Publications by Year: 2023

PURPOSE OF REVIEW: Lupus nephritis is associated with significant mortality and morbidity. We lack effective therapeutics and biomarkers mostly because of our limited understanding of its complex pathogenesis. We aim to present an overview of the recent advances in the field to gain a deeper understanding of the underlying cellular and molecular mechanisms involved in lupus nephritis pathogenesis. RECENT FINDINGS: Recent studies have identified distinct roles for each resident kidney cell in the pathogenesis of lupus nephritis. Podocytes share many elements of innate and adaptive immune cells and they can present antigens and participate in the formation of crescents in coordination with parietal epithelial cells. Mesangial cells produce pro-inflammatory cytokines and secrete extracellular matrix contributing to glomerular fibrosis. Tubular epithelial cells modulate the milieu of the interstitium to promote T cell infiltration and formation of tertiary lymphoid organs. Modulation of specific genes in kidney resident cells can ward off the effectors of the autoimmune response including autoantibodies, cytokines and immune cells. SUMMARY: The development of lupus nephritis is multifactorial involving genetic susceptibility, environmental triggers and systemic inflammation. However, the role of resident kidney cells in the development of lupus nephritis is becoming more defined and distinct. More recent studies point to the restoration of kidney resident cell function using cell targeted approaches to prevent and treat lupus nephritis.

Inhibitory immune receptors set thresholds for immune cell activation, and their deficiency predisposes a person to autoimmune responses. However, the agonists of inhibitory immune receptors remain largely unknown, representing untapped sources of treatments for autoimmune diseases. Here, we show that V-set and transmembrane domain-containing 1 (VSTM1) is an inhibitory receptor and that its binding by the competent ligand soluble galectin-1 (Gal1) is essential for maintaining neutrophil viability mediated by downregulated reactive oxygen species production. However, in patients with systemic lupus erythematosus (SLE), circulating Gal1 is oxidized and cannot be recognized by VSTM1, leading to increased intracellular reactive oxygen species levels and reduced neutrophil viability. Dysregulated neutrophil function or death contributes significantly to the pathogenesis of SLE by providing danger molecules and autoantigens that drive the production of inflammatory cytokines and the activation of autoreactive lymphocytes. Interestingly, serum levels of glutathione, an antioxidant able to convert oxidized Gal1 to its reduced form, were negatively correlated with SLE disease activity. Taken together, our findings reveal failed inhibitory Gal1/VSTM1 pathway activation in patients with SLE and provide important insights for the development of effective targeted therapies.

Immune therapeutics holds great promise in the treatment of type 1 diabetes (T1D). Nonetheless, their progress is hampered by limited efficacy, equipoise, or issues of safety. To address this, a novel and specific nanodelivery platform for T1D that targets high endothelial venules (HEVs) presented in the pancreatic lymph nodes (PLNs) and pancreas is developed. Data indicate that the pancreata of nonobese diabetic (NOD) mice and patients with T1D are unique in their expression of newly formed HEVs. Anti-CD3 mAb is encapsulated in poly(lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles (NPs), the surfaces of which are conjugated with MECA79 mAb that recognizes HEVs. Targeted delivery of these NPs improves accumulation of anti-CD3 mAb in both the PLNs and pancreata of NOD mice. Treatment of hyperglycemic NOD mice with MECA79-anti-CD3-NPs results in significant reversal of T1D compared to those that are untreated, treated with empty NPs, or provided free anti-CD3. This effect is associated with a significant reduction of T effector cell populations in the PLNs and a decreased production of pro-inflammatory cytokine in the mice treated with MECA79-anti-CD3-NPs. In summary, HEV-targeted therapeutics may be used as a means by which immune therapeutics can be delivered to PLNs and pancreata to suppress autoimmune diabetes effectively.

Patients with systemic lupus erythematosus experience high rates of infections. The use of immunosuppressive drugs to treat the disease, along with the fact that both the innate and adaptive branches of the immune system are compromised, account for the development of infections. In this communication, we briefly discuss the aberrant function of the immune system in patients with systemic lupus erythematosus and review the occurrence of infections that have been reported in clinical trials conducted to develop new therapeutics. Understanding the immune dysfunction in patients with systemic lupus erythematosus and the appearance of infections while trying to control the disease using immunosuppressive or immunomodulatory drugs should help limit infections and mitigate the associated morbidity and mortality.

OBJECTIVE: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA. METHODS: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively. RESULTS: CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors. CONCLUSION: Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis.

Kidney diseases represent a major public health problem, affecting millions of people worldwide. Moreover, the treatment of kidney diseases is burdened by the problematic effects of conventional drug delivery, such as systemic drug toxicity, rapid drug clearance, and the absence of precise targeting of the kidney. Although the use of nanotechnology in medicine is in its early stage and lacks robust translational studies, nanomedicines have already shown great promise as novel drug-delivery systems for the treatment of kidney disease. On the basis of our current knowledge of renal anatomy and physiology, pathophysiology of kidney diseases, and physicochemical characteristics of nanoparticles, an expansive repertoire and wide use of nanomedicines could be developed for kidney diseases in the near future. Some limitations have slowed the transition of these agents from preclinical studies to clinical trials, however. In this review, we summarize the current knowledge on renal drug-delivery systems and recent advances in renal cell targeting; we also demonstrate their important potential as future paradigm-shifting therapies for kidney diseases.

Immune cell microenvironment plays a major role in the aberrant function of immune cells in systemic lupus erythematosus. Zeng and co-authors show that in human and murine lupus, splenic stromal cell-derived acetylcholine switches B cell metabolism to fatty acid oxidation and promotes B cell autoreactivity and disease development.

Autoimmune manifestations were reported in people infected with SARS-CoV-2. Repetitive exposure of mice to foreign antigen may lead to the onset of autoimmunity. We therefore investigated whether repetitive exposure to the SARS-CoV-2 spike protein could result in autoimmunity. To address this hypothesis, we repeatedly immunized C57Bl/6 mice with spike protein injected intraperitoneally. At the end of the immunization, mice which received spike protein produced anti-spike IgG but none of them developed anti-dsDNA antibodies or proteinuria. In conclusion, repetitive immunization with SARS-CoV-2 spike protein does not induce autoimmunity in the present mice model. Albeit reassuring, these results need to be confirmed by large epidemiological study evaluating the incidence of autoimmune diseases in individuals with repetitive SARS-CoV-2 antigen exposure.

Immune-mediated inflammatory diseases (IMIDs) are characterized by excessive and uncontrolled inflammation and thrombosis, both of which are responsible for organ damage, morbidity and death. Platelets have long been known for their role in primary haemostasis, but they are now also considered to be components of the immune system and to have a central role in the pathogenesis of IMIDs. In patients with IMIDs, platelets are activated by disease-specific factors, and their activation often reflects disease activity. Here we summarize the evidence showing that activated platelets have an active role in the pathogenesis and the progression of IMIDs. Activated platelets produce soluble factors and directly interact with immune cells, thereby promoting an inflammatory phenotype. Furthermore, platelets participate in tissue injury and promote abnormal tissue healing, leading to fibrosis. Targeting platelet activation and targeting the interaction of platelets with the immune system are novel and promising therapeutic strategies in IMIDs.