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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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Autontibodies on the surface of CD4+ T cells in ND macaques.(A) Autoantibodies on the surface of CD4+ T cells from ND (H709, left) and MD (H718, right) macaques in representative flow cytometric analysis. Frozen PBMC samples at death were stained with antibodies against CD4 (FITC), human IgG (PE), 7-AAD (PerCP), and CD3 (APC). Autoantibodies were examined by anti-IgG reactivity (blue) on the surface of live CD4+ T cells (7-AAD−CD3+CD4+). Dashed line, staining with IgG1 isotype control (PE) instead of anti-human IgG (PE). (B) The percent of autoantibody positive CD4+ T cells at death were compared between ND (n = 8) and MD (n = 4) macaques. Percentages of IgG+ (left) or IgM+ (right) CD4+ T cells were determined by the Overton cumulative histogram subtraction using a mouse IgG1 isotype control. (C) Correlation between autoantibodies on CD4+ T cells and log naïve/memory ratio in CD4+ T cells at death. Percentages of IgG+ cells in CD4+ T cells and log naïve/memory ratio in CD4+ T cells were plotted using ND (blue circles, n = 8) and MD (red triangles, n = 4) macaques.
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ppat-1000372-g010: Autontibodies on the surface of CD4+ T cells in ND macaques.(A) Autoantibodies on the surface of CD4+ T cells from ND (H709, left) and MD (H718, right) macaques in representative flow cytometric analysis. Frozen PBMC samples at death were stained with antibodies against CD4 (FITC), human IgG (PE), 7-AAD (PerCP), and CD3 (APC). Autoantibodies were examined by anti-IgG reactivity (blue) on the surface of live CD4+ T cells (7-AAD−CD3+CD4+). Dashed line, staining with IgG1 isotype control (PE) instead of anti-human IgG (PE). (B) The percent of autoantibody positive CD4+ T cells at death were compared between ND (n = 8) and MD (n = 4) macaques. Percentages of IgG+ (left) or IgM+ (right) CD4+ T cells were determined by the Overton cumulative histogram subtraction using a mouse IgG1 isotype control. (C) Correlation between autoantibodies on CD4+ T cells and log naïve/memory ratio in CD4+ T cells at death. Percentages of IgG+ cells in CD4+ T cells and log naïve/memory ratio in CD4+ T cells were plotted using ND (blue circles, n = 8) and MD (red triangles, n = 4) macaques.

Mentions: The heightened immune activation and the propensity for autoimmune manifestations in the ND macaques led us to explore the possibility that autoimmune mechanisms might account for the loss of naive CD4+ T cells in these animals. We therefore examined terminal plasma samples for antibodies that bound the surface of CD4+ T cells from healthy, uninfected donor macaques. In addition, terminal CD4+ T cells of study macaques were analyzed for surface IgG and IgM. As shown in Figure 9A and 9B, antibodies that bound CD4+ T cells were detected exclusively in plasma or purifed IgG from ND macaques. Moreover, the level of anti-CD4+ T cell IgG correlated significantly with B cells count at 16 wpi, when activation of B cells were apparent (Figure 9C and Figure 5B). Most importantly, the level of anti-CD4+ T cell IgG correlated significantly with a lower naïve/memory ratio of CD4+ T cells, an indicator of naïve depletion (Figure 9D) as well as with absolute naïve CD4+ T cell counts at death (Figure 9E). We next examined T cells from PBMC samples from ND and MD macaques for the presence of surface-bound IgG by flow cytometry. In vivo antibody binding was also exclusively detected on the surface of CD4+ T cells from ND macaques, as shown by representative flow cytometry plots in Figure 10A. The percentage of CD4+ T cells with surface IgG was significantly higher in the ND versus the MD group (Figure 10B). In vivo binding of IgM was also detected on the CD4+ T cells from ND macaques, though there was no significant difference between the two groups (Figure 10B). Similar to plasma antibodies, a significant inverse correlation was observed between the percent of IgG+CD4+ T cells and the memory/naïve CD4+ T cell ratio (Figure 10C); macaques with higher anti-CD4+ T cell antibodies had lower naïve/memory ratio, indicative of naïve CD4+ T cell depletion.


