Emerging Biomarkers and Therapeutic Strategies for Refractory Bullous Pemphigoid

Zhou, Tong; Peng, Bin; Geng, Shuang

doi:10.3389/fimmu.2021.718073

Cited by 8 publications

(7 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These regimens are associated with a high number of relapses and considerable adverse effects and are, in part, responsible for the increased mortality in BP (38)(39)(40). As such, there is a high medical need for safer and more effective treatment options for this fragile patient population (41,42). Among the innovative treatment concepts, including inhibitors of IL-4R, IL-5R, IL-17, FcRn, and eotaxin, specifically targeting complement activation appears to be an attractive approach based on the data obtained in various mouse models of BP (16,(43)(44)(45)(46)(47).…”

Section: Introductionmentioning

confidence: 99%

Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients

et al. 2022

View full text Add to dashboard Cite

Bullous pemphigoid (BP), the by far most frequent autoimmune subepidermal blistering disorder (AIBD), is characterized by the deposition of autoantibodies against BP180 (type XVII collagen; Col17) and BP230 as well as complement components at the dermal-epidermal junction (DEJ). The mechanisms of complement activation in BP patients, including the generation of C5a and regulation of its two cognate C5aRs, i.e., C5aR1 and C5aR2, are incompletely understood. In this study, transcriptome analysis of perilesional and non-lesional skin biopsies of BP patients compared to site-, age-, and sex-matched controls showed an upregulated expression of C5AR1, C5AR2, CR1, and C3AR1 and other complement-associated genes in perilesional BP skin. Of note, increased expressions of C5AR2 and C3AR1 were also observed in non-lesional BP skin. Subsequently, double immunofluorescence (IF) staining revealed T cells and macrophages as the dominant cellular sources of C5aR1 in early lesions of BP patients, while C5aR2 mainly expressed on mast cells and eosinophils. In addition, systemic levels of various complement factors and associated molecules were measured in BP patients and controls. Significantly higher plasma levels of C3a, CD55, and mannose-binding lectin-pathway activity were found in BP patients compared to controls. Finally, the functional relevance of C5aR1 and C5aR2 in BP was explored by two in vitro assays. Specific inhibition of C5aR1, resulted in significantly reduced migration of human neutrophils toward the chemoattractant C5a, whereas stimulation of C5aR2 showed no effect. In contrast, the selective targeting of C5aR1 and/or C5aR2 had no effect on the release of reactive oxygen species (ROS) from Col17-anti-Col17 IgG immune complex-stimulated human leukocytes. Collectively, this study delineates a complex landscape of activated complement receptors, complement factors, and related molecules in early BP skin lesions. Our results corroborate findings in mouse models of pemphigoid diseases that the C5a/C5aR1 axis is pivotal for attracting inflammatory cells to the skin and substantiate our understanding of the C5a/C5aR1 axis in human BP. The broad expression of C5aRs on multiple cell types critical for BP pathogenesis call for clinical studies targeting this axis in BP and other complement-mediated AIBDs.

show abstract

Section: Introductionmentioning

confidence: 99%

Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Reparixin, an allosteric CXCR1 and CXCR2 blocker, did not progress past a phase 3 trial as a drug adjuvant for pancreatic islet allotransplantation to treat type 1 diabetes, but it is still a candidate for ongoing trials for metastatic breast cancer and COVID-19 related acute lung injury ( 102 – 104 ). Alternatively, blocking chemokines may decrease autoinflammation, and an antibody drug bertilimumab targeting CCL11 was designed to prevent eosinophil-mediated autoimmune damage in bullous pemphigoid skin disorder and inflammatory bowel disease ( 105 , 106 ). Administration of anti-CXCL10 antibody was a promising strategy to limit cytotoxic T-cell liver damage, but clinical utility was hindered by continuous CXCL10 secretion and retention on endothelial cells ( 107 , 108 ).…”

Section: Ackr1 and Pathoinflammationmentioning

confidence: 99%

Prospects for targeting ACKR1 in cancer and other diseases

Crawford

Volkman

2023

Front. Immunol.

