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462 Elevated levels of IL–9 in serum of bullous pemphigoid: Possible association with the pathogenicity of bullous pemphigoid
Inflammation, Immunity and Infection | ABSTRACTS 460
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Assessment of the anti-inflammatory effects of fluorinated semi-synthetic phytocannabinoids in human in vitro inflammatory keratinocyte model systems J Mihaly1, N Miltner2, V Tubak3, R Mechoulam4, E Russo4 and T Bı´ro´1,4 1 Department of Immunology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary, 2 Department of Physiology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary, 3 Creative Laboratory Ltd., Szeged, Hungary and 4 Phytecs Ltd., Los Angeles, CA It is common wisdom in pharmacology that fluorination can significantly increase the efficacy of the active components in pharmaceuticals e actually, ca. 30% of the best-selling drugs worldwide contain fluorinated compounds. The laboratory of Prof. Mechoulam has recently synthesized a series of fluorinated derivatives of cannabidiol (CBD), the major non-psychoactive component of the plant Cannabis sativa. The goal of the current study was to assess the potential cutaneous anti-inflammatory actions of these compounds (F-CBDs). Effects of CBD and F-CBDs (HUF-101, HUF-103 and HU-559a) were investigated in seven, previously established in vitro human epidermal keratinocyte models (employing the immortalized HaCaT and HPV-KER keratinocyte cell lines) which mimic, as closely as possible, various human inflammatory skin conditions and diseases (e.g. microbial, UVB-induced, allergic, contact, and atopic dermatitis). Gene expression and protein release were assessed by RTqPCR and ELISA, respectively. As expected, expressions of certain pro-inflammatory cytokines (e.g. interleukin [IL]-1a, IL-1b, IL-6 and IL-8) were significantly down-regulated upon the administration of CBD and F-CBDs in most models. Of great importance, however, all FCBDs exhibited significantly higher efficacies in comparison to the non-fluorinated counterpart CBD, with the rank order of efficacy in the in vitro human epidermal keratinocyte models being HUF103 > HU559a > HU101. Our study provides the first evidence that FCBDs exert remarkable anti-inflammatory actions on human epidermal keratinocytes. These intriguing data invite further pre-clinical and clinical studies to exploit the therapeutic potential of certain F-CBDs in a various cutaneous inflammatory conditions.
Diversity of Propionibacterium acnes phylotypes according to body localization in acne patients versus healthy controls M Dagnelie1, S Corvec1,2, M Saint-Jean1,5, V Bourde`s4, J Nguyen1,3, A Khammari1,5 and B Dreno1,5 1 CIC, Inserm U1232, Nantes, France, 2 Bacteriology and Hygiene Unit, Biology Institute, Nantes University Hospital, Nantes, France, 3 Biostatistic Department, PIMES, Saint-Jacques Hospital, Nantes University Hospital, Nantes, France, 4 Evaluation Department - CUTIS - Galderma R&D, Biot (Sophia Antipolis), France and 5 Department of Dermatology, Nantes University Hospital, Nantes, France Propionibacterium acnes (P. acnes) is a major member of the human normal skin microbiota. Recent papers revealed P. acnes phylotypes diversity in skin diseases, especially in acne. We investigated P. acnes phylotypes and Single Locus Sequence-based types (SLST)/ Clonal Complexes (CCs) found in patients with severe back acne comparing with healthy controls, on face and back. Both groups were selected according to medical criteria and cutaneous microbiota was sampled on both locations. After culture, 68 P. acnes and four Propionibacterium sp. were isolated. Phylotypes, CCs and SLST-types were determined. First, in 71.4% of severe acne patients, P. acnes phylotypes were identical from face to back localization, whereas only 45.5% of healthy controls. Then, healthy group demonstrated mainly phylotypes IA1 (39.1%) and II (43.4%) compared to an extreme predominance of phylotype IA1 in acne group (84.4%), especially on back zone (95.6%). There was a higher diversity of phylotypes on face versus back zone, in both groups. For the first time, SLST molecular typing method shows A1 as the predominant type in severe back acne patients comparing with the large diversity observed in healthy controls. This study shows an important phylotype diversity loss in severe acne context, comparing with healthy controls. This work leads to a better understanding of anatomic distribution of dominant clones in acne, and may open the path to further investigate new treatment alternatives, including vaccination and skin probiotic systems.
