Oral lichenoid lesions in CTLA‐4 haploinsufficiency: Targeting IFN‐γ‐driven mucosal immunopathology

Dear Editor,

Aberrant type 1 immunity, characterized by enhanced interferon (IFN)‐γ signalling, has emerged as a key mechanism underlying mucosal barrier defects, highlighting opportunities for targeted therapy. ¹ , ² , ³ Here, we describe a patient with CTLA‐4 haploinsufficiency who developed severe, IFN‐γ‐driven lesions mimicking oral lichen planus (OLP) that responded favourably to JAK inhibitors.

The patient was a 37‐year‐old female with a complex history of multiorgan lymphocytic infiltration, autoimmunity (type 1 diabetes, immune thrombocytopenia), hypogammaglobulinaemia and an Epstein–Barr virus (EBV)‐positive lymphoproliferative disorder in remission after chemoimmunotherapy. She was diagnosed with CTLA‐4 haploinsufficiency (heterozygous, c.223C>T, p.Arg75Trp), a prototypic immune dysregulatory disorder caused by defective regulatory T (Treg) cell function and was treated with abatacept (CTLA‐4‐Fc fusion protein). ⁴

She presented with a 6‐month history of progressively worsening oral lesions, with features resembling OLP, including striations of the lower labial mucosa and diffuse bilateral ulceration of the tongue (Figure 1a). There was no oral thrush. Microbiological evaluation was negative for herpes simplex virus and Candida species. In addition, no lichenoid lesions were identified at other anatomic sites, and no hypermetabolic lesions were observed on whole‐body positron emission tomography (PET). Multiple empiric therapies, including topical and intralesional corticosteroids, cyclosporine oral rinse and oral prednisone, were ineffective. The abatacept dose was increased to address possible uncontrolled immune activation from CTLA‐4 haploinsufficiency, but without clinical benefit. Temporary discontinuation of abatacept also failed to improve the lesions, suggesting that they were not treatment‐related adverse effects.

FIGURE 1.

Clinical features of IFN‐γ‐driven oral lesions in CTLA‐4 haploinsufficiency. (a) Representative images of oral mucosal lesions: Upper panel, baseline, active; middle panel, ~ 6 months after JAK inhibitor therapy, improved; lower panel, ~27 months after JAK inhibitor, healed. (b) Histology of oral mucosal biopsy. From left to right: Haematoxylin and eosin stain (H&E); CD4 (brown) and CD8 (red) by immunohistochemistry; CXCL9 by RNAscope; phospho‐STAT1 by immunohistochemistry. (c) Longitudinal evaluation of blood biomarkers, including plasma CXCL9, serum IFN‐γ, C‐reactive protein, soluble CD25 and Treg. Dashed lines indicate the upper limits of normal for each biomarker.

Biopsy revealed a dense, band‐like subepithelial lymphocytic infiltrate with hydropic degeneration of the basal epithelial cells, mirroring the histological features of LP (Figure 1b). However, the inflammatory infiltrate was predominantly composed of CD4⁺ T cells, with a CD4/CD8 ratio of greater than 8:1, which differs markedly from classic LP, where lesions are typically driven by CD8⁺ cytotoxic T cells with a reported CD4/CD8 ratio of 1:2 to 2:1. ⁵ Additionally, increased phospho‐STAT1 staining and CXCL9 expression were observed, indicating an aberrant T_H1 response. Concurrently, her plasma CXCL9 levels were significantly elevated, whereas serum IFN‐γ levels were normal (Figure 1c). To further define the immunological features, we performed bulk RNA sequencing of affected mucosal tissue, which demonstrated increased T cell activation with a heightened IFN‐γ tissue response, ¹ along with downregulation of barrier function‐related processes (Figure 2a,b). Notably, an increased Treg signature was observed. Although Treg cells are physiologically recruited to inflammatory sites, ⁶ they are functionally impaired in CTLA‐4 haploinsufficiency, ⁴ and IFN‐γ in the tissue microenvironment promotes Treg fragility. ⁷ T cell expansion and infiltration were polyclonal based on T cell receptor repertoire analysis (Figure 2c,d). Collectively, these findings suggest a localized, IFN‐γ‐driven mucosal immunopathology, distinct from classic OLP, which prompted the initiation of JAK inhibitor therapy.

FIGURE 2.

Immunological characterization of IFN‐γ‐driven oral lesions in CTLA‐4 haploinsufficiency. (a) Pathway analysis of bulk RNA sequencing from oral mucosal tissue, comparing the patient's baseline sample to healthy controls (n = 4). (b) Heatmap of differential gene expression (z‐score) of IFN‐γ, T helper 1 (T_H1) and Treg‐associated signatures, comparing the patient to healthy controls (HC, n = 4). T1, pre‐treatment; T2, ~1 week after JAK inhibitor therapy; T3, ~27 months after JAK inhibitor therapy. (c, d) T cell receptor repertoire analysis of oral mucosa tissue, comparing the patient to healthy controls (HC, n = 4). (c) Numbers of unique T cell clonotypes; (d) True diversity index.

She was started on baricitinib (4 mg daily), with rapid suppression of T_H1 and IFN‐γ signatures within 1 week (Figure 2b). Because of leukopenia, therapy was switched to ruxolitinib (15 mg, twice daily), resulting in marked clinical improvement after 6 months of therapy. However, she developed pulmonary embolism and was found to be heterozygous for the Factor V Leiden (c.1601G>A, p.Arg534Gln). Ruxolitinib was discontinued, and her oral lesions worsened within 1 month. Upadacitinib was therefore started (induction 45 mg daily for 12 weeks, followed by 15 mg daily). At her most recent follow‐up, after 8 months on upadacitinib, oral lesions had completely healed. Oral mucosal tissue transcriptome showed normalization of the heightened IFN‐γ and Treg signatures. The number of T cell clonotypes was reduced and plasma CXCL9 levels normalized (Figures 1c and 2c,d). Throughout the treatment, blood EBV viral loads remained undetectable, and a follow‐up PET scan showed no evidence of lymphoma recurrence.

These findings align with recent reports that IFN‐γ‐driven, localized immunopathology can underlie mucosal barrier defects. ¹ , ² By integrating personalized tissue signature profiling with targeted therapy, ⁸ we showed promising clinical and immunologic responses to JAK inhibitors, although adverse effects remain a concern. More selective JAK inhibitors may offer advantages. ⁹ Further investigations are warranted to define mechanisms driving IFN‐γ signalling at mucosal barriers, particularly given the benefits of JAK inhibitors in selected patients with OLP/LP. ¹⁰

FUNDING INFORMATION

This research was supported by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. G.U. was also supported by NIH Bench‐to‐Bedside and Back Program (BtB).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICAL APPROVAL

The patient was enrolled in Institutional Review Boardu‐approved clinical protocols (NCT00001355 and NCT01568697) at the National Institutes of Health (Bethesda, Maryland, USA).

ETHICS STATEMENT

The patient in this manuscript has provided informed consent.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.