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Derry Roopenian

Publications and source records attributed to Derry Roopenian.

8 recordsLinked to original sources
PubMed2006

The MHC class I-related FcRn ameliorates murine Lyme arthritis.

The identification of the neonatal FcR (FcRn) as an IgG homeostasis regulator has led to research aimed at delineating a role for FcRn in humorally mediated disease. FcRn is a class I-related molecule that prolongs the half-life of serum IgG by preferentially binding IgG at low pH and inhibiting its degradation. Its role in protective immunity to infectious organisms is unknown. We investigated the function of FcRn in the murine model of Lyme arthritis, caused by infection with Borrelia burgdorferi. We infected FcRn(-/-) and wild-type mice with B. burgdorferi and monitored the development of arthritis. Infected FcRn(-/-) mice demonstrated decreased serum levels of anti-B. burgdorferi antibodies and borreliacidal activity. Moreover, these mutant mice developed increased ankle swelling and joint histopathology following infection. Our data suggest that FcRn ameliorates murine Lyme arthritis by preventing the degradation of protective borreliacidal antibodies.

Animals↗
PubMed2005

Direct regulatory role of NKT cells in allogeneic graft survival is dependent on the quantitative strength of antigenicity.

The role of NKT cells during immune responses is diverse, ranging from antiviral and antitumor activity to the regulation of autoimmune diseases; however, the regulatory function of CD1d-dependent NKT cells in rejection responses against allogeneic graft is uncertain. In this study, we demonstrated the direct regulatory effects of CD1d-dependent NKT cells using an allogeneic skin transplantation model. H-Y-mismatched skin graft survival was shortened in CD1d-/- recipients compared with wild-type recipients. Adoptive transfer of syngeneic NKT cells via splenocytes or hepatic mononuclear cells into CD1d-/- recipients restored graft survival times to those of wild-type recipients. alpha-Galactosylceramide, a specific activator of NKT cells, further prolonged graft survival. Although CD1d-dependent NKT cells did not extend skin graft survival in either major or complete minor histocompatibility-mismatched models, these cells affected graft survival in minor Ag mismatch models according to the magnitude of the antigenic difference. The afferent arm of NKT cell activation during transplantation required CD1d molecules expressed on host APCs and the migration of CD1d-dependent NKT cells into grafts. Moreover, the regulatory effects of CD1d-dependent NKT cells against alloantigen were primarily IL-10 dependent. Taken together, we concluded that CD1d-dependent NKT cells may directly affect the outcome of allogeneic skin graft through an IL-10-dependent regulatory mechanism.

Animals↗
PubMed2005

Activated NKT cells inhibit autoimmune diabetes through tolerogenic recruitment of dendritic cells to pancreatic lymph nodes.

NKT cell activation by alpha-galactosylceramide (alpha-GalCer) inhibits autoimmune diabetes in NOD mice, in part by inducing recruitment to pancreatic lymph nodes (PLNs) of mature dendritic cells (DCs) with disease-protective effects. However, how activated NKT cells promote DC maturation, and what downstream effect this has on diabetogenic T cells was unknown. Activated NKT cells were found to produce a soluble factor(s) inducing DC maturation. Initially, there was a preferential accumulation of mature DCs in the PLNs of alpha-GalCer-treated NOD mice, followed by a substantial increase in T cells. Adoptive transfer of a diabetogenic CD8 T cell population (AI4) induced a high rate of disease (75%) in PBS-treated NOD recipients, but not in those pretreated with alpha-GalCer (8%). Significantly, more AI4 T cells accumulated in PLNs of alpha-GalCer than PBS-treated recipients, while no differences were found in mesenteric lymph nodes from each group. Compared with those in mesenteric lymph nodes, AI4 T cells entering PLNs underwent greater levels of apoptosis, and the survivors became functionally anergic. NKT cell activation enhanced this process. Hence, activated NKT cells elicit diabetes protection in NOD mice by producing a soluble factor(s) that induces DC maturation and accumulation in PLNs, where they subsequently recruit and tolerize pathogenic T cells.

