B1-cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation

Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis (LN) remain largely unclear. Here, we report a pathogenic role of anti-phosphatidylserine (PS) autoantibodies in the development of LN. Elevated serum PS-specific IgG levels were measured in model mice and SLE patients, especially in those with LN. PS-specific IgG accumulation was found in the kidney biopsies of LN patients. Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice. ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients. Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice, whereas depletion of B1a cells attenuated lupus progression. In culture, PS-specific B1a cells were significantly expanded upon treatment with chromatin components, while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells. Thus, our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development. Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.

Epigenetic regulation in B-cell maturation and its dysregulation in autoimmunity

B cells have a critical role in the initiation and acceleration of autoimmune diseases, especially those mediated byautoantibodies. In the peripheral lymphoid system, mature B cells are activated by self or/and foreign antigens andsignals from helper T cells for differentiating into either memory B cells or antibody-producing plasma cells.Accumulating evidence has shown that epigenetic regulations modulate somatic hypermutation and class switchDNA recombination during B-cell activation and differentiation. Any abnormalities in these complex regulatoryprocesses may contribute to aberrant antibody production, resulting in autoimmune pathogenesis such as systemiclupus erythematosus. Newly generated knowledge from advanced modern technologies such as next-generationsequencing, single-cell sequencing and DNA methylation sequencing has enabled us to better understand B-cellbiology and its role in autoimmune development. Thus this review aims to summarize current research progress inepigenetic modifications contributing to B-cell activation and differentiation, especially under autoimmuneconditions such as lupus, rheumatoid arthritis and type 1 diabetes.

The pathogenic role of innate lymphoid cells in autoimmune-related and inflammatory skin diseases

Innate lymphoid cells(ILCs),as an important component of the innate immune system,arise from a common lymphoid progenitor and are located in mucosal barriers and various tissues,including the intestine,skin,lung,and adipose tissue.ILCs are heterogeneous subsets of lymphocytes that have emerging roles in orchestrating immune response and contribute to maintain metabolic homeostasis and regulate tissue inflammation.Currently,more details about the pathways for the development and differentiation of ILCs have largely been elucidated,and cytokine secretion and downstream immune cell responses in disease pathogenesis have been reported.Recent research has identified that several distinct subsets of ILCs at skin barriers are involved in the complex regulatory network in local immunity,potentiating adaptive immunity and the inflammatory response.Of note,additional studies that assess the effects of ILCs are required to better define how ILCs regulate their development and functions and how they interact with other immune cells in autoimmune-related and inflammatory skin disorders.In this review,we will distill recent research progress in ILC biology,abnormal functions and potential pathogenic mechanisms in autoimmune-related skin diseases,including systemic lupus erythematosus(SLE),scleroderma and inflammatory diseases,as well as psoriasis and atopic dermatitis(AD),thereby giving a comprehensive review of the diversity and plasticity of ILCs and their unique functions in disease conditions with the aim to provide new insights into molecular diagnosis and suggest potential value in immunotherapy.

AIM2 deficiency in B cells ameliorates systemic lupus erythematosus by regulating Blimp-1-Bcl-6 axis-mediated B-cell differentiation

Absent in melanoma 2(AIM2)has been reported to be a component of inflammasomes in innate immune cells.Surprisingly,AIM2 is expressed by B cells,and higher AIM2 expression is observed in the B cells from lupus patients.To date,the inflammasome-indepe ndent functi on of AIM2 in B cells remai ns un clear.Here,we report in creased expressi on of AIM2 in human tonsil memory and germinal center(GC)B cells and in memory B cells and plasma cells from the circulation and skin lesions of lupus patients.Conditional knockout of AIM2 in B cells reduces the CD19^(+)B-cell frequency in lymph nodes and spleens,and dampens KLH-induced lgG1-antibody production.In a pristane-induced mouse model of lupus,AIM2 deficiency in B cells attenuates lupus symptoms and reduces the frequency of GC B cells,T follicular helper(Tfh)cells,plasmablast cells,and plasma cells.Furthermore,the loss of AIM2 in human B cells leads to the increased expression of Blimp-1 and reduces the expression of Bcl-6.However,the silendng of Blimp-1 and Bcl-6 has no significant effect on AIM2 expression,indicating that AIM2 might be the upstream regulator for Blimp-1 and Bcl-6.In addition,IL-10 is found to upregulate AIM2 expression via DNA demethylation.Together,our findings reveal that AIM2 is highly expressed in the B cells of lupus patients and promotes B-cell differentiation by modulating the Bcl-6-Blimp-1 axis,providing a novel target for SLE treatment.

Epigenetic regulation of B cells and its role in autoimmune pathogenesis

B cells play a pivotal role in the pathogenesis of autoimmune diseases.Although previous studies have shown many genetic polymorphisms associated with B-cell activation in patients with various autoimmune disorders,progress in epigenetic research has revealed new mechanisms leading to B-cell hyperactivation.Epigenetic mechanisms,including those involving histone modifications,DNA methylation,and noncoding RNAs,regulate B-cell responses,and their dysregulation can contribute to the pathogenesis of autoimmune diseases.Patients with autoimmune diseases show epigenetic alterations that lead to the initiation and perpetuation of autoimmune inflammation.Moreover,many clinical and animal model studies have shown the promising potential of epigenetic therapies for patients.In this review,we present an up-to-date overview of epigenetic mechanisms with a focus on their roles in regulating functional B-cell subsets.Furthermore,we discuss epigenetic dysregulation in B cells and highlight its contribution to the development of autoimmune diseases.Based on clinical and preclinical evidence,we discuss novel epigenetic biomarkers and therapies for patients with autoimmune disorders.