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By altering ocular immune privilege, bone marrow-derived cells pathogenically contribute to DBA/2J pigmentary glaucoma.

Mo JS, Anderson MG, Gregory M, Smith RS, Savinova OV, Serreze DV, Ksander BR, Streilein JW, John SW - J. Exp. Med. (2003)

Bottom Line: Strikingly, we show that D2 eyes exhibit defects of the normally immunosuppressive ocular microenvironment including inability of aqueous humor to inhibit T cell activation, failure to support anterior chamber (AC)-associated immune deviation, and loss of ocular immune privilege.Using bone marrow chimeras, we show that lymphohematopoietic cell lineages largely dictate the progression of pigment dispersion, the ability of the eye to support induction of AC-associated immune deviation, and the integrity of the blood/ocular barrier.These results suggest previously unsuspected roles for bone marrow-derived cells and ocular immune privilege in the pathogenesis of PG.

View Article: PubMed Central - PubMed

Affiliation: The Howard Hughes Medical Institute, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.

ABSTRACT
Pigment dispersion syndrome causes iris pigment release and often progresses to elevated intraocular pressure and pigmentary glaucoma (PG). Because melanin pigment can have adjuvant like properties and because the Gpnmb gene, which contributes to pigment dispersion in DBA/2J (D2) mice, is expressed in dendritic cells, we tested the hypothesis that ocular immune abnormalities participate in PG phenotypes. Strikingly, we show that D2 eyes exhibit defects of the normally immunosuppressive ocular microenvironment including inability of aqueous humor to inhibit T cell activation, failure to support anterior chamber (AC)-associated immune deviation, and loss of ocular immune privilege. Histologic analysis demonstrates infiltration of inflammatory leukocytes into the AC and their accumulation within the iris, whereas clinical indications of inflammation are typically very mild to undetectable. Importantly, some of these abnormalities precede clinical indications of pigment dispersal, suggesting an early role in disease etiology. Using bone marrow chimeras, we show that lymphohematopoietic cell lineages largely dictate the progression of pigment dispersion, the ability of the eye to support induction of AC-associated immune deviation, and the integrity of the blood/ocular barrier. These results suggest previously unsuspected roles for bone marrow-derived cells and ocular immune privilege in the pathogenesis of PG.

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D2 AqH lacks immunosuppressive properties. T cells were added to medium containing AqH at various concentrations, as shown here for 20% AqH from BALB or D2 mice of the indicated ages. Cells were stimulated with anti-CD3 antibodies for 48 h and assayed for [3H]thymidine incorporation into proliferating cells. Single pools of AqH were used for each age in the assay, each pool consisting of 6–10 eyes. Values are mean cpm ± SEM of three to six wells.
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fig1: D2 AqH lacks immunosuppressive properties. T cells were added to medium containing AqH at various concentrations, as shown here for 20% AqH from BALB or D2 mice of the indicated ages. Cells were stimulated with anti-CD3 antibodies for 48 h and assayed for [3H]thymidine incorporation into proliferating cells. Single pools of AqH were used for each age in the assay, each pool consisting of 6–10 eyes. Values are mean cpm ± SEM of three to six wells.

Mentions: Normal AqH is strongly immunosuppressive and profoundly inhibits T cell activation in vitro (23). We tested AqH from D2 and control BALB mice for capacity to suppress anti-CD3–driven T cell proliferation in vitro (Fig. 1) . As expected, AqH from BALB eyes completely suppressed T cell proliferation whereas D2 AqH never inhibited T cell proliferation and actually displayed mitogenic activity, demonstrating the existence of a compromised intraocular immunosuppressive environment. Similar results were obtained using BALB and D2 AqH at concentrations of 3, 10, and 20%. AqH from D2 eyes lacked immunosuppressive properties at both 2 and 4 mo, ages that actually precede clinically detectable pigment dispersion.


