| Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae(M.leprae),which selectively destroys the skin and peripheral nerves after infecting susceptible individuals,and can cause disability in the late stage.Psoriasis is a chronic inflammatory disease characterized by abnormal proliferation of keratinocytes,angiectasis and infiltration of immune cells.Epidemiological studies show that there are clear regional and ethnic differences in the prevalence of leprosy and psoriasis:At present,there are 200,000 new cases of leprosy in the world,mainly concentrated in developing countries in Asia,America and Africa such as India,Indonesia and Brazil;Psoriasis occurs in almost all regions of the world,with the highest prevalence in Europe,followed by Asia,but it’s rare in Africa.A study reported that only 20 out of 145,661 leprosy patients(0.014%)had psoriasis,significantly lower than that among healthy population.In terms of pathogenesis,leprosy is a complex disease caused by both genetic and environmental factors.Thl-and Th2-mediated immune responses are involved in the pathogenesis of tuberculoid leprosy(TT)and lepromatous leprosy(LL),respectively.Psoriasis is a chronic relapsing inflammatory skin disease caused by a combination of genetic and environmental factors.It is characterized by a significantly enhanced innate immunity and a highly activated Th1 and Th17 adaptive immune response,and such an immune state can effectively exert antibacterial mechanisms.Both diseases have a strong genetic background,and the association with human leukocyte antigen(HLA)has been widely reported.Genetic studies have found that HLA-Cw*06,HLA-DR B1*04,IL23R,IL12B genes are susceptibility genes for leprosy and psoriasis,and the susceptibility loci of some of these genes play opposite roles in the two diseases.Based on this,some scholars have proposed that there is mutual exclusion between leprosy and psoriasis,especially lepromatous leprosy and psoriasis.This is also consistent with the hygiene hypothesis,that is,a strong immune or inflammatory response can effectively resist the invasion of pathogenic bacteria,but increases the risk of occurrence of immune or inflammatory diseases.Even so,there are still a few rare cases of leprosy complicated with psoriasis reported.In this study,we collected a patient with borderline-lapromayous leprosy and psoriasis.The patient had generalized scaly erythema and mixed infiltrating papules and nodules.Mycobacterium leprae was detected not only in the skin lesion and blood of the two types of lesions,but also in normal skin and blood.Especially,M.leprae was still found under the skin lesions of psoriasis,and the DNA of M.leprae could be detected in peripheral blood,which was inconsistent with the hypothesis that leprosy and psoriasis were mutually exclusive.To elucidate the clinical and genetic features and the underlying immunological mechanisms of patients with leprosy and psoriasis.We first conducted a literature review,and analyzed all the cases of leprosy complicated with psoriasis reported at home and abroad,so as to better understand this rare complication.Meanwhile,we used our genome-wide association data to analyze the genetic features of the two diseases,and used single-cell sequencing technique to analyze the skin lesions and peripheral blood mononuclear cells(PBMCs)samples of leprosy patients with psoriasis,leprosy patients,psoriasis patients and healthy controls.Immunohistochemistry and single cell RNA sequencing were carried out to further explore the pathogenesis of leprosy complicated with psoriasis while clarifying the differences in immune status between leprosy and psoriasis patients.Part One:Analysis of clinical and genetic characteristics behind the rare coexistence of leprosy and psoriasisResearch background:Leprosy is a chronic infectious disease,while psoriasis is an inflammatory disease.The two are quite different diseases.Epidemiological data show that these two diseases are almost mutually exclusive,and only a few cases of their coexistence have been reported.This study analyzed the patients with leprosy complicated with psoriasis previously reported in order to preliminarily explore the causes of this unusual reverse coexistence.Objective:To elucidate the clinical and genetic features of patients with leprosy and psoriasis.We first conducted a literature review,and analyzed all the cases of leprosy complicated with psoriasis reported at home and abroad,so as to better understand this rare complication.Meanwhile,we used our genome-wide association data to analyze the genetic features of the two diseases.Ressearch Methods:1.The clinical data of 12 patients with leprosy complicated with psoriasis retrieved through Pubmed and CNKI were retrospectively analyzed.Statistical analysis of clinical characteristics,including the patient’s sex,age,residence,first-episode disease,type of leprosy complications,etc.2.We utilized existing leprosy GWAS data and queried the GWAS Catalog database(https://www.ebi.ac.uk/gwas/)for published leprosy and psoriasis GWAS data.We also searched articles on leprosy and psoriasis GWAS and candidate gene studies in PUBMED to explore the effect relationship of common loci in leprosy and psoriasis(identical effect,opposite effect,independent effect).Research Results:1.There were 2 cases(17%)of psoriasis complicated with tumor-type leprosy,3 cases(25%)of borderline paraneoplastic leprosy,1 case(8%)of borderline tuberculous leprosy,and 3 cases(25%)of uncertain leprosy type.Among the 5 patients in India,2 were borderline tuberculoid leprosy,1 borderline tuberculoid leprosy and 2 uncertain leprosy;Two of the four previously reported patients in China were complicated with tumor-type leprosy,one was complicated with borderline