Session Type: Abstract Submissions (ACR)
Background/Purpose: Up-regulated expression of type I interferon-regulated genes has consistently been observed within the peripheral blood in a large proportion of patients with active systemic lupus erythematosus (SLE). The activation of this pathway in inflamed tissues (e.g, the kidneys of patients with lupus nephritis [LN]) has been less studied. We investigated pathways most altered in the blood and kidney of LN to better understand the molecular and cellular mediators, and elucidate the concordance of type I IFN activation between the disease site and periphery.
Methods: Blood specimens were procured from 32 healthy and 94 LN Chinese subjects and kidney biopsies from 6 healthy and 80 LN Chinese subjects (75 matched). Among these patients, the distribution of the International Society of Nephrology and the Renal Pathology Services (ISN/RPS) classifications included: 1 Class-I, 2 Class-II, 16 proliferative LN (Class-III or -IV), 13 membranous LN (Class-V) and 21 mixed LN (Class-IV and -V or Class-V and -III), with SLEDAI scores ranging from 4-25. The Affymetrix U133+ array was used to transcript profile specimens. In the blood, 389 genes were significantly over-expressed in LN subjects (fold change (FC)≥2; p< 0.01) and 704 genes were under-expressed (FC≤ -2; p< 0.01). In the kidney, 166 genes were over-expressed in LN subjects (FC≥2; p< 0.05) and 66 genes were under-expressed (FC≤ -2; p< 0.05). Gene signatures were identified from ex vivo stimulation experiments with whole blood and pathway enrichment analysis was conducted.
Results: Within the blood specimens, type I IFN signaling was the most activated pathway, while complement system activation ranked first in kidney specimens. To further investigate the molecular landscape between blood and kidney in LN subjects, we surveyed a panel of different well characterized gene signatures. In both blood and kidney, a type I IFN signature was elevated in LN patients (73% and 43% patients with FC≥2, p< 0.0001 and p=0.001, respectively); the 75 matched specimens were well correlated (r=0.82; p<0.0001). A plasma cell gene signature showed no difference between LN patients and healthy controls in either blood or kidney tissues. However, in blood, a B cell gene signature was significantly lower in LN patients compared to healthy controls (59% patients with FC≤-2, p< 0.0001); the difference in kidney tissues was not observed. A macrophage gene signature was elevated in kidney tissue of LN patients compared to controls (54% patients with FC≥2, p= 0.0005).
Conclusion: Transcript profiling was used to better understand the molecular differences between the blood and disease site of patients with LN. The significantly decreased B cell gene signature in the blood, and not kidney of LN patients may reflect the migration of B cells from the periphery to local tissues, as well as the phenotype of lymphopenia in SLE patients. An elevated macrophage gene signature in the kidney may indicate the increased macrophage infiltration in diseased tissue from the blood. Type I IFN signaling was concordantly activated in both the blood and kidney tissue of LN subjects, suggesting a potential patient subgroup to target for anti-type I IFN therapies.
C. A. Morehouse,
B. W. Higgs,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcript-profiling-of-blood-and-kidney-biopsies-from-chinese-patients-with-lupus-nephritis-reveals-concordant-activation-of-type-i-ifn-signaling-in-the-blood-and-kidney-reduced-b-cell-presence-in-t/