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Targeting RA Inflammation
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or TNF-
and was accompanied by an increased release of intracellular calcium from stores in the nonendoplasmic reticulum compartment, which were larger in RA, vs OA, FLS. Cyclosporin A, used clinically to control inflammation in RA, partially inhibited IL-1- or TNF--stimulated production of IL-6 and several matrix metalloproteinases in RA FLS cultures. Whereas mRNA and protein for calcineurin-binding protein, a natural noncompetitive inhibitor of calcineurin, are expressed equally in RA and OA FLS, overexpression of the inhibitory domain by transfection of synoviocytes reduced calcineurin phosphatase activity and lowered levels of IL-6 and some matrix metalloproteinases. Injection of cyclosporin A into mice after induction of collagen-induced arthritis significantly decreased arthritis symptoms compared with controls. The authors suggest that calcium and calcineurin A play significant roles in the initiation and progression of synovial inflammation in RA and propose that cyclosporin A acts, in part, by blocking calcineurin A activity. CDR3 Loops Positively Select CD8+ T Cells
Although interaction of a peptide-MHC complex with the TCR is required for positive selection of a T cell, the roles of the complementarity determining regions (CDRs) of the TCR in that interaction are not well understood. Ferreira et al. (p. 2477
) found skewed selection of the TCR- chain variable segment 9 (AV9) by tetramer binding to CD8+ T cells from anti-HY Ag TCR- chain transgenic female H2b mice immunized with syngeneic male cells. Semiquantitative AV transcript analysis confirmed the tetramer binding results and showed that H2k and H2q mice transgenic for the same TCR- chain had different dominant AV segments. H2b hypervariable anti-CDR3 loops used longer, more flexible 5' AJ sequences reflective of the preselection recombination blueprint, whereas non-H2b CDR3 loops used shorter, more rigid central AJ segments that did not resemble the recombination blueprint. AV9 CDR3 loop variability was high in H2b mice but very low in non-H2b animals. HY peptides with variant N-terminal amino acids were bound equally well by CD8+ T cells from thymi and spleens of H2b mice. Purified transgenic H2b CD8+ T cells that bound the HY tetramer had a very high proportion of AV9 rearrangements (flexible type I loops); purified cells that bound a variant HY tetramer with high affinity had a variant AJ profile consisting of shorter, less flexible type II loops. The data indicate that type I AJ rearrangements dominant in the presence of H2b are more peptide tolerant and lead to positive selection, whereas type II AJ rearrangements use rare V-J joins and require more extensive peptide-MHC engagement.
CD8+ T Cells in CNS Demyelination
Although mice given CD4+ T cells reactive for specific myelin Ags develop a disease similar to multiple sclerosis, several lines of evidence implicate CD8+ T cells in CNS demyelination. In a follow-up to their earlier work, Brisebois et al. (p. 2403
) showed that demyelinating disease onset and CNS infiltration by CD8+ T cells in mice transgenic for the costimulation molecule B7.2 (B7.2 Tg) were accelerated in the absence of CD4+ T cells. CDR3 spectratype analysis of V chain TCR transcripts indicated single peaks or skewed distributions of several V families in CNS infiltrating, but not peripheral, CD8+ T cells from preclinical B7.2 Tg mice lacking CD4+ T cells; in animals with overt disease, a Gaussian CDR3 length distribution was detected for all V families. Up-regulated surface expression of MHC class I and costimulatory molecules occurred on microglia in preclinical and diseased B7.2 Tg mice but not in a disease-resistant line of B7.2 Tg mice lacking microglial expression of B7.2. IFN-
R–/– B7.2 Tg mice did not develop neurological disease, had few CD8+ T cells infiltrating the CNS, and exhibited no up-regulated MHC expression on microglia. The investigators demonstrate in this novel mouse model for spontaneous demyelinating disease that autoreactive CD8+ T cells in the CNS are the primary effectors and require early IFN--dependent activation of microglia expressing B7.2.
