OA2‐AM23‐ST‐10 | Antibody‐Dependent Cellular Cytotoxicity is an Important Mechanism of Red Blood Cell Destruction in Antibody‐Mediated Hemolysis
Bibliographic record
Abstract
The underlying cause for immune hemolysis by antibodies to human red cell antigens continues to be the subject of investigational studies on immune-mediated red cell destruction. The pathophysiology of antibody-mediated red blood cell (RBC) destruction has been thought to occur via extravascular phagocytosis by monocyte-macrophages. In some cases, rapid, including intravascular, hemolysis is present with no clear understanding of the mechanism. Antibody-dependent cellular cytotoxicity (ADCC) hemolysis mediated by natural killer cells (NK) is thought to occur in these cases, although this has not been thoroughly studied. We have used a monocyte monolayer assay (MMA) and NK-mediated ADCC to compare antibodies of different specificities to mediate either mechanism of RBC hemolysis. Examples of human, single specificity antibodies with a positive AHG-IAT reaction were tested for their phagocytic index using the MMA (>5 indicates a clinically significant antibody) and/or ADCC-mediated cytotoxicity (>2% specific cell death). For MMA, PBMCs were isolated from fresh whole blood or buffy coats and plated into chamber slides for evaluation of phagocytosis of opsonized antigen-positive RBCs. For ADCC, NK cells were purified using negative selection and specific cell lysis determined using a 51-Chromium release method of opsonized antigen-positive RBCs. Fifteen IgG alloantibodies, reactive by IAT, of the following specificities were examined: two anti-D, seven anti-E, two anti-K, two anti-Fya, and two anti-P1. Results indicate that 2/2 anti-K reacting 3+-mediated both significant MMA and ADCC results. One 4+ anti-D was positive by MMA and ADCC but one 1+ anti-D was positive with ADCC but not MMA. Out of seven anti-E samples, four reacting 3+ all gave insignificant results in the MMA, while two gave positive results in ADCC. Three anti-E reacting week to 2+ were negative by MMA but one of these was positive by ADCC. One 3+ anti-Fya was positive by MMA while one was positive by ADCC. Both anti-P1 were negative by MMA but one was positive by ADCC. Although a small sampling, we conclude that ADCC, in addition to phagocytosis, may contribute to immune hemolysis in patients who are actively hemolyzing. This is especially likely with anti-K. We also conclude that anti-E antibodies are usually benign, not clinically significant, not mediating either a significant MMA or ADCC result. We also find that ADCC can be positive without a positive MMA, especially with anti-D and anti-E. Thus, potential clinical significance of RBC antibodies my require both MMA and ADCC testing. ADCC likely plays a role in severe autoimmune hemolytic anemias and in hyperhemolysis in sickle cell patients, but we did not test these hypotheses. We are continuing to test additional antibodies to accumulate additional data to support our conclusions.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".