The etiology and underlying mechanism of Meniere's disease(MD)development are still unknown,although inflammation and autoimmunity have been implicated as underlying mechanisms.The human endolymphatic sac(ES)has b...The etiology and underlying mechanism of Meniere's disease(MD)development are still unknown,although inflammation and autoimmunity have been implicated as underlying mechanisms.The human endolymphatic sac(ES)has been reported to have innate and adaptive immune capacity in local immune reactions.In vivo demonstration of inflammation of the ES in patients with MD is missing in the literature.We report the case of a 47-year-old female patient diagnosed with unilateral MD with genetic variants and cytokine markers indicating inflammation and vascular congestion of the ES.Endolymphatic hydrops in the right cochlea(grade 2)and vestibulum(grade 3)were detected using MRI.She carried heterozygous variants in MEFV(c.442G>C),IRF8(c.1157G>T),ADA(c.445C>T),PEPD(c.151G>A),NBAS(c.4049T>C),CSF2RB(c.2222C>T),HPS6(c.277G>T),IL2RB(c.1109C>T),IL12RB1(c.1384G>T),IL17RC(c.260_271del GCAAGAGC TGGG),LIG1(c.746G>A),RAG1(c.650C>A),and SLX4(c.1258G>C,c.5072A>G).In the serum,the levels of granulocyte colony-stimulating factor(G-CSF),macrophage inflammatory protein 1a,and IL7 were significantly elevated,and the level of IL2Ra was reduced.Intratympanic administration of dexamethasone temporarily alleviated her hearing loss.Her vertigo was significantly relieved but remained slight after ES administration of corticosteroids.展开更多
Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations.Plaque psoriasis,which is the most common manifestation of psoriasis,is located on one end of the spectrum,domi...Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations.Plaque psoriasis,which is the most common manifestation of psoriasis,is located on one end of the spectrum,dominated by adaptive immune responses,whereas the rarer pustular psoriasis lies on the opposite end,dominated by innate and autoinflammatory immune responses.In recent years,genetic studies have identified six genetic variants that predispose to pustular psoriasis,and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis.In this review,we discuss the presentation and clinical subtypes of pustular psoriasis,contribution of genetic predisposing variants,critical role of the IL-36 family of cytokines in disease pathophysiology,and treatment perspectives for pustular psoriasis.We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.展开更多
Generalized pustular psoriasis(GPP)is a rare and life-threatening autoinflammatory skin disease characterized by recurrent and sudden episodes of widespread rashes with scattered sterile pustules.Clinical and genetic ...Generalized pustular psoriasis(GPP)is a rare and life-threatening autoinflammatory skin disease characterized by recurrent and sudden episodes of widespread rashes with scattered sterile pustules.Clinical and genetic evidence indicates that the pathogenesis of GPP both overlaps and is separate from psoriasis vulgaris(PV).Interleukin(IL)-23/IL-17 immune pathway is well known to play a critical role in the immunopathogenesis of PV,while the inflammation of GPP is more inclined to involve the innate immune response via the IL-1/IL-36-chemokine pathway.Mutations in IL36RN,CARD13,AP1S3,MPO,TNIP1,SERPINA3,and SERPINA1 have been shown to be associated with GPP,among which loss-of-function mutation in IL36RN is the dominant mutation with the highest prevalence.Recent studies have shown that interaction of the IL-36 pathway and the IL-23/IL-17 axis underlies the immunological disturbances of GPP,indicating that innate and adaptive immune responses intertwine in the pathogenesis of GPP.With this deeper understanding of the pathogenesis of GPP,treatment by biologics targeting the IL-1/IL-36 pathway appears to be promising.IL-1 inhibitors,anakinra,canakinumab,and gevokizumab have reportedly been effective in some cases.Spesolimab and imsidolimab,which are antibodies to the IL-36 receptor,are undergoing investigation in a phase II trial and showing promising results.In the present review,we illustrate the current understanding of the pathogenesis of GPP based on recent updates on the molecular genetics and immunopathology of GPP and review recent clinical trials and case reports of novel biologics in the treatment of GPP.展开更多
The SHP-1 protein encoded by the Ptpn6 gene has been extensively studied in hematopoietic cells in the context of inflammation.A point mutation in this gene(Ptpn6spin)causes spontaneous inflammation in mice,which has ...The SHP-1 protein encoded by the Ptpn6 gene has been extensively studied in hematopoietic cells in the context of inflammation.A point mutation in this gene(Ptpn6spin)causes spontaneous inflammation in mice,which has a striking similarity to neutrophilic dermatoses in humans.Recent findings highlighted the role of signaling adapters and kinases in promoting inflammation in Ptpn6spin mice;however,the underlying transcriptional regulation is poorly understood.Here,we report that SYK is important for driving neutrophil infiltration and initiating wound healing responses in Ptpn6spin mice.Moreover,we found that deletion of the transcription factor Ets2 in myeloid cells ameliorates cutaneous inflammatory disease in Ptpn6spin mice through transcriptional regulation of its target inflammatory genes.Furthermore,Ets-2 drives IL-1α-mediated inflammatory signaling in neutrophils of Ptpn6spin mice.Overall,in addition to its well-known role in driving inflammation in cancer,Ets-2 plays a major role in regulating IL-1α-driven Ptpn6spin-mediated neutrophilic dermatoses.展开更多
基金supported by the National Natural Science Foundation of China (81771006)
文摘The etiology and underlying mechanism of Meniere's disease(MD)development are still unknown,although inflammation and autoimmunity have been implicated as underlying mechanisms.The human endolymphatic sac(ES)has been reported to have innate and adaptive immune capacity in local immune reactions.In vivo demonstration of inflammation of the ES in patients with MD is missing in the literature.We report the case of a 47-year-old female patient diagnosed with unilateral MD with genetic variants and cytokine markers indicating inflammation and vascular congestion of the ES.Endolymphatic hydrops in the right cochlea(grade 2)and vestibulum(grade 3)were detected using MRI.She carried heterozygous variants in MEFV(c.442G>C),IRF8(c.1157G>T),ADA(c.445C>T),PEPD(c.151G>A),NBAS(c.4049T>C),CSF2RB(c.2222C>T),HPS6(c.277G>T),IL2RB(c.1109C>T),IL12RB1(c.1384G>T),IL17RC(c.260_271del GCAAGAGC TGGG),LIG1(c.746G>A),RAG1(c.650C>A),and SLX4(c.1258G>C,c.5072A>G).In the serum,the levels of granulocyte colony-stimulating factor(G-CSF),macrophage inflammatory protein 1a,and IL7 were significantly elevated,and the level of IL2Ra was reduced.Intratympanic administration of dexamethasone temporarily alleviated her hearing loss.Her vertigo was significantly relieved but remained slight after ES administration of corticosteroids.
