Welcome to the 13th International Congress on Autoimmunity interactive program

Abstract Body

Regulatory B (Breg) cells are key players in the prevention and cure of many inflammatory and autoimmune diseases. Bregs regulate the proliferation of T cells through the induction of Foxp3+ Tregs whose expansion is induced by direct CD40-CD40L cell-to-cell contact while Bregs control the proinflammatory Th1 polarization by the production of IL-10. A functional impairment of Bregs has been demonstrated in systemic lupus erythematosus (SLE). They are not sensitive to CD40 stimulation, are unable to regulate the proliferation of T cells, produce less IL-10 and cannot efficiently control Th1 polarization. The management of the Breg cell properties thus emerges as a promising therapeutic strategy to improve the treatment of SLE restoring the control of immune responses. In the current work, we search for the possibility to stimulate activities of healthy Bregs and to restore the defective SLE Breg functions.

Glatiramer acetate (GA) is a synthetic polypeptide that is used in the treatment of inflammatory and autoimmune diseases. We experimented with an in vitro coculture system to determine its direct effects on the Breg cell properties. When healthy B cells were stimulated by GA, the B cell production of IL-10 was further enhanced, the T cell proliferation and their Th1 IFN-γ polarization were further inhibited. GA bound preferentially to the memory B cells and GA-dependent increased Breg cell activities were specifically supported by the memory B cell compartment. Interestingly, GA stimulation of SLE B cells induced the production of IL-10, and in the coculture experiments restored the control of the T cell proliferation and the modulation of the Th1 IFN-γ secretion.

These data demonstrate that GA can stimulate the Bregs primarily by shifting the memory B cells known to contribute to the T cell–dependent inflammatory response, and can reverse the defective functions of SLE Bregs. Drugs such as GA appear as a useful therapeutic strategy for the restoration of the Breg cell activities and consequently for the recovery of immune homeostasis in SLE.

Abstract Body

The prognosis of SLE has improved significantly in recent decades. This is mainly due to better diagnostics and more consistent use of known immunosuppressive substances. In addition, more and more mild cases are being detected. However, we are still a long way from personalised medicine for those affected. On the one hand, this is due to the lack of suitable biomarkers that reliably identify the pathophysiological processes; on the other hand, we also still lack specific interventions for the various pathophysiological targets in SLE. Together with the heterogeneity of the disease expression, this all contributes to less successful studies.

One way to circumvent this complexity is T2T, standardising the target and, through response, recognising the differences between individual sufferers. The definition of remission and low disease activity in SLEs sets the stage for a T2T approach in SLE. Analyses of different cohorts from all regions of the world have shown that a state of remission is associated with less damage acquisition, better quality of life and less pain. This finding can be well explained by a selection of milder disease cases. So far, it has not been shown for SLE, in contrast to rheumatoid arthritis, that intensified treatment to achieve remission leads to comparable results. Most importantly, compared with definitions of remission in other diseases, SLE also involves limiting therapy - prednisolone ≤ 5mg/d.

We have developed two study designs to evaluate the T2T concept in SLE.

Background and Aims

Naturally-occurring autoantibodies to certain components of autophagy processes have been described in a few autoimmune diseases, but their fine specificity, their relationships with clinical phenotypes, and their potential pathogenic functions remain elusive.

Methods

We explored IgG autoantibodies reacting with a panel of cytoplasmic endosomal/lysosomal antigens and individual heat-shock proteins, all of which share links to autophagy.

Results

Sera from autoimmune patients and from MRL/lpr and NZB/W lupus-prone mice reacted with the C-terminal residues of lysosome-associated membrane glycoprotein (LAMP)2A. No cross-reaction was observed with LAMP2B or LAMP2C variants, with dsDNA or mononucleosomes, or with heat-shock protein A8. Moreover, administering chromatography-purified LAMP2A autoantibodies to MRL/lpr mice accelerated mortality. Furthermore, flow cytometry revealed elevated cell-surface expression of LAMP2A on MRL/lpr B cells.

Conclusions

These findings reveal the involvement of a new class of autoantibodies targeting the C-terminus of LAMP2A, a receptor for cytosolic proteins targeted for degradation via chaperone-mediated autophagy. These autoantibodies could affect the autophagy process, which is abnormally upregulated in lupus. The data presented support a novel connection between autophagy dysregulation, autoimmune processes and pathophysiology in lupus.

