Autoantibodies as biomarkers in autoimmune diseases

Macchiarella, Giulio. Autoantibodies as biomarkers in autoimmune diseases. 2023, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: https://edoc.unibas.ch/94801/

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The immune system plays a critical role in the homeostasis and protection of our body, but its dysregulation is often associated with the pathogenesis of autoimmune diseases. The cellular and molecular components of the immune system have been explored as therapeutic targets or biomarkers with the aim of curing autoimmunity. Although studied since decades, autoantibodies’ use as biomarker in clinical trials is still limited to a handful of well-known markers. The aim of the thesis was to test autoantibody profiling as an exploratory tool to identify new biomarkers in the context of clinical trials conducted in three autoimmune diseases.
In the first part of the PhD, I tested a large set of autoantibodies on baseline serum samples from a phase III anti-IL17 clinical trial of Psoriatic Arthritis, with the aim of identifying a group of biomarkers that could discriminate between responders and non-responders to the treatment. Numerous autoantibodies of either IgG, IgM and IgA isotype were found more expressed in clinical non-responders when compared to responders. Such autoantibodies were directed against molecules related to IL17 pathway, a commensal bacterium (Lachnospiraceae) and antigens linked to Rheumatoid Arthritis. Overall, these markers allowed a discrimination of 40% of non-responders from responders population, which was judged as a too low sensitivity in order to start the development of a companion diagnostic. However, the technical knowledge acquired during this first project was fundamental for the rest of the PhD. In the second part of the PhD, I applied autoantibody profiling, using a targeted set of antigens, on serum samples from a phase II anti-IL17 treatment clinical trial of Hidradenitis Suppurativa (HS). The aim of this project was to demonstrate the presence of autoantibodies that could support the hypothesis of an autoimmune component of HS pathogenesis. We found IgG anti-Carboxyethyl-lysine (CEL) autoantibodies with specific high levels in HS when compared to healthy volunteers and other comorbidities such as Crohn’s disease and Ulcerative Colitis. B-cells producing anti-CEL antibodies were detected in HS lesional skin as well. Sera with high levels of anti-CEL autoantibodies activated macrophages and complement pathway in presence of CEL-BSA. The majority of IgG anti-CEL antibodies was of IgG2 subclass and no cross-reactivity with similar molecules such as Carboxymethyl-lysine and Octopine was found. Overall, these results suggested a role for oxidative stress and advanced glycation events in the pathogenesis of HS. In the third part of the PhD, I detected anti-FceR1a autoantibodies in serum from Chronic Spontaneous Urticaria (CSU) from a phase II clinical trial of anti-IgE treatment. It was hypothesized that patients expressing anti-FceR1a autoantibodies may activate mast cells degranulation in an IgE-free manner, which would make them resistant to anti-IgE treatment. The results showed no correlation between the presence of anti-FceR1a autoantibodies and clinical response to IgE treatment. The detection of the soluble form of FceR1a (sFceR1a) at different time-points throughout the treatment showed a dose-dependent decrease of sFceR1a concentration, similarly to what already published for FceR1a expression on basophils surface. The data showed in this thesis suggested that sFceR1a might be a substitute mechanistic marker of cell-bound FceR1a.
In conclusion, although autoantibody profiling did not allow identifying specific markers for anti-IL17 treatment response in PsA, the knowledge acquired during this project was critically important. Indeed, the same approach allowed the finding of anti-CEL autoantibodies abundance and specificity in HS and the testing of anti-FceR1a autoantibodies and sFceR1a in CSU, which gave new insights in these diseases. The results presented in this thesis show the potential and limitations of autoantibodies profiling when applied to clinical trials of autoimmune diseases.
Advisors:Avrameas, Alexandre
Committee Members:Pieters, Jean and Robbiani, Davide F.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Infection Biology > Biochemistry (Pieters)
UniBasel Contributors:Pieters, Jean
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:15034
Thesis status:Complete
Number of Pages:132
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss150343
edoc DOI:
Last Modified:06 Jul 2023 07:18
Deposited On:05 Jul 2023 14:35

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