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Elevated levels of ILe9 in serum of bullous pemphigoid: Possible association with the pathogenicity of bullous pemphigoid H Koga, K Teye, N Ishii and T Nakama Department of Dermatology, Kurume University School of Medicine, Kurume, Japan Interleukine9 (ILe9) is expressed by multiple T helper (Th) cell subsets, including Th2, Th9, Th17 and regulatory T (Treg) cells, natural killer T (NKT) cells and mast cells. IL-9 exerts various effects including promotion of mast cell growth and activation, proliferation of Th17, TGFb production and downregulation of IL-12 production in antigen-presenting cells (APCs). Some studies also showed that ILe9 was involved in IgE class switch. ILe9 is thought to have detrimental roles in allergy such as asthma, autoimmunity including experimental autoimmune encephalomyelitis, type I diabetes, and parasitic infection. Recently, anti-tumor effect of IL-9, especially to melanoma, has been reported. Bullous pemphigoid, one of the autoimmune bullous diseases is characterized immunologically by the presence of circulating autoantibodies directed to BP180 (type XVII collagen) and BP230, components of hemidesmosomes at the basement membrane zone of the skin. The binding of autoantibodies to target proteins at basement membrane zone is necessary for blister formation, while mast cell degranulation has a key role in inflammation of the disease. In addition, previous studies suggested that Th2, Th17 and their related cytokines, including, IL-4, IL-5, IL-13, IL-17 and IL21 appeared to be involved in BP pathogenicity. In this study, we conducted investigation into the impact of IL-9 in BP. We measured serum levels of IL-9 in patients with BP (n¼22) and healthy volunteers (n¼30). We found significantly higher levels of IL-9 in sera of patients with BP (7.8696.511 vs 1.9830.232, p<0.0001). We also compared serum levels of IL-9 in active disease and clinical remission stage of BP. Next, we evaluated infiltration of IL-9 positive cells in lesional skin as compared with skin from normal volunteers and atopic dermatitis and psoriasis patients. Furthermore we examined what kind of cells produce IL-9 in the skin. Our study suggests pathological relevance of IL-9 in BP and IL-9 may be therapeutic target in BP.
Absence of somatic mutations in linear localized scleroderma R Higgins1,3, A Smith1,2, R Wa¨lchli1,2, M Theiler1,2, L Weibel1,2 and A Navarini1,3 1 Department of Dermatology, Universita¨tsSpital Zu¨rich, Zu¨rich, Switzerland, 2 Department of Dermatology, Kinderspital Zu¨rich, Zu¨rich, Switzerland and 3 Department of Dermatology, University of Zurich, Zu¨rich, Switzerland Linear localized scleroderma (LLS) is a rare connective tissue disorder (2.7/100’000 per year). It is characterised by chronic inflammation and accumulation of collagen resulting in hardening and thickening of the lesion and eventually atrophy. The linear, sharply delimited lesions, can affect patients throughout the body and more rarely the face in sutypes en coup de sabre and Parry-Romberg syndrome leading to terrible disfigurement. The disease affects mostly children and is limited in treatment options. Little is understood about the condition in terms of genetic and clinical aetiology. It has been shown that LLS follows Blaschko’s lines, the patterns of cell migration and proliferation during embryological development. Multiple skin conditions like LLS have been shown to follow Blaschko’s lines several of which have been demonstrated to be caused by a de novo somatic mutation causing a cutaneous mosaicism. Here we tested the hypothesis that LLS is caused by a somatic genetic mutation. Blood and affected skin taken from 19 confirmed LLS patients was Whole Exome Sequenced. Somatic mutations were called using 3 somatic callers. All SNPs and indels were analysed and no rare and damaging mutation was found in common. 5 patients had damaging germline SNP mutations in PRSS3, a gene involved in metabolism and the immune system. No minor allelic frequency data is available for any of the PRSS3 mutations found so comparison with internal controls has shown 2 of 5 to be rare. 4 patients with similar lesions were chosen for deep sequencing (DP of >300). Somatic analysis of these samples revealed no causative mutation. CGH was performed on 3 patients to find large scale chromosomal aberrations. No rare aberrations were found in patients. A related work recently analysed three samples of LLS on the transcription level. No signal survived after correction for multiple testing. Taken together, our analysis revealed the absence of genetic mosaicism in LLS.