paraneoplastic leprosy,and one was borderline paratuberculous leprosy.2.1n our summary of GWAS data,10 loci on 5 genes were finally located and included for analysis.Among these 5 genes,rs76418789 loci on HLA-CW*06,HLA-DRB1*04 and IL23R genes showed opposite effects in leprosy and psoriasis.Three sites related to psoriasis(rs2546890,rs2082412 and rs3213094)and lepris-related site rs6871626 on IL12B gene were independent signals.The loci on the TYK2 gene could not determine the effect relationship between the two diseases due to insufficient evidence.Discussion:The clinical types of leprosy are spectrum-like,and there are three borderline leprosy types between the two ends:BL,BB,and BT.TT is mainly related to the immune response mediated by Th1CD4+T cells,which produce cytokines such as IL-2,IFN-y,and TNF-B to maintain the inflammatory response.While LL is mainly related to the immune response mediated by Th2CD4+cells,which release a series of cytokines,such as IL-4,IL-5,IL10,and IL-13.While BB’s immune response to pathogen invasion is unstable,resulting in various clinical manifestations.Enhanced innate immunity in psoriasis partially protects patients from infectious diseases,and Thl and Th17-mediated responses limit the proliferation of Mycobacterium leprae infection.A review of previous genetic studies of psoriasis and leprosy also found support for the genetic evidence associated with this hypothesis.Leprosy,especially LL,should occur less frequently with psoriasis.However,from the cases we summarized,we found that among the 12 concurrent cases,psoriasis complicated by neoplastic leprosy and BL leprosy accounted for the most,accounting for 42%.Besides,it is particularly noteworthy that among the 12 cases we summarized,there are 9 cases with definite types.Among these 9 patients,there were 6 cases of BL and BT,accounting for 67%,further confirming that the immune response of BB to the invasion of pathogenic bacteria is unstable,resulting in a variety of clinical manifestations.This result provides an immunological basis for BB leprosy complicated with psoriasis.A pleiotropic analysis of the common sites of leprosy and psoriasis has revealed that there are multiple common susceptible sites in leprosy and psoriasis that play a pleiotropic role:the effects appear to be identical in the molecular recognition phase of the initial infection and opposite in the subsequent immune response phase.The rs76418789 locus of HLA-CW*06,HLA-DRB1*04 and IL23R showed opposite effect in leprosy and psoriasis.Three sites related to psoriasis(rs2546890,rs2082412 and rs3213094)and lepris-related site rs6871626 on IL12B gene were independent signals.The loci on the TYK2 gene could not determine the effect relationship between the two diseases due to insufficient evidence.These results indicate that leprosy and psoriasis share a common genetic background with genetic diversity and complexity.These results provide a genetic basis for psoriasis associated with leprosy.Part Two:Analysis of immunological characteristics behind the rare coexistence of leprosy and psoriasisMethods:Collected the leprosy skin lesions,psoriasis skin lesions and normal tissue samples of one case of leprosy patients with psoriasis,leprosy skin lesions of 5 cases of leprosy patients,psoriasis skin lesions of 10 cases of psoriasis patients and 7 cases of healthy control skin samples,and carried out immunohistochemistry of LL37,FOXP3,IL-17,IL-22,IL-4,IL-9,etc.Collected peripheral blood samples from 1 patient with leprosy and psoriasis,3 patients with leprosy,3 patients with psoriasis and 3 healthy controls.Peripheral blood mononuclear cells(PBMC)were extracted,and CD45+immune cells were sorted by fluorescence activated cell sorting,and then single-cell RNA sequencing was performed.Results:1.The expression of the antimicrobial peptide LL37 in leprosy and psoriasis lesions of patients with leprosy and psoriasis is higher than that of patients with leprosy and psoriasis alone.2.The expression of IL-22,IL-4 and IL-9 in psoriasis lesions of leprosy patients with psoriasis was significantly higher than that of patients with psoriasis alone.3.In leprosy patients,the signal pathways related to infection and immunity are activated as a whole,including bacterial and viral infection-related pathways,phagosomes,lysosome-related signaling pathways and antigen-presenting signaling pathways.4.In patients with psoriasis,inflammatory immune-related signal pathways,such as FOXO signal pathway,MAPK signal pathway,NF,are activated as a whole-κB signal pathway,Th17 cell differentiation related signal pathway,IL-17 signal pathway,etc.5.In patients with leprosy and psoriasis,the signal pathways related to infection immunity and inflammation immunity are activated.6.There are significantly up-regulated genes NEAT1 and AAK1 in T cells and monocytes of leprosy patients with psoriasis,which are specific to leprosy and psoriasis,suggesting that they are closely related to the occurrence of leprosy complicated with psoriasis.Conclusion:1.In the process of leprosy infection,the increased secretion of the antimicrobial peptide LL37 plays an antibacterial role and further promotes the occurrence of psoriasis.2.IL-22,IL-4 and IL-9 cells play a certain role in the pathogenesis of leprosy with psoriasis.3.In patients with leprosy and psoriasis,the signal pathways related to infection and inflammatory immunity are activated,thus inducing the occurrence and development of disease in patients with leprosy and psoriasis.4.The high expression of NEAT1 and AAK1 may increase the incidence of infection while promoting the inflammatory reaction,thus promoting the occurrence of leprosy complicated with psoriasis. |
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