# Pathogenic Role of Malondialdehyde-Acetaldehyde Adducts in Rheumatoid Arthritis

> **NIH VA I01** · OMAHA VA  MEDICAL CENTER · 2020 · —

## Abstract

It has been estimated that rheumatologist-diagnosed Rheumatoid arthritis (RA) is seen in up to 2% of the
users of VA healthcare. Moreover, compared to RA in women, RA in men (the primary VA demographic)
leads to greater morbidity, a higher frequency of extra-articular manifestations, and worse disease-related
outcomes. With an aging and predominantly male veteran population, it is anticipated that the burden posed by
RA will grow dramatically in the VA in coming years. This is highly relevant given the association of RA with;
substantially higher mortality risk among veterans, in addition to high rates of work-related disability, and annual
societal costs approaching $40 billion in the US alone. Over the past few years, there have been substantial
advances in our understanding of RA pathogenesis. Anti-citrullinated protein antibody (ACPA) is highly specific
to RA with recent studies suggesting that ACPA are pathogenic with seropositivity portending a poor
prognosis including more rapid joint destruction. However, the mechanism(s) by which citrullinated proteins/
peptides are recognized and processed and presented in the context of co-stimulatory molecules is still not
well understood. Studies have shown that a unique post-translational modification of proteins that
occurs under oxidative stress by malondialdehyde (MDA) and acetaldehyde (AA), termed MAA, up-
regulates MHC Class II, increases co-stimulatory molecules and generates cytotoxic and pro-inflammatory
responses in the absence of exogenous adjuvant. For the first time, our group has shown that MAA modified
proteins are detected in synovial tissues of RA patients and co-localize with citrullinated antigen. Additionally,
anti-MAA antibody isotypes are independently associated with ACPA concentration (p < 0.0001) in patients
with established RA. Therefore, our overarching hypothesis is that these two post-translational
modifications (MAA modification and citrullination) act in concert to drive tolerance loss resulting in
the anti-citrulline autoimmune responses characteristic of RA. To investigate this hypothesis, studies in
Aim 1 will evaluate adaptive immune responses (autoantibody and T cell responses) to citrullinated and/or
MAA-modified proteins. We anticipate that compared to antigens that are only citrullinated or only MAA
modified, immune responses to co-modified proteins will be higher in mice following immunization and in RA
patients. As prior data has demonstrated that SRs mediate the biological effects of MAA-modified proteins
on APCs and other cells, Aim 2 is designed to identify the specific SRs that mediate the effects of
citrullinated and/or MAA-modified proteins in RA. In Sub-Aim #1, studies will leverage Chinese Hamster
Ovary (CHO) cell lines that are already available in our laboratory and that have been transfected with
each of the various SRs. Results of initial experiments will inform the design of subsequent binding studies
using human APCs (that simultaneously express ...

## Key facts

- **NIH application ID:** 9780820
- **Project number:** 1I01BX004660-01
- **Recipient organization:** OMAHA VA  MEDICAL CENTER
- **Principal Investigator:** TED RICHARD MIKULS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9780820

## Citation

> US National Institutes of Health, RePORTER application 9780820, Pathogenic Role of Malondialdehyde-Acetaldehyde Adducts in Rheumatoid Arthritis (1I01BX004660-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9780820. Licensed CC0.

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