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Association of progressive CD4(+) T cell decline in SIV infection with the induction of autoreactive antibodies.

Kuwata T, Nishimura Y, Whitted S, Ourmanov I, Brown CR, Dang Q, Buckler-White A, Iyengar R, Brenchley JM, Hirsch VM - PLoS Pathog. (2009)

Bottom Line: Depletion of naïve CD4(+) T cells was associated with plasma antibodies autoreactive with CD4(+) T cells, increasing numbers of IgG-coated CD4(+) T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa), dsDNA, and phospholipid (aPL).Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events.These results suggest an important role of autoreactive antibodies in the CD4(+) T cell decline observed during progression to AIDS.

View Article: PubMed Central - PubMed

Affiliation: Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan.

ABSTRACT
The progressive decline of CD4(+) T cells is a hallmark of disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. Whereas the acute phase of the infection is dominated by virus-mediated depletion of memory CD4(+) T cells, chronic infection is often associated with a progressive decline of total CD4(+) T cells, including the naïve subset. The mechanism of this second phase of CD4(+) T cell loss is unclear and may include immune activation-induced cell death, immune-mediated destruction, and regenerative or homeostatic failure. We studied patterns of CD4(+) T cell subset depletion in blood and tissues in a group of 20 rhesus macaques inoculated with derivatives of the pathogenic SIVsmE543-3 or SIVmac239. Phenotypic analysis of CD4(+) T cells demonstrated two patterns of CD4(+) T cell depletion, primarily affecting either naïve or memory CD4(+) T cells. Progressive decline of total CD4(+) T cells was observed only in macaques with naïve CD4(+) T cell depletion (ND), though the depletion of memory CD4(+) T cells was profound in macaques with memory CD4(+) T cell depletion (MD). ND macaques exhibited lower viral load and higher SIV-specific antibody responses and greater B cell activation than MD macaques. Depletion of naïve CD4(+) T cells was associated with plasma antibodies autoreactive with CD4(+) T cells, increasing numbers of IgG-coated CD4(+) T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa), dsDNA, and phospholipid (aPL). Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events. More importantly for AIDS pathogenesis, the level of autoreactive antibodies significantly correlated with the extent of naïve CD4(+) T cell depletion. These results suggest an important role of autoreactive antibodies in the CD4(+) T cell decline observed during progression to AIDS.

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Autoimmune manifestation and autoantibodies in SIV-Infected macaques.(A) Progressive decline of platelets in the blood in ND macaques (n = 8, left), contrasted with more stable levels in MD macaques (n = 4, right). (B) Platelet counts in blood at death were significantly different between ND (n = 12) and MD (n = 8) macaques. (C) A trend to higher frequency of anti-platelet antibodies was observed in plasma samples at death in ND (n = 12) as compared to MD (n = 8) macaques. (D) Anti-phospholipid (aPL) Ab titers at death were significantly higher in ND (n = 12) than in MD (n = 8) macaques. (E) Higher levels of anti-dsDNA Ab titer at death in ND (n = 12) versus MD (n = 8) macaques. (F) A significant correlation was observed between aPL titer and platelet count. Platelet count and aPL titer at death were plotted using ND (blue circles, n = 12) and MD (red triangles, n = 8) macaques. A linear regression analysis indicated a regression line with a slope = −4.66±2.17 (R2 = 0.204). (G) Anti-phospholipid antibody titers at death were compared between macaques with thrombosis (n = 6) and without thrombosis (n = 14). Macaques with thrombosis showed a significantly higher level of aPL antibodies.
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ppat-1000372-g007: Autoimmune manifestation and autoantibodies in SIV-Infected macaques.(A) Progressive decline of platelets in the blood in ND macaques (n = 8, left), contrasted with more stable levels in MD macaques (n = 4, right). (B) Platelet counts in blood at death were significantly different between ND (n = 12) and MD (n = 8) macaques. (C) A trend to higher frequency of anti-platelet antibodies was observed in plasma samples at death in ND (n = 12) as compared to MD (n = 8) macaques. (D) Anti-phospholipid (aPL) Ab titers at death were significantly higher in ND (n = 12) than in MD (n = 8) macaques. (E) Higher levels of anti-dsDNA Ab titer at death in ND (n = 12) versus MD (n = 8) macaques. (F) A significant correlation was observed between aPL titer and platelet count. Platelet count and aPL titer at death were plotted using ND (blue circles, n = 12) and MD (red triangles, n = 8) macaques. A linear regression analysis indicated a regression line with a slope = −4.66±2.17 (R2 = 0.204). (G) Anti-phospholipid antibody titers at death were compared between macaques with thrombosis (n = 6) and without thrombosis (n = 14). Macaques with thrombosis showed a significantly higher level of aPL antibodies.