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Altered expression of Cartilage oligomeric matrix protein (COMP) in psoriasis R Bozo´1, E Sze´l1, E´ Hunyadi-Gulya´s2, Z Bata-Cso¨rgo¨1,3, L Keme´ny1,3 and G Groma1,3 1 Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary, 2 Institute of Biochemistry, Biological Research Center, Szeged, Hungary and 3 MTA-SZTE Dermatological Research Group, Szeged, Hungary In a large scale psoriatic proteomic approach where uninvolved, involved and healthy skin was compared the protein level of COMP was found to be altered in the uninvolved skin. Since the psoriatic uninvolved skin of patients is more sensitive to mechanical stress and COMP has a mechanoresponsive region in its promoter and can interact with several proteins proposed to influence inflammation and keratinocyte proliferation including a5b1 integrin (ITG) and fibronectin we aimed to characterize the observed difference further. In most, but not all examined psoriatic patients Western blot analysis confirmed the observed increase in uninvolved skin relative to controls (4 out of 6). Similarly, in the large majority of uninvolved samples (8 out of 10) immunofluorescent staining revieled a more even deposition of COMP in the papillary dermis that extended deeper into the dermis compared to healthy controls. In the involved skin COMP was found to be often detached, discontinues or nearly completely missing from the papillary dermis, while just below the papillary dermis COMP was detected in patches with uneven distribution. The keratinocyte proliferation of the psoriatic skin shows some similarities to wound healing and our results are well in line with a previous report indicating that in non-healing wounds the level of COMP is elevated while in healing wounds the amount of COMP is minimal. To investigate if COMP could potentially influence basal keratinocytes by direct interaction, COMP was co-stained with ITG b1. COMP to some extent colocalized with ITG b1 positive basal keratinocytes in all three skin types, but the joint occurrence of the two proteins was the most frequent in uninvolved, and the lowest in the involved skin. Therefore, we conclude that COMP may directly interact with basal keratinocytes and hypothesize that it may influence keratinocyte proliferation in psoriasis.
Identification of Atopic Dermatitis endotypes based on serum biomarker analysis J Thijs1,2, I Strickland3, C Bruijnzeel-Koomen1, S Nierkens2, B Giovanonne1,2, E Csomor3, B Sellman3, T Mustelin4, M Sleeman3, M de Bruin-Weller1, A Herath3, J Drylewicz2, R May3 and D Hijnen1,2 1 Dermatology, UMC Utrecht, Utrecht, Netherlands, 2 Laboratory of Translational Immunology, UMC Utrecht, Utrecht, Netherlands, 3 MedImmune, Cambridge, United Kingdom and 4 MedImmune, Gaithersburg, MD Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. It is however unclear whether this diversity also exists at a biological level. Our objective was to test the hypothesis that AD is heterogeneous at the biological level of inflammatory mediators. Serum from 193 moderate to severe adult AD patients (geomean) SASSAD of 22.3 and 39.1 respectively, and 30 non-AD healthy controls was analysed for 147 serum mediators, total IgE and 130 allergen specific IgEs. Population heterogeneity was assessed by principal component analysis (PCA) followed by unsupervised k-means cluster analysis of the principal components. AD patients showed pronounced evidence of inflammation compared to healthy controls. PCA of AD serum data revealed the presence of four AD patient clusters. Each cluster has a distinct profile of soluble mediators that together may indicate these clusters are driven by distinct underlying pathways, representing possible endotypes of AD. Cluster 1 had high SASSAD and BSA with the highest levels of PARC, TIMP1 and sCD14. Cluster 2 had low SASSAD with the lowest levels of IFN-g, TIMP-1 and VEGF. Cluster 3 had high SASSAD with the lowest levels of IFN-b, IL-1 and epithelial cytokines. Cluster 4 had low SASSAD but highest levels of inflammatory markers: IL-1, IL-4, IL-13 and TSLP. AD is a heterogeneous disease both clinically and biologically. Four distinct AD patient clusters have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents such as biologics.