Glycans on Activated T Cells
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Lipoic Acid and MS
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-lipoic acid LA) protected rats against induced EAE and decreased leukocyte infiltration into the brain and spinal cord in a dose-dependent fashion. Impaired migration across a monolayer of brain endothelial cells in vitro was demonstrated for monocytes from LA-treated rats with EAE and for monocytes from healthy animals in the presence of LA or serum from LA-treated EAE rats or after preincubation with LA. Leakage of FITC-dextran through primary rat brain cell monolayers with adhered monocytes was reduced by LA. Colocalization of fluorescent-labeled actin with F-actin stress fibers was visualized by real-time confocal microscopy of brain endothelial cells exposed to superoxide; no F-actin stress fibers formed in the presence of LA. The data indicate that LA reverses the deleterious effect of monocytes breaching the blood-brain barrier in EAE by inhibiting their transendothelial migration and by preventing cytoskeleton rearrangement in endothelial cells exposed to superoxide. Presentation of MBP in MS
The Goverman laboratory showed that myelin basic protein (MBP)-specific T cells are stimulated to proliferate ex vivo by splenic dendritic cells (DCs). Since MBP-specific T cells are critical effectors of the CNS demyelinization seen in multiple sclerosis (MS), it is important to determine whether they are exposed to MBP in other peripheral lymphoid tissues. In work from the same group, Seamons et al. (p. 2097
) determined that purified CD8+ or CD8– DCs, or to a lesser extent resting B cells, from mouse lymph nodes stimulated naive and MBP-activated MBP-specific T cells to proliferate ex vivo. Resting B cells from lymph nodes of mice transgenic for a BCR specific for a different Ag, of nontransgenic mice, or of irradiated Rag–/–MBP+/+ mice given MBP–/– bone marrow were equally stimulatory. Activated MBP-specific T cells exposed to resting MBP+/+ B cells proliferated less and produced lower amounts of IL-2 and IFN- during subsequent incubation with irradiated MBP+/+ lymph node cells than controls exposed to resting MBP–/– B cells. Addition of exogenous MBP peptide to the resting MBP+/+ B cells increased the T cell proliferative and cytokine responses. The authors show that both lymph node B cells and DCs stimulate proliferation of naive MBP-specific T cells but that presentation of endogenous MBP peptide by B cells tolerizes activated MBP-specific T cells. Tolerance is overcome by addition of exogenous MBP peptide to the B cells.
Antigenic Mimicry in Chronic Lyme Arthritis
The etiologic agent of Lyme disease, the tick-borne spirochete Borrelia burgdorferi, is eradicated with antibiotic treatment. However, a subset of patients continues to have chronic joint inflammation accompanied by germinal center formation in the arthritic lesions in the absence of B. burgdorferi. To determine the target Ag, Ghosh et al. (p. 2486 ) isolated synovial plasma cells from treatment-resistant Lyme arthritis patients and synthesized single chain variable region fragments (scFvs) of highly expressed Igs. Additionally, scFvs were developed from Abs of PBMCs that recognized the prominent outer surface protein A (Osp A) of B. burgdorferi. VH and VL domains were cloned into expression vectors to generate seven anti-scFv and anti-Osp A mAbs. Mass spectrometry identified the intracellular scaffolding protein cytokeratin 10 (CK10) as the molecule in human joint tissue lysates that bound to an anti-scFv mAb affinity column; immunoblotting and ELISA using purified CK10 confirmed the identification. Sera from treatment-resistant Lyme arthritis patients bound CK10 in ELISA more strongly than control sera. Of two anti-Osp A mAbs, the one containing fewer V region mutations bound Osp A strongly but CK10 weakly, whereas the one with more V region mutations bound more strongly to CK10 and more weakly to Osp A. This combination of molecular biology and proteomics identifies autoantibodies against CK10 that cross-react with the major spirochete protein Osp A in treatment-resistant Lyme arthritis and suggest that antigenic mimicry is involved in the chronic condition.
Vav1 Signaling in NK Cells
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Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
CDR3 Loop Audition Regulates Positive Selection
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