Aquaporin 4‐specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter

Abstract

Objective Aquaporin-4 (AQP4)-specific autoantibodies in neuromyelitis optica (NMO) are IgG1, a T cell-dependent Ig subclass, indicating AQP4-specific T cells participate in NMO pathogenesis. Our goal was to identify and characterize AQP4-specific T cells in NMO patients and healthy controls (HC). Methods Peripheral blood T cells from NMO patients and HC were examined for recognition of AQP4 and production of proinflammatory cytokines. Monocytes were evaluated for production of T cell-polarizing cytokines and expression of costimulatory molecules. Results T cells from NMO patients and HC proliferated to intact AQP4 or AQP4 peptides (p11-30, p21-40, p61-80, p131-150, p156-170, p211-230 and p261-280). T cells from NMO patients demonstrated greater proliferation to AQP4 than HC, and responded most vigorously to p61-80, a naturally processed immunodominant determinant of intact AQP4. T cells were CD4+, and corresponding to association of NMO with HLA-DRB1*0301 and DRB3, AQP4 p61-80-specific T cells were HLA-DR-restricted. The T cell epitope within AQP4 p61-80 was mapped to 63-76, which contains ten residues with 90% homology to a sequence within Clostridium perfringens ABC transporter permease. T cells from NMO patients proliferated to this homologous bacterial sequence and cross-reactivity between it and self-AQP4 was observed, supporting molecular mimicry. In NMO, AQP4 p61-80-specific T cells exhibited Th17 polarization, and furthermore, monocytes produced more IL-6, a Th17-polarizing cytokine, and expressed elevated CD40 and CD80 costimulatory molecules, suggesting innate immunologic dysfunction. Interpretation AQP4-specific T cell responses are amplified in NMO, exhibit a Th17 bias and display cross-reactivity to a protein of an indigenous intestinal bacteria, providing new perspectives for investigating NMO pathogenesis.

Gut microbiome analysis in neuromyelitis optica reveals overabundance of Clostridium perfringens

“…Third, it is possible that C. perfringens might participate in more than one CNS autoimmune disease. In this regard, one year after we identified the potential link between C. perfringens and NMO,3 C. perfringens was implicated in MS pathogenesis 19. Another study found that Clostridium species within clusters XIVa and IV, which do not contain C. perfringens (a member of cluster I), are reduced in relapsing–remitting MS patients 20.…”

“…Previously, we observed that T cells from NMO patients proliferate more vigorously in response to AQP4 than T cells from healthy controls (HC) 3. In NMO, T‐cell recognition of the immunodominant determinant peptide (p) 63–76 was associated with Th17 polarization.…”

TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased Central Nervous System Demyelinating Autoimmune Disease

“…The composition of the gut microbiota varies between monozygotic twins (27) and influences the development of the immune system (28). The composition of the gut commensal microbiota has recently been identified as an environmental factor that can trigger CNS demyelinating autoimmune disease (14,29,30 …”

“…In contrast to EAE and MS, complement-activating autoantibodies against aquaporin 4 (AQP4), the predominant CNS water channel, have been implicated in the induction of inflammatory demyelination in humans with NMO (13). More recently, AQP4-specific T cells exhibiting a Th17 bias and displaying cross-reactivity to the gut commensal bacteria Clostridium perfringens have also been implicated (14,15).…”

Cytokine Therapies in Neurological Disease

“…Initial therapeutic targets in NMO were against B cells given their role in antibody production. Recent efforts have helped to clarify the role of other immune cells in this process, including Th17 cells in producing these destructive lesions [47]. IL-6, which promotes antibody production in activated B cells as well as Th17 differentiation, was present in elevated levels in the serum and CSF has been shown to be elevated in patients with NMO, especially during relapse [48].…”