Rho GTPase-activating protein 10 (ARHGAP10/GRAF2) is a novel autoantibody target in patients with autoimmune encephalitis

Abstract

Background In 2010, we described a novel immunoglobulin G (IgG) autoantibody (termed anti-Ca after the index case) targeting Rho GTPase-activating protein 26 (ARHGAP26, also termed GTPase regulator associated with focal adhesion kinase [GRAF], or oligophrenin-like protein 1 [OPHN1L]) in autoimmune cerebellar ataxia (ACA). Later, ARHGAP26-IgG/anti-Ca was reported in patients with limbic encephalitis/cognitive decline or peripheral neuropathy. In several of the reported cases, the syndrome was associated with cancer. ARHGAP10/GRAF2, which is expressed throughout the central nervous system, shares significant sequence homology with ARHGAP26/GRAF. Mutations in the ARHGAP10 gene have been linked to cognitive and psychiatric symptoms and schizophrenia. Objective To assess whether ARHGAP26-IgG/anti-Ca co-reacts with ARHGAP10. Methods Serological testing for ARHGAP10/GRAF2 autoantibodies by recombinant cell-based assays and isotype and IgG subclass analyses. Results 26/31 serum samples (84%) from 9/12 (75%) ARHGAP26-IgG/anti-Ca-positive patients and 4/6 ARHGAP26-IgG/anti-Ca-positive CSF samples from four patients were positive also for ARHGAP10-IgG. ARHGAP10-IgG (termed anti-Ca2) remained detectable in the long-term (up to 109 months) and belonged mainly to the complement-activating IgG1 subclass. Median ARHGAP26-IgG/anti-Ca and median ARHGAP10-IgG/anti-Ca2 serum titres were 1:3200 and 1:1000, respectively, with extraordinarily high titres in some samples (ARHGAP26-IgG/anti-Ca: up to 1:1000,000; ARHGAP10-IgG: up to 1:32,000). ARHGAP26/anti-Ca serum titres exceeded those of ARHGAP10-IgG in all samples but one. A subset of patients was positive also for ARHGAP10-IgM and ARHGAP10-IgA. CSF/serum ratios and antibody index calculation suggested intrathecal production of ARHGAP26-IgG/anti-Ca and anti-ARHGAP10. Of 101 control samples, 100 were completely negative for ARHGAP10-IgG; a single control sample bound weakly (1:10) to the ARHGAP10-transfected cells. Conclusions We demonstrate that a substantial proportion of patients with ARHGAP26-IgG/anti-Ca-positive autoimmune encephalitis co-react with ARHGAP10. Further studies on the clinical and diagnostic implications of ARHGAP10-IgG/anti-Ca2 seropositivity in patients with autoimmune encephalitis are warranted.

Rho GTPase-activating protein 17 (ARHGAP17) as additional autoimmune target in ARHGAP26-IgG/anti-Ca autoantibody-associated autoimmune encephalitis

“…1 B) [ 18 ], which is not shared by those 12 ARHGAPs that did not show a significant reaction with the patient’s IgG in the same microarray experiment and only partly shared by ARHGAP2, which yielded only a weak signal (Supplementary Figure), rendering the RhoGAP domain a potential binding site recognized by the patient’s anti-ARHGAP antibodies in all three ARHGAP proteins. The assumption of cross-reactivity is also strongly corroborated by the fact that we could demonstrate a significant correlation of ARHGAP10-IgG/anti-Ca2 titres with ARHGAP26-IgG/anti-Ca titres ( p < 0.0001) in our previous study [ 15 ]. Moreover, co-reactivity with ARHGAP10 was observed in almost all ARHGAP26-IgG/anti-Ca-positive patients in that study [ 15 ], which renders a coincidence highly unlikely.…”

“…The assumption of cross-reactivity is also strongly corroborated by the fact that we could demonstrate a significant correlation of ARHGAP10-IgG/anti-Ca2 titres with ARHGAP26-IgG/anti-Ca titres ( p < 0.0001) in our previous study [ 15 ]. Moreover, co-reactivity with ARHGAP10 was observed in almost all ARHGAP26-IgG/anti-Ca-positive patients in that study [ 15 ], which renders a coincidence highly unlikely. Taken together, this strongly favors cross-reactivity of a single antibody entity recognizing a shared epitope present in all three ARHGAPs in our patient over the presence of three distinct antibody entities with different epitope specificities.…”

“…Recently, we demonstrated in a study published in this journal that ARHGAP26-IgG/anti-Ca-positive sera cross-react in the vast majority of cases with ARHGAP10 (GRAF2; not to be mixed up with ARHGAP21, which has been occasionally falsely referred to as ARHGAP10 [ 12 ]). ARHGAP10 shares a significant sequence homology with ARHGAP26 and has been shown to be expressed at the RNA level throughout the CNS and at the protein level in the cerebellum in particular [ 13 – 15 ]. Here, we report that IgG from the ARHGAP26-IgG/ARHGAP10-IgG-positive index patient [ 1 ], who had presented with acute cerebellar ataxia (with cerebellar atrophy on MRI), diplopia, hyperekplexia, restlessness, anxiety and severe depression, reacts in addition with ARHGAP17 (also termed RhoGAP interacting with CIP4 homologs protein 1 [RICH-1]).…”

“…Interestingly, all three Rho GTPase-activating antigens targeted by this patient’s serum IgG – ARHGAP26 [ 1 ], ARHGP10 [ 15 ], and ARHGAP17 –, activate, at least according to in vitro data, the GTPase Cdc42. It is therefore worth mentioning that in addition significant reactivity of this patient’s serum to the Rho GTPase binding/CDC42 effector proteins 3 and 2 (CDC42EP3, CDC42EP2) was observed (signal rank 54 and 172, respectively, of 9483 proteins; median signal intensities: 3374 and 1489; median Z -factors: 0.85 and 0.78).…”

Case report: Anti-ARHGAP26 autoantibodies in atypical dementia with Lewy bodies

“…As he has undergone no further follow-up, we have no further access to data on his neuropsychological profile or how he is tolerating the acetylcholine esterase inhibitor donepezil. During the disease course, he should undergo oncologic screening such as whole-body positron emission computed tomography because a paraneoplastic syndrome may precede a tumor by years, as in patients with Rho GTPase-activating protein 10 (Jarius et al, 2022 ). In addition, anti-ARHGAP26 autoantibodies associated with isolated cognitive impairment have also been reported to be associated with tumors (Bartels et al, 2018 ).…”