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

Abstract

Background Glutamic acid decarboxylase (GAD) is a rate-limiting enzyme in the synthesis of gamma-amino butyric acid (GABA) and an important autoantigen both in patients with type 1 diabetes (T1D) and stiff-person syndrome (SPS). Autoantibodies (GADA) to the 65-kDa isoform of GAD are a characteristic feature in both diseases. Approximately 30% of patients with SPS develop diabetes, yet, it is unclear to which extent co-existing autoimmunity to GAD65 and other islet autoantigens determines the risk of developing T1D.

Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: Protean additions to the autoimmune central neuropathies

“…In a similar study on a non-T1D SPS patient, GAD65 failed to elicit any meaningful T cell stimulatory responses although, when a GAD65-specific T-cell line was developed by in vitro stimulation, the cloned T cells did specifically respond to the GAD65 peptide sequence 341e360 [59]; the elicited cytokine profile tended to be non-inflammatory, with raised levels of IFN gamma and IL-10 and a low level of IL-4. In another study [60] the in vitro cytokine profile of an SPS patient was followed over 46 months and, as in the above case [59], the profile became more Th 2 prominent over this time, with GAD65 stimulation leading to marked IFN gamma and IL-13 production and low levels of IL-4; consistent with the previous report [59], the best response was to the GAD65 peptide sequence, aa 339e352. The T cell epitope sequence aa 341e360 was not among the peptides mapped by Fenalti et al [34], but those sequences were all DR4-restricted whereas the 341e360 sequence of GAD65 was DR3-restricted [59].…”

Stiff-person syndrome: insights into a complex autoimmune disorder

“…These peripheral T-cells react to GAD regions 81–171 and 313–403, which contrasts with their counterparts in patients with T1D that react mainly to GAD regions 161–243 and 473–555 63. Other studies have demonstrated a T-cell response to GAD region between 339 and 565 in patients with SPS 62 64 65. Attempts to detect and clone the T-cells responding to GAD65 have been more successful using CSF than peripheral lymphocytes from patients with SPS 65.…”

Anti-glutamic acid decarboxylase antibody positive neurological syndromes

“…Whereas in SPS patients, the very high anti-GAD titers are found with a type-2 helper T cells response. This leads to the release of cytokines like interleukin-4 and interleukin-6, hence suppressing a T-cell-mediated cytotoxicity 73,74. On the other hand, Burton et al,75 using a mouse model demonstrated that the monoclonal GAD65-specific CD4(+) T cell population (4B5, PA19.9G11, or PA17.9G7) response caused SPS-like encephalomyelitis by altering the GABAergic neurons’ functionality 75.…”