Mentions: As is also commonly observed in HIV-infection [31],[32], many SIV-infected macaques exhibited thrombocytopenia during their disease course [33],[34]. As shown in Figure 7A, a progressive decline was observed throughout the course of infection in ND macaques and the platelet count at the time of death was significantly lower in ND than MD macaques (Figure 7B). Antibodies against platelet glycoproteins were detected in ND macaques more frequently than in MD macaques (Figure 7C). Similar to immune thrombocytopenia in HIV infection, anti-GPIIIa was the most frequently observed platelet autoantibody [31]. Many of the macaques with severe thrombocytopenia died suddenly due to thrombosis of a major vessel and this finding was unique to ND macaques. Although such thrombotic events and associated arteriopathy are commonly associated with chronic SIV-infection, their etiology is unclear. In HIV-infected patients, a hypercoagulable state induced by autoantibodies to phospholipid (aPL) and other clotting factors can lead to thrombotic events [35]. We therefore examined plasma samples from these macaques for the presence of aPL antibodies. As shown in Figure 7D, a significant increase in aPL was observed in ND but not MD macaques. ND macaques also exhibited elevated dsDNA antibodies, suggesting a generalized autoimmune dysregulation in ND macaques (Figure 7E). Consistent with a functional consequence in macaques, aPL titers inversely correlated with platelet counts and aPL titers were significantly higher in macaques with catastrophic thrombotic events (Figure 7F and 7G).


Association of progressive CD4(+) T cell decline in SIV infection with the induction of autoreactive antibodies.

Kuwata T, Nishimura Y, Whitted S, Ourmanov I, Brown CR, Dang Q, Buckler-White A, Iyengar R, Brenchley JM, Hirsch VM - PLoS Pathog. (2009)

Autoimmune manifestation and autoantibodies in SIV-Infected macaques.(A) Progressive decline of platelets in the blood in ND macaques (n = 8, left), contrasted with more stable levels in MD macaques (n = 4, right). (B) Platelet counts in blood at death were significantly different between ND (n = 12) and MD (n = 8) macaques. (C) A trend to higher frequency of anti-platelet antibodies was observed in plasma samples at death in ND (n = 12) as compared to MD (n = 8) macaques. (D) Anti-phospholipid (aPL) Ab titers at death were significantly higher in ND (n = 12) than in MD (n = 8) macaques. (E) Higher levels of anti-dsDNA Ab titer at death in ND (n = 12) versus MD (n = 8) macaques. (F) A significant correlation was observed between aPL titer and platelet count. Platelet count and aPL titer at death were plotted using ND (blue circles, n = 12) and MD (red triangles, n = 8) macaques. A linear regression analysis indicated a regression line with a slope = −4.66±2.17 (R2 = 0.204). (G) Anti-phospholipid antibody titers at death were compared between macaques with thrombosis (n = 6) and without thrombosis (n = 14). Macaques with thrombosis showed a significantly higher level of aPL antibodies.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2662887&req=5

