OP0198 COMPARATIVE IMMUNOMICS OF CHILDHOOD AND ADULT-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS REVEALS DISTINCT MECHANISTIC DIFFERENCES WITH THERAGNOSTIC APPLICATIONS
Authors: J. G. Yeo, K. Nay Yaung, A. Law Hui Nee, M. Wasser, S. L. Poh, K. L. Teh, L. Das, Y. X. Book, C. Huang, T. Arkachaisri, J. Thumboo, A. Low, S. Albani
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Systemic Lupus Erythematosus (SLE) is a complex disease afflicting children and adults. Patients with childhood-onset SLE (cSLE) tend to have more severe clinical manifestations and are vulnerable to the toxicity of steroids on bone health and growth. Despite these, cSLE treatment is often extrapolated from adult studies with the assumption that the underlying disease mechanisms are similar. Its immunopathogenic complexity and a lack of insight into the differences between childhood and adult-onset lupus demand a holistic, comparative immunomics study to identify mechanistically relevant commonalities and differences in its pathogenesis. <h3>Objectives:</h3> To compare the childhood and adult-onset SLE immunome holistically and address our hypothesis that distinct age-dependent differences in the immunoregulatory axis and immune effector system exist between the two entities. <h3>Methods:</h3> Peripheral blood mononuclear cells (PBMC) from 26 adult-onset and 26 childhood-onset SLE patients were interrogated with a 43 markers mass cytometry panel. The adult lupus patients (23 females) had a median age of 39.5 (interquartile range [IQR]: 28 to 53.5) years with a median SLEDAI 2K score of 4 (IQR: 0 to 8) while the childhood-onset SLE (cSLE, 20 females) had a median age of 14 (IQR: 11.8 to 15) years with a median SLEDAI 2K score of 8 (IQR: 2 to 13.5). Quality check, batch-effect correction, cell clustering and visualisation after t-distributed stochastic neighbour embedding (tSNE) dimensional reduction were done using our extended polydimensional immunome characterisation (EPIC) pipeline [1]. Frequencies are expressed as a percentage of total CD45<sup>+</sup> PBMC. Statistical significance is defined as p&lt;0.05 (Mann-Whitney U test). <h3>Results:</h3> Derangements in all the major immune lineages were observed with a major involvement of the CD4<sup>+</sup> T cell population (Figure 1). Notably, we found cSLE-specific changes with an increase in activated memory (CD45RA<sup>-</sup>) HLADR<sup>+</sup>OX40<sup>+</sup>CLA<sup>+</sup>CD4<sup>+</sup> (SLE versus healthy: 0.26 [0.14 to 0.39]% versus 0.10 [0.05 to 0.17]%, p&lt;0.0001), memory IL2<sup>+</sup>IL21<sup>+</sup>CD4<sup>+</sup> (SLE versus healthy: 0.41 [0.23 to 0.68]% versus 0.17 [0.13 to 0.29]%, p=0.0002) and memory CD25<sup>-</sup>FoxP3<sup>+</sup>CTLA4<sup>+</sup>TIGIT<sup>+</sup>CLA<sup>+</sup>CD4<sup>+</sup> T cells (SLE versus healthy: 0.68 [0.36 to 1.24]% versus 0.35 [0.25 to 0.53]%, p=0.0038). These suggest an underlying immunopathogenic difference between cSLE and adult-onset SLE. Conversely, there were adult-specific lupus changes with a significant reduction in the naïve (CD45RA<sup>+</sup>) and memory (CD45RA<sup>-</sup>) effector CD4<sup>+</sup> T cells (CD25<sup>-</sup>FoxP3<sup>-</sup>) expressing CTLA4, a key immune checkpoint inhibitor (SLE versus healthy: 1.61 [0.85 to 2.63]% versus 4.65 [3.20 to 7.18]%, p&lt;0.0001 and 0.54 [0.34 to 0.79]% versus 1.46 [1.00 to 2.06]%, p&lt;0.0001 respectively) (Figure 1C). Lastly, there were commonalities present in childhood and adult-onset SLE, specifically, an increase in memory (CD45RA<sup>-</sup>) T regulatory-like cells (CD25<sup>-</sup>FoxP3<sup>+</sup>CTLA4<sup>+</sup>TIGIT<sup>+</sup>PD1<sup>±</sup>). <h3>Conclusion:</h3> There are multiple derangements in lupus consistent with its complex immunopathogenesis. Interestingly, the increase of cSLE-specific memory T cells expressing OX40 (co-stimulatory receptor), IL21 (cytokine expressed by T follicular helper cells) and non-T regulatory cells (CD25<sup>-</sup> but Foxp3<sup>+</sup>) expressing immune checkpoint inhibitors (CTLA4 and TIGIT) that homes into the skin (CLA<sup>+</sup>) suggest a distinct immunopathogenic mechanism from adult-onset SLE. Conversely, the reduced CTLA4 expression in both naïve and adult effector T cells suggests a perturbed negative feedback mechanism in the effector system in adult lupus. This highlights the need for us to further examine the mechanistic basis of the reduced CTLA4 in adult lupus and consider strategies for its restoration to achieve immune homoeostasis. <h3>REFERENCES:</h3> [1] Yeo JG et al. Nat Biotechnol. 2020 Jun;38(6):679-684. <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>