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Assessment of the anti-inflammatory effects of fluorinated semi-synthetic phytocannabinoids in human in vitro inflammatory keratinocyte model systems J Mihaly1, N Miltner2, V Tubak3, R Mechoulam4, E Russo4 and T Bı´ro´1,4 1 Department of Immunology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary, 2 Department of Physiology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary, 3 Creative Laboratory Ltd., Szeged, Hungary and 4 Phytecs Ltd., Los Angeles, CA It is common wisdom in pharmacology that fluorination can significantly increase the efficacy of the active components in pharmaceuticals e actually, ca. 30% of the best-selling drugs worldwide contain fluorinated compounds. The laboratory of Prof. Mechoulam has recently synthesized a series of fluorinated derivatives of cannabidiol (CBD), the major non-psychoactive component of the plant Cannabis sativa. The goal of the current study was to assess the potential cutaneous anti-inflammatory actions of these compounds (F-CBDs). Effects of CBD and F-CBDs (HUF-101, HUF-103 and HU-559a) were investigated in seven, previously established in vitro human epidermal keratinocyte models (employing the immortalized HaCaT and HPV-KER keratinocyte cell lines) which mimic, as closely as possible, various human inflammatory skin conditions and diseases (e.g. microbial, UVB-induced, allergic, contact, and atopic dermatitis). Gene expression and protein release were assessed by RTqPCR and ELISA, respectively. As expected, expressions of certain pro-inflammatory cytokines (e.g. interleukin [IL]-1a, IL-1b, IL-6 and IL-8) were significantly down-regulated upon the administration of CBD and F-CBDs in most models. Of great importance, however, all FCBDs exhibited significantly higher efficacies in comparison to the non-fluorinated counterpart CBD, with the rank order of efficacy in the in vitro human epidermal keratinocyte models being HUF103 > HU559a > HU101. Our study provides the first evidence that FCBDs exert remarkable anti-inflammatory actions on human epidermal keratinocytes. These intriguing data invite further pre-clinical and clinical studies to exploit the therapeutic potential of certain F-CBDs in a various cutaneous inflammatory conditions.
Diversity of Propionibacterium acnes phylotypes according to body localization in acne patients versus healthy controls M Dagnelie1, S Corvec1,2, M Saint-Jean1,5, V Bourde`s4, J Nguyen1,3, A Khammari1,5 and B Dreno1,5 1 CIC, Inserm U1232, Nantes, France, 2 Bacteriology and Hygiene Unit, Biology Institute, Nantes University Hospital, Nantes, France, 3 Biostatistic Department, PIMES, Saint-Jacques Hospital, Nantes University Hospital, Nantes, France, 4 Evaluation Department - CUTIS - Galderma R&D, Biot (Sophia Antipolis), France and 5 Department of Dermatology, Nantes University Hospital, Nantes, France Propionibacterium acnes (P. acnes) is a major member of the human normal skin microbiota. Recent papers revealed P. acnes phylotypes diversity in skin diseases, especially in acne. We investigated P. acnes phylotypes and Single Locus Sequence-based types (SLST)/ Clonal Complexes (CCs) found in patients with severe back acne comparing with healthy controls, on face and back. Both groups were selected according to medical criteria and cutaneous microbiota was sampled on both locations. After culture, 68 P. acnes and four Propionibacterium sp. were isolated. Phylotypes, CCs and SLST-types were determined. First, in 71.4% of severe acne patients, P. acnes phylotypes were identical from face to back localization, whereas only 45.5% of healthy controls. Then, healthy group demonstrated mainly phylotypes IA1 (39.1%) and II (43.4%) compared to an extreme predominance of phylotype IA1 in acne group (84.4%), especially on back zone (95.6%). There was a higher diversity of phylotypes on face versus back zone, in both groups. For the first time, SLST molecular typing method shows A1 as the predominant type in severe back acne patients comparing with the large diversity observed in healthy controls. This study shows an important phylotype diversity loss in severe acne context, comparing with healthy controls. This work leads to a better understanding of anatomic distribution of dominant clones in acne, and may open the path to further investigate new treatment alternatives, including vaccination and skin probiotic systems.
