We report the identification of three new collagen VI genes at a single locus on human chromosome 3q22.1. The three new genes are COL6A4, COL6A5, and COL6A6 that encode the ␣4(VI), ␣5(VI), and ␣6(VI) chains. In humans, the COL6A4 gene has been disrupted by a chromosome break. Each of the three new collagen chains contains a 336-amino acid triple helix flanked by seven N-terminal von Willebrand factor A-like domains and two (␣4 and ␣6 chains) or three (␣5 chain) C-terminal von Willebrand factor A-like domains. In humans, mRNA expression of COL6A5 is restricted to a few tissues, including lung, testis, and colon. In contrast, the COL6A6 gene is expressed in a wide range of fetal and adult tissues, including lung, kidney, liver, spleen, thymus, heart, and skeletal muscle. Antibodies to the ␣6(VI) chain stained the extracellular matrix of human skeletal and cardiac muscle, lung, and the territorial matrix of articular cartilage. In cell transfection and immunoprecipitation experiments, mouse ␣4(VI)N6-C2 chain co-assembled with endogenous ␣1(VI) and ␣2(VI) chains to form trimeric collagen VI molecules that were secreted from the cell. In contrast, ␣5(VI)N5-C1 and ␣6(VI)N6-C2 chains did not assemble with ␣1(VI) and ␣2(VI) chains and accumulated intracellularly. We conclude that the ␣4(VI)N6-C2 chain contains all the elements necessary for trimerization with ␣1(VI) and ␣2(VI). In summary, the discovery of three additional collagen VI chains doubles the collagen VI family and adds a layer of complexity to collagen VI assembly and function in the extracellular matrix.Collagen VI is an extracellular component that is present in virtually all connective tissues, where it forms abundant and structurally unique microfibrils in close association with basement membranes. Collagen VI interacts with a range of ECM 2 components. However, its precise role is not clearly understood. Several recent studies have suggested that collagen VI functions to anchor the basement membrane to the pericellular matrix in muscle (1-3). Other data suggest a role for collagen VI in cell signaling and cell migration (4, 5).Three genetically distinct collagen VI chains, ␣1(VI), ␣2(VI), and ␣3(VI), encoded by the COL6A1, COL6A2, and COL6A3 genes were first described more than 20 years ago (6 -8). The COL6A1 and COL6A2 genes are located in tandem on chromosome 21q22.3. The ␣1(VI) and ␣2(VI) chains are similar in size and domain structure. They contain a short 335-or 336-amino acid triple helix with a glycine triplet repeat motif that is characteristic of all collagens. Flanking the triple helix are domains homologous to the A-type domains found in von Willebrand factor (VWA domains). ␣1(VI) and ␣2(VI) contain one VWA domain N-terminal to the triple helix (N1) and two VWA domains on the C-terminal flank of the helix (C1 and C2). In contrast, the ␣3(VI) chain, encoded by the COL6A3 gene on 2q37.3, is much larger with 10 N-terminal (N1-N10), two C-terminal VWA domains (C1 and C2), and several other identifiable types of domains at the C terminus (C3-C5).A...
In a previous study, we demonstrated that myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide could induce severe chronic experimental autoimmune encephalomyelitis (EAE) in HLA-DR2+ transgenic mice lacking all mouse MHC class II genes. We used this model to evaluate clinical efficacy and mechanism of action of a novel recombinant TCR ligand (RTL) comprised of the α1 and β1 domains of DR2 (DRB1*1501) covalently linked to the encephalitogenic MOG-35-55 peptide (VG312). We found that the MOG/DR2 VG312 RTL could induce long-term tolerance to MOG-35-55 peptide and reverse clinical and histological signs of EAE in a dose- and peptide-dependent manner. Some mice treated with lower doses of VG312 relapsed after cessation of daily treatment, but the mice could be successfully re-treated with a higher dose of VG312. Treatment with VG312 strongly reduced secretion of Th1 cytokines (TNF-α and IFN-γ) produced in response to MOG-35-55 peptide, and to a lesser degree purified protein derivative and Con A, but had no inhibitory effect on serum Ab levels to MOG-35-55 peptide. Abs specific for both the peptide and MHC moieties of the RTLs were also present after treatment with EAE, but these Abs had only a minor enhancing effect on T cell activation in vitro. These data demonstrate the powerful tolerance-inducing therapeutic effects of VG312 on MOG peptide-induced EAE in transgenic DR2 mice and support the potential of this approach to inhibit myelin Ag-specific responses in multiple sclerosis patients.
