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Diffuse large B-cell lymphoma and red cell autoimmunity: clinical role and pathogenesis
Caitlin Coombes1, Keisuke Horikawa2, Sanjiv Jain3
1School of Medicine and Psychology, College of Health and Medicine, Australian National University, Canberra, ACT, Australia; Haematology Translational Research Unit, Haematology Department, Canberra Health Services, Canberra, ACT, Australia.
Pathology
|November 24, 2022
Summary
Diffuse large B-cell lymphoma (DLBCL) is linked to red cell autoimmunity, evidenced by direct antiglobulin test (DAT) positivity. Specific gene mutations, like BIRC3 and FOXO1, were found only in DAT-positive DLBCL, suggesting potential therapeutic targets.
Area of Science:
- Hematology
- Immunology
- Oncology
Background:
- Diffuse large B-cell lymphoma (DLBCL) is the most prevalent B-cell non-Hodgkin lymphoma (B-NHL), associated with significant morbidity and mortality.
- Autoimmune diseases and lymphomas share underlying breakdowns in cell regulatory pathways, with epidemiological links suggesting bidirectional risk.
- Red cell autoimmunity, indicated by direct antiglobulin test (DAT) positivity, has been associated with DLBCL, with emerging molecular insights into its pathogenesis.
Purpose of the Study:
- To investigate the relationship between red cell autoimmunity and DLBCL.
- To identify specific genetic mutations associated with DAT positivity in DLBCL patients.
- To explore the role of immunoglobulin genotype IGHV4-34 in antigen-driven lymphomagenesis in DLBCL.
Main Methods:
- Comparison of DAT positivity rates between DLBCL patients and healthy controls.
- High-throughput sequencing to analyze gene mutations in DLBCL samples from DAT-positive (DAT+) and DAT-negative (DAT-) patients.
- Analysis of immunoglobulin genotype IGHV4-34 and its hydrophobic patch mutations in DLBCL clones.
Main Results:
- DAT positivity was significantly more common in DLBCL patients (20.4%) than in healthy controls (3.7%).
- Mutations in BIRC3, FOXO1, and CARD11 were exclusively found in DAT+ DLBCL samples.
- IGHV4-34 was over-represented in the DLBCL cohort, with unmutated hydrophobic patch mutations observed in 5 out of 6 IGHV4-34-expressing samples, suggesting antigen-driven lymphomagenesis.
Conclusions:
- Red cell autoimmunity is a significant finding in DLBCL, potentially linked to specific genetic mutations.
- Mutations in genes such as BIRC3, FOXO1, and CARD11 may play a role in DLBCL development in the context of red cell autoimmunity.
- The findings support the antigen-driven lymphomagenesis theory, particularly for IGHV4-34-expressing DLBCL, and highlight potential targets for future therapies.
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