rs115161931 — CTSS

CTSS — The Antigen-Presentation Protease Driving Eczema Risk

Cathepsin S¹¹ Cathepsin S
A lysosomal cysteine protease encoded by CTSS on chromosome 1q21.3. It is expressed almost exclusively in professional antigen-presenting cells — dendritic cells, macrophages, and B cells — where it catalyses the final, rate-limiting step of MHC class II peptide loading sits at an unusual intersection: it is both an essential engine of adaptive immunity and, when expressed at elevated levels in the skin, a direct trigger of itch. A large-scale genome-wide association study meta-analysis identified rs115161931 as one of three independent genetic signals at the CTSS locus associated with atopic dermatitis (eczema), with each signal representing a distinct regulatory mechanism acting on the same gene.

rs115161931 is an intronic variant at chromosome 1:151,063,299 (GRCh38) within the CTSS chromosomal neighbourhood. The T allele is uncommon globally (~2.5%) but more prevalent in European populations (~4%), and is nearly absent in East Asian and African populations. Its effect on CTSS expression in primary immune cells has not yet been directly measured by eQTL studies, but the biological case for CTSS as the causal gene at this locus is strong: CTSS is the only gene in this region with established roles in both immune dysregulation and cutaneous itch.

The Mechanism

MHC class II molecules require a precise loading sequence before they can present antigens to CD4+ T helper cells. Newly assembled complexes in the endoplasmic reticulum are blocked by the invariant chain (Ii/CD74)²² invariant chain (Ii/CD74)
A chaperone protein that occupies the peptide-binding groove of MHC class II, directing the complex through the secretory pathway. In the lysosome it must be fully degraded before antigenic peptides can load. Cathepsin S is the specific enzyme responsible for the final Ii cleavage step — removing the CLIP fragment to expose the groove. Neither cathepsin B, H, nor D can substitute. Without sufficient cathepsin S, MHC class II complexes stall with the Ii fragment intact; with excess cathepsin S, antigen presentation is amplified, increasing the risk of priming autoreactive or hyperreactive T cells.

In the skin, cathepsin S has a second, independent mechanism of harm: extracellular secretion by skin-resident dendritic cells and keratinocytes, where it directly activates protease-activated receptor 2 (PAR2) on TRPV1-expressing sensory nerve endings³³ extracellular secretion by skin-resident dendritic cells and keratinocytes, where it directly activates protease-activated receptor 2 (PAR2) on TRPV1-expressing sensory nerve endings
PAR2 is a G-protein-coupled receptor that, when cleaved by cathepsin S, triggers downstream TRPV1 calcium signalling in nociceptors — producing itch independent of histamine. This histamine-independent itch pathway is mechanistically important because it explains why antihistamines are often inadequate for atopic dermatitis itch, and why CTSS inhibitors represent a distinct therapeutic target.

The Evidence

Budu-Aggrey et al. (Nature Communications, 2023)⁴⁴ Budu-Aggrey et al. (Nature Communications, 2023) conducted a multi-stage GWAS including 65,107 atopic dermatitis cases and 1,021,287 controls in the European discovery phase, subsequently expanded to a multi-ancestry cohort of 765,209 individuals and independently replicated in a 23andMe European cohort of 2,904,664 individuals. Twenty-nine novel atopic dermatitis loci were identified. The CTSS region yielded three independent signals — rs187080438, rs146527530, and rs115161931 — with this variant showing an odds ratio of approximately 1.18 for atopic dermatitis per T allele. The three signals were statistically independent (conditionally significant after accounting for each other), indicating they tag distinct regulatory mechanisms at the CTSS locus.

Animal model evidence directly links CTSS overexpression to atopic dermatitis-like disease. Kim et al. (Journal of Investigative Dermatology, 2012)⁵⁵ Kim et al. (Journal of Investigative Dermatology, 2012) generated CTSS-overexpressing transgenic mice that spontaneously develop chronic skin disease resembling atopic dermatitis. The phenotype was driven by PAR-2 upregulation in dendritic cells, which promoted CD4+ T cell differentiation and induced scratching behaviour alongside altered Th1/Th2 cytokine profiles. This experiment established that excess CTSS activity alone — in the absence of any external allergen — is sufficient to produce atopic dermatitis pathology through immune cell activation.

The itch mechanism was characterised in detail by Chung et al. (Neurobiology of Pain, 2019)⁶⁶ Chung et al. (Neurobiology of Pain, 2019). Intradermal injection of recombinant cathepsin S induced dose-dependent scratching in mice via PAR2 on TRPV1-expressing sensory neurons; TRPV1 knockout reduced scratching by 50% and PAR2 antagonists abolished it completely. This confirms that cathepsin S operates as a molecular pruritogen — an itch-triggering signal released by activated skin antigen-presenting cells — entirely separate from its role in antigen presentation.

Beyond atopic dermatitis, elevated CTSS expression is mechanistically linked to systemic autoimmunity. Rupanagudi et al. (Annals of the Rheumatic Diseases, 2015)⁷⁷ Rupanagudi et al. (Annals of the Rheumatic Diseases, 2015) demonstrated that selective CTSS inhibition prevents lupus nephritis in mice, confirming that this protease is non-redundant for MHC class II-driven autoantibody production. Thanei et al. (Biochemical Pharmacology, 2017)⁸⁸ Thanei et al. (Biochemical Pharmacology, 2017) showed that CatS inhibition in SLE patient-derived macrophages reduces IL-6, TNFα, and IL-10 secretion and decreases MHC class II surface expression on B cells and monocytes.

Practical Actions

For T allele carriers, the actionable insights focus on the two downstream consequences of altered CTSS activity: amplified skin antigen presentation (reducing antigen entry limits the downstream immune activation), and direct PAR2/TRPV1-mediated itch (distinct from histamine pathways and requiring different treatment targeting). The OR of 1.18 represents a modest individual risk increase, but its biological specificity — pointing to a protease with both antigen-presentation and direct pruritogenic roles — informs management more precisely than generic atopic risk.

Interactions

rs115161931 is one of three independent signals at the CTSS locus for atopic dermatitis (alongside rs187080438 and rs146527530). Co-carriage of risk alleles at multiple CTSS locus signals compounds the individual effect additively; the three signals represent distinct regulatory mechanisms acting on the same gene rather than the same functional change. Within the broader atopic architecture, CTSS acts downstream of epithelial barrier genes (FLG, SPINK5) — antigen penetration through a defective barrier is amplified by elevated CTSS-driven antigen presentation. Individuals carrying both barrier-gene variants and CTSS-locus risk alleles face a dual hit: more antigen getting in and a more sensitive presentation machinery acting on it.