ppat-1000372-g007: Autoimmune manifestation and autoantibodies in SIV-Infected macaques.(A) Progressive decline of platelets in the blood in ND macaques (n = 8, left), contrasted with more stable levels in MD macaques (n = 4, right). (B) Platelet counts in blood at death were significantly different between ND (n = 12) and MD (n = 8) macaques. (C) A trend to higher frequency of anti-platelet antibodies was observed in plasma samples at death in ND (n = 12) as compared to MD (n = 8) macaques. (D) Anti-phospholipid (aPL) Ab titers at death were significantly higher in ND (n = 12) than in MD (n = 8) macaques. (E) Higher levels of anti-dsDNA Ab titer at death in ND (n = 12) versus MD (n = 8) macaques. (F) A significant correlation was observed between aPL titer and platelet count. Platelet count and aPL titer at death were plotted using ND (blue circles, n = 12) and MD (red triangles, n = 8) macaques. A linear regression analysis indicated a regression line with a slope = −4.66±2.17 (R2 = 0.204). (G) Anti-phospholipid antibody titers at death were compared between macaques with thrombosis (n = 6) and without thrombosis (n = 14). Macaques with thrombosis showed a significantly higher level of aPL antibodies.
Mentions: As is also commonly observed in HIV-infection [31],[32], many SIV-infected macaques exhibited thrombocytopenia during their disease course [33],[34]. As shown in Figure 7A, a progressive decline was observed throughout the course of infection in ND macaques and the platelet count at the time of death was significantly lower in ND than MD macaques (Figure 7B). Antibodies against platelet glycoproteins were detected in ND macaques more frequently than in MD macaques (Figure 7C). Similar to immune thrombocytopenia in HIV infection, anti-GPIIIa was the most frequently observed platelet autoantibody [31]. Many of the macaques with severe thrombocytopenia died suddenly due to thrombosis of a major vessel and this finding was unique to ND macaques. Although such thrombotic events and associated arteriopathy are commonly associated with chronic SIV-infection, their etiology is unclear. In HIV-infected patients, a hypercoagulable state induced by autoantibodies to phospholipid (aPL) and other clotting factors can lead to thrombotic events [35]. We therefore examined plasma samples from these macaques for the presence of aPL antibodies. As shown in Figure 7D, a significant increase in aPL was observed in ND but not MD macaques. ND macaques also exhibited elevated dsDNA antibodies, suggesting a generalized autoimmune dysregulation in ND macaques (Figure 7E). Consistent with a functional consequence in macaques, aPL titers inversely correlated with platelet counts and aPL titers were significantly higher in macaques with catastrophic thrombotic events (Figure 7F and 7G).

Bottom Line: Depletion of naïve CD4(+) T cells was associated with plasma antibodies autoreactive with CD4(+) T cells, increasing numbers of IgG-coated CD4(+) T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa), dsDNA, and phospholipid (aPL).Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events.These results suggest an important role of autoreactive antibodies in the CD4(+) T cell decline observed during progression to AIDS.

View Article: PubMed Central - PubMed

Affiliation: Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan.

ABSTRACT
The progressive decline of CD4(+) T cells is a hallmark of disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. Whereas the acute phase of the infection is dominated by virus-mediated depletion of memory CD4(+) T cells, chronic infection is often associated with a progressive decline of total CD4(+) T cells, including the naïve subset. The mechanism of this second phase of CD4(+) T cell loss is unclear and may include immune activation-induced cell death, immune-mediated destruction, and regenerative or homeostatic failure. We studied patterns of CD4(+) T cell subset depletion in blood and tissues in a group of 20 rhesus macaques inoculated with derivatives of the pathogenic SIVsmE543-3 or SIVmac239. Phenotypic analysis of CD4(+) T cells demonstrated two patterns of CD4(+) T cell depletion, primarily affecting either naïve or memory CD4(+) T cells. Progressive decline of total CD4(+) T cells was observed only in macaques with naïve CD4(+) T cell depletion (ND), though the depletion of memory CD4(+) T cells was profound in macaques with memory CD4(+) T cell depletion (MD). ND macaques exhibited lower viral load and higher SIV-specific antibody responses and greater B cell activation than MD macaques. Depletion of naïve CD4(+) T cells was associated with plasma antibodies autoreactive with CD4(+) T cells, increasing numbers of IgG-coated CD4(+) T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa), dsDNA, and phospholipid (aPL). Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events. More importantly for AIDS pathogenesis, the level of autoreactive antibodies significantly correlated with the extent of naïve CD4(+) T cell depletion. These results suggest an important role of autoreactive antibodies in the CD4(+) T cell decline observed during progression to AIDS.

Show MeSH
Related in: MedlinePlus