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The role of idiopathic multicentric Castleman Disease patient-derived CABIN1 mutation in Germinal Center Response.

Award Number: K08AI199050
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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The role of idiopathic multicentric Castleman Disease patient-derived CABIN1 mutation in Germinal Center Response. - Summary Germinal centers (GCs) are specialized structures within the lymphoid organs where B-cells undergo activation and affinity maturation with the help of T follicular helper (Tfh) cells and play a critical role in humoral immunity. Although there is a growing body of knowledge on the regulation of GC response under physiologic conditions, our understanding of its role in diseases is limited. The goal of this project is to elucidate the role of CABIN1 in Tfh development and GC reaction through a mutation (V2185M) that has been identified in an idiopathic multicentric Castleman Disease (iMCD) patient. iMCD is a rare hematologic disorder characterized by abnormal GC formation and episodic systemic hypercytokinemia. I recently developed a mouse model of iMCD, where the CABIN1 V2185M mutation was knocked into the endogenous CABIN1 locus. CABIN1 is known to play a role in T-cell activation as a negative regulator of calcineurin and MEF2. Although normal at baseline, I found that compared to wildtype (WT) mice, V2185M mice harbored increased numbers of Tfh-like CXCR5+CD4+ T-cells upon LCMV infection and after immunization with ovalbumin (model antigen) mRNA lipid nanoparticles (OVA-LNP). Interestingly, however, despite increased numbers of Tfh-like cells, the mice displayed regressed GCs, reminiscent of pathology seen in lymph node biopsies of iMCD patients. These data suggest that the CABIN1 mutation causes aberrant Tfh generation, leading to a reduced GC response. At a mechanistic level, V2185M T-cells displayed abnormal AP-1-independent NFAT signaling (a direct substrate of calcineurin), which is a well-known contributor to Tfh differentiation, as well as MEF2 dysregulation. In addition, V2185M T-cells exhibited decreased SAP expression, which is a critical component of the B:T synapse formation, and is known to be negatively regulated by MEF2D. Based on these findings, I hypothesize that the CABIN1 V2185M mutation contributes to increased but functionally defective Tfh differentiation that leads to abnormal GC formation by increasing NFAT and MEF2D signaling. I will test this hypothesis in two Aims. In Aim 1, using an array of in vivo and in vitro studies, I will determine whether dysregulated AP-1-independent calcineurin-NFAT signaling is the driver of aberrant Tfh-like differentiation in CABIN V2185M mutant mice. In Aim 2, I will determine whether the aberrant Tfh-like population is responsible for the reduced GC response. In addition, I will determine the contribution of MEF2D dysregulation and decreased SAP expression in this process. Successful completion of this project will enhance our fundamental understanding of how signaling pathways involving CABIN1 play a complex role in Tfh generation and function. This could explain the aberrant Tfh function and GC response seen in immune dysregulation disorders such as iMCD. This research will serve as an excellent training platform for enhancing my research skills in mechanistic scientific investigation.


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 = $86,768 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	5/13/2026	NEW	$86,768
														Subtotal = $86,768

Grand Total All Awards = $86,768

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The role of idiopathic multicentric Castleman Disease patient-derived CABIN1 mutation in Germinal Center Response.

Award Number: K08AI199050

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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