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Elevated levels of ILe9 in serum of bullous pemphigoid: Possible association with the pathogenicity of bullous pemphigoid H Koga, K Teye, N Ishii and T Nakama Department of Dermatology, Kurume University School of Medicine, Kurume, Japan Interleukine9 (ILe9) is expressed by multiple T helper (Th) cell subsets, including Th2, Th9, Th17 and regulatory T (Treg) cells, natural killer T (NKT) cells and mast cells. IL-9 exerts various effects including promotion of mast cell growth and activation, proliferation of Th17, TGFb production and downregulation of IL-12 production in antigen-presenting cells (APCs). Some studies also showed that ILe9 was involved in IgE class switch. ILe9 is thought to have detrimental roles in allergy such as asthma, autoimmunity including experimental autoimmune encephalomyelitis, type I diabetes, and parasitic infection. Recently, anti-tumor effect of IL-9, especially to melanoma, has been reported. Bullous pemphigoid, one of the autoimmune bullous diseases is characterized immunologically by the presence of circulating autoantibodies directed to BP180 (type XVII collagen) and BP230, components of hemidesmosomes at the basement membrane zone of the skin. The binding of autoantibodies to target proteins at basement membrane zone is necessary for blister formation, while mast cell degranulation has a key role in inflammation of the disease. In addition, previous studies suggested that Th2, Th17 and their related cytokines, including, IL-4, IL-5, IL-13, IL-17 and IL21 appeared to be involved in BP pathogenicity. In this study, we conducted investigation into the impact of IL-9 in BP. We measured serum levels of IL-9 in patients with BP (n¼22) and healthy volunteers (n¼30). We found significantly higher levels of IL-9 in sera of patients with BP (7.8696.511 vs 1.9830.232, p<0.0001). We also compared serum levels of IL-9 in active disease and clinical remission stage of BP. Next, we evaluated infiltration of IL-9 positive cells in lesional skin as compared with skin from normal volunteers and atopic dermatitis and psoriasis patients. Furthermore we examined what kind of cells produce IL-9 in the skin. Our study suggests pathological relevance of IL-9 in BP and IL-9 may be therapeutic target in BP.
Absence of somatic mutations in linear localized scleroderma R Higgins1,3, A Smith1,2, R Wa¨lchli1,2, M Theiler1,2, L Weibel1,2 and A Navarini1,3 1 Department of Dermatology, Universita¨tsSpital Zu¨rich, Zu¨rich, Switzerland, 2 Department of Dermatology, Kinderspital Zu¨rich, Zu¨rich, Switzerland and 3 Department of Dermatology, University of Zurich, Zu¨rich, Switzerland Linear localized scleroderma (LLS) is a rare connective tissue disorder (2.7/100’000 per year). It is characterised by chronic inflammation and accumulation of collagen resulting in hardening and thickening of the lesion and eventually atrophy. The linear, sharply delimited lesions, can affect patients throughout the body and more rarely the face in sutypes en coup de sabre and Parry-Romberg syndrome leading to terrible disfigurement. The disease affects mostly children and is limited in treatment options. Little is understood about the condition in terms of genetic and clinical aetiology. It has been shown that LLS follows Blaschko’s lines, the patterns of cell migration and proliferation during embryological development. Multiple skin conditions like LLS have been shown to follow Blaschko’s lines several of which have been demonstrated to be caused by a de novo somatic mutation causing a cutaneous mosaicism. Here we tested the hypothesis that LLS is caused by a somatic genetic mutation. Blood and affected skin taken from 19 confirmed LLS patients was Whole Exome Sequenced. Somatic mutations were called using 3 somatic callers. All SNPs and indels were analysed and no rare and damaging mutation was found in common. 5 patients had damaging germline SNP mutations in PRSS3, a gene involved in metabolism and the immune system. No minor allelic frequency data is available for any of the PRSS3 mutations found so comparison with internal controls has shown 2 of 5 to be rare. 4 patients with similar lesions were chosen for deep sequencing (DP of >300). Somatic analysis of these samples revealed no causative mutation. CGH was performed on 3 patients to find large scale chromosomal aberrations. No rare aberrations were found in patients. A related work recently analysed three samples of LLS on the transcription level. No signal survived after correction for multiple testing. Taken together, our analysis revealed the absence of genetic mosaicism in LLS.
