Abnormal apoptosis in chronic granulomatous disease and autoantibody production characteristic of lupus

Sanford, Amy N.; Suriano, A. R.; Herche, D.; Dietzmann, K.; Sullivan, Kathleen E.

doi:10.1093/rheumatology/kei135

Cited by 58 publications

(44 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1F). We hypothesize that the loss of G2A signaling contributes to the accumulation of apoptotic cells, a feature generally indicative of defects in clearance found in many models of chronic inflammation and autoimmunity (15,30,42,53,(65)(66)(67). We also speculate that dysregulation at any of these various steps of the G2A signaling pathway defined here (e.g.…”

Section: Discussionmentioning

confidence: 52%

Signaling via Macrophage G2A Enhances Efferocytosis of Dying Neutrophils by Augmentation of Rac Activity

Frasch¹,

Fernandez-Boyanapalli²,

Berry

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Phosphatidylserine (PS) and oxidized PS species have been identified as key ligands on apoptotic cells important for their recognition and removal (efferocytosis) by phagocytes, a requisite step for resolution of inflammation. We have recently demonstrated that lysophosphatidylserine (lyso-PS) generated and retained on neutrophils following short term activation of the NADPH oxidase in vitro and in vivo enhanced their clearance via signaling through the macrophage G-protein-coupled receptor G2A. Here, we investigated the signaling pathway downstream of G2A. Lyso-PS, either made endogenously in apoptosing neutrophils or supplied exogenously in liposomes along with lyso-PS neg apoptotic cells, signaled to macrophages in a G2A-dependent manner for their enhanced production of prostaglandin E 2 (PGE 2 ) via a calcium-dependent cytosolic phospholipase A 2 /cyclooxygenase-mediated mechanism. Subsequent signaling by PGE 2 via EP2 receptors activated macrophage adenylyl cyclase and protein kinase A. These events, in turn, culminated in enhanced activity of Rac1, resulting in an increase in both the numbers of macrophages efferocytosing apoptotic cells and the numbers of cells ingested per macrophage. These data were surprising in light of previous reports demonstrating that signaling by PGE 2 and adenylyl cyclase activation are associated with macrophage deactivation and inhibition of apoptotic cell uptake. Further investigation revealed that the impact of this pathway, either the enhancement or inhibition of efferocytosis, was exquisitely sensitive to concentration effects of these intermediaries. Together, these data support the hypothesis that lyso-PS presented on the surface of activated and dying neutrophils provides a tightly controlled, proresolution signal for high capacity clearance of neutrophils in acute inflammation.

show abstract

Section: Discussionmentioning

confidence: 52%

Signaling via Macrophage G2A Enhances Efferocytosis of Dying Neutrophils by Augmentation of Rac Activity

Frasch¹,

Fernandez-Boyanapalli²,

Berry

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…It has been proposed that the inability of phagocytic cells to completely destroy and clear microbial pathogens would result in an exaggerated and perpetuated inflammatory response that would favor autoimmunity. 26 Moreover, NOX2-deficient T cells have a bias toward Th1 differentiation, which could favor the development of autoimmune disorders. 27 Our results showing reduced cross-presentation in NOX2-defective DCs suggest an alternative mechanism to link NADPH oxidase defects and autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells

Mantegazza

Savina

Vermeulen

et al. 2008

Blood

274

244

View full text Add to dashboard Cite

The phagocyte NADPH oxidase (NOX2) is critical for the bactericidal activity of phagocytic cells and plays a major role in innate immunity. We showed recently that NOX2 activity in mouse dendritic cells (DCs) prevents acidification of phagosomes, promoting antigen cross-presentation. In order to investigate the role of NOX2 in the regulation of the phagosomal pH in human DCs, we analyzed the production of reactive oxygen species (ROS) and the phagosomal/endosomal pH in monocytederived DCs and macrophages (MØs) from healthy donors or patients with chronic granulomatous disease (CGD). As expected, we found that human MØs acidify their phagosomes more efficiently than human DCs. Accordingly, the expression of the vacuolar proton ATPase (V-H ؉ -ATPase) was higher in MØs than in DCs. Phagosomal ROS production, however, was also higher in MØs than in DCs, due to higher levels of gp91phox expression and recruitment to phagosomes. In contrast, in the absence of active NOX2, the phagosomal and endosomal pH decreased. Both in the presence of a NOX2 inhibitor and in DCs derived from patients with CGD, the cross-presentation of 2 model tumor antigens was impaired. We conclude that NOX2 activity participates in the regulation of the phagosomal and endosomal pH in human DCs, and is required for efficient antigen crosspresentation. (Blood. 2008;112:4712-4722)

show abstract

“…Data on protein levels or activity of the classical complement pathway are not available in our group of carrier mothers. However, both the process of apoptosis and clearance of apoptotic cells are impaired in patients with X-CGD with impaired expression of phosphatidyl serine, which is crucial for apoptotic cell clearance, and impaired production of prostaglandin D2 and transforming growth factor b, both potent anti-inflammatory agents, during the phagocytosis of opsonized and nonopsonized apoptotic targets [24,25]. Together this suggests that in X-CGD damaged cells undergo abnormal apoptosis, are poorly cleared by the reticuloendothelial system and the normal anti-inflammatory response is impaired.…”

Section: Discussionmentioning

confidence: 99%

Cutaneous and other lupus-like symptoms in carriers of X-linked chronic granulomatous disease: incidence and autoimmune serology

Cale

Morton

Green

2007

Clinical and Experimental Immunology

132

View full text Add to dashboard Cite

SummaryThe objective of this study was to determine the utility of anti-nuclear antibody (ANA) testing in the investigation of cutaneous and other lupus symptoms in female carriers of X-linked chronic granulomatous disease (CGD). We undertook a prospective study of 19 carrier mothers attending our institution, with direct questioning of carriers concerning symptoms and testing for anti-nuclear and anti-phospholipid antibodies. A total of 58% reported significant photosensitive skin rashes, 42% reported mouth ulcers and 37% complained of joint pains that could not be attributed to other known causes. Anti-nuclear antibody (ANA) testing was negative in 73% of all carriers. The five positive ANAs were of low titre (maximum 1 : 320 on Hep 2 cells in two women) and only one weak positive double-stranded DNA antibody and no extractable nuclear antibodies were found. Several of the mothers, despite negative serology, benefited from referral to a specialist, and in some cases to specific treatment. A history of skin rashes, joint pain, fatigue and mouth ulcers should be sought actively in the female relatives of X-CGD patients but negative lupus serology should not preclude referral to appropriate dermatology or rheumatology services. as symptoms may respond well to appropriate treatment.

show abstract

Abnormal apoptosis in chronic granulomatous disease and autoantibody production characteristic of lupus

Cited by 58 publications

References 15 publications

Signaling via Macrophage G2A Enhances Efferocytosis of Dying Neutrophils by Augmentation of Rac Activity

Signaling via Macrophage G2A Enhances Efferocytosis of Dying Neutrophils by Augmentation of Rac Activity

NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells

Cutaneous and other lupus-like symptoms in carriers of X-linked chronic granulomatous disease: incidence and autoimmune serology

Contact Info

Product

Resources

About