Adjuvants, Immunologic↗
PubMed2004

The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease.

The MHC class I family-like Fc receptor, FcRn, is normally responsible for extending the life span of serum IgG Ab's, but whether this molecule contributes to autoimmune pathogenesis remains speculative. To determine directly whether this function contributes to humoral autoimmune disease, we examined whether a deficiency in the FcRn heavy chain influences autoimmune arthritis in the K/BxN mouse model. FcRn deficiency conferred either partial or complete protection in the arthritogenic serum transfer and the more aggressive genetically determined K/BxN autoimmune arthritis models. The protective effects of an FcRn deficiency could be overridden with excessive amounts of pathogenic IgG Ab's. The therapeutic saturation of FcRn by high-dose intravenous IgG (IVIg) also ameliorated arthritis, directly implicating FcRn blockade as a significant mechanism of IVIg's anti-inflammatory action. The results suggest that FcRn is a potential therapeutic target that links the initiation and effector phases of humoral autoimmune disease.

Animals↗
PubMed2003

Customized molecular phenotyping by quantitative gene expression and pattern recognition analysis.

Description of the molecular phenotypes of pathobiological processes in vivo is a pressing need in genomic biology. We have implemented a high-throughput real-time PCR strategy to establish quantitative expression profiles of a customized set of target genes. It enables rapid, reproducible data acquisition from limited quantities of RNA, permitting serial sampling of mouse blood during disease progression. We developed an easy to use statistical algorithm--Global Pattern Recognition--to readily identify genes whose expression has changed significantly from healthy baseline profiles. This approach provides unique molecular signatures for rheumatoid arthritis, systemic lupus erythematosus, and graft versus host disease, and can also be applied to defining the molecular phenotype of a variety of other normal and pathological processes.

Algorithms↗
PubMed2002

How H13 histocompatibility peptides differing by a single methyl group and lacking conventional MHC binding anchor motifs determine self-nonself discrimination.

The mouse H13 minor histocompatibility (H) Ag, originally detected as a barrier to allograft transplants, is remarkable in that rejection is a consequence of an extremely subtle interchange, P4(Val/Ile), in a nonamer H2-D(b)-bound peptide. Moreover, H13 peptides lack the canonical P5(Asn) central anchor residue normally considered important for forming a peptide/MHC complex. To understand how these noncanonical peptide pMHC complexes form physiologically active TCR ligands, crystal structures of allelic H13 pD(b) complexes and a P5(Asn) anchored pD(b) analog were solved to high resolution. The structures show that the basis of TCRs to distinguish self from nonself H13 peptides is their ability to distinguish a single solvent-exposed methyl group. In addition, the structures demonstrate that there is no need for H13 peptides to derive any stabilization from interactions within the central C pocket to generate fully functional pMHC complexes. These results provide a structural explanation for a classical non-MHC-encoded H Ag, and they call into question the requirement for contact between anchor residues and the major MHC binding pockets in vaccine design.

Amino Acid Motifs↗
PubMed2002

The immunogenomics of minor histocompatibility antigens.

Minor histocompatibility (H) antigens are a diverse assemblage of major histocompatibility complex (MHC)-bound peptides with the unifying property of acting as alloantigens that induce allogeneic tissue rejection. They are a consequence of any form of accumulated genetic variation that translates to differential MHC-presented peptide epitopes, the most common form of which is simple sequence polymorphisms. The universe of potential minor H antigens is large when transplantation is performed between genetically unrelated, MHC-matched individuals, especially considering the remarkable discriminative sensitivity of T cells. However, the phenomenon of immunodominance greatly simplifies immune responses that ensue. One mouse minor H antigen, H60, stands out in that the preponderance of the CD8 T cell response elicited in a complex alloantigenic setting is directed against this single minor H antigen epitope. Its immunodominance is because mice lacking H60 develop an unusually robust T cell repertoire dedicated to this single minor H antigen. The now well-characterized mouse minor H antigen system should provide a vehicle to assess the degree to which immunodominant alloantigens contribute to transplant rejection.

Alleles↗