| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
In the groove
|
CD4+ T cells and autoimmune hepatitis
Although liver biopsies from patients suffering from autoimmune hepatitis contain large numbers of CD4+ T cells, the role of those cells in the disease is unclear. Gorham et al. previously used a BALB/c mouse model to show that the cytokine TGF-
1 protects against necroinflammatory liver disease. In a continuation of those studies, Rudner et al. (p. 4785
) demonstrated that mice deficient in TGF-1 had an increase in T cells and macrophages in their livers and died before 18 days of age. An anti-CD3 redirected lysis assay showed high levels of hepatic T cell cytolytic activity. Mice doubly deficient in TGF-1 and RAG-1, and therefore lacking mature B and/or T cells, had prolonged survival and failed to develop autoimmune hepatitis. Ab-mediated depletion of CD4+ T cells in young BALB/c-TFG-1-/- mice prevented liver damage, thus implicating CD4+ T cells in the disease process. The exact mechanism by which CD4+ T cells engineer the death of the hepatocytes is unknown. However, the ability of TGF-1 to inhibit cytolytic T cells may be useful in exploring normal liver immune function and in understanding liver pathologies such as infections, tumor growth, and drug toxicity.
Lymphoid neogenesis
Naive T cells enter into nonlymphoid tissues in several conditions, including autoimmune diseases, and form tertiary lymphoid tissue in a process called lymphoid neogenesis. Chemokines such as CCR7 ligands have been implicated in the process. Weninger et al. (p. 4638 ) superfused the cremaster muscles of T-GFP mice with the CCR7 ligand, CCL21, and used intravital microscopy to detect the sticking of green fluorescent protein-expressing naive (CD44low) T cells to the microvasculature. The primary adhesion molecule was LFA-1, as prior injection of the cremaster muscle with anti-LFA-1 blocking mAb abolished T cell adherence. Positive immunohistochemical detection of CCL21 in blood vessels and in situ hybridization of CCL21 mRNA in vascular endothelial cells was seen in samples from patients with ulcerative colitis and rheumatoid arthritis, but not with psoriasis. Naive T cells were detected in the ulcerative colitis and rheumatoid arthritis tissues but rarely in psoriasis tissues. The authors suggest that endothelial cell presentation of CCL21 triggers an influx of naive T cells into tertiary tissues, a process that may be targeted for disruption in treating chronic inflammation.
CD1-Ag interactions: low affinity but stable
|
2-microglobulins function similarly to MHC in presenting Ags to 
TCRs. However, CD1 presents lipids and glycolipids rather than peptides. Published functional assays measured the half-life of the binding interaction of a glycolipid, -galactosylceramide (GC), with mouse CD1d at 
1 day, whereas biophysical measurements using surface plasmon resonance (SPR) reported interactions of less than 1 min. Cantu et al. (p. 4673
) evaluated SPR against several new biochemical and biophysical methods they developed to resolve the discrepancies in the published reports. The authors determined that recombinant soluble CD1d interacted nonspecifically with hydrophobic surfaces in SPR experiments. Isoelectric focusing binding assays and thermal titration calorimetry experiments showed that CD1d bound lipids with low affinity but that the dissociation of the resulting CD1d-lipid complexes took more than 1 day. Temperature and ionic strength did not affect the interactions. The CD1d-GC complex was recognized by the TCR of NK T cells. Pairing of the V14 chain of the TCR with a variety of -chains in soluble complexes did not alter binding with the CD1d-GC complex. The thermodynamics of the CD1d/GC-V14 TCR interactions suggested that the rigid structure of the lipid sugar moiety was the most important part of the ligand seen by the TCR. Cytokines and Th2 differentiation
Dendritic cells (DC) orchestrate Th1/Th2 subset differentiation of CD4+ Th cells. Two factors that determine the path of differentiation are expression of DC surface markers and secretion of specific cytokines by DC. Dodge et al. (p. 4457
) examined DC from lung and spleen and found that the lung population was CD8- and contained a subpopulation of cells expressing high levels of CD11b. LPS-stimulated pulmonary DC secreted higher levels of IL-6 and much lower levels of IL-12 than spleen DC. LPS-stimulated pulmonary DC from IL-6-/- mice produced elevated levels of IL-12 and induced a strong Th1 response in naive CD4+ T cells. Pulmonary DC cocultured with naive CD4+ T cells in the presence of anti-IL-6 neutralizing Ab had increased IFN-
levels, decreased IL-4 levels, and Th1 polarization. These results indicate that the high levels of IL-6 produced by pulmonary DC inhibit secretion of IL-12, thus diminishing Th1-mediated chronic inflammatory responses in the lung.
Less fas
|
12,14-PGJ2 (15d-PGJ2), is an anti-inflammatory molecule produced by immune and other cells. In an attempt to understand the mechanism of 15d-PGJ2 action on Fas-FasL-mediated apoptosis, Cippitelli et al. (p. 4578
) analyzed fas-L mRNA expression in activated T cells in the absence and presence of 15d-PGJ2. 15d-PGJ2 significantly decreased activation-induced cell death and decreased fas-L mRNA expression through direct interaction with the fas-L promoter as determined by luciferase reporter assays. The interaction was independent of PPAR coexpression. 15d-PGJ2 decreased the activity and expression of transcription factors EGR-3, NF-
B, cMyc, and AP-1 and increased the activity and expression of EGR-1 and Nur77. The reactive portion of 15d-PGJ2 was found to reside in the cyclopentenone ring. The complex effects of 15d-PGJ2 on the transcriptional activity of molecules, especially fas-L, involved in the inflammatory process suggest that 15d-PGJ2 could be a useful therapeutic agent to control autoimmune and inflammatory disorders. Two pathways to lupus nephritis?
The degree of lupus nephritis that accompanies human systemic lupus erythematosus (SLE) can range from severe inflammation to glomerulosclerosis and renal failure. The mechanisms responsible for the different patterns of nephritis are not understood. Singh et al. (p. 4818
) studied two mouse models of SLE, the New Zealand Mixed (NZM.2410) strain, which develops severe glomerulosclerosis, and the MRL-lpr strain, which develops severe kidney inflammation. Using a sensitive in vivo cytokine capture assay, the authors showed that compared with nonautoimmune mouse strains, NZM.2410 mice overproduced the type 2 cytokine, IL-4, whereas MLR-lpr mice overproduced the type 1 cytokine, IFN-. Anti-IL-4 mAb treatment of NZM.2410 mice decreased the incidence of glomerulosclerosis as did a STAT6 null mutation, implicating IL-4 and STAT6 in the severe inflammation. NZM.2410 mice deficient in STAT4 had an increase in kidney disease but lower levels of IgG autoantibodies, suggesting a major role for type 1 cytokines in the production of anti-dsDNA Abs. If the delineation of two specific subsets of nephritis, characterized by different cytokine and STAT protein contributions, holds up for human patients, it may be possible to tailor therapy to distinct manifestations of kidney disease in SLE.
Along for the ride
|
BCR signaling and autoimmunity
|
Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
12,14-Prostaglandin J2 Inhibits CD95 Ligand Gene Expression in T Lymphocytes: Interference with Promoter Activation Via Peroxisome Proliferator-Activated Receptor--Independent Mechanisms
-Galactosylceramide: Low Affinity, Low Specificity for CD1d, High Affinity for TCRs
1-Deficient Mice Requires CD4+ T Cells
| ||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
