Project description:Leprosy is a disease caused by Mycobacterium leprae where the clinical spectrum correlates with the patient immune response. Erythema Nodosum Leprosum (ENL) is an immune-mediated inflammatory complication, which causes significant morbidity in affected leprosy patients. The underlying cause of ENL is not conclusively known. However, immune-complexes and cell-mediated immunity have been suggested in the pathogenesis of ENL. The aim of this study was to investigate the regulatory T-cells in patients with ENL. Forty-six untreated patients with ENL and 31 non-reactional lepromatous leprosy (LL) patient controls visiting ALERT Hospital, Ethiopia were enrolled to the study. Blood samples were obtained before, during and after prednisolone treatment of ENL cases. Peripheral blood mononuclear cells (PBMCs) were isolated and used for immunophenotyping of regulatory T-cells by flow cytometry. Five markers: CD3, CD4 or CD8, CD25, CD27 and FoxP3 were used to define CD4+ and CD8+ regulatory T-cells. Clinical and histopathological data were obtained as supplementary information. All patients had been followed for 28 weeks. Patients with ENL reactions had a lower percentage of CD4+ regulatory T-cells (1.7%) than LL patient controls (3.8%) at diagnosis of ENL before treatment. After treatment, the percentage of CD4+regulatory T-cells was not significantly different between the two groups. The percentage of CD8+ regulatory T-cells was not significantly different in ENL and LL controls before and after treatment. Furthermore, patients with ENL had higher percentage of CD4+ T-ells and CD4+/CD8+ T-cells ratio than LL patient controls before treatment. The expression of CD25 on CD4+ and CD8+ T-cells was not significantly different in ENL and LL controls suggesting that CD25 expression is not associated with ENL reactions while FoxP3 expression on CD4+ T-cells was significantly lower in patients with ENL than in LL controls. We also found that prednisolone treatment of patients with ENL reactions suppresses CD4+ T-cell but not CD8+ T-cell frequencies. Hence, ENL is associated with lower levels of T regulatory cells and higher CD4+/CD8+ T-cell ratio. We suggest that this loss of regulation is one of the causes of ENL.

Project description:BackgroundThe numbers of circulating regulatory T cells (Tregs) are increased in lepromatous leprosy (LL) but reduced in erythema nodosum leprosum (ENL), the inflammatory complication of LL. It is unclear whether the suppressive function of Tregs is intact in both these conditions.MethodsA longitudinal study recruited participants at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before and after 24 weeks of prednisolone treatment for ENL and multidrug therapy (MDT) for participants with LL. We evaluated the suppressive function of Tregs in the peripheral blood mononuclear cells (PBMCs) of participants with LL and ENL by analysis of TNFα, IFNγ and IL-10 responses to Mycobacterium leprae (M. leprae) stimulation before and after depletion of CD25+ cells.Results30 LL participants with ENL and 30 LL participants without ENL were recruited. The depletion of CD25+ cells from PBMCs was associated with enhanced TNFα and IFNγ responses to M. leprae stimulation before and after 24 weeks treatment of LL with MDT and of ENL with prednisolone. The addition of autologous CD25+ cells to CD25+ depleted PBMCs abolished these responses. In both non-reactional LL and ENL groups mitogen (PHA)-induced TNFα and IFNγ responses were not affected by depletion of CD25+ cells either before or after treatment. Depleting CD25+ cells did not affect the IL-10 response to M. leprae before and after 24 weeks of MDT in participants with LL. However, depletion of CD25+ cells was associated with an enhanced IL-10 response on stimulation with M. leprae in untreated participants with ENL and reduced IL-10 responses in treated individuals with ENL. The enhanced IL-10 in untreated ENL and the reduced IL-10 response in prednisolone treated individuals with ENL was abolished by addition of autologous CD25+ cells.ConclusionThe findings support the hypothesis that the impaired cell-mediated immune response in individuals with LL is M. leprae antigen specific and the unresponsiveness can be reversed by depleting CD25+ cells. Our results suggest that the suppressive function of Tregs in ENL is intact despite ENL being associated with reduced numbers of Tregs. The lack of difference in IL-10 response in control PBMCs and CD25+ depleted PBMCs in individuals with LL and the increased IL-10 response following the depletion of CD25+ cells in individuals with untreated ENL suggest that the mechanism of immune regulation by Tregs in leprosy appears independent of IL-10 or that other cells may be responsible for IL-10 production in leprosy. The present findings highlight mechanisms of T cell regulation in LL and ENL and provide insights into the control of peripheral immune tolerance, identifying Tregs as a potential therapeutic target.

Project description:BackgroundThere are no recent studies with a focus on the histopathology of erythema nodosum leprosum (ENL).ObjectivesTo describe the histopathological spectrum of ENL.Materials and methodsDigital records from the pathology department were searched, and 125 slides were included. The histopathologic findings were recorded using a pre-designed proforma.ResultsSeveral patterns were noted with the most common being a superficial and deep, perivascular and peri-appendageal, well-circumscribed dermal infiltrate that was seen in 70 (56.0%) biopsies. Other dermal patterns included a similar but loose infiltrate in 19 (15.2%) biopsies, diffuse dermal involvement in 9 (7.2%), top-heavy in 9 (7.2%), and bottom-heavy infiltrates in 12 (9.6%). Subcutaneous tissue was included in 107 biopsies. Extension of dermal infiltrates to the subcutis was noted in 71 (66.4%) biopsies and predominant involvement of the subcutis was noted in 6 (4.8%) biopsies, with lobular involvement in 60 (56.1%), septal involvement in 3 (2.8%), and septo-lobular involvement in 14 (13.1%). In 30 (28.0%) biopsies, the subcutaneous fat was uninvolved. The infiltrates contained neutrophils and foamy histiocytes in variable proportions, along with lymphocytes and plasma cells. Eosinophils were noted occasionally. Medium and/or small vessel vasculitis was noted in 11 (8.8%) biopsies. Fite-Faraco staining was available for 112 biopsies and revealed mainly fragmented and granular acid-fast bacilