C5a/C5aR1 mediates IMQ-induced psoriasiform skin inflammation by promoting IL-17A production from γδ-T cells.

Psoriasis is a chronic relapsing inflammatory skin disease, affecting up to 3% of the global population. Accumulating evidence suggests that the complement system is involved in its pathogenesis. Our previous study revealed that the C5a/C5aR1 pathway is crucial for disease development. However, the underlying mechanisms remain largely unknown. To explore potential mechanisms, psoriatic skin lesions and histological changes were assessed following imiquimod (IMQ) cream treatment. Inflammatory cytokine expression was tested by real-time RT-PCR. Immunohistochemistry and flow cytometry were used to identify inflammatory cell infiltration and interleukin (IL-17A) IL-17A expression. A C5aR1 antagonist (C5aR1a) and PI3K inhibitor (wortmannin) were used for blocking experiments (both in vivo and in vitro) to explore the mechanism. C5a/C5aR1-pathway inhibition significantly attenuated psoriasis-like skin lesions with decreased epidermal hyperplasia, downregulated type 17-related inflammatory gene expression, and reduced IL-17A-producing γδ-T cell responses. Mechanistically, C5a/C5aR1 promoted the latter phenotype via PI3K-Akt signaling. Consistently, C5aR1 deficiency clearly ameliorated IMQ-induced chronic psoriasiform dermatitis, with a significant decrease in IL-17A expression. Finally, blocking C5aR1 signaling further decreased psoriasiform skin inflammation in IL-17-deficient mice. Results suggest that C5a/C5aR1 mediates experimental psoriasis and skin inflammation by upregulating IL-17A expression from γδ-T cells. Blocking C5a/C5aR1/IL-17A axis is expected to be a promising strategy for psoriasis treatment.

Use of etanercept to treat rheumatoid arthritis in an HIV-positive patient: a case-based review.

Rheumatoid arthritis (RA) is a relatively common autoimmune disease that is associated with progressive disability and systemic complications, with a relatively high socioeconomic burden. The treatment of RA has been revolutionized by the use of biological drugs, such as anti-tumor necrosis factor (TNF) agents. A wide spectrum of RA disease severity has been reported among patients with human immunodeficiency virus (HIV) infection. Yet, only a few cases using anti-TNF therapy have been described in this clinical population. Therefore, the aim of our case-based review was to describe the successful use of etanercept in a 38-year-old female patient with RA concomitant with HIV infection, who had been resistant to the first-line anti-rheumatic therapies. As per routine care guidelines, the patient was screened for hepatitis virus infection, latent tuberculosis, and other infectious conditions, prior to the initiation of etanercept treatment. CD4 cell count, HIV viral load, and adverse effects were closely monitored during the treatment. The HIV infection remained stable with etanercept treatment, without the need for anti-retrovirus agents. No adverse effects and serious infections were identified during the treatment. Therefore, anti-TNF therapy is a viable alternative for the treatment of RA in patients with HIV, who do not respond to conventional anti-rheumatic therapies. The relationship between TNF-α and HIV infection, as well as cautionary guidelines regarding the utilization of anti-TNF therapy in this clinical population, is discussed.

Tuberculosis-associated hemophagocytic lymphohistiocytosis misdiagnosed as systemic lupus erythematosus: A case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with rapid progression and high mortality. HLH occurs mostly due to infection, malignant tumors, and immune disorders. Among infections that cause HLH, viral infections, especially Epstein-Barr virus infections, are common, whereas tuberculosis is rare. Tuberculosis-associated HLH has a wide range of serological and clinical manifestations that are similar to those of systemic lupus erythematosus (SLE). CASE SUMMARY: This study describes a case of tuberculosis-associated HLH misdiagnosed as SLE because of antinuclear antibody (ANA), Smith (Sm) antibody and lupus anticoagulant positivity; leukopenia; thrombocytopenia; pleural effusion; decreased C3, quantitatively increased 24 h urinary protein and fever. The patient was initially treated with glucocorticoids, which resulted in peripheral blood cytopenia and symptom recurrence. Then, caseating granulomas and hemophagocytosis were observed in her bone marrow. She was successfully treated with conventional category 1 antituberculous drugs. In addition, we reviewed the literature on tuberculosis-associated HLH documented in PubMed, including all full-text articles published in English from December 2009 to December 2019, and summarized the key points, including the epidemiology, clinical manifestations, diagnosis, and treatment of tuberculosis-associated HLH and the differences of the present case from previous reports. CONCLUSION: Tuberculosis should be considered in patients with fever or respiratory symptoms. Antituberculous drugs are important for treating tuberculosis-associated HLH.

Response to belimumab in thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus: a case-based review.

Thrombotic thrombocytopenic purpura (TTP), a life-threatening syndrome characterized by acute microangiopathic hemolytic anemia, thrombocytopenia, and visceral ischemia, can be classified as congenital TTP (inherited due to a mutation in ADAMTS13) and acquired TTP. The acquired TTP is further classified as idiopathic and secondary TTP. Systemic lupus erythematosus (SLE) is regarded as one of the most common causes of secondary TTP (SLE-TTP). In contrast to patients with idiopathic TTP, some patients with SLE-TTP, especially those diagnosed with refractory TTP, are resistant to plasma exchange and high-dose corticosteroids and usually require second-line drugs, including newly developed biologicals. Belimumab, a B-lymphocyte stimulator-specific inhibitor, was the first approved new therapy for SLE in the past 50 years. Only two cases of SLE-TTP using belimumab have been reported; however, detailed information has not been made available. Herein, we describe a 28-year-old female patient who presented with palm petechiae, strong tawny urine, and yellow stained skin and sclera, and was diagnosed with SLE-TTP supported by high anti-ANA titers; positive anti-SSA/SM; pleural effusion; decreased platelet count, hemoglobin, and complement C3/C4 counts; increased lactate dehydrogenase level, along with increased schistocytes; and a significant deficiency of ADAMTS13 activity. Belimumab (10 mg/kg) was administered after six plasma exchanges. Good efficiency and outcomes without any adverse events, SLE, or TTP relapse were observed during 12 months of follow-up. Therefore, belimumab is a promising choice for SLE-TTP management. In addition, we provide a focused review of the existing literature on the pathogenesis, diagnosis, and therapeutic strategies for SLE-TTP.

LIGHT deficiency attenuates acute kidney disease development in an in vivo experimental renal ischemia and reperfusion injury model.

Ischemia-reperfusion (I/R), a leading risk factor of acute kidney injury (AKI), is associated with high mortality and risk of progression to chronic kidney disease. However, the molecular mechanism of I/R-AKI remains not fully understood, which hinders its efficient clinical treatment. In this study, we observed that LIGHT deficiency remarkably attenuated I/R-AKI, as evidenced by rescued renal function, ameliorated tubular cell apoptosis, and alleviated inflammatory responses. Consistently, blocking LIGHT signaling with its soluble receptor fusion proteins (HVEM-IgG-Fc or LTßR-IgG-Fc) improved I/R renal dysfunction. RNA-sequencing and corresponding results indicated that LIGHT promoted oxidative stress and inflammation triggered by ischemic injury. Moreover, LIGHT signaling augmented ischemic stress-induced mitochondrial dysfunction characterized by an imbalance in mitochondrial fission and fusion, decreased mtDNA copies, impaired mitophagy, and increased mitochondrial membrane potential (ΔΨm). Mechanistically, LIGHT promoted mitochondrial fission by enhancing Drp1 phosphorylation (Ser616) and its translocation to the mitochondria. In conclusion, these results suggest that LIGHT-HVEM/LTßR signaling is critical for the I/R-AKI pathogenesis and it is further confirmed to be related to the increase in I/R-induced oxidative stress and mitochondria dysfunction, which may be the underlying mechanism of LIGHT signaling-mediated I/R-AKI.

Complement component 3 prevents imiquimod-induced psoriatic skin inflammation by inhibiting apoptosis in mice.

