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Abnormal cytokine response and autoantigen production in IgA-producing subpopulations in IgA nephropathy

Award Number: R03DK122194
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract IgA nephropathy (IgAN) is the most common primary glomerulonephritis. It leads to end-stage kidney disease (ESKD) in 40-50% of patients. IgAN patients often exhibit macroscopic hematuria, commonly associated with upper-respiratory tract infections. This exacerbation of kidney injury seen during episodes of mucosal infection and inflammation suggests a connection between the two. In biopsies of IgAN patients, the defining characteristic of this disease is the deposits of polymeric IgA1, typically with IgG and complement C3 co- deposits. Analysis of the deposited IgA1 revealed enrichment for galactose-deficient IgA1 (Gd-IgA1) compared to circulatory IgA1. In addition, the co-deposited IgG is specific for Gd-IgA1. This appears to be immune complex deposition, which is also found in circulation of patients. Serum levels of Gd-IgA1 and anti-Gd-IgA1- IgG autoantibodies are elevated in IgAN patients, associate with disease progression, and can be found complexed in circulation. This circulatory autoantigen (Gd-IgA1) is typically found in the polymeric form, which is unique to the mucosal region. This suggests that a subset of IgA1-producing cells could be migrating from mucosal regions, or there is abnormal IgA1-producing cells formed elsewhere. Initial observations that mucosal infections associated with transient hematuria in IgAN patients led to the thesis that pro-inflammatory stimulation could increase circulatory Gd-IgA1-containing immune complexes, causing renal injury. We recently published that IL-6 stimulation in EBV-immortalized IgA1-producing cells from IgAN patients, but not controls, preferentially increased Gd-IgA1 production due to an enhanced and prolonged STAT3 activation. In addition, preliminary data in our lab from single-cell transcriptome profiling using immortalized IgA-producing cells from IgAN patients and healthy controls revealed multiple populations of IgA1-producing cells that have differential responses to cytokine stimulation. These observations led to our hypothesis that enhanced Gd- IgA1 production is a result of abnormal cytokine response in a subset of IgA1-producing cells. In Aim 1, we will test the hypothesis that cytokine exposure has differential effects on subsets of IgA1-producing cells in EBV- immortalized IgA1-producing cells from IgAN patients vs. healthy and disease controls. In Aim 2, we will test the hypothesis that subsets of IgA1-producing cells that have differential responses to cytokine stimulation are preferentially producing Gd-IgA1. The combination of these two aims will help identify the specific IgA1- producing cell subsets that contribute to autoantigen production. These studies will enable testing of novel research hypotheses and yield new preliminary data towards a competitive R01 proposal.


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: 2023 ( Subtotal = -$6,572 )
2023	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/9/2022	NON-COMPETING CONTINUATION	-$6,572
														Subtotal = -$6,572

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $111,375 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/22/2020	NON-COMPETING CONTINUATION	$111,375
														Subtotal = $111,375

Issue Date FY: 2019 ( Subtotal = $111,375 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/24/2019	NEW	$111,375
														Subtotal = $111,375

Grand Total All Awards = $216,178

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Abnormal cytokine response and autoantigen production in IgA-producing subpopulations in IgA nephropathy

Award Number: R03DK122194

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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