Anti-neuronal and anti-mitochondrial autoantibodies are associated with lower functional status [...] respiratory symptoms in [PCS], 2025,Vogelgesang+

[forestglip]

Anti-neuronal and anti-mitochondrial autoantibodies are associated with lower functional status and more severe respiratory symptoms in post COVID syndrome

Antje Vogelgesang, Anke Steinmetz, Angela Stufano, Valentina Schino, Domenico Plantone, Agnes Flöel, Guglielmo Lucchese

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Introduction
We previously identified IgG autoantibodies targeting epitopes within brainstem proteins-disabled homolog 1 (DAB1), apoptosis-inducing factor 1 (AIFM1), and surfeit locus protein 1 (SURF1)-as markers of severe acute COVID-19. This study investigates whether the same autoantibodies contribute to the pathophysiology of Post COVID Syndrome (PCS).

Methods
Using a multiplexed bead-based immunoassay, we measured IgG levels against 18 synthetic peptides derived from DAB1, AIFM1, and SURF1 in serum samples from 45 PCS patients and 30 post-COVID controls without long-term symptoms.

We employed generalized linear mixed models (GLMM) and nonlinear principal component analysis (CATPCA) to explore associations between antibody levels and clinical variables, including functional status (PCFS), respiratory symptoms, fatigue, cognitive impairment (as assessed by the Montreal Cognitive Assessment, MoCA), and mood.

Results
Higher IgG levels against the three autoantigens significantly predicted PCS at 3 months postinfection (t=2.21, p=0.03), whereas antibodies against a control peptide (polio) showed no such association.

CATPCA identified a principal component capturing respiratory symptoms and functional impairment (PCFS), which was also significantly predicted by autoantibody levels (t=2.04, p=0.04).

MoCA scores did not correlate with autoantibody levels, and subjective cognitive complaints were paradoxically linked to lower antibody titers and fewer physical symptoms.

Conclusions
The findings from the present explorative study, although largely correlative, appear to suggest a sustained autoimmune response targeting neuronal and mitochondrial proteins in PCS, particularly associated with respiratory dysfunction and reduced functional capacity. The results also highlight potential limitations of standard cognitive screening tools like the MoCA in detecting subtle deficits in PCS.

The identified autoantibodies may serve as biomarkers for persistent post-COVID disability. Future research replicating present results on larger samples and specifically investigating a causal link between occurrence of the Auto-Abs and PCS is needed for shaping future immunomodulatory therapeutic strategies.

Web | PDF | Frontiers in Immunology | Open Access

 

[SNT Gatchaman]

We previously hypothesized a role of IgG against DAB1, AIFM1, and SURF1 in cognitive impairment in COVID-19, given the well-described functions of the three proteins in neurogenesis and synaptic plasticity. Nevertheless, the current exploratory study seems to challenge this idea. Specifically, no significant link was found between the autoimmune response to these proteins and cognitive performance as measured by the MoCA.

Interestingly, self-reported cognitive symptoms—captured by the third principal component—were paradoxically associated with lower antibody levels.

MoCA may lack sensitivity in detecting mild to moderate cognitive impairment in post-COVID syndrome (PCS). This aligns with clinical observations from consultations, where a significant proportion of patients—estimated at around 25%—do not score below the MoCA cutoff of 26 points, yet require up to twice the typical time to complete the test.

PCS patients consistently rated their own well-being and cognitive performance as lower, whereas neuropsychological batteries failed to unveil any differences, with the exception of verbal fluency. One additional possible explanation for our paradoxical finding is that patients with greater functional limitations and more severe respiratory symptoms may report fewer cognitive complaints, perhaps because their attention is directed more toward the physical aspects of their condition.