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Anti-citrullinated Protein Antibodies in the Female Reproductive Tract

Award Number: R21AI195003
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/12/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Anti-citrullinated Protein Antibodies in the Female Reproductive Tract - Rheumatoid arthritis (RA) is a chronic autoimmune disease that can be defined by the production of anti- citrullinated protein antibodies (ACPA). Despite the central role of ACPA in RA, there is a limited understanding of the initiating events including the mucosal site where and mechanisms by which autoimmunity to peptidylarginine deiminase (PAD) catalyzed citrullinated (cit)-proteins released by neutrophil extracellular traps (NETs) is initially triggered. This gap in knowledge is particularly adverse for women who have a 3 fold higher incidence of RA, face a delay in diagnosis and treatment, and have worse clinical outcomes compared to men. Our long-term goal is to determine whether RA-related autoimmunity initiates in the female reproductive tract (FRT) - a finding that could explain sex differences in RA. The objective of this proposal is to establish how PADs, NETs, cit-proteins, and ACPA change in female reproductive tract in mice and women during the estrous/menstrual cycle and pregnancy and postpartum periods. Our data demonstrate that fluid from the healthy female reproductive tract contains active PAD enzymes, cit-proteins, and ACPA that fluctuate across the menstrual cycle. In FRT fluid from women with RA, ACPA are significantly elevated compared to samples from healthy women. Our mass spectrometry studies identified cit-proteins whose levels differ substantially between FRT fluid samples from healthy women and those at risk for and with RA. We propose a model in which NETs release cit-proteins that stimulate ACPA production in the FRT during times of mucosal tissue disruption and inflammation; however, as this process repeats with each menstrual cycle, during pregnancy and postpartum, it increases the likelihood of autoimmunity in women. Our central hypothesis is that NETs release cit-proteins that trigger ACPA production in the FRT during reproductive cycles, pregnancy, and postpartum. The central hypothesis will be tested with the following specific aims: (1) Identify the mouse FRT fluid citrullinome and determine whether protein citrullination is necessary for ACPA production in the FRT; (2) Determine whether ACPA in FRT fluid from healthy women and those with RA are higher during pregnancy and postpartum and identify the changes in the FRT fluid citrullinome. This work is significant because it is a critical step to characterize ACPA production in the FRT, which may underlie the increased incidence of RA in women. The proposed research is innovative because these studies will provide critical data to support clinical studies to target the FRT for diagnosis, treatment, or prevention of RA.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $226,404 )
2026	2026	UNIVERSITY OF WYOMING	1000 E UNIVERSITY AVE	LARAMIE	WY	82071	ALBANY	USA	Allergy and Infectious Diseases Research	000	1	8/12/2026	NEW	$226,404
														Subtotal = $226,404

Grand Total All Awards = $226,404

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Anti-citrullinated Protein Antibodies in the Female Reproductive Tract

Award Number: R21AI195003

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/12/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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