Cathy Yunjia Zhao

TLR4 Activation Promotes Podocyte Injury and Interstitial Fibrosis in Diabetic Nephropathy

Toll like receptor (TLR) 4 has been reported to promote inflammation in diabetic nephropathy. However the role of TLR4 in the complicated pathophysiology of diabetic nephropathy is not understood. In this study, we report elevated expression of TLR4, its endogenous ligands and downstream cytokines, chemokines and fibrogenic genes in diabetic nephropathy in WT mice with streptozotocin (STZ) diabetes. Subsequently, we demonstrated that TLR4−/− mice were protected against the development of diabetic nephropathy, exhibiting less albuminuria, inflammation, glomerular hypertrophy and hypercellularity, podocyte and tubular injury as compared to diabetic wild-type controls. Marked reductions in interstitial collagen deposition, myofibroblast activation (α-SMA) and expression of fibrogenic genes (TGF-β and fibronectin) were also evident in TLR4 deficient mice. Consistent with our in vivo results, high glucose directly promoted TLR4 activation in podocytes and tubular epithelial cells in vitro, resulting in NF-κB activation and consequent inflammatory and fibrogenic responses. Our data indicate that TLR4 activation may promote inflammation, podocyte and tubular epithelial cell injury and interstitial fibrosis, suggesting TLR4 is a potential therapeutic target for diabetic nephropathy.

Absence of MyD88 Signaling Induces Donor-Specific Kidney Allograft Tolerance

Toll-like receptors (TLRs) play a fundamental role in innate immunity and provide a link between innate and adaptive responses to an allograft; however, whether the development of acute and chronic allograft rejection requires TLR signaling is unknown. Here, we studied TLR signaling in a fully MHC-mismatched, life-sustaining murine model of kidney allograft rejection. Mice deficient in the TLR adaptor protein MyD88 developed donor antigen-specific tolerance, which protected them from both acute and chronic allograft rejection and increased their survival after transplantation compared with wild-type controls. Administration of an anti-CD25 antibody to MyD88-deficient recipients depleted CD4(+)CD25(+)FoxP3(+) cells and broke tolerance. In addition, defective development of Th17 immune responses to alloantigen both in vitro and in vivo occurred, resulting in an increased ratio of Tregs to Th17 effectors. Thus, MyD88 deficiency was associated with an altered balance of Tregs over Th17 cells, promoting tolerance instead of rejection. This study provides evidence that targeting innate immunity may be a clinically relevant strategy to facilitate transplantation tolerance.

Preconditioning with recombinant high-mobility group box 1 protein protects the kidney against ischemia–reperfusion injury in mice

A preconditioning effect occurs when exposure to a nonharmful quantity of a mediator of injury provides protection against injury upon subsequent reexposure. High-mobility group box 1 (HMGB1) protein, an endogenous ligand for Toll-like receptor (TLR) 4, is a TLR4-dependent mediator of kidney ischemia-reperfusion injury. Here we determined whether preconditioning with recombinant HMGB1 can block kidney ischemia-reperfusion injury, whether this effect is TLR4 dependent and, if so, how preconditioning downregulates TLR signaling. Wild-type mice pretreated with rHMGB1 before ischemia were protected against kidney ischemia-reperfusion injury, indicated by lower serum creatinine, less tubular damage, less tubulointerstitial neutrophil and macrophage infiltration, and less tubular epithelial cell apoptosis versus control mice. Gene expression of TLR-downstream cytokines and chemokines in ischemia-reperfusion injury kidney were also significantly reduced. While TLR4 and TLR2 knockout mice were protected against kidney ischemia-reperfusion injury, HMGB1 preconditioning provided additional protection to TLR2 but not TLR4 knockout mice. The protective effect of rHMGB1 preconditioning involved Siglec-G upregulation, a negative regulator of HMGB1-mediated TLR4 pathway activation. Thus, preconditioning with rHMGB1 affords significant protection from TLR4-dependent kidney ischemia-reperfusion injury, indicating therapeutic potential.

PD‐1 inhibitor‐associated lichenoid inflammation with incidental suprabasilar acantholysis or vesiculation—Report of 4 cases

Immune checkpoint agents targeting programmed cell death‐1 protein (PD1) or cytotoxic T‐lymphocyte‐associated protein‐4 (CTLA‐4) receptors are increasingly utilized in treatment of advanced malignancies. However, these immunotherapies are commonly associated with idiosyncratic cutaneous adverse reactions. Thus, recognition and awareness of these reactions are necessary.

Melanocytic lesion evolution patterns with targeted therapies and immunotherapies for advanced metastatic melanoma: An observational study.

Various cutaneous side‐effects have been reported with anti‐melanoma systemic therapies. This study investigated the changes in melanocytic lesion pigmentation in patients on four different therapies.

Epidermal growth factor receptor inhibitor-induced papulopustular eruption successfully treated with low-dose oral dapsone

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Naevus lightening in melanoma patients under BRAF/MEK inhibitor combination therapy versus checkpoint immunotherapy: A histological and immunohistochemistry analysis

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/pcmr.12669 This article is protected by copyright. All rights reserved. DR. CATHY YUNJIA ZHAO (Orcid ID : 0000-0003-4722-9673)

Is it worthy to treat hidradenitis suppurativa with adalimumab in patients with melanoma and other debilitating systemic diseases? A series of clinical dilemmas

Hidradenitis suppurativa is a chronic skin disease with debilitating effects on quality of life. Studies have shown that patients with Hurley Stage II and III have a mean dermatology life quality index (DLQI) scores of 8.3–11.5 and 17.6–19.3 respectively. These are much worse than other chronic skin disease such as psoriasis and vitiligo, with mean DLQI scores of 9.0 and 5.3, respectively. Recently, the TNF-a inhibitor adalimumab has been approved in Australia for the management of severe treatment-resistant hidradenitis suppurativa, after showing significant efficacies by 12 weeks in two phase 3 trials. We present four cases that presented a clinical dilemma at the time of initiating or continuing adalimumab. Case 1 developed a melanoma in situ during therapy, Case 2 was treated for metastatic melanoma with immunotherapies, Case 3 has a diagnosis of Charcot–Marie–Tooth syndrome, and Case 4 has most likely developed drug-induced lupus (Table 1). Cases 1 and 2 illustrated the need to weigh the risks of melanoma against hidradenitis suppurativa. A recent meta-analysis on the risks of TNF-a inhibitors and malignancy development notes that TNF-a inhibitors could be associated with a slightly elevated risk of developing melanoma, with hazard ratios of 1.5 and 1.79. After discussions with the medical oncologist both patients decided to continue or start adalimumab and both patients are under regular 6-monthly full skin examinations with total body photography. Case 3 illustrated the need to weigh the risks of demyelination disorders against the burden of hidradenitis suppurativa. Studies have shown that TNF-a inhibitors may aggravate central nervous system demyelination by decreasing TNF receptor, especially in multiple sclerosis. However, evidence for Charcot–Marie–Tooth syndrome is limited. After discussions with the patient and his neurologist the patient decided to initiate adalimumab. After 6 months, some clinical worsening in his neurological condition was detected, but the patient decided to continue as the treatment had led to a significant improvement in his quality of life. The neurologist is monitoring the patient’s symptoms closely. Case 4 illustrated the need to balance the risks of adalimumab-induced lupus against the burden of hidradenitis suppurativa. In a large systematic review of over 7000 patients the hazard ratio for the development of lupuslike events in rheumatic patients on adalimumab compa-