# CARD9 in Ankylosing Spondylitis

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2024 · —

## Abstract

Arthritis is a major health concern to the Veteran population who have 35% incidence rates. Ankylosing
spondylitis (AS), a type of inflammatory arthritis that results in chronic back pain, sacroiliac joint and/or
vertebral joint fusion and permanent spinal deformity. Although the cause of AS is not known, genetic studies
suggest that CD4+ T helper cells that produce the pro-inflammatory cytokine IL-17 (Th17 cells) drive the
pathogenesis of AS. In support, pharmacological inhibition of IL-17 (IL-17i) has had great utility in moderating
AS symptoms. Although Th17 responses appear to be key in driving symptomatic disease, less is understood
of the underlying innate cellular mechanisms that initiate pathologic Th17 cell responses. Given our limited
understanding of immunopathogenesis of AS physicians are challenged with administering one of several
approved anti-rheumatic biologics (i.e. IL-17i, TNFi, JAKi) to patients without mechanistic insight into who will
respond best to each drug. Thus, development of treatment response biomarkers is urgently needed to
increase therapeutic responses and alleviate pain in patients suffering from this debilitating disease. To move
this field forward we are in urgent need of more research to reveal genetic and molecular mediators of IL-17-
mediated AS. An emerging paradigm suggests that self-reactive T cells (autoimmune) and aberrant innate
immunity (autoinflammation) conspire to drive AS pathogenesis. In support, a mutation in the microbial-
signaling molecule CARD9 (i.e. rs4077515) is associated with increased susceptibility to AS. The CARD9-
signaling axis is essential for fungal immunity, yet how dysregulation of CARD9 might regulate sterile
inflammation in AS has not been studied. This application is based on our finding that CARD9 is a genetic
determinant of AS in genetically susceptible SKG mice. CARD9 appears to be functioning within neutrophils to
induce arthritogenic Th17 responses. Given our data we hypothesize that CARD9 is an important regulator of
arthritogenic Th17 cells in AS. The goal of this Merit proposal is to determine the mechanism by which innate
cellular processes induce arthritogenic Th17 cells in AS and use this information to develop a biomarker of IL-
17i treatment responders in the clinic. Importantly, clinical studies proposed in this application will be focused
on AS patients previously enrolled in or newly enrolled in from the Veteran Program to Understand Longterm
Outcomes of Spondyloarthritis (PULSAR). These studies will reveal crucial cellular networks and molecules
that cause AS and ultimately contribute knowledge needed to develop future patient-tailored treatment
strategies to improve the health of Veterans.

## Key facts

- **NIH application ID:** 10807453
- **Project number:** 1I01BX006436-01
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** RUTH NAPIER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807453

## Citation

> US National Institutes of Health, RePORTER application 10807453, CARD9 in Ankylosing Spondylitis (1I01BX006436-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10807453. Licensed CC0.

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