Equine SCID: mechanistic analysis and comparison with murine SCID

Leber, Ray; Wilera, Rhonda; Perryman, Lance E.; Meek, Katheryn

doi:10.1016/s0165-2427(98)00174-3

Cited by 16 publications

(5 citation statements)

References 29 publications

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“…Signal joint ligation is even less affected, being virtually normal in some cells and depressed by only as much as 10-fold in some experimental systems. In contrast, DNA-PKcs deficiency in horses results in a much more substantial block of V(D)J recombination, resulting in a 5-log depression in coding joints and a 4-log depression in signal joints (21,29,47). The data presented in this report demonstrate that DNA-PKcs deficiency in dogs results in V(D)J recombination defects which are intermediate between those observed in horses and mice.…”

Section: Discussionmentioning

confidence: 50%

SCID in Jack Russell Terriers: A New Animal Model of DNA-PKcs Deficiency

Meek

Kienker

Dallas

et al. 2001

The Journal of Immunology

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We recently described the incidence of a SCID disease in a litter of Jack Russell terriers. In this study, we show that the molecular defect in these animals is faulty V(D)J recombination. Furthermore, we document a complete deficit in DNA-dependent protein kinase activity that can be explained by a marked diminution in the expression of the catalytic subunit DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We conclude that as is the case in C.B-17 SCID mice and in Arabian SCID foals, the defective factor in these SCID puppies is DNA-PKcs. In mice, it has been clearly established that DNA-PKcs deficiency produces an incomplete block in V(D)J recombination, resulting in “leaky” coding joint formation and only a modest defect in signal end ligation. In contrast, DNA-PKcs deficiency in horses profoundly blocks both coding and signal end joining. Here, we show that although DNA-PKcs deficiency in canine lymphocytes results in a block in both coding and signal end joining, the deficit in both is intermediate between that seen in SCID mice and SCID foals. These data demonstrate significant species variation in the absolute necessity for DNA-PKcs during V(D)J recombination. Furthermore, the severity of the V(D)J recombination deficits in these three examples of genetic DNA-PKcs deficiency inversely correlates with the relative DNA-PK enzymatic activity expressed in normal fibroblasts derived from these three species.

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Section: Discussionmentioning

confidence: 50%

SCID in Jack Russell Terriers: A New Animal Model of DNA-PKcs Deficiency

Meek

Kienker

Dallas

et al. 2001

The Journal of Immunology

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“…Our initial studies of endogenous Ig light chain rearrangements from SCID foals revealed two differences from SCID mice: 1) undetectable V -J signal joints in equine lymphocytes as compared with murine lymphocytes; and 2) a lack of leakiness when analyzing light chain coding joints from SCID foals as compared with SCID mice (9,48). Since in our initial studies only Ig light chain rearrangements were analyzed (because of limited available sequence information of horse immune receptor genes), it might be argued that the lack of observed signal joints might actually reflect tighter temporal control of Ig gene rearrangement in equine vs murine lymphocytes.…”

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confidence: 99%

Analyses of TCRB Rearrangements Substantiate a Profound Deficit in Recombination Signal Sequence Joining in SCID Foals: Implications for the Role of DNA-Dependent Protein Kinase in V(D)J Recombination

Shin

Rijkers

Pastink

et al. 2000

The Journal of Immunology

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We reported previously that the genetic SCID disease observed in Arabian foals is explained by a defect in V(D)J recombination that profoundly affects both coding and signal end joining. As in C.B-17 SCID mice, the molecular defect in SCID foals is in the catalytic subunit of the DNA-dependent protein kinase (DNA-PKCS); however, in SCID mice, signal end resolution remains relatively intact. Moreover, recent reports indicate that mice that completely lack DNA-PKCS also generate signal joints at levels that are indistinguishable from those observed in C.B-17 SCID mice, eliminating the possibility that a partially active version of DNA-PKCS facilitates signal end resolution in SCID mice. We have analyzed TCRB rearrangements and find that signal joints are reduced by ∼4 logs in equine SCID thymocytes as compared with normal horse thymocytes. A potential explanation for the differences between SCID mice and foals is that the mutant DNA-PKCS allele in SCID foals inhibits signal end resolution. We tested this hypothesis using DNA-PKCS expression vectors; in sum, we find no evidence of a dominant-negative effect by the mutant protein. These and other recent data are consistent with an emerging consensus: that in normal cells, DNA-PKCS participates in both coding and signal end resolution, but in the absence of DNA-PKCS an undefined end joining pathway (which is variably expressed in different species and cell types) can facilitate imperfect signal and coding end joining.

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“…Historically, the most common immunophenotyping assay performed in human medicine was enumeration of CD4ϩ helper and CD8ϩ (cytotoxic) T lymphocytes in patients infected with human immunodeficiency virus. In the horse, important diagnostic applications of immunophenotyping have been to characterize B and T lymphocytes in Arabian foals with combined immunodeficiency syndrome 3 and to evaluate lymphoid cells in suspected cases of immune deficiency. 4 Immunophenotyping technology has helped define normal variation that occurs in immune cells of foals during growth and development as well as lymphoid cell responses in foals and adult horses after exposure to environmental antigens.…”

Section: Immunophenotypingmentioning

confidence: 99%

Flow Cytometry: Clinical Applications in Equine Medicine

2002

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The use of flow cytometry in veterinary diagnostics is becoming a valuable clinical tool with a broad range of applications. Physical characteristics of cells can be determined by the flow cytometer laser and electronics through the measurement of changes in light scatter properties. Other components and functions of cells can be defined through the application of fluorochrome dyes that have an affinity for cellular components. Traditionally, common clinical applications are immunophenotyping of cells of the hematopoietic system with fluorescent-labeled antibodies raised against specific cell surface proteins. Other approaches have been used to elucidate changes in cell function and DNA content. This review is intended to provide the reader with the fundamental uses of flow cytometry. Examples of clinical applications in equine patients include immune-mediated hemolytic anemia, immune-mediated thrombocytopenia (IMT), chronic inflammatory disease, and neoplasia.

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Equine SCID: mechanistic analysis and comparison with murine SCID

Cited by 16 publications

References 29 publications

SCID in Jack Russell Terriers: A New Animal Model of DNA-PKcs Deficiency

SCID in Jack Russell Terriers: A New Animal Model of DNA-PKcs Deficiency

Analyses of TCRB Rearrangements Substantiate a Profound Deficit in Recombination Signal Sequence Joining in SCID Foals: Implications for the Role of DNA-Dependent Protein Kinase in V(D)J Recombination

Flow Cytometry: Clinical Applications in Equine Medicine

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