Welcome to the Autoimmunity 2021 Congress Calendar

Background and Aims

The role of polyautoimmunity (PolyA) on clinical manifestations of autoimmune diseases (ADs) is not well defined. We aimed to characterize PolyA and evaluate its influence on clinical features in autoimmune rheumatic diseases (ARDs).

Methods

This was a one-year multicenter cross-sectional study in which 214 consecutive patients with rheumatoid arthritis (RA,n:135), systemic lupus erythematosus (SLE,n:40), and other ARDs (n:39) were included. A total of 33 autoantibodies were measured by ELISA and immunoblot. The coexistence of two or more ADs fulfilling classification criteria was termed “Overt PolyA”, whereas, “Latent PolyA” corresponded to the presence of autoantibodies unrelated to the index AD not fulfilling classification criteria for other ADs. Data was analyzed using Fisher-exact and Kruskall-Wallis tests.

Results

Overt and latent PolyA were present in 30.84% and 31.31% of patients, respectively. The most prevalent AD in both types of PolyA was autoimmune thyroid disease (AITD) (Figure 1A), characterized by a high frequency of anti-TPO positivity (Figure 1B). Age at onset, duration of disease, and medication status based on PolyA were not different. Patients with SLE showed the highest frequency of overt and latent PolyA (p: 0.007).

Conclusions

One in three patients with ARDs disclosed PolyA, with AITD being the most frequent. As a corollary, all patients with ARDs must be routinely evaluated for thyroid autoimmunity. Latent PolyA deserves further evaluation in clinical settings as predictor of overt PolyA.

Background and Aims

Therapies for autoimmune diseases are traditional immunosuppressive regimens, exposing patients to higher risks of opportunistic infection and other discomforts. Here, we propose a novel strategy for antigen-specific tolerance induction that is completely proteinaceous, based on the use of adducts formed between alpaca-derived single domain antibody fragments (VHHs/nanobodies) and a diverse set of autoantigens.

Methods

We have reported that we have developed VHHs that recognize MHC-II molecules and hence, target all subsets of professional antigen presenting cells (APCs). We also established an engineering strategy that uses chemo-enzymatic approaches that enable the site-specific modifications of these VHHs at their C-terminus. These methods allow the installation of various autoantigens involved in various autoimmune diseases. We hypothesize that targeted antigen delivery to the APCs in a tolerogenic manner in the steady state and in the absence of inflammatory signal will lead to antigen-specific tolerance.

Results

We found that transfusion of a single dose of VHH_MHCII-MOG_35-55 completely prevents signs of disease in an experimental autoimmune encephalomyelitis. These mice are protected for the rest of their lifetime. To test the applicability of our strategy beyond a specific organ and genetic background, we expanded our tolerogenic strategy to a mouse model of type 1 diabetes; mice transfused with our VHH_MHCII-p31 maintain normoglycemia in prophylactic and semi-therapeutic settings. This tolerogenic process is antigen-specific, leaving the rest of the immune system intact.

Conclusions

These results highlight the potential of these nanobody-antigen adducts to induce antigen-specific tolerance. We envision these engineered nanobodies as a novel means for treating a wide range of autoimmune diseases.

Background and Aims

Background and Aims: Understanding the molecular mechanisms underlying immune disorder is helpful for improving therapeutic strategies for treating RA. We report the molecular programmes of isolated Treg cells controlling treatment-naïve RA patients using single-cell RNA sequencing (scRNA-seq).

Methods

Methods: PBMCs were isolated from early treatment-naïve RA patients. 1×10⁶ cells were cultured with anti-CD3 and anti-CD28in the presence or absence of As₂O₃ (0.1 µM). Then, Treg cells isolated by FACS from PBMCs . Treg cells were performed by single-cells analysis to gain variance gene.

Results

Results: To define populations and identify genome-wide gene expression, we isolated Treg with or without As₂O₃ (0.1 µM) from treatment-naïve RA patients and performed scRNA-seq. We performed a volcano plot visualization of gene expression between the cells of early treatment-naive RA patients.

Conclusions

Conclusions: In conclusion, four novel mRNAs were used to generate a valuable target gene, which can serve as an independent indicator to predict the immune status of treatment-naïve RA patients due to their influences on the distinct signaling pathways.

Background and Aims

IgG4 autoimmune diseases are an emerging group of severe autoimmune diseases such as MuSK Myasthenia gravis, pemphigus vulgaris or thrombotic thrombocytopenic purpura. They are caused by IgG4 autoantibodies that are pathogenic by a direct blocking mechanism. The aetiology of IgG4 autoimmunity is not known. Polymorphisms in the human leukocyte antigen (HLA) gene locus, particularly in HLA-DRB1, are known to contribute to a genetic susceptibility to develop autoimmune diseases. We hypothesized that IgG4 autoimmune diseases (IgG4-AID) collectively may also share genetic associations with the HLA gene locus.

Methods

To address this possibility, we conducted a systematic review to identify case-control studies on class I IgG4 autoimmune diseases based on the HuGENet guidelines for genetic association studies and MOOSE guidelines on Meta-analysis Of Observational Studies in Epidemiology.

Results

We identified an increased frequency of HLA-DRB1*14 (genotype frequency: OR 4.31; 95% CI 2.82-6.59; p < 0.00001; allele frequency: OR 4.78; 95% CI 3.52-6.49; p <0.00001) and HLA-DQB1*05 (genotype frequency: OR 3.8; 95% CI 2.44-5.9; p < 0.00001; allele frequency: OR 2.54; 95% CI 1.82-3.55; p < 0.00001) and the HLA-DRB1*14-DQB1*05 haplotype (n: OR 6.3; 95% CI 3.28-12.09; p < 0.00001, 2n: OR 4.98; 95% CI 3.8-6.53; p < 0.00001), and a decreased frequency of HLA-DRB1*13 (genotype frequency: OR 0.48; 95% CI 0.34-0.68; p <0.0001; allele frequency: OR 0.46; 95% CI 0.34-0.62; p < 0.00001) in patients with IgG4-autoimmune diseases.

Conclusions

The HLA-DRB1*14 and DQB1*05 allele may contribute as genetic risk factors to the susceptibility to develop IgG4 autoimmune disease, while HLA-DRB1*13 may have a protective effect.

Background and Aims

Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling and has important functions in immune regulation acting on multiple intracellular pathways. Animal models predict autoimmunity dominated phenotypes and early death in complete knockout of SOCS1. Recently SOCS1 haploinsufficiency has been associated with novel Inborn error of immunity (IEI) in humans. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has pleiotropic effects in humans.

We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency.

Methods

We assessed impacts of reduced SOCS1 expression across immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells.

Results

SOCS1 haploinsufficiency phenotypes straddle across classifications of IEI. Reduced SOCS1 expression leads to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. These findings might explain clinical overlaps between SOCS1 haploinsufficiency and IEIs like STAT1GOF and STAT3LOF. Immune dysregulation in SOCS1 haploinsufficiency might further be explained by reduced E3 ligase functions of SOCS1 leading to increased FAK in immune cells resulting in increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also find Toll-like receptor responses being increased in SOCS1 patients.

Conclusions

SOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain variable clinical phenotypes associated with this new condition. Knowledge of additional dysregulated pathways is important when considering specific treatment options for these patients.