Complement component 3 (C3), a pivotal molecule in the complement system, is an essential immune mediator in various diseases, including psoriasis. However, the mechanistic role of C3 in psoriasis pathology and development remains elusive. Here, we showed that C3 deficiency dramatically augmented imiquimod-induced psoriasis-like skin inflammation, characterized by greater epidermal hyperplasia, inflammatory cell infiltration, and inflammatory gene expression than those in wild-type counterparts. In addition, C3 deficiency promoted imiquimod-induced skin cell apoptosis and supported greater proportions of IFN-γ+ T cells in the inflamed tissues. Accordingly, C3 supplement in the C3 deficient mice reduced skin inflammation and cells apoptosis. Moreover, blocking apoptosis with Z-VAD-FMK, a broad caspase inhibitor, markedly attenuated imiquimod-induced psoriasis-like skin inflammation and IFN-γ+ T cell responses in C3-deficient mice. Collectively, our results suggest that C3 prevents imiquimod-induced psoriasis-like skin inflammation by inhibiting apoptosis.

C5a/C5aR1 Pathway Is Critical for the Pathogenesis of Psoriasis.

Psoriasis is one of the most common chronic inflammatory skin diseases, affecting ~2% of the population. The lack of characterization of the pathogenesis of psoriasis has hindered efficient clinical treatment of the disease. In our study, we observed that expression of complement component 5a receptor 1(C5aR1) was significantly increased in skin lesions of both imiquimod (IMQ) and IL23-induced psoriatic mice and patients with psoriasis. C5aR1 deficiency or treatment with C5a receptor 1 antagonist (C5aR1a) in mice significantly attenuated psoriasis-like skin lesions and expression of inflammatory cytokines and chemokines. Moreover, C5aR1 deficiency significantly decreased IMQ-induced infiltration of plasmacytoid dendritic cells (pDCs), monocytes and neutrophils in psoriatic skin lesions and functions of pDCs, evidenced by the remarkable reduction in the IMQ-induced production of interferon-α (IFN-α) and tumor necrosis factor α (TNF-α), and FMS-like tyrosine kinase 3 ligand (FLT3L)-dependent pDCs differentiation. Accordingly, in vitro treatment with recombinant C5a accelerated pDCs migration and the differentiation of bone marrow cells into pDCs. Furthermore, biopsies of psoriatic patients showed a dramatic increase of C5aR1+ pDCs infiltration in psoriatic skin lesions, compared to healthy subjects. Our results provide direct evidence that C5a/C5aR1 signaling plays a critical role in the pathogenesis of psoriasis. Inhibition of C5a/C5aR1 pathway is expected to be beneficial in the treatment of patients with psoriasis.

Complement component 3 deficiency prolongs MHC-II disparate skin allograft survival by increasing the CD4(+) CD25(+) regulatory T cells population.

Recent reports suggest that complement system contributes to allograft rejection. However, its underlying mechanism is poorly understood. Herein, we investigate the role of complement component 3 (C3) in a single MHC-II molecule mismatched murine model of allograft rejection using C3 deficient mice (C3(-/-)) as skin graft donors or recipients. Compared with C3(+/+) B6 allografts, C3(-/-) B6 grafts dramatically prolonged survival in MHC-II molecule mismatched H-2(bm12) B6 recipients, indicating that C3 plays a critical role in allograft rejection. Compared with C3(+/+) allografts, both Th17 cell infiltration and Th1/Th17 associated cytokine mRNA levels were clearly reduced in C3(-/-) allografts. Moreover, C3(-/-) allografts caused attenuated Th1/Th17 responses, but increased CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cell expression markedly in local intragraft and H-2(bm12) recipients. Depletion of Treg cells by anti-CD25 monoclonal antibody (mAb) negated the survival advantages conferred by C3 deficiency. Our results indicate for the first time that C3 deficiency can prolong MHC-II molecule mismatched skin allograft survival, which is further confirmed to be associated with increased CD4(+) CD25(+) Treg cell population expansion and attenuated Th1/Th17 response.