Homeostatic Expansion of CD4+ T Cells Promotes Cortical and Trabecular Bone Loss, Whereas CD8+ T Cells Induce Trabecular Bone Loss Only

Weitzmann, M. Neale; Vikulina, Tatyana; Roser‐Page, Susanne; Yamaguchi, Masayoshi; Ofotokun, Ighovwerha

doi:10.1093/infdis/jix444

Cited by 15 publications

(9 citation statements)

References 33 publications

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“…The finding that higher CD4 counts are associated with markers of beta cell dysfunction could reflect a negative beta cell effect of increasing CD4 counts in the context of HIV. Interestingly, there is some precedent for a protective effect of immunosuppression in this context, as immune reconstitution and restoration of CD4 counts in immunosuppressed HIV positive individuals is associated with significant worsening of HIV related bone loss [ 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function

et al. 2018

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HIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts <350 cells/μL, PI:C ratios were lower than in HIV- controls (p<0.01), suggesting a reduction in intrinsic beta cell stress among this group. By contrast, HIV+ participants on ART had higher fasting glucose (p<0.0001) and lower HOMA%B (p<0.001) compared to HIV- controls. Among the entire HIV+ population, higher HIV RNA correlated with lower fasting glucose (r = -0.57, p<0.001), higher HOMA%B (r = 0.40, p = 0.001), and lower PI:C ratios (r = -0.42, p<0.001), whereas higher CD4 counts correlated with higher PI:C ratios (r = 0.2, p = 0.00499). Our results suggest that HIV seropositivity in the absence of ART does not worsen beta cell function or glucose homeostasis, but immune reconstitution with ART may be associated with worsened beta cell function.

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Section: Discussionmentioning

confidence: 99%

Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function

et al. 2018

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“…It has been reported that CD4 + T cells can increase the levels of RANKL and TNF to promote bone resorption, affecting both trabecular and cortical compartments, whereas CD8 + T cells increase bone marrow TNF levels and induce trabecular bone loss only. 31 Our results indicate that the percentage of CD4 + lymphocytes in patients with ONFH was significantly increased compared to that in healthy controls, of which the percentage in idiopathic-, traumatic-, and alcoholic-ONFH was higher than that in GC-ONFH. According to a systematic review conducted by Mont et al, 32 the prevalence of collapse in corticosteroid-related ONFH was 26%, excessive alcohol consumption related to ONFH was 47%, and idiopathic-ONFH had a 38% prevalence.…”

Section: Discussionmentioning

confidence: 46%

Imbalanced T-Cell Subsets May Facilitate the Occurrence of Osteonecrosis of the Femoral Head

Chen¹,

Xin²,

Luo³

et al. 2022

JIR

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Background Osteonecrosis of the femoral head (ONFH) is a complex disease resulting in degeneration of the hip joint. The pathogenesis of ONFH is largely unknown, but alterations in immunological factors have been proposed to play a role. Methods We included 109 patients with ONFH and 109 age-, sex-, and body mass index-matched healthy controls in this study. The percentage of circulating CD3 + , CD4 + , and CD8 + lymphocytes among the total lymphocytes was identified by flow cytometry and compared between the cases and controls. Subgroup analysis within each etiological group and correlation analysis of T-cell subset levels with disease duration were performed. Furthermore, we compared the expression patterns of CD4, RANKL, and FoxP3 in the femoral head of healthy and glucocorticoid (GC)-treated ONFH rats. Results The results showed that CD3 + and CD4 + T-cell counts and the CD4 + /CD8 + ratio were significantly higher in patients with ONFH and that CD3 + lymphocyte levels were negatively correlated with disease duration. The CD4 + T-cell levels and CD4 + /CD8 + ratios in the GC-ONFH etiological group were lower than those in the idiopathic-, traumatic-, and alcoholic-ONFH groups, while the CD8 + T-cell levels were higher. Furthermore, the CD3 + , CD4 + , and CD8 + T-cell counts and the CD4 + /CD8 + ratio were higher in the GC-ONFH group than in the control group. Finally, we observed diminished levels of FoxP3/CD4 double-positive T regulatory cells and increased RANKL + T-cell levels in the bone marrow of the femoral head in GC-ONFH rats. Conclusion The imbalance of T-cell subsets might be involved in the pathophysiological process of ONFH, and diminished CD4 + /FoxP3 + T regulatory cells may be associated with increased RANKL + T cells in the bone marrow of the femoral head in GC-ONFH, which may facilitate bone resorption and collapse of the femoral head. Trial Registration This study was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2100042642).

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“…Reports have shown that T cell reconstitution and immune activation is associated with bone loss ( 53 – 56 ). In PBMCs (Peripheral Blood Mononuclear Cells) from PWH, both CD4 and CD8 T cells express higher RANKL and decreased OPG, and its ratio is correlated with BMD suggesting a potential contribution of T cells in bone loss ( 53 , 54 , 57 , 58 ).…”

Section: Introductionmentioning

confidence: 99%

IL-27 Modulates the Cytokine Secretion in the T Cell–Osteoclast Crosstalk During HIV Infection

Hadigan

Whitlock

et al. 2022

Front. Immunol.

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In People with HIV (PWH), chronic immune activation and systemic inflammation are associated with increased risk to develop comorbidities including bone loss. Numerous cells of the immune system, namely, T cells are involved in the regulation of the bone homeostasis and osteoclasts (OCs) activity. IL-27, a cytokine that belongs to the IL-12 family can regulate the secretion of pro- and anti-inflammatory cytokines by T cells, however its role in the setting of HIV is largely unknown. In the present study, we determined the impact of OCs in T cell secretion of cytokines and whether IL-27 can regulate this function. We found that the presence of OCs in the T cell cultures significantly enhanced secretion of IFNγ, TNFα, IL-17, RANKL, and IL-10 in both PWH and healthy controls. In PWH, IL-27 inhibited IL-17 secretion and downregulated surface expression of RANKL in CD4 T cells. All together these results suggest that in the context of HIV infection IL-27 may favor IFNγ and TNFα secretion at the sites of bone remodeling.

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Homeostatic Expansion of CD4+ T Cells Promotes Cortical and Trabecular Bone Loss, Whereas CD8+ T Cells Induce Trabecular Bone Loss Only

Cited by 15 publications

References 33 publications

Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function

Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function

Imbalanced T-Cell Subsets May Facilitate the Occurrence of Osteonecrosis of the Femoral Head

IL-27 Modulates the Cytokine Secretion in the T Cell–Osteoclast Crosstalk During HIV Infection

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