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)

Autontibodies on the surface of CD4+ T cells in ND macaques.(A) Autoantibodies on the surface of CD4+ T cells from ND (H709, left) and MD (H718, right) macaques in representative flow cytometric analysis. Frozen PBMC samples at death were stained with antibodies against CD4 (FITC), human IgG (PE), 7-AAD (PerCP), and CD3 (APC). Autoantibodies were examined by anti-IgG reactivity (blue) on the surface of live CD4+ T cells (7-AAD−CD3+CD4+). Dashed line, staining with IgG1 isotype control (PE) instead of anti-human IgG (PE). (B) The percent of autoantibody positive CD4+ T cells at death were compared between ND (n = 8) and MD (n = 4) macaques. Percentages of IgG+ (left) or IgM+ (right) CD4+ T cells were determined by the Overton cumulative histogram subtraction using a mouse IgG1 isotype control. (C) Correlation between autoantibodies on CD4+ T cells and log naïve/memory ratio in CD4+ T cells at death. Percentages of IgG+ cells in CD4+ T cells and log naïve/memory ratio in CD4+ T cells were plotted using ND (blue circles, n = 8) and MD (red triangles, n = 4) macaques.
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ppat-1000372-g010: Autontibodies on the surface of CD4+ T cells in ND macaques.(A) Autoantibodies on the surface of CD4+ T cells from ND (H709, left) and MD (H718, right) macaques in representative flow cytometric analysis. Frozen PBMC samples at death were stained with antibodies against CD4 (FITC), human IgG (PE), 7-AAD (PerCP), and CD3 (APC). Autoantibodies were examined by anti-IgG reactivity (blue) on the surface of live CD4+ T cells (7-AAD−CD3+CD4+). Dashed line, staining with IgG1 isotype control (PE) instead of anti-human IgG (PE). (B) The percent of autoantibody positive CD4+ T cells at death were compared between ND (n = 8) and MD (n = 4) macaques. Percentages of IgG+ (left) or IgM+ (right) CD4+ T cells were determined by the Overton cumulative histogram subtraction using a mouse IgG1 isotype control. (C) Correlation between autoantibodies on CD4+ T cells and log naïve/memory ratio in CD4+ T cells at death. Percentages of IgG+ cells in CD4+ T cells and log naïve/memory ratio in CD4+ T cells were plotted using ND (blue circles, n = 8) and MD (red triangles, n = 4) macaques.
Mentions: The heightened immune activation and the propensity for autoimmune manifestations in the ND macaques led us to explore the possibility that autoimmune mechanisms might account for the loss of naive CD4+ T cells in these animals. We therefore examined terminal plasma samples for antibodies that bound the surface of CD4+ T cells from healthy, uninfected donor macaques. In addition, terminal CD4+ T cells of study macaques were analyzed for surface IgG and IgM. As shown in Figure 9A and 9B, antibodies that bound CD4+ T cells were detected exclusively in plasma or purifed IgG from ND macaques. Moreover, the level of anti-CD4+ T cell IgG correlated significantly with B cells count at 16 wpi, when activation of B cells were apparent (Figure 9C and Figure 5B). Most importantly, the level of anti-CD4+ T cell IgG correlated significantly with a lower naïve/memory ratio of CD4+ T cells, an indicator of naïve depletion (Figure 9D) as well as with absolute naïve CD4+ T cell counts at death (Figure 9E). We next examined T cells from PBMC samples from ND and MD macaques for the presence of surface-bound IgG by flow cytometry. In vivo antibody binding was also exclusively detected on the surface of CD4+ T cells from ND macaques, as shown by representative flow cytometry plots in Figure 10A. The percentage of CD4+ T cells with surface IgG was significantly higher in the ND versus the MD group (Figure 10B). In vivo binding of IgM was also detected on the CD4+ T cells from ND macaques, though there was no significant difference between the two groups (Figure 10B). Similar to plasma antibodies, a significant inverse correlation was observed between the percent of IgG+CD4+ T cells and the memory/naïve CD4+ T cell ratio (Figure 10C); macaques with higher anti-CD4+ T cell antibodies had lower naïve/memory ratio, indicative of naïve CD4+ T cell depletion.

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