Related Experiment Video
Updated: Jun 2, 2026
Flow Cytometric Analysis of Lymphocyte Infiltration in Central Nervous System during Experimental Autoimmune Encephalomyelitis
Published on: November 17, 2020
Functional energetics of CD4+-cellular immunity in monoclonal antibody-associated progressive multifocal
Aiden Haghikia1, Moritz Perrech, Bartosz Pula
1Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
Background:
Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system- (CNS-) infection that typically occurs in a subset of immunocompromised individuals. An increasing incidence of PML has recently been reported in patients receiving monoclonal antibody (mAb) therapy for the treatment of autoimmune diseases, particularly those treated with natalizumab, efalizumab and rituximab. Intracellular CD4(+)-ATP-concentration (iATP) functionally reflects cellular immunocompetence and inversely correlates with risk of infections during immunosuppressive therapy. We investigated whether iATP may assist in individualized risk stratification for opportunistic infections during mAb-treatment.
Methodology/Principal Findings:
iATP in PHA-stimulated, immunoselected CD4(+)-cells was analyzed using an FDA-approved assay. iATP of mAb-associated PML (natalizumab (n = 8), rituximab (n = 2), efalizumab (n = 1)), or other cases of opportunistic CNS-infections (HIV-associated PML (n = 2), spontaneous PML, PML in a psoriasis patient under fumaric acids, natalizumab-associated herpes simplex encephalitis (n = 1 each)) was reduced by 59% (194.5±29 ng/ml, mean±SEM) in comparison to healthy controls (HC, 479.9±19.8 ng/ml, p<0.0001). iATP in 14 of these 16 patients was at or below 3(rd) percentile of healthy controls, similar to HIV-patients (n = 18). In contrast, CD4(+)-cell numbers were reduced in only 7 of 15 patients, for whom cell counts were available. iATP correlated with mitochondrial transmembrane potential (ΔΨ(m)) (iATP/ΔΨ(m)-correlation:tau = 0.49, p = 0.03). Whereas mean iATP of cross-sectionally analysed natalizumab-treated patients was unaltered (448.7±12 ng/ml, n = 150), iATP was moderately decreased (316.2±26.1 ng/ml, p = 0.04) in patients (n = 7) who had been treated already during the pivotal phase III trials and had received natalizumab for more than 6 years. 2/92 (2%) patients with less than 24 months natalizumab treatment revealed very low iATP at or below the 3(rd) percentile of HC, whereas 10/58 (17%) of the patients treated for more than 24 months had such low iATP-concentrations.
Conclusion:
Our results suggest that bioenergetic parameters such as iATP may assist in risk stratification under mAb-immunotherapy of autoimmune disorders.
Insights
Intracellular CD4(+)-ATP-concentration (iATP) is reduced in patients with opportunistic infections during monoclonal antibody (mAb) therapy. Measuring iATP may help stratify infection risk in patients undergoing immunosuppressive treatment.
Area of Science:
- Immunology
- Neuroscience
- Biochemistry
Background:
- Progressive multifocal leukoencephalopathy (PML) is a CNS infection in immunocompromised individuals.
- Increasing PML incidence is observed in patients on monoclonal antibody (mAb) therapy for autoimmune diseases.
- Intracellular CD4(+)-ATP-concentration (iATP) reflects cellular immunocompetence and infection risk.
Purpose of the Study:
- To investigate if iATP can aid in individualized risk stratification for opportunistic infections during mAb treatment.
- To assess the relationship between iATP levels and opportunistic infections in patients on immunosuppressive therapy.
Main Methods:
- Analyzed iATP in PHA-stimulated, immunoselected CD4(+) cells using an FDA-approved assay.
- Compared iATP levels in patients with mAb-associated PML and other CNS infections to healthy controls (HC).
- Correlated iATP with CD4(+) cell counts and mitochondrial transmembrane potential (ΔΨ(m)).
Main Results:
- iATP was significantly reduced (59%) in patients with mAb-associated PML and other CNS infections compared to HC (p<0.0001).
- 14 of 16 patients with infections had iATP at or below the 3rd percentile of HC.
- Longer natalizumab treatment (>6 years) was associated with moderately decreased iATP and a higher prevalence of very low iATP levels.
Conclusions:
- Reduced iATP levels are indicative of impaired cellular immunocompetence in patients with opportunistic infections during mAb therapy.
- Bioenergetic parameters like iATP show potential for risk stratification in patients undergoing mAb immunotherapy for autoimmune disorders.
