Functional Energetics of CD4+-Cellular Immunity in Monoclonal Antibody-Associated Progressive Multifocal Leukoencephalopathy in Autoimmune Disorders

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

Complications neurologiques de l'infection par le virus d'immunodéficience humaine

Neurological complications may occur even before immunosuppression is clinically observed, and can thus reveal HIV infection. Aseptic meningitis, subacute encephalitis, vacuolar myelopathy, inflammatory myopathy, and different types of polyneuropathies seem to be associated with HIV, but their pathogenesis has only recently begun to be understood. These complications must be distinguished from opportunistic infections and from intra-cerebral tumors with which they often coexist. The Sixth International Conference on AIDS in San Francisco has defined the extent and limits of our present knowledge, and has given new directions for research in this last, but not least important chapter of modern neurology

Neuro-otological manifestations in different stages of HIV infection

A systematic investigation of the incidence and type of peripheral and central auditory and vestibular disorders occurring in different stages of HIV infection was performed: 43 HIV-seropositive patients (14 were symptomatic with manifestation of AIDS or related complex and 29 were clinically asymptomatic) were compared with a matched control group of 33 HIV-seronegative homosexual volunteers. Among the symptomatic patients 8 (57%) out of 14 and among the asymptomatic HIV-positive patients, 13 (45%) out of 29 had abnormal results in various audiological, vestibular and electrophysiological tests. Only minor anomalies were found in 4 (12%) of the 33 seronegative homosexuals. Our results indicate a high incidence of neuro-otological disorders among patients suffering from AIDS. The numerous electrophysiological abnormalities found in asymptomatic HIV-seropositive persons suggest furthermore an early subclinical involvement of the auditory and vestibular systems