Welcome to the Autoimmunity 2021 Congress Calendar

Background and Aims

Where there are helminthes , autoimmunity is rare. The aim of the helminthes is to protect themselves via immunomodulation of the host immune network. We have constructed a bi-functional compound consists of phosporylcholine-tuftsin (TPC). The aim was to prove its immunomodulatory function in murine models of autoimmune diseases and in ex-vivo human models.

Methods

We introduced TPC to murine models of autoimmune diseases such as lupus NZBxW/F1 mice, collagen-induced-arthritis (CIA), dextransulfatsodiumsalt-(DSS)-induced-colitis, experimental-autoimmune-encephalomyelitis (EAE) and showed its cytokines production and Tregulatory profile. Ex-vivo using human peripheral-mononuclear-cells (PBMCs) or biopsies from patients with giant-cell-arteritis (GCA) and lupus were analyzed for cytokines production.

Results

TPC attenuated the clinical score of murine autoimmune models of lupus CIA, DSS-induced-colitis and EAE . TPC decreased significantly the secretion of inflammatory cytokines (TNFa, IL-1b, IL-6, IFNg) and enhanced production of anti-inflammatory IL-10, expanded T and B regulatory cells. Likewise, TPC had an equal effect as methylprednisolone in a mouse model of lupus, inhibiting disease development in established lupus. Furthermore, The immunomodulatory activity of TPC was proven also ex-vivo in lupus and GCA reducing the inflammatory cytokines production by patients PBMCs and in biopsies from GCA.

The bi-functional immunomodulatory activity of TPC was attributed to: a) The PC part which inhibited significantly TLR4 expression by HEKTM-mTLR4 cells, through NFkB expression; b) TPC shifts macrophage cells from pro-inflammatory macrophages M1 to anti-inflammatory M2-secreting IL-10 and induce Tregs through the neuropilin-1.

Conclusions

Our data propose the potential novel therapy to treat autoimmune condition.Our data propose the potential novel therapy to treat autoimmune condition.

Background and Aims

Improved anti-tumour responses under immune checkpoint inhibition (ICI) are associated with concomitant autoimmune disease development termed immune-related adverse events (irAEs), of which approximately 5% are rheumatic in nature. We have reviewed the literature to assess whether immunosuppression therapy of irAEs may negatively affect the patient's outcome.

Methods

Review of the literature

Results

Oncologists and other specialists vigorously treat irAEs in spite of the generally accepted beneficial effect of irAEs on tumour survival. Herein, we highlight mechanistic insights on how tumour responses and certain types of autoimmunity appear to be inextricably linked around CD8+ T-cell mediated responses and those strategies that interfere with such shared immunopathogenesis could impact survival. We discuss the possible circumstances in which intensive immunosuppressive therapy for irAEs that occur with ICIs might blunt anti-tumour immunity. We also discuss potential therapeutic strategies for emergent ICI related autoimmunity and propose some treatment considerations and research questions to minimize the impact of overzealous immunosuppression strategies on tumour responses. Thus, refraining from using powerful therapeutic armamentarium to treat irAEs, especially when these are not considered as life-threating might improve the prognosis of ICI therapy.

Conclusions

Permitting the controlled “fire burning” of an activated immune response to ultimately stall cancer progression and further improve long-term survival is a strategy, which merits consideration. Adopting the view that survival is better in cases with irAEs who receive corticosteroids compared to subjects who do not develop irAEs is potentially ignoring the further improved survival attainable by letting the immune fire continues to burn.

Background and Aims

Optineurin (OPTN) is an autophagy receptor with multiple properties and has been reported to act as a negative regulator of osteoclastogenesis in osteoclast precursors. Since RANKL expressed on synovial fibroblasts (SFs) plays a major role in osteoclastogenesis in rheumatoid arthritis (RA) joint, we aimed to explore the role of OPTN in SFs form RA patients (RASFs).

Methods

The expression of OPTN was analyzed in RASFs using RT-qPCR and western blot. Cell surface expression of RANKL was analyzed by flow cytometry. OPTN was downregulated in RASFs using siRNA. Monocytes were cocultured with OPTN-reduced RASFs and stained with Tartrate-Resistant Acid Phosphatase (TRAP) to evaluate osteoclast differentiation. Protein levels of IκBα and nuclear NF-κB1 were measured to evaluate NF-κB signaling.

Results

OPTN was upregulated by TNF-α or IFN-γ in RASFs at both mRNA and protein levels. Cell surface RANKL was significantly increased following treatment with TNF-α or IFN-γ and the effect was further pronounced in OPTN-reduced RASFs compared to control RASFs, while osteoprotegerin levels remained unchanged after OPTN knockdown. Monocytes cocultured with OPTN-reduced RASFs differentiated more into TRAP+ multinucleated cells compared to those cocultured with control RASFs. MMP3 and IL-6 were upregulated while GATA-3, CHST15 and HAS1 were downregulated in OPTN-reduced RASFs. IκBα degradation and nuclear NF-κB1 expression following TNF-α treatment was prolonged in OPTN-reduced RASFs.