基金This work was supported by the Babcock Endowment Fund(L.C.T.and J.E.G.),the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award numbers R01-AR060802(J.E.G.),P30-AR075043(J.E.G.),and K01-AR072129(L.C.T.),and the National Institute of Allergy and Infectious Diseases under award number R01-AR069071(J.E.G.),the A.Alfred Taubman Medical Research Institute(J.E.G.and J.M.K.),the National Psoriasis Foundation(J.E.G,N.L.W.,J.M.K.,E.M.,and L.C.T.),and the Parfait Emerging Scholar Award(J.M.K.).L.C.T.is supported by the Dermatology Foundation,the Arthritis National Research Foundation,and the National Psoriasis Foundation.
文摘Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations.Plaque psoriasis,which is the most common manifestation of psoriasis,is located on one end of the spectrum,dominated by adaptive immune responses,whereas the rarer pustular psoriasis lies on the opposite end,dominated by innate and autoinflammatory immune responses.In recent years,genetic studies have identified six genetic variants that predispose to pustular psoriasis,and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis.In this review,we discuss the presentation and clinical subtypes of pustular psoriasis,contribution of genetic predisposing variants,critical role of the IL-36 family of cytokines in disease pathophysiology,and treatment perspectives for pustular psoriasis.We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.
文摘Generalized pustular psoriasis(GPP)is a rare and life-threatening autoinflammatory skin disease characterized by recurrent and sudden episodes of widespread rashes with scattered sterile pustules.Clinical and genetic evidence indicates that the pathogenesis of GPP both overlaps and is separate from psoriasis vulgaris(PV).Interleukin(IL)-23/IL-17 immune pathway is well known to play a critical role in the immunopathogenesis of PV,while the inflammation of GPP is more inclined to involve the innate immune response via the IL-1/IL-36-chemokine pathway.Mutations in IL36RN,CARD13,AP1S3,MPO,TNIP1,SERPINA3,and SERPINA1 have been shown to be associated with GPP,among which loss-of-function mutation in IL36RN is the dominant mutation with the highest prevalence.Recent studies have shown that interaction of the IL-36 pathway and the IL-23/IL-17 axis underlies the immunological disturbances of GPP,indicating that innate and adaptive immune responses intertwine in the pathogenesis of GPP.With this deeper understanding of the pathogenesis of GPP,treatment by biologics targeting the IL-1/IL-36 pathway appears to be promising.IL-1 inhibitors,anakinra,canakinumab,and gevokizumab have reportedly been effective in some cases.Spesolimab and imsidolimab,which are antibodies to the IL-36 receptor,are undergoing investigation in a phase II trial and showing promising results.In the present review,we illustrate the current understanding of the pathogenesis of GPP based on recent updates on the molecular genetics and immunopathology of GPP and review recent clinical trials and case reports of novel biologics in the treatment of GPP.
基金supported by the K22 NIAID Career Transition Award Al 127836 to P.G.,the National Institutes of Health grants CAI 63507,AR056296,Al 124346 and AI101935 and by the American Lebanese Syrian Associated Charities to T.-D.K。
文摘The SHP-1 protein encoded by the Ptpn6 gene has been extensively studied in hematopoietic cells in the context of inflammation.A point mutation in this gene(Ptpn6spin)causes spontaneous inflammation in mice,which has a striking similarity to neutrophilic dermatoses in humans.Recent findings highlighted the role of signaling adapters and kinases in promoting inflammation in Ptpn6spin mice;however,the underlying transcriptional regulation is poorly understood.Here,we report that SYK is important for driving neutrophil infiltration and initiating wound healing responses in Ptpn6spin mice.Moreover,we found that deletion of the transcription factor Ets2 in myeloid cells ameliorates cutaneous inflammatory disease in Ptpn6spin mice through transcriptional regulation of its target inflammatory genes.Furthermore,Ets-2 drives IL-1α-mediated inflammatory signaling in neutrophils of Ptpn6spin mice.Overall,in addition to its well-known role in driving inflammation in cancer,Ets-2 plays a major role in regulating IL-1α-driven Ptpn6spin-mediated neutrophilic dermatoses.
