United StatesAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University School of Medicine, Atlanta, GA, United StatesHumoral immunity to factor VIII (FVIII) represents a significant challenge for the treatment of patients with hemophilia A. Current paradigms indicate that neutralizing antibodies against FVIII (inhibitors) occur through a classical CD4 T cell, germinal center (GC) dependent process. However, clinical observations suggest that the nature of the immune response to FVIII may differ between patients. While some patients produce persistent low or high inhibitor titers, others generate a transient response. Moreover, FVIII reactive memory B cells are only detectable in some patients with sustained inhibitor titers. The determinants regulating the type of immune response a patient develops, let alone how the immune response differs in these patients remains incompletely understood. One hypothesis is that polymorphisms within immunoregulatory genes alter the underlying immune response to FVIII, and thereby the inhibitor response. Consistent with this, studies report that inhibitor titers to FVIII differ in animals with the same F8 pathogenic variant but completely distinct backgrounds; though, how these genetic disparities affect the immune response to FVIII remains to be investigated. Given this, we sought to mechanistically dissect how genetics impact the underlying immune response to FVIII. In particular, as the risk of producing inhibitors is weakly associated with differences in HLA, we hypothesized that genetic factors other than HLA influence the immune response to FVIII and downstream inhibitor formation. Our data demonstrate that FVIII deficient mice encoding the same MHC and F8 variant produce disparate inhibitor titers, and that the type of inhibitor response formed associates with the ability to generate GCs. Interestingly, the formation of antibodies through a GC or non-GC pathway does not appear to be due to differences in CD4 T cell immunity, as the CD4 T cell response to an immunodominant epitope in FVIII was similar in these mice. These results indicate that genetics can impact the process by which inhibitors develop and may in part explain the apparent propensity of patients to form distinct inhibitor responses. Moreover, these data highlight an underappreciated immunological pathway of humoral immunity to FVIII and lay the groundwork for identification of biomarkers for the development of approaches to tolerize against FVIII.https://www.frontiersin.org/articles/10.3389/fimmu.2022.880829/fullhemophilia Agerminal centerB cellsneutralizing antibodies (inhibitors)extrafollicular pathway |
| spellingShingle | Seema R. Patel Taran S. Lundgren Taran S. Lundgren Wallace Hunter Baldwin Courtney Cox Ernest T. Parker John F. Healey Ryan P. Jajosky Patricia E. Zerra Patricia E. Zerra Cassandra D. Josephson Christopher B. Doering Sean R. Stowell Shannon L. Meeks Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway Frontiers in Immunology hemophilia A germinal center B cells neutralizing antibodies (inhibitors) extrafollicular pathway |
| title | Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway |
| title_full | Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway |
| title_fullStr | Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway |
| title_full_unstemmed | Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway |
| title_short | Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway |
| title_sort | neutralizing antibodies against factor viii can occur through a non germinal center pathway |
| topic | hemophilia A germinal center B cells neutralizing antibodies (inhibitors) extrafollicular pathway |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.880829/full |
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