Conclusions

OPTN plays a protective role in RA with its upregulation when immersing with pro-inflammatory cytokines. Absence of OPTN might worsen RA by generating joint destructive state including increased RANKL expression on RASFs and subsequent osteoclast differentiation.

Background and Aims

Idiopathic CD4 lymphopenia (ICL) is a heterogenous condition of unknown etiology defined by persistent low CD4 counts (<300 cells/µL), after excluding any infection or condition known to cause lymphopenia. Autoimmune diseases have been reported in ICL but it is unclear whether autoimmunity plays a role in pathogenesis. We aimed to investigate the prevalence and potential pathogenicity of autoantibodies in ICL.

Methods

We evaluated 72 patients with ICL and healthy controls (HC) of similar age and sex. Autoantibodies (IgG and IgM) were measured by a protoarray against 124 know targets. The ability of sera to bind lymphocytes was tested by flow cytometry. ADCC and CDC experiments were performed to evaluate function (cytotoxicity) of autoantibodies.

Results

ICL patient sera tested positive for a large number of IgG and IgM autoantibodies at >2-fold level (p<0.0004) compared to HC independent of autoimmune disease status and exhibited higher autoreactivity to many targets across the human proteome. 31% sera had IgG antibodies (mostly IgG1 and/or IgG4) and 29% had IgM that remained stable over time and could bind healthy control T lymphocytes. Functionally, plasma from 50% of patients with IgG1 or IgG3 autoantibodies induced ADCC against healthy T-lymphocytes. Sera from 20% of patients with anti-lymphocyte antibodies induced complement deposition on healthy T cells and 1/3 of these induced CDC. Complement deposition on T lymphocytes was observed in 14% of the patients directly ex vivo.

Conclusions

We report a high prevalence and pathogenicity of autoantibodies in ICL that may hinder recovery from lymphopenia and represent a potential therapeutic target.

Background and Aims

Systemic lupus erythematosus is an autoimmune syndrome characterized by the development of autoantibodies to a wide range of antigens. T cells have an important contribution in disease progression as being responsible for inflammatory cytokines secretion, B cell activation, and promoting amplification of inflammatory response. Annexin A1 is expressed by many cell types and binds to phospholipids in a Ca²⁺ dependent manner. Abnormal expression of annexin A1 was found on activated B/T cells in both murine and human autoimmunity suggesting its potential role as a therapeutic target.

The purpose of our study is to prove that it is possible to down-modulate the activity of autoreactive T and B cells by targeting them with monoclonal antibody against Annexin A1 in lupus-prone MRL/lpr mice.

Methods

Groups of lupus-prone MRL/lpr mice were treated with an anti-annexin A1 monoclonal antibody and the disease activity and survival of the animals were monitored. ELISA and ELISpot assays, RT-PCR, cell proliferation assay, flow cytometry, histological and immunofluorescence kidney analyses were used to determine the levels of cytokines, anti-dsDNA antibodies and kidney injuries.

Results

Administration of anti-annexin A1 monoclonal antibody resulted in suppression of IgG anti-dsDNA antibody production and of proteinuria, modulation of cytokine production, improved kidney histology, decreased disease activity and prolonged survival compared to the control group.

Conclusions

The anti-Annexin A1 antibody therapy targets over-activated autoreactive cells. It has a beneficial effect on earlier stage of lupus development and by using such a therapy it is possible to down-regulate the activity of lupus-associated lymphocytes.

Background and Aims

Intravenous tocilizumab is a therapy for moderate-severe active thyroid eye disease. We decribe efficacy and safety of subcutaneous tocilizumab in a patient with thyroid eye disease.

Methods

A 41-year-old white, non smoker, woman disclosed a 3-year history of hyperthyroidism. Partial response of thyroid function after methimazole and carbimazole was observed. Bilateral eye changes developed including upper eyelid inflammation, limitation of extraocular motility with eye proptosis, with important impact in her quality of life. The CAS was 4 on a scale of 7. Laboratory tests revealed free T4 2.4 pmol/L, low thyroid-stiumulating hormone (0.01 mIU/L), high anti-TSH-receptor antibodies (26.8 IU/L) and high serum IL-6 levels (14.84 ng/L, n.v. 0.00-6.40). IL2-R levels (556 U/mL) and regulatory CD4+CD25+CD127+ percentages (2.2%) were normal. After discussing with the patient therapeutical options we decided administer subcutaneous tocilizumab 162 mg each 8-9 days for a total of 16 doses (8 mg/kg/month). Baseline safety evaluation (complete blood count, immunoglobulin, complement, lymphocyte subset levels, liver function testing and tuberculosis screening) was normal. Pneumococcal vaccine was administered.

Results

After the first four doses of subcutaneous tocilizumab a significant improvement of thyroid eye disease with reduction of proptosis, eye symptoms and extraocular motility was observed. Infusions were were tolerated. No adverse reactions were observed. Laboratory tests revealed low thyroid-stimulating hormone (<0.01 mIU/L), a decrease of anti-TSH-receptor antibodies (from 26.8 to 9 IU/L and normal liver function tests.

Conclusions

Subcutaneous tocilizumab was efficacious and safe in a patient with thyroid eye disease. The potential role of this therapy should be evaluated in a clinical trial.