POS1271 ACTIVATION STATE OF PERIPHERAL T LYMPHOCYTES PREDICTS RESPONSE TO ABATACEPT IN PATIENTS WITH IgG4-RELATED DISEASE
Authors: J. Mahajne, C. Minici, M. Lanzillotta, E. Della Torre
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> The pathogenesis of IgG4-Related Disease (IgG4-RD) remains largely undeciphered. A population of CD4+ cytotoxic T cells (CTLs) expressing the exhaustion marker CD57 has been recently identified as the predominant infiltrating cell type in IgG4-RD lesions. This cell population is also expanded in patients with CTLA-4 haploinsufficiency. Abatacept (a synthetic CTLA-4 replica) represents the treatment of choice for CTLA-4 insufficiency and has also been used with variable efficacy in IgG4-RD. <h3>Objectives:</h3> In this study we aimed to study the expression of the inhibitory molecule CTLA-4 and T cell activation in patients with IgG4-RD and to correlate these immunological features with clinical response to abatacept. <h3>Methods:</h3> Ten patients fulfilling the 2019 ACR and EULAR classification criteria for IgG4-RD were recruited. Disease activity was assessed by means of the IgG4-RD Responder Index. Multicolor flow-cytometry was used to study the expression of the activation marker CD25 as well as the exhaustion markers CTLA-4, TIM-3, and PD-1 on total CD4+ T-cells, CD4+CTLs, and T regulatory cells. Ten sex and age-matched healthy individuals were enrolled as controls for in vitro studies. <h3>Results:</h3> Basal expression of CD25 on CD4+ T cells, CD4+CTLs, and regulatory T cells was similar in IgG4-RD patients and healthy individuals. No difference was observed in the expression of the exhaustion markers PD-1 and TIM-3 (p value &gt;0.05). CTLA-4 was significantly upregulated in all three subsets of T cells in IgG4-RD patients compared to controls suggesting an atypical activated/exhausted profile. Upon in vitro activation, expression of CD25 in the three cell subsets physiologically increased in IgG4-RD patients; however, CD4+ T cells, CD4+ CTLs and T regulatory cells from IgG4-RD patients upregulated CTLA-4 less proficiently than healthy individuals (p value &lt;0.05). Four patients with active IgG4-RD were treated with abatacept without concomitant glucocorticoids. Two patients responded to abatacept and two patients did not. Responders and not responders displayed similar baseline expression of CD25 and CTLA-4 on CD4+ T cells, CD4+ CTLs, and T regulatory cells. Upon activation, responding patients showed increased CD25 and less proficient upregulation of CTLA-4 compared to non -responders and controls. Six months after treatment with abatacept, the kinetic of CD25 expression on T cells upon activation in responder patients mirrored that of healthy controls. <h3>Conclusion:</h3> CD4+ T cells from patients with IgG4-RD show an atypical activation/exhaustion profile characterized by increased basal CTLA-4 expression and defective CTLA-4 upregulation upon stimulation. This is generally not associated to an hyperactivation of T cells except in some patients that ultimately appear to respond to abatacept. Together, these findings indicate that complimentary mechanisms regulate T cell activation and that dysfunction of CTLA-4 in some patients might contribute to disease pathogenesis, thus providing the rationale for personalized therapeutic approaches. <h3>REFERENCES: NIL.Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>