Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation. DOI Creative Commons
Hrishikesh S. Kulkarni, Laneshia K. Tague, Daniel R. Calabrese

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

ABSTRACT A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause mortality after transplantation, is needed to improve outcomes. The complement system links innate adaptive immune responses and activated early post-lung transplantation form C3 convertase, a critical enzyme that cleaves central component C3. We hypothesized LTx recipients with genetic predisposition enhanced activation have worse CLAD-free survival mediated through increased alloimmunity. interrogated known functional polymorphism (C3R102G) increases impaired convertase inactivation in two independent recipient cohorts. C3R102G, identified at least one out three recipients, was associated survival, particularly subset who developed donor-specific antibodies (DSA). In mouse orthotopic model, regulation resulted more severe obstructive airway lesions when compared wildtype controls, despite only moderate differences graft-infiltrating effector T cells. Impaired promoted intragraft accumulation memory B cells antibody-secreting cells, resulting DSA levels. summary, cell survival. BRIEF SUMMARY Lung transplant genetically predisposed demonstrate rejection-free This phenotype cell-activation antibodies.

Language: Английский

mSphere of Influence: Complement activity beyond systemic circulation—implications in the context of infections DOI Creative Commons
Jigar V. Desai

mSphere, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

ABSTRACT Jigar V. Desai works in the field of immunology, studying mucosal and systemic complement systems their roles regulating immune response. In this mSphere Influence article, he reflects on how papers by Kemper, Kulkarni, Kasper laboratories made an impact his ongoing work investigating cell-intrinsic extrinsic regulation its impacts immunity.

Language: Английский

Citations

0
Complement and fungal diseases DOI
Jigar V. Desai, Michail S. Lionakis

Journal of Allergy and Clinical Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

0
The C3-C3aR axis modulates trained immunity in alveolar macrophages DOI Open Access
Alexander P Earhart, Rafael Aponte Alburquerque, Marick Starick

et al.

Published: March 31, 2025

Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids microbe elimination and enhances inflammation. While trained immunity – enhanced secondary of innate cells after prior exposure well-studied, role complement system remains unclear. We investigated found that vivo , wild-type mice showed significantly elevated pro-inflammatory cytokines increased C3a levels upon a second stimulus, whereas C3-deficient exhibited blunted cytokine response heightened evidence lung injury. Ex alveolar macrophages (AMs) displayed reduced chemokine output training, which was restored by exogenous but not C3a. Inhibiting C3aR, both pharmacologically with genetic C3aR knockout, prevented this restoration, indicating necessity engagement. Mechanistically, WT AMs demonstrated glycolytic activity compared to defect corrected C3aR-dependent manner. These findings reveal modulates through signaling, affecting production metabolic reprogramming, highlight novel immunity.

Language: Английский

Citations

0
The C3-C3aR axis modulates trained immunity in alveolar macrophages DOI Open Access
Alexander P Earhart, Rafael Aponte Alburquerque, Marick Starick

et al.

Published: March 31, 2025

Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids microbe elimination and enhances inflammation. While trained immunity – enhanced secondary of innate cells after prior exposure well-studied, role complement system remains unclear. We investigated found that vivo , wild-type mice showed significantly elevated pro-inflammatory cytokines increased C3a levels upon a second stimulus, whereas C3-deficient exhibited blunted cytokine response heightened evidence lung injury. Ex alveolar macrophages (AMs) displayed reduced chemokine output training, which was restored by exogenous but not C3a. Inhibiting C3aR, both pharmacologically with genetic C3aR knockout, prevented this restoration, indicating necessity engagement. Mechanistically, WT AMs demonstrated glycolytic activity compared to defect corrected C3aR-dependent manner. These findings reveal modulates through signaling, affecting production metabolic reprogramming, highlight novel immunity.

Language: Английский

Citations

0
The Establishment of Complement System Is from Gene Duplication and Domain Shuffling DOI Open Access
Jiejie Sun, Chang Liu, Lingling Wang

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8119 - 8119

Published: July 25, 2024

The mammalian complement system constitutes a highly sophisticated body defense machinery. evolutionary origin of the can be traced to Coelenterata as presence central component C3 and two activation proteases BF MASP. In present study, main components were screened analyzed from genomes different species in metazoan subphyla/phyla. C1q with classical domains Annelida, ficolin MBL Urochordata. C1r C1s are only found Chondrichthyes even higher species, MASP is Coelenterata. tree, Vertebrates close MASP1/2/3 Deuterostomia Coelenterata, MASP-like protease (MASPL) Arthropoda, Mollusca, Annelida. C2, BF, DF Porifera, respectively. There no clear C2 branches tree. C4 C5 species. three C3, C4, C6-like (C6L) C8 Urochordata, C7-like (C7L) Cephalochordara. C6L, C7L, Urochordata Cephalochordara provide structural conditions for formation Vertebrate MAC components. findings unveil principles insight into its sophistication.

Language: Английский

Citations

0
The C3-C3aR axis modulates trained immunity in alveolar macrophages DOI Creative Commons
Alexander P Earhart, Rafael Aponte Alburquerque, Marick Starick

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 3, 2024

ABSTRACT Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids microbe elimination and enhances inflammation. While trained immunity – enhanced secondary of innate cells after prior exposure well-studied, role complement system remains unclear. We investigated found that vivo , wild-type mice showed significantly elevated pro-inflammatory cytokines increased C3a levels upon a second stimulus, whereas C3-deficient exhibited blunted cytokine response heightened evidence lung injury. Ex alveolar macrophages (AMs) displayed reduced chemokine output training, which was restored by exogenous but not C3a. Inhibiting C3aR, both pharmacologically with genetic C3aR knockout, prevented this restoration, indicating necessity engagement. Mechanistically, WT AMs demonstrated glycolytic activity compared to defect corrected C3aR-dependent manner. These findings reveal modulates through signaling, affecting production metabolic reprogramming, highlight novel immunity.

Language: Английский

Citations

0
Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation. DOI Creative Commons
Hrishikesh S. Kulkarni, Laneshia K. Tague, Daniel R. Calabrese

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

ABSTRACT A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause mortality after transplantation, is needed to improve outcomes. The complement system links innate adaptive immune responses and activated early post-lung transplantation form C3 convertase, a critical enzyme that cleaves central component C3. We hypothesized LTx recipients with genetic predisposition enhanced activation have worse CLAD-free survival mediated through increased alloimmunity. interrogated known functional polymorphism (C3R102G) increases impaired convertase inactivation in two independent recipient cohorts. C3R102G, identified at least one out three recipients, was associated survival, particularly subset who developed donor-specific antibodies (DSA). In mouse orthotopic model, regulation resulted more severe obstructive airway lesions when compared wildtype controls, despite only moderate differences graft-infiltrating effector T cells. Impaired promoted intragraft accumulation memory B cells antibody-secreting cells, resulting DSA levels. summary, cell survival. BRIEF SUMMARY Lung transplant genetically predisposed demonstrate rejection-free This phenotype cell-activation antibodies.

Language: Английский

Citations

0