Pathogenic heterozygous variants in PSTPIP1 lead to excessive IL1 mediated inflammation, which is the cause of rare autoinflammatory syndromes: PAPA (pyogenic arthritis, pyoderma gangrenosum, acne) and the more recently described PAMI (PSTPIP1-associated myeloid-related proteinemia inflammatory). We investigated gene expression in patients reported in the following table to better understand the molecular pathogenesis of these diseases.
| Family | Patient (pt) | PSTPIP1 mutations | Clinical symptoms | Treatment | Reference (PMID) |
| Family-1 (PAPA) | Pt1-father | A230T | Arthritis, acne | Anakinra | 15580218 |
| Pt2-son | A230T | Arthritis | Canakinumab | ||
| Family-2 (PAMI) | Pt3-brother | E250K | Leukopenia, neutropenia, acne | Anakinra | 28628471 |
| Pt4-sister | E250K | Leukopenia, neutropenia | Anakinra | ||
| Family-3 (PAMI) | Pt5 | E250K | Leukopenia, Atypical: SLE-like features (autoantibodies,nephritis, pulmonary arterial hypertension) | Hydroxychloroquine (HCQ) |
Transcriptomic studies of blood cells from our patients compared with a group of healthy subjects and pathway over-representation analysis to investigate the main biological processes involved.
Transcriptomics analysis highlighted the heme metabolism pathway which is over-expressed among all the patients compared with controls, already known to be involved in physiological and pathological processes. Patients with PAMI showed neutrophils degranulation pathway over-represented, probably due to neutrophiles hyper-activation. Only pt5 presented a high-interferon-score that recovered after therapy with HCQ.
The presence of lupus-like manifestations in PAMI has never reported so far. Even if only one of our patients with PAMI displayed interferon-related inflammation, we can speculate a possible cross-talk between IL1 and interferon pathways. A possible hypothesis, which could be worth investigating, is that the increased neutrophil activation pathway found in PAMI could be associated to the release of NETs and to the activation of interferon signaling.