Ref. Wilhelm, M., Bonam, S.R., Schall, N., Bendorius, M., Korganow, A.-A., Lumbroso C. & Muller, S. (2021) Implication of a lysosomal antigen in the pathogenesis of lupus erythematosus. J. Autoimmunity 120, 102633

Background and Aims

6-sulfoLacNAc+ monocytes (slanMos) are a subset of nonclassical monocytes, which are considered pro-inflammatory cells in different diseases, including the autoimmune ones, such as systemic lupus erythematosus (SLE). Reduction and dysfunction of circulating nonclassical monocytes and recruitment of these cells to inflammation sites in SLE patients have been previously reported by our Group. We proposed encapsulating Itacitinib into nanoparticles to inhibit the JAK-STAT pathway in SlanMo from SLE patients and other chronic inflammatory diseases.

Methods

Monocyte subpopulations were evaluated in SLE patients (n=10, from ARTMEDICA) and healthy controls (n=10) by flow cytometry markers (CD14, CD16, HLA-DR, and Slan). SlanMos were isolated using a commercial kit. Inhibition of the JAK-STAT pathway was evaluated with Baricitinib or Itacitinib and stimulated with IFN-γ. HLA-DR, CD64, and CD69, p-STAT-1, and TNF-α accumulation were determined by flow cytometry. We evaluated the specific binding of Poly-lactic-co-glycolic acid (PLGA), galactosamine-PLGA, and wheat germ agglutinin (WGA)-PLGA nanoparticles by leukocytes.

Results

Patients had a significantly lower number of circulating SlanMo. Itactinib had the highest inhibitory effect on the JAK-STAT pathway. Then, we will design an Itacitinib encapsulated nanoparticle to target the SlanMo. We had established that PLGA-WGA nanoparticles were uptook efficiently by monocytes compared with other leukocytes. Suggesting the potential role of these nanoparticles to target monocytes and possibly more specifically SlanMos for the treatment of SLE.

Conclusions

The uptake of PLGA-WGA nanoparticles by monocytes suggests the potential role of these nanoparticles to target these cells and possibly more specifically SlanMo for the treatment of SLE.

Financial support: Minciencias 111584467267/111584467246, contract 925-2019/919-2019.

Background and Aims

Systemic Lupus Erythematous (SLE) is a classical autoimmune disease that remains an important clinical challenge both in terms of diagnosis and treatment. Glycosylation, as a cell-, tissue-specific modification is associated with organisms’ evolutionary conservation, representing a distinction factor between self- and non-self. Dysregulation of protein N-glycosylation has been reported by others and us to occur in major diseases such as cancer and autoimmune diseases. In this work we aimed to identify glycosylation alterations in autoimmunity and infection and assess its relationship with pro-inflammatory immune responses.

Methods

A combination of advanced tissue mass spectrometry imaging, in situ glyco-characterization and ex vivoglycophenotyping of human kidney biopsies were performed to structurally map the N-glycans repertoire in Lupus Nephritis (LN) samples. In the context of infection, we have glycophenotyped T cells from SARS-CoV-2-infected individuals by FACS.

Results

Interestingly, LN revealed a unique glycan signature characterized by an increased abundance of unusual mannose-enriched glycans that are typically found in lower microorganisms; this glycosignature was specific of LN and has shown to predict the development of chronic kidney disease (CKD) with 93% of specificity. Moreover, this phenotype was associated with increased frequency of a specific T cell subset, equipped with glycan-recognizing receptor, DC-SIGN. Finally, in an in vitro setup, we have observed that this T cell subset is able to sense mannosylated-antigens, leading to its pathogenic activation.

Conclusions

Taken together, this work revealed a unique immunological mechanism based in mannosylated antigens/T-cells/IL-17a axis in SLE immunopathogenesis, proposing glycans as a key target in the comprehension of autoimmunity and infection.

Background and Aims

Patients with systemic lupus erythematosus (SLE) are at high risk of atherosclerosis development. Serum atherogenicity, the ability of blood serum to induce intracellular cholesterol accumulation in cultured cells is a potential marker for cardiovascular risk assessment. The aim of this study was to estimate the association of serum atherogenicity of SLE patients with disease activity and corticosteroids (CS) administration.

Methods

Patients with systemic lupus erythematosus (SLE) are at high risk of atherosclerosis development. Serum atherogenicity, the ability of blood serum to induce intracellular cholesterol accumulation in cultured cells is a potential marker for cardiovascular risk assessment. The aim of this study was to estimate the association of serum atherogenicity of SLE patients with disease activity and corticosteroids (CS) administration.

Results

90% participants with SLE and only 15% of control participants possessed high atherogenic potential of blood serum. Serum atherogenicity in group without CS was higher than in group received CS (221±13% and 185±11% respectively, p=0.044). Serum atherogenicity correlated with SLEDAI index (r=0.82, p=0.04). No correlation was found between atherogenicity and blood lipids.

Conclusions

Serum atherogenicity is associated with disease activity in SLE patients that suggests the significance of immunological changes in pathogenesis of atherosclerosis. This work was supported by the Russian Science Foundation (Grant # 22-15-00198).