Publications by Year: 2024

2024

Schmauch, E., Severin, Y., Xing, X., Mangold, A., Conrad, C., Johannsen, P., Kahlenberg, M., Mellett, M., Navarini, A., Nobbe, S., Sarkar, M. K., Satyam, A., Tsoi, L. C., French, L. E., Nilsson, J., Linna-Kuosmanen, S., Kaikkonen, M. U., Snijder, B., Kellis, M., … Kolios, A. G. A. (2024). Targeting IL-1 controls refractory pityriasis rubra pilaris.. Science Advances, 10(27), eado2365. https://doi.org/10.1126/sciadv.ado2365 (Original work published 2024)
Publisher's Version

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1β as a key mediator, orchestrating an NF-κB-mediated IL-1β-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1β. With the central role of IL-1β underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1β antagonists in PRP.

Pan, W., Tsokos, M. G., Scherlinger, M., Li, W., & Tsokos, G. C. (2024). The PP2A regulatory subunit PPP2R2A controls NAD+ biosynthesis to regulate T cell subset differentiation in systemic autoimmunity.. Cell Reports, 43(7), 114379. https://doi.org/10.1016/j.celrep.2024.114379 (Original work published 2024)
Publisher's Version

The protein phosphatase 2A (PP2A) regulatory subunit PPP2R2A is involved in the regulation of immune response. We report that lupus-prone mice with T cells deficient in PPP2R2A display less autoimmunity and nephritis. PPP2R2A deficiency promotes NAD+ biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells. NR inhibits murine Th17 and promotes Treg cell differentiation, in vitro, by PΑRylating histone H1.2 and causing its reduced occupancy in the Foxp3 loci and increased occupancy in the Il17a loci, leading to increased Foxp3 and decreased Il17a transcription. NR treatment suppresses disease in MRL.lpr mice and restores NAD+-dependent poly [ADP-ribose] polymerase 1 (PARP1) activity in CD4 T cells from patients with systemic lupus erythematosus (SLE), while reducing interferon (IFN)-γ and interleukin (IL)-17 production. We conclude that PPP2R2A controls the level of NAD+ through the NR-directed salvage pathway and promotes systemic autoimmunity. Translationally, NR suppresses lupus nephritis in mice and limits the production of proinflammatory cytokines by SLE T cells.

Xu, M., Ito-Kureha, T., Kang, H.-S., Chernev, A., Raj, T., Hoefig, K. P., Hohn, C., Giesert, F., Wang, Y., Pan, W., Ziętara, N., Straub, T., Feederle, R., Daniel, C., Adler, B., König, J., Feske, S., Tsokos, G. C., Wurst, W., … Heissmeyer, V. (2024). The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression.. Nature Communications, 15(1), 2194. https://doi.org/10.1038/s41467-024-46371-z (Original work published 2024)
Publisher's Version

The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21-bound transcriptome reveals strong interactions with the Rag1 3'-UTR. Arpp21-deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3'-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.

Alduraibi, F. K., & Tsokos, G. C. (2024). Lupus Nephritis Biomarkers: A Critical Review. Int J Mol Sci, 25, Article 2. https://doi.org/10.3390/ijms25020805805ijms25020805 [pii]ijms-25-00805 [pii]
Lupus nephritis (LN), a major complication in individuals diagnosed with systemic lupus erythematosus, substantially increases morbidity and mortality. Despite marked improvements in the survival of patients with severe LN over the past 50 years, complete clinical remission after immunosuppressive therapy is achieved in only half of the patients. Therefore, timely detection of LN is vital for initiating prompt therapeutic interventions and improving patient outcomes. Biomarkers have emerged as valuable tools for LN detection and monitoring; however, the complex role of these biomarkers in LN pathogenesis remains unclear. Renal biopsy remains the gold standard for the identification of the histological phenotypes of LN and guides disease management. However, the molecular pathophysiology of specific renal lesions remains poorly understood. In this review, we provide a critical, up-to-date overview of the latest developments in the field of LN biomarkers.
Furuya, H., Nguyen, C. T., Chan, T., Marusina, A. I., Merleev, A. A., Garcia-Hernandez, M. L., Hsieh, S. L., Tsokos, G. C., Ritchlin, C. T., Tagkopoulos, I., Maverakis, E., & Adamopoulos, I. E. (2024). IL-23 induces CLEC5A(+) IL-17A(+) neutrophils and elicit skin inflammation associated with psoriatic arthritis. J Autoimmun, 143, 103167. https://doi.org/S0896-8411(24)00001-5 [pii]10.1016/j.jaut.2024.103167
IL-23-activation of IL-17 producing T cells is involved in many rheumatic diseases. Herein, we investigate the role of IL-23 in the activation of myeloid cell subsets that contribute to skin inflammation in mice and man. IL-23 gene transfer in WT, IL-23R(GFP) reporter mice and subsequent analysis with spectral cytometry show that IL-23 regulates early innate immune events by inducing the expansion of a myeloid MDL1(+)CD11b(+)Ly6G(+) population that dictates epidermal hyperplasia, acanthosis, and parakeratosis; hallmark pathologic features of psoriasis. Genetic ablation of MDL-1, a major PU.1 transcriptional target during myeloid differentiation exclusively expressed in myeloid cells, completely prevents IL-23-pathology. Moreover, we show that IL-23-induced myeloid subsets are also capable of producing IL-17A and IL-23R(+)MDL1(+) cells are present in the involved skin of psoriasis patients and gene expression correlations between IL-23 and MDL-1 have been validated in multiple patient cohorts. Collectively, our data demonstrate a novel role of IL-23 in MDL-1-myelopoiesis that is responsible for skin inflammation and related pathologies. Our data open a new avenue of investigations regarding the role of IL-23 in the activation of myeloid immunoreceptors and their role in autoimmunity.
Scherlinger, M., Li, H., Pan, W., Li, W., Karino, K., Vichos, T., Boulougoura, A., Yoshida, N., Tsokos, M. G., & Tsokos, G. C. (2024). CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses. Nat Commun, 15, Article 1. https://doi.org/10.1038/s41467-024-45080-x84010.1038/s41467-024-45080-x [pii]45080 [pii]
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell compartment responsible for the production of autoantibodies. Here, we show that T cell-specific expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) leads to T follicular helper (T(fh)) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the T(fh)-specific transcription factor B cell lymphoma 6 (Bcl6) at the transcriptional level through the cAMP responsive element modulator alpha (CREMalpha). In the absence of CaMK4 in T cells, germinal center formation and humoral immunity is impaired in immunized mice, resulting in reduced anti-dsDNA titres, as well as IgG and complement kidney deposition in the lupus-prone B6.lpr mouse. In human T(fh) cells, CaMK4 inhibition reduced BCL6 expression and IL-21 secretion ex vivo, resulting in impaired plasmablast formation and IgG production. In patients with SLE, CAMK4 mRNA levels in T(fh) cells correlated with those of BCL6. In conclusion, we identify CaMK4/CREMalpha as a driver of T cell-dependent B cell dysregulation in autoimmunity.