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Altered expression of Cartilage oligomeric matrix protein (COMP) in psoriasis R Bozo´1, E Sze´l1, E´ Hunyadi-Gulya´s2, Z Bata-Cso¨rgo¨1,3, L Keme´ny1,3 and G Groma1,3 1 Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary, 2 Institute of Biochemistry, Biological Research Center, Szeged, Hungary and 3 MTA-SZTE Dermatological Research Group, Szeged, Hungary In a large scale psoriatic proteomic approach where uninvolved, involved and healthy skin was compared the protein level of COMP was found to be altered in the uninvolved skin. Since the psoriatic uninvolved skin of patients is more sensitive to mechanical stress and COMP has a mechanoresponsive region in its promoter and can interact with several proteins proposed to influence inflammation and keratinocyte proliferation including a5b1 integrin (ITG) and fibronectin we aimed to characterize the observed difference further. In most, but not all examined psoriatic patients Western blot analysis confirmed the observed increase in uninvolved skin relative to controls (4 out of 6). Similarly, in the large majority of uninvolved samples (8 out of 10) immunofluorescent staining revieled a more even deposition of COMP in the papillary dermis that extended deeper into the dermis compared to healthy controls. In the involved skin COMP was found to be often detached, discontinues or nearly completely missing from the papillary dermis, while just below the papillary dermis COMP was detected in patches with uneven distribution. The keratinocyte proliferation of the psoriatic skin shows some similarities to wound healing and our results are well in line with a previous report indicating that in non-healing wounds the level of COMP is elevated while in healing wounds the amount of COMP is minimal. To investigate if COMP could potentially influence basal keratinocytes by direct interaction, COMP was co-stained with ITG b1. COMP to some extent colocalized with ITG b1 positive basal keratinocytes in all three skin types, but the joint occurrence of the two proteins was the most frequent in uninvolved, and the lowest in the involved skin. Therefore, we conclude that COMP may directly interact with basal keratinocytes and hypothesize that it may influence keratinocyte proliferation in psoriasis.
Identification of Atopic Dermatitis endotypes based on serum biomarker analysis J Thijs1,2, I Strickland3, C Bruijnzeel-Koomen1, S Nierkens2, B Giovanonne1,2, E Csomor3, B Sellman3, T Mustelin4, M Sleeman3, M de Bruin-Weller1, A Herath3, J Drylewicz2, R May3 and D Hijnen1,2 1 Dermatology, UMC Utrecht, Utrecht, Netherlands, 2 Laboratory of Translational Immunology, UMC Utrecht, Utrecht, Netherlands, 3 MedImmune, Cambridge, United Kingdom and 4 MedImmune, Gaithersburg, MD Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. It is however unclear whether this diversity also exists at a biological level. Our objective was to test the hypothesis that AD is heterogeneous at the biological level of inflammatory mediators. Serum from 193 moderate to severe adult AD patients (geomean) SASSAD of 22.3 and 39.1 respectively, and 30 non-AD healthy controls was analysed for 147 serum mediators, total IgE and 130 allergen specific IgEs. Population heterogeneity was assessed by principal component analysis (PCA) followed by unsupervised k-means cluster analysis of the principal components. AD patients showed pronounced evidence of inflammation compared to healthy controls. PCA of AD serum data revealed the presence of four AD patient clusters. Each cluster has a distinct profile of soluble mediators that together may indicate these clusters are driven by distinct underlying pathways, representing possible endotypes of AD. Cluster 1 had high SASSAD and BSA with the highest levels of PARC, TIMP1 and sCD14. Cluster 2 had low SASSAD with the lowest levels of IFN-g, TIMP-1 and VEGF. Cluster 3 had high SASSAD with the lowest levels of IFN-b, IL-1 and epithelial cytokines. Cluster 4 had low SASSAD but highest levels of inflammatory markers: IL-1, IL-4, IL-13 and TSLP. AD is a heterogeneous disease both clinically and biologically. Four distinct AD patient clusters have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents such as biologics.
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