Innate immune dysregulation in monocytes in sickle cell disease
Bibliographic record
Abstract
Abstract Background : Sickle cell disease (SCD) is the most common genetic hematological disorder affecting ~100,000 people in the United States, resulting from a single base pair mutation resulting in a glutamic acid to valine substitution at position 6 in the beta-globin protein. Individuals with SCD have higher morbidity and mortality due to infectious diseases. A significant portion of patients with SCD, ~65% in some series, show impaired vaccine response and remain under-protected against vaccine-preventable infections. Chronic hemolysis associated with SCD results in splenic infarction and functional asplenia, but also overwhelms mechanisms to sequester heme and other damage-associated molecular patterns (DAMPs) released from erythrocytes that activate innate immune pattern recognition receptors such as Toll-like Receptors (TLRs). We aimed to investigate TLR function in monocytes and assess the effects of TLR 2/6, TLR4, and TLR7/8 agonists, lipoteichoic acid (LTA), lipopolysaccharide (LPS), and Resiquimod (R848) respectively, on cytokine production in monocytes from patients with and without SCD. Methods : Peripheral blood mononuclear cells (PBMC) were isolated from pediatric and young adult patients with SCD (n=17) and age and race-matched healthy participants (n=10), cryopreserved, and thawed before stimulation. We used flow cytometry to identify monocyte subsets and cytokine production by monocytes after stimulation with LTA, R848, or LPS. Monocyte subsets were classified as classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14dimCD16+). Cytokine production was evaluated in these populations using intracellular cytokine staining to detect TNF-a, IL-1b, IL-6, IL-8, and MCP-1. Statistical significance was compared using Mann-Whitney tests with a significance cutoff value of p=0.05. Results : SCD participants had total white blood cell counts and monocyte percentages within the normal range for their age. The median WBC count was 9.0x103 cell/µL, IQR 7.3x103 cell/µL-10.3x103 cells/µL, and the median monocyte percentage was 10%, IQR 8%-12.25%. SCD patients had a lower proportion of classical (CD14++CD16-) monocytes compared to healthy controls in the unstimulated group (p=0.0004), and in LTA (p=0.002), LPS (p=0.008), and R848 (p=0.03) groups after a 6-hour stimulation. There was a statistically significant increase in non-classical (CD14dimCD16+) monocytes in SCD patients in the unstimulated (p=0.02) group, and in the LTA (p=0.005) and R848 (p=0.04) groups following a 6-hour stimulation. After stimulation with LTA, there was a significant decrease in the percentage of classical monocytes producing IL-6 (p=0.02) in SCD patients compared to healthy controls and an increase in the percentage of classical monocytes producing IL-8 (p=0.006) in SCD patients compared to healthy controls. Following LPS stimulation, there was a significant increase in the percentage of classical monocytes producing IL-8 in SCD patients compared to healthy controls (p=0.002). After stimulation with R848, there was a significant increase in the percentage of classical monocytes producing IL-6 (p=0.04), IL-1b (p=0.0001), and IL-8 (p=<0.000001) compared to healthy controls. Conclusion: Monocytes from SCD patients show trends toward increased inflammatory responses, especially following TLR7/8 stimulation, compared to monocytes from age and race-matched healthy controls. This suggests alterations in TLR function in individuals with SCD, resulting in dysregulated innate immunity that may contribute to impaired responses to infection or vaccination.
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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) | 0.001 | 0.000 |
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".