Increased T-cell immunity against aquaporin-4 and proteolipid protein in neuromyelitis optica

Abstract

In neuromyelitis optica (NMO), B-cell autoimmunity to aquaporin-4 (AQP4) has been shown to be essential. However, the role of T cells remains ambiguous. Here, we first showed an increase in CD69+ activated T cells in PBMCs during NMO relapses. Next, T-cell responses to AQP4 and myelin peptides were studied in 12 NM0 patients, 10 multiple sclerosis (MS) patients and 10 healthy subjects (HS). Four hours after adding 1 of 28 overlapping AQP4 peptides, a mixture of AQP4 peptides (AQP4-M) or one of six distinct myelin peptides to 2-day cultured PBMC, CD69 expression on CD4+ T cells was examined. Data were analyzed by paired t-test, frequency of samples with 3-fold increase of CD69 on CD4+ cells (fSI3) and mean stimulation index (mSI). The T-cell response to AQP4-M was significantly increased in NMO (fSI3 = 10/12, mSI = 5.50), with AQP4 (11-30) and AQP4 (91-110) representing the two major epitopes (AQP4 (11-30), fSI3 = 11/12, mSI = 16.0 and AQP4 (91-110), fSI3 = 11/12, mSI = 13.0). Significant but less extensive responses to these two epitopes were also observed in MS and HS. Significant reactivities against AQP4 (21-40), AQP4 (61-80), AQP4 (101-120), AQP4 (171-190) and AQP4 (211-230) were exclusively found in NMO. In addition, responses to AQP4 (81-100) were higher and more frequently detected in NMO, without reaching statistical significance. Interestingly, among the six myelin peptides studied, proteolipid protein (95-116) induced a significant T-cell response in NMO (fSI3 = 7/12, mSI = 4.60). Our study suggests that cellular as well as humoral responses to AQP4 are necessary for NMO development and that the immune response to myelin protein may contribute to disease pathogenesis.

Variable results after rituximab in neuromyelitis optica

“…In experimental animals, B cell depletion improves autoimmune encephalomyelitis induced with whole myelin oligodendrocyte protein (MOG), but worsens T cell-mediated disease induced by a MOG peptide [10]. Anti-aquaporin T cells have been demonstrated to be present in humans with NMO and are pathogenic in experimental animals [11,12]. It is possible that our patients with continued relapses had T cell mediated disease.…”

Neuromyelitis optica in a patient with pemphigus foliaceus

“…The role of T cells remains ambiguous in NMO [30], however an antigen-specific T-cell response has been proposed as a response to immunization with AQP4 and leading to NMO lesions [31,32]. Circulating T cells reactive to desmoglein and circulating B cells producing anti-desmoglein were detected in patients with pemphigus and it was postulated that both T and B cells were needed for antibody formation [33][34][35].…”

Expanding Role of T Cells in Human Autoimmune Diseases of the Central Nervous System

“…In fact, activated T cells infiltrate NMO patient-derived lesions (190) and clonal expansion of T cells was reported (191). Efforts have been made to define the immunodominant epitope by identifying which peptide from a human AQP4 (hAQP4) peptide library induced the greatest T cell proliferation when cultured with peripheral blood mononuclear cells (PBMCs) from anti-AQP4 antibody-positive NMO patients compared to MS subjects and healthy controls (165, 168, 169). However, further studies are required to precisely define the dominant target region as these epitopes differed greatly between studies.…”