Murine systemic autoimmune disease induced by mercuric chloride (HgCl2): Hg-specific helper T-cells react to antigen stored in macrophages

AbstractAnimal models with impaired thymic negative selection do not always cause autoimmune diseases despite the development of an autoreactive T-cell repertoire. We investigated the requirements for the de velopment of systemic autoimmune disease by using bone marrow chimeras that lacked expression of major histocompatibility complex (MHC) class II on thymic antigen-presenting cells (APCs), leading to impaired negative selection. We found that impaired negative selection mediated by absence of MHC class II, but not MHC class I, permitted the development of systemic autoimmune disease that is indistinguishable from acute graft-versus-host disease (GVHD). Thymectomy prevented disease, confirming the causal association of the thymus with its development. Adoptive transfer of CD4+ T cells caused GVHD in secondary hosts only when they were irradiated, and cotransfer of peripheral CD4+ and CD8+ T cells from naive mice prevented the disease. These results demonstrate that impaired thymic negative selection can cause lethal autoimmune disease indistinguishable from acute GVHD in the context of a proinflammatory milieu when peripheral regulatory mechanisms are absent.

Download Full-text

The Phenotype of Circulating Follicular-Helper T Cells in Patients with Rheumatoid Arthritis Defines CD200 as a Potential Therapeutic Target

Clinical and Developmental Immunology ◽

10.1155/2012/948218 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 23

Author(s):

Aron Chakera ◽

Sophia C. Bennett ◽

Olivier Morteau ◽

Paul Bowness ◽

Raashid A. Luqmani ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Therapeutic Target ◽

Patient Characteristics ◽

Helper T Cells ◽

Immunoglobulin Superfamily ◽

Systemic Autoimmune Disease ◽

Follicular Helper T Cells ◽

Potential Therapeutic Target ◽

Follicular Helper

Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily affecting synovial joints in which the development of autoantibodies represents a failure of normal tolerance mechanisms, suggesting a role for follicular helper T cells (TFH) in the genesis of autoimmunity. To determine whether quantitative or qualitative abnormalities in the circulatingTFHcell population exist, we analysed by flow cytometry the number and profile of these cells in 35 patients with RA and 15 matched controls. Results were correlated with patient characteristics, including the presence of autoantibodies, disease activity, and treatment with biologic agents. CirculatingTFHcells from patients with RA show significantly increased expression of the immunoglobulin superfamily receptor CD200, with highest levels seen in seropositive patients (P=0.0045) and patients treated with anti-TNFαagents (P=0.0008). This occurs in the absence of any change inTFHnumbers or overt bias towards Th1, Th2, or Th17 phenotypes. CD200 levels did not correlate with DAS28 scores (P=0.887). Although the number of circulatingTFHcells is not altered in the blood of patients with RA, theTFHcells have a distinct phenotype. These differences associateTFHcells with the pathogenesis of RA and support the relevance of the CD200/CD200R signalling pathway as a potential therapeutic target.

Download Full-text

Rheumatoid Arthritis: Pathogenic Roles of Diverse Immune Cells

International Journal of Molecular Sciences ◽

10.3390/ijms23020905 ◽

2022 ◽

Vol 23 (2) ◽

pp. 905

Author(s):

Sunhee Jang ◽

Eui-Jong Kwon ◽

Jennifer Jooha Lee

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Autoimmune Disease ◽

Immune Cells ◽

Cartilage Destruction ◽

Systemic Autoimmune Disease ◽

Pannus Formation ◽

Systemic Complications ◽

Tissue Proliferation ◽

Novel Therapeutic

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease associated with synovial tissue proliferation, pannus formation, cartilage destruction, and systemic complications. Currently, advanced understandings of the pathologic mechanisms of autoreactive CD4+ T cells, B cells, macrophages, inflammatory cytokines, chemokines, and autoantibodies that cause RA have been achieved, despite the fact that much remains to be elucidated. This review provides an updated pathogenesis of RA which will unveil novel therapeutic targets.

Download Full-text

Self-limiting systemic autoimmune disease during reconstitution of T cell-deficient mice with syngeneic T cells: support for a multifaceted role of T cells in the maintenance of peripheral B cell tolerance

International Immunology ◽

10.1093/intimm/12.11.1483 ◽

2000 ◽

Vol 12 (11) ◽

pp. 1483-1497 ◽

Cited By ~ 5

Author(s):

Vicky M. Lentz ◽

Tim Manser

Keyword(s):

T Cells ◽

T Cell ◽

Autoimmune Disease ◽

B Cell ◽

Systemic Autoimmune Disease ◽

Cell Tolerance ◽

B Cell Tolerance ◽

Deficient Mice

Download Full-text

Autoimmune disease in mice due to integration of an endogenous retrovirus in an apoptosis gene.

Journal of Experimental Medicine ◽

10.1084/jem.178.2.461 ◽

1993 ◽

Vol 178 (2) ◽

pp. 461-468 ◽

Cited By ~ 188

Author(s):

J Wu ◽

T Zhou ◽

J He ◽

J D Mountz

Keyword(s):

T Cells ◽

Autoimmune Disease ◽

T Cell Development ◽

Cdna Probe ◽

Endogenous Retrovirus ◽

Complete Sequence ◽

Endogenous Retroviruses ◽

Systemic Autoimmune Disease ◽

Polymerase Chain ◽

Apoptosis Gene

The MRL-lpr/lpr mouse strain is a model of systemic autoimmune disease. In this model, intrinsic defects of intrathymic T cell development include defective deletion of self-reactive T cells and expression of endogenous retroviruses. Defective deletion of self-reactive T cells in the thymus has been proposed to be due to germline mutation in the Fas apoptosis gene. Using different fragments of a Fas cDNA probe, we determined that the lpr/lpr mutation is a 5.3-kb insertion of DNA within the second intron of the Fas gene. cDNA corresponding to this region was then derived from thymic RNA from MRL-lpr/lpr and MRL- +/+ mice using the polymerase chain reaction. All thymic RNA samples from MRL-lpr/lpr mice yielded a unique product that was 168 bp larger than that of MRL- +/+ mice. Complete sequence analysis indicated that this inserted sequence had 98% homology with a sequence from the 3' long terminal repeat of the early transposon (ETn). RNA analysis indicated higher expression of ETn RNA in the thymus of MRL-lpr/lpr than MRL- +/+ mice. The interdependence of ETn expression and abnormal Fas expression was then analyzed in a CD2-Fas transgenic mouse model in which a full-length murine Fas cDNA under the regulation of the CD2 promoter and enhancer was used to correct defective Fas expression in T cells of MRL-lpr/lpr mice. In these mice, reduced thymic ETn expression was observed, confirming that high ETn expression is related to abnormal Fas expression. These results establish a link between endogenous retrovirus expression, abnormal Fas expression, and autoimmune disease.

Download Full-text