Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

The role of autophagy in B cell tolerance

Award Number: R21AI193857
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: 04/23/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2028

Group Awards By:

View Award Description

The role of autophagy in B cell tolerance - PROJECT SUMMARY Autophagy is a crucial cellular process that maintains homeostasis by recycling or degrading unwanted cellular components. Canonical autophagy involves the formation of double membrane autophagosomes, which fuse with lysosomes for degradation. Non-canonical autophagy utilizes part of the autophagy machinery to generate single-membrane vesicles for lysosomal fusion. Recent findings reveal significant interactions between autophagy and other cellular degradative pathways. Importantly, autophagy defects have been linked to B cell tolerance loss in autoimmune diseases, notably Systemic Lupus Erythematosus (SLE). The proposal seeks to investigate how autophagy contributes to the loss of B cell tolerance, particularly in relation to crosstalk with endosomal Toll-like receptors (TLRs) that recognize nucleic acids. While these TLRs play a vital role in immune responses to infectious pathogens, their hyperactivation can lead to autoimmunity. Specifically, TLR7 and TLR9, which detect single-stranded (ss)RNA and double-stranded (ds)DNA, respectively, are critical in autoantibody responses in SLE. TLR7 overexpression has been shown to exacerbate SLE in animal models, with human polymorphisms enhancing TLR7 function also linked to the disease. TLR7 activation promotes B cell proliferation and plasma cell formation and is essential for spontaneous germinal center formation in SLE models. By contrast, although TLR9 is required for anti-dsDNA autoantibody production, its loss can worsen SLE by enhancing TLR7 signaling. Complete loss of all autophagy pathways in B cells can prevent SLE in mouse models. We generated SLE- prone mice with B cell deficiency of ATG14 (canonical autophagy only) and of Rubicon (involved in both autophagy pathways) and found that they both protect lupus-prone mice from autoantibody production and nephritis-related mortality, without significantly impacting responses to protein antigens. We hypothesize that the mechanism for this protection is via interference with vesicular trafficking and downregulation of endosomal TLR signals. In our first aim we will determine whether deficiencies in ATG14 or Rubicon affect immune responses to RNA or DNA viruses. In our second aim we will investigate how these deficiencies influence autoreactive B cell selection by utilizing flow cytometry to identify at which B cell stage autoreactivity is censored and B cell subset repertoire analysis to identify selection mechanisms known to be influenced by TLRs. In our third aim we will assess whether deficiencies in ATG14 or Rubicon reduce TLR signaling in activated B cells due to altered autophagosome and endolysosome traffic. This will involve analyzing endosomal traffic using confocal microscopy and measuring downstream signaling events and effector functions in B cells, along with investigating the function of newly identified Rubicon isoforms. Overall, our studies will elucidate the role of autophagy in B cell tolerance and inform new therapeutic strategies that maintain immune tolerance without excessive immunosuppression.


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 = $209,375 )
2026	2026	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	1	4/27/2026	NEW	$209,375
														Subtotal = $209,375

Grand Total All Awards = $209,375

Top

All Categories

About

Search

Reports

Data Submission

Award Information

The role of autophagy in B cell tolerance

Award Number: R21AI193857

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: 04/23/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer