Introduction

Autoimmunity is the failure of an organism inrecognizing its own constituent parts and leading to an immune response againstits own molecules, cells and tissues. Diseases that results from such immuneresponses are called autoimmune disease. Systemic lupus erythematosus (SLE) isa complex autoimmune disorder characterized by the loss of tolerance toself-nuclear antigens, leading to pathogenic autoantibody formation, immunecomplex deposition, and multiple organ damage. Rheumatoidarthritis(RA) is an autoimmunediseasethat results in a chronic, systemicinflammatory disorderthat principally attacksflexible joints.The etiologyof the disease,as a combination of multiple genetic and environmentalfactors,is highly heterogeneous.Current research focuses includes cellular regulation ofimmune responses in autoimmune diseases;regulation of autoimmune -susceptible gene expressionsby epigenetic alterations as well as microRNAs; biomarkers with highsensitivity or specificity for disease risk prediction and prognosis; andspecific therapeutic strategies for autoimmune disease.

Our focus

1）The productionof autoimmune antibodies

DNAcontaining ICs could induce the activation and proliferation ofautoreactive B cells via BCR and TLR9 by activating NF-kB via both canonicaland noncanonical pathways.HMGB1 couldactivate the TLR2/MyD88/miR-155 pathway and contributes to plasmacyticdifferentiation of B cells. Both effects lead to increased anti-dsDNA Abproduction in patients with SLE.

2）Activation of immune system by auto-antigens

ALD-DNA triggered DNA sensors AIM2 and DAI in macrophage, leading to itsactivation and M2b polarization via NF-kB and IRF3 pathways.Notch1 signaling is also activated by ALD-DNAand facilitates macrophage M2b differentiation through PI3K/Akt/ERK and p38MAPK pathways .Application of SAP and MBL inhibits while GRN elevates the M2bpolarization of macrophage.

3）Identification of diagnostic and prognostic markers forautoimmune diseases.

In autoimmunity, aberrant glycosylation can be aneffective diagnostic and prognostic marker. Previous studieshave reported that altered N-glycosylation occurs in rheumatoid arthritis (RA),particularly the reduction in galactose residues in IgG. To further observe theN-glycans in RA disease, we apply comprehensive profiling approaches to findthe most significant glycosylation changes in RA. Our preliminary results willprovide a promising method both for studies of RA mechanisms and diagnosis.

Achievements and Significance

1. We generated the first inducible SLE animal modeltriggered by a physiological agent, activated lymphocyte-derived DNA (ALDDNA),in healthy mice. Unlike the spontaneous mouse models that allow forprobing of the genetic causes of disease, our model facilitated theinvestigation of the mechanisms involved in theonset and development of thedisease, as well aspotential therapies of SLE.

2. We found that HMGB1 was crucial for the induction ofanti-dsDNAAb in patients with SLE and ALD-DNA-induced mouse model, through theTLR2 and MyD88/miR-155 mediated pathway. TLR9 signaling was also involved inthe production of anti-dsDNA autoantibodiesin B cells.

3. We demonstrated that ALD-DNA inducedmacrophage activationand its M2b polarization in the SLE murine model, leading to autoimmuneresponses and tissue damages.This is mediated by DNA sensors AIM2 and DAI inmacrophage, via Notch1/PI3k/MAPK as well as NF-kB/IRF3 signal pathways.

4. We have showed that SAP andMBL supplement in vivo couldameliorateALD-DNA-induced lupus nephritis(LN) by inhibiting macrophage M2bpolarization, while GRN aggravatedLN via facilitating macrophage M2b phenotype.The results provided potential strategies for treatment of SLE.

5. We haveshowed comprehensive profiling approaches found that the most significantchange seen in RA was decreased levels of both mono-galactosyl bi-antennaryN-glycans and dual-galactosyl bi-antennary N-glycans. Our results showed therewas a higher expression level of beta galactosidase in RA serum than control.Furthermore, we discovered that there may exist some immonogloblins specificfor redundant agalactosylated N-glycans.