Functional and hyperfunctional siRNA

Spontaneous Autoimmune Disease in FcγRIIB-Deficient Mice Results from Strain-Specific Epistasis

https://cbdm.hms.harvard.edu/assets/Publications/2002pub/JiImmunity.pdf

Arthritis Critically Dependent on Innate Immune System Players

The y-linked autoimmune accelerating (yaa) locus is a potent autoimmune disease allele. Transcription profiling of yaa-bearing B cells revealed the overexpression of a cluster of X-linked genes that included Tlr7. FISH analysis demonstrated the translocation of this segment onto the yaa chromosome. The resulting overexpression of Tlr7 increased in vitro responses to Toll-like receptor (TLR) 7 signaling in all yaa-bearing males. B6.yaa mice are not overtly autoimmune, but the addition of Sle1, which contains the autoimmune-predisposing Slam/Cd2 haplotype, causes the development of fatal lupus with numerous immunological aberrations. B6.Sle1yaa CD4 T cells develop the molecular signature for TFH cells and also show expression changes in numerous cytokines and chemokines. Disease development and all component autoimmune phenotypes were inhibited by Sles1, a potent suppressor locus. Sles1 had no effect on yaa-enhanced TLR7 signaling in vitro, and these data place Sles1 downstream from the lesion in innate immune responses mediated by TLR7, suggesting that Sles1 modulates the activation of adaptive immunity in response to innate immune signaling.

https://www.pnas.org/content/pnas/103/26/9970.full.pdf

A Tlr7 translocation accelerates systemic autoimmunity in murine lupus.

Delineating the genetic basis of systemic lupus erythematosus.

In systemic lupus erythematosus, the renal deposition of complement-containing immune complexes initiates an inflammatory cascade resulting in glomerulonephritis. Activation of the classical complement pathway with deposition of C3 is pathogenic in lupus nephritis. Although the alternative complement pathway is activated in lupus nephritis, its role in disease pathogenesis is unknown. To determine the role of the alternative pathway in lupus nephritis, complement factor B-deficient mice were backcrossed to MRL/lpr mice. MRL/lpr mice develop a spontaneous lupus-like disease characterized by immune complex glomerulonephritis. We derived complement factor B wild-type (B+/+), homozygous knockout (B-/-), and heterozygous (B+/-) MRL/lpr mice. Compared with B+/- or B+/+ mice, MRL/lpr B-/- mice developed significantly less proteinuria, less glomerular IgG deposition, and decreased renal scores as well as lower IgG3 cryoglobulin production and vasculitis. Serum C3 levels were normal in the B-/- mice compared with significantly decreased levels in the other two groups. These results suggest that: 1) factor B plays an important role in the pathogenesis of glomerulonephritis and vasculitis in MRL/lpr mice; and 2) activation of the alternative pathway, either by the amplification loop or by IgA immune complexes, has a prominent effect on serum C3 levels in this lupus model.

/pdf/modulation-of-renal-disease-in-mrl-lpr-mice-genetically-2u4qxx6ynk.pdf

Modulation of Renal Disease in MRL/lpr Mice Genetically Deficient in the Alternative Complement Pathway Factor B

The present invention provides a method of treating or preventing complement-mediated immune disease in a subject, comprising administering to the subject an inhibitor of synthesis or activity of Factor B, whereby the inhibition of synthesis or activity of Factor B treats or prevents the immune disease. Also provided are an antibody to Factor B, an anti-sense oligonucleotide which blocks the mRNA which encodes Factor B and a peptide which competitively binds C3, the receptor for Factor B. The present invention further provides a vector comprising the nucleic acid of this invention and a cell comprising the vector. Also provided is a method of administering to a subject in a pharmaceutically acceptable carrier an antibody, oligonucleotide, peptide and vector of the invention. The present invention further provides a method of determining the predisposition of a subject to complement-mediated immune disease and a method of determining efficacy of treatment in and prognosis of a subject with complement-mediated immune disease. Further, the present invention also provides a mutant transgenic mouse.

Blocking factor b to treat complement-mediated immune disease

IgA was purified from chicken bile and intestinal secretions by using Sephadex G-200 gel-filtration and DEAE-cellulose chromatography. The molecular structure of biliary IgA in chickens resembled the serum type of high polymeric IgA since it lacked a secretory component (SC), and had a molecular weight of 800,000 to 900,000. On the other hand, IgA in chicken intestinal secretions was different from the biliary IgA but was quite similar to mammalian secretory IgA (SIgA) since it was associated with a protein homologous to mammalian SC and had the value of 300,000 to 500,000. It can be predicted that the two types of chicken IgA show phylogenically intermediate characteristics of SIgA system.

Peculiar secretory IgA system identified in chickens.

A homologue of a free secretory component (SC) was identified in chicken intestinal secretion by criteria based on its antigenic relationship with intestinal secretory IgA (SIgA), molecular size, sugar content, and electrophoretic mobility, as well as its elution characteristic from ion-exchange chromatography. SC was obtained in a form free from IgA from the intestinal secretion by salting out and DEAE chromatography, followed by density ultracentrifuguation or Sephadex G-200 gel-filtration. However, the free SC revealed some antigenic deficiency when compared to bound SC of intestinal SIgA and showed a failure of binding to serum-type-polymeric IgA of biliary IgA in vitro. Several kinds of chicken external secretions were examined for detection of SC and immunoglobulin classes of IgG, IgA, and IgM. In spite of the wide distribution of immunoglobulins in the external secretions, SC antigen could be detected only in intestinal secretion. Most IgA in the secretions had a molecular structure of a tetramer of serum-type IgA, lacking in SC and having 17S to 18.5S and 600,000 to 700,000 daltons. On the other hand, IgA in the intestinal secretion showed close similarity to the mammalian SIgA, associated with SC and having 11.2S and 350,000 daltons. Presence of antibody activity in the intestinal IgA to avian reovirus was confirmed by plaque reduction tests.

Peculiar secretory IgA system identified in chickens. II. Identification and distribution of free secretory component and immunoglobulins of IgA, IgM, and IgG in chicken external secretions.

Effect of a Genetic Deficiency of Terminal Deoxynucleotidyl Transferase on Autoantibody Production by C57BL6 Faslpr Mice

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