Our previous studies demonstrated that oligomeric recombinant TCR ligands (RTL) can treat clinical signs of experimental autoimmune encephalomyelitis (EAE) and induce long-term T cell tolerance against encephalitogenic peptides. In the current study, we produced a monomeric I-As/PLP 139-151 peptide construct (RTL401) suitable for use in SJL/J mice that develop relapsing disease after injection of PLP 139-151 peptide in CFA. RTL401 given i.v. or s.c. but not empty RTL400 or free PLP 139-151 peptide prevented relapses and significantly reduced clinical severity of EAE induced by PLP 139-151 peptide in SJL/J or (C57BL/6 × SJL)F1 mice, but did not inhibit EAE induced by PLP 178-191 or MBP 84-104 peptides in SJL/J mice, or MOG 35-55 peptide in (C57BL/6 × SJL/J)F1 mice. RTL treatment of EAE caused stable or enhanced T cell proliferation and secretion of IL-10 in the periphery, but reduced secretion of inflammatory cytokines and chemokines. In CNS, there was a modest reduction of inflammatory cells, reduced expression of very late activation Ag-4, lymphocyte function-associated Ag-1, and inflammatory cytokines, chemokines, and chemokine receptors, but enhanced expression of Th2-related factors, IL-10, TGF-β3, and CCR3. These results suggest that monomeric RTL therapy induces a cytokine switch that curbs the encephalitogenic potential of PLP 139-151-specific T cells without fully preventing their entry into CNS, wherein they reduce the severity of inflammation. This mechanism differs from that observed using oligomeric RTL therapy in other EAE models. These results strongly support the clinical application of this novel class of peptide/MHC class II constructs in patients with multiple sclerosis who have focused T cell responses to known encephalitogenic myelin peptides.
The use of HLA class II-transgenic (Tg) mice has facilitated identification of antigenic T cell epitopes that may contribute to inflammation in T cell-mediated diseases such as rheumatoid arthritis and multiple sclerosis (MS). In this study, we compared the encephalitogenic activity of three DR2-restricted myelin determinants [mouse (m) myelin oligodendrocyte glycoprotein (MOG)-35-55, human (h)MOG-35-55 and myelin basic protein (MBP)-87-99] in Tg mice expressing the MS-associated DR2 allele, DRB1*1501. We found that mMOG-35-55 peptide was strongly immunogenic and induced moderately severe chronic experimental autoimmune encephalomyelitis (EAE) with white matter lesions after a single injection in Freund's complete adjuvant followed by pertussis toxin. hMOG-35-55 peptide, which differs from mMOG-35-55 peptide by a proline for serine substitution at position 42, was also immunogenic, but not encephalitogenic, and was only partially cross-reactive with mMOG-35-55. In contrast, MBP-87-99, which can induce EAE in double-Tg mice expressing both HLA-DR2 and a human MBP-specific TCR, was completely non-encephalitogenic in HLA-DR2-Tg mice lacking the human TCR transgene. These findings demonstrate potent encephalitogenic activity of the mMOG-35-55 peptide in association with HLA-DR2, thus providing a strong rationale for further study of hMOG-35-55 peptide as a potential pathogenic determinant in humans.
Gender influences mediated by 17-estradiol (E2) have been associated with susceptibility to and severity of autoimmune diseases such as diabetes, arthritis, and multiple sclerosis. In this regard, we have shown that estrogen receptor-␣ (Esr1) is crucial for the protective effect of 17-estradiol (E2) in murine experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis. The expression of estrogen receptors among various immune cells (eg, T and B lymphocytes, antigen-presenting cells) suggests that the therapeutic effect of E2 is likely mediated directly through specific receptor binding. However, the target immune cell populations responsive to E2 treatment have not been identified. In the current study, we induced EAE in T-cell-deficient, severe combined immunodeficient mice or in immunocompetent mice with encephalitogenic T cells from wildtype Esr1؉/؉ or Esr1 knockout (Esr1؊/؊) donors and compared the protective E2 responses. The results showed that E2-responsive, Esr1؉/؉ diseaseinducing encephalitogenic T cells were neither necessary nor sufficient for E2-mediated protection from EAE. Instead, the therapeutic response appeared to be mediated through direct effects on nonlymphocytic, E2-responsive cells and down-regulation of the inflammatory response in the central nervous system. These results provide the first demonstration that the protective effect of E2 on EAE is not mediated directly through E2-responsive T cells and raise the alternative possibility that nonlymphocytic cells such as macrophages, dendritic cells, or other nonlymphocytic cells are primarily responsive to E2 treatment in
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