View full text Add to dashboard Cite

The chemokine network is comprised of a family of signal proteins that encode messages for cells displaying chemokine G-protein coupled receptors (GPCRs). The diversity of effects on cellular functions, particularly directed migration of different cell types to sites of inflammation, is enabled by different combinations of chemokines activating signal transduction cascades on cells displaying a combination of receptors. These signals can contribute to autoimmune disease or be hijacked in cancer to stimulate cancer progression and metastatic migration. Thus far, three chemokine receptor-targeting drugs have been approved for clinical use: Maraviroc for HIV, Plerixafor for hematopoietic stem cell mobilization, and Mogalizumab for cutaneous T-cell lymphoma. Numerous compounds have been developed to inhibit specific chemokine GPCRs, but the complexity of the chemokine network has precluded more widespread clinical implementation, particularly as anti-neoplastic and anti-metastatic agents. Drugs that block a single signaling axis may be rendered ineffective or cause adverse reactions because each chemokine and receptor often have multiple context-specific functions. The chemokine network is tightly regulated at multiple levels, including by atypical chemokine receptors (ACKRs) that control chemokine gradients independently of G-proteins. ACKRs have numerous functions linked to chemokine immobilization, movement through and within cells, and recruitment of alternate effectors like β-arrestins. Atypical chemokine receptor 1 (ACKR1), previously known as the Duffy antigen receptor for chemokines (DARC), is a key regulator that binds chemokines involved in inflammatory responses and cancer proliferation, angiogenesis, and metastasis. Understanding more about ACKR1 in different diseases and populations may contribute to the development of therapeutic strategies targeting the chemokine network.

show abstract

“…These treatments notably result in debilitating side effects, with significant morbidity/mortality in the elderly patients. The most effective adjuvant agents for refractory cases include mycophenolate mofetil, the combination of tetracycline and niacinamide, azathioprine, methotrexate, dapsone, and biologics such as rituximab, omalizumab, and dupilumab [ 19 , 20 , 21 ]. First-line combination therapy with rituximab and corticosteroids significantly improves complete remission rates along with reducing the cumulative dose of steroids without increasing the rate of complications [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…The most effective adjuvant agents for refractory cases include mycophenolate mofetil, the combination of tetracycline and niacinamide, azathioprine, methotrexate, dapsone, and biologics such as rituximab, omalizumab, and dupilumab [ 19 , 20 , 21 ]. First-line combination therapy with rituximab and corticosteroids significantly improves complete remission rates along with reducing the cumulative dose of steroids without increasing the rate of complications [ 21 ]. Intravenous immunoglobin (IVIG), mainly comprised of IgG1 and IgG2, provides an alternative, safe and effective treatment for treatment-resistant BP patients.…”

Section: Introductionmentioning

confidence: 99%

A Review of the Immunologic Pathways Involved in Bullous Pemphigoid and Novel Therapeutic Targets

Afarideh

Borucki

Werth

2022

JCM

View full text Add to dashboard Cite

Bullous pemphigoid (BP) is a rare, chronic antibody-mediated autoimmune blistering disease primarily affecting the elderly, with an age of onset over 60. Current treatment options are limited and involve the use of corticosteroids and immunosuppressants, but their long-term use is associated with significant morbidity and mortality. In Japan, human intravenous immunoglobin is approved for the treatment of corticosteroid-refractory BP. However, no treatment option is approved by the Food and Drug Administration for the management of BP. Therefore, developing effective therapies free of debilitating side effects is imperative. In this review, we summarize the main immunologic pathways involved in the pathogenesis of BP, with an emphasis on the role of eosinophils, immunoglobulins, cytokines such as the interleukin (IL)-4 and IL-5, and complements. We further discuss the latest advances with novel therapeutic targets tested for the management of BP. Ongoing efforts are needed to run well-designed controlled trials and test the efficacy and safety of investigational drugs while providing much-needed access to these medications for refractory patients who will not otherwise be able to afford them as off-label prescriptions.

show abstract

Emerging Biomarkers and Therapeutic Strategies for Refractory Bullous Pemphigoid

Cited by 8 publications

References 116 publications

Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients

Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients

Prospects for targeting ACKR1 in cancer and other diseases

A Review of the Immunologic Pathways Involved in Bullous Pemphigoid and Novel Therapeutic Targets

Contact Info

Product

Resources

About