By altering ocular immune privilege, bone marrow-derived cells pathogenically contribute to DBA/2J pigmentary glaucoma.

Mo JS, Anderson MG, Gregory M, Smith RS, Savinova OV, Serreze DV, Ksander BR, Streilein JW, John SW - J. Exp. Med. (2003)

D2 AqH lacks immunosuppressive properties. T cells were added to medium containing AqH at various concentrations, as shown here for 20% AqH from BALB or D2 mice of the indicated ages. Cells were stimulated with anti-CD3 antibodies for 48 h and assayed for [3H]thymidine incorporation into proliferating cells. Single pools of AqH were used for each age in the assay, each pool consisting of 6–10 eyes. Values are mean cpm ± SEM of three to six wells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193785&req=5

fig1: D2 AqH lacks immunosuppressive properties. T cells were added to medium containing AqH at various concentrations, as shown here for 20% AqH from BALB or D2 mice of the indicated ages. Cells were stimulated with anti-CD3 antibodies for 48 h and assayed for [3H]thymidine incorporation into proliferating cells. Single pools of AqH were used for each age in the assay, each pool consisting of 6–10 eyes. Values are mean cpm ± SEM of three to six wells.
Mentions: Normal AqH is strongly immunosuppressive and profoundly inhibits T cell activation in vitro (23). We tested AqH from D2 and control BALB mice for capacity to suppress anti-CD3–driven T cell proliferation in vitro (Fig. 1) . As expected, AqH from BALB eyes completely suppressed T cell proliferation whereas D2 AqH never inhibited T cell proliferation and actually displayed mitogenic activity, demonstrating the existence of a compromised intraocular immunosuppressive environment. Similar results were obtained using BALB and D2 AqH at concentrations of 3, 10, and 20%. AqH from D2 eyes lacked immunosuppressive properties at both 2 and 4 mo, ages that actually precede clinically detectable pigment dispersion.

Bottom Line: Strikingly, we show that D2 eyes exhibit defects of the normally immunosuppressive ocular microenvironment including inability of aqueous humor to inhibit T cell activation, failure to support anterior chamber (AC)-associated immune deviation, and loss of ocular immune privilege.Using bone marrow chimeras, we show that lymphohematopoietic cell lineages largely dictate the progression of pigment dispersion, the ability of the eye to support induction of AC-associated immune deviation, and the integrity of the blood/ocular barrier.These results suggest previously unsuspected roles for bone marrow-derived cells and ocular immune privilege in the pathogenesis of PG.

View Article: PubMed Central - PubMed

Affiliation: The Howard Hughes Medical Institute, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.

ABSTRACT
Pigment dispersion syndrome causes iris pigment release and often progresses to elevated intraocular pressure and pigmentary glaucoma (PG). Because melanin pigment can have adjuvant like properties and because the Gpnmb gene, which contributes to pigment dispersion in DBA/2J (D2) mice, is expressed in dendritic cells, we tested the hypothesis that ocular immune abnormalities participate in PG phenotypes. Strikingly, we show that D2 eyes exhibit defects of the normally immunosuppressive ocular microenvironment including inability of aqueous humor to inhibit T cell activation, failure to support anterior chamber (AC)-associated immune deviation, and loss of ocular immune privilege. Histologic analysis demonstrates infiltration of inflammatory leukocytes into the AC and their accumulation within the iris, whereas clinical indications of inflammation are typically very mild to undetectable. Importantly, some of these abnormalities precede clinical indications of pigment dispersal, suggesting an early role in disease etiology. Using bone marrow chimeras, we show that lymphohematopoietic cell lineages largely dictate the progression of pigment dispersion, the ability of the eye to support induction of AC-associated immune deviation, and the integrity of the blood/ocular barrier. These results suggest previously unsuspected roles for bone marrow-derived cells and ocular immune privilege in the pathogenesis of PG.

Show MeSH
Related in: MedlinePlus