T-cell reactivity to glutamic acid decarboxylase in stiff-man syndrome and cerebellar ataxia associated with polyendocrine autoimmunity

Abstract

SUMMARYAntibodies to glutamic acid decarboxilase (GAD-Abs) are present in the serum of 60-80% of newly diagnosed type 1 diabetes (DM1) patients and patients with autoimmune polyendocrine syndrome (APS) associated with DM1. Higher titre of GAD-Abs are also present in the serum of 60% of patients with stiff-man syndrome (SMS) and all reported patients with cerebellar ataxia associated with polyendocrine autoimmunity (CAPA). Several studies suggest that GAD-Abs may play a critical role in the pathogenesis of SMS and CAPA but little is known about T-cell responsiveness to GAD-65 in these neurological diseases. To analyse cell-mediated responses to GAD, we studied the peripheral blood lymphocyte proliferation and cytokine responses to recombinant human GAD-65 in 5 patients with SMS, 6 with CAPA, 9 with DM1, 8 with APS and 15 control subjects. GAD-65-specific cellular proliferation was significantly higher in SMS than in CAPA, DM1, APS or controls. In contrast, only T cells from CAPA patients showed a significantly high production of interferon-g after GAD stimulation, compared to all other patients and controls. No differences were found for IL-4 production. These results suggest that, despite similar humoral autoreactivity, cellular responses to GAD are different between SMS and CAPA, with a greater inflammatory response in CAPA, and this difference may be relevant to the pathogenesis of these diseases.

Characterization of CD4+ T cells specific for glutamic acid decarboxylase (GAD65) and proinsulin in a patient with stiff‐person syndrome but without type 1 diabetes

“…T-cell responses and levels of GADA have been studied only in SPS patients who were already affected by T1D. [24, 28, 50] An early study by Hummel and co-workers demonstrated a weak but detectable T-cell response to GAD65 and IA-2 with IFN-γ production that decreased in response to immunosuppressive therapy. [24] Schloot et al reported lack of primary T-cell response to GAD65 in a non-diabetic SPS patient.…”

Stiff-person syndrome: insights into a complex autoimmune disorder

“…Some of the T-cell clones in SPS produce Th2 cytokines supporting an antigen-driven collaboration between T and B cells leading to a sustained intrathecal production of oligoclonal anti-GAD IgG antibodies 65. Furthermore, a Th2 anti-inflammatory response in SPS has been proposed as a protective mechanism against the development of T1D in the majority of patients with SPS 67. The T-cell response in patients with SPS seem to be different from those with cerebellar ataxia and anti-GAD antibodies, with the latter having higher IFNγ production and lower proliferative response to GAD65 by T-cells 67.…”

“…Furthermore, a Th2 anti-inflammatory response in SPS has been proposed as a protective mechanism against the development of T1D in the majority of patients with SPS 67. The T-cell response in patients with SPS seem to be different from those with cerebellar ataxia and anti-GAD antibodies, with the latter having higher IFNγ production and lower proliferative response to GAD65 by T-cells 67. It is unclear what mechanisms are involved in the reactivation of T cells, once inside the CNS.…”

Intrathecal-specific glutamic acid decarboxylase antibodies at low titers in autoimmune neurological disorders

“…Furthermore, the intrathecal production of GAD-specific antibodies was described in previous studies that demonstrated elevated GAD-Ab indices in the majority of patients with various GADassociated neurological syndromes (Arino et al, 2014;Dalakas et al, 2001b;Malter et al, 2010). Given that neurological manifestations with high serum titers of GAD-Abs were frequently accompanied by polyendocrine autoimmunity (Costa et al, 2002), the absence of coexisting autoimmune diseases in our subjects also corresponded to humoral immunity limited to the CNS. In addition to GAD-Abs, Results are presented as number (%) or median (range).…”