Biology subjects

Inamo, J.

Publications and source records attributed to Inamo, J..

4 recordsLinked to original sources

bioRxiv2024

Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis

Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based pathologic immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation in patients with LN and to identify correlates of renal parameters and treatment response. Unbiased analysis identified 3 immunologically distinct groups of patients with LN that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells at baseline showed more severe disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized primarily by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive by immunophenotyping at enrollment but with chronic renal injuries. Main immune profiles could be distilled down to 5 simple cytometric parameters that recapitulate several of the associations, highlighting the potential for blood immune profiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.

immunology↗

bioRxiv2023

Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease with currently no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in At-Risk populations prior to clinical disease onset is crucial to establishing effective prevention strategies. Here, we applied mass cytometry to deeply characterize the immunophenotypes in blood from At-Risk individuals identified through the presence of serum antibodies to citrullinated protein antigens (ACPA) and/or first-degree relative (FDR) status (n=52), as compared to established RA (n=67), and healthy controls (n=48). We identified significant cell expansions in At-Risk individuals compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5low naive B cell population was expanded in ACPA-positive FDRs. Further, we developed an "RA immunophenotype score" classification method based on the degree of enrichment of cell states relevant to established RA patients. This score significantly distinguished At-Risk individuals from controls. In all, we systematically identified activated lymphocyte phenotypes in At-Risk individuals, along with immunophenotypic differences among both ACPA+ and ACPA-FDR At-Risk subpopulations. Our classification model provides a promising approach for understanding RA pathogenesis with the goal to further improve prevention strategies and identify novel therapeutic targets.

genomics↗

bioRxiv2022

CiDRE+ M2c macrophages hijacked by SARS-CoV-2 cause COVID-19 severity

Infection of the lungs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin I converting enzyme 2 (ACE2) receptor induces a type of systemic inflammation known as a cytokine storm. However, the precise mechanisms involved in severe coronavirus disease 2019 (COVID-19) pneumonia are unknown. Here, we show that interleukin-10 (IL-10) changed normal alveolar macrophages into ACE2-expressing M2c-type macrophages that functioned as spreading vectors for SARS-CoV-2 infection. The depletion of alveolar macrophages and blockade of IL-10 attenuated SARS-CoV-2 pathogenicity. Furthermore, genome-wide association and quantitative trait locus analyses identified novel mRNA transcripts in human patients, COVID-19 infectivity enhancing dual receptor (CiDRE), which has unique synergistic effects within the IL-10-ACE2 system in M2c-type macrophages. Our results demonstrate that alveolar macrophages stimulated by IL-10 are key players in severe COVID-19. Collectively, CiDRE expression levels are potential risk factors that predict COVID-19 severity, and CiDRE inhibitors might be useful as COVID-19 therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/510331v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1e96c82org.highwire.dtl.DTLVardef@1d2dc32org.highwire.dtl.DTLVardef@7689d1org.highwire.dtl.DTLVardef@520d17_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Immune Isoform Atlas: Landscape of alternative splicing in human immune cells

Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generated a comprehensive full-length isoform annotation of human immune cells, Immune Isoform Atlas, by long-read sequencing for 29 cell subsets. Our atlas contained a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE. We profiled functional characteristics of isoforms including encoded domains, inserted repetitive elements, and translational efficiency, and we showed that repetitive elements significantly explained the diversity of unannotated isoforms. Some of the isoforms are expressed in a cell-type specific manner, whose alternative 3-UTRs usage contributed to their specificity. Further, we identified a number of disease-associated isoforms by isoform switch analysis and by integration of several quantitative trait loci analyses with genome-wide association study data. Our findings will promote the elucidation of the pathomechanism of diseases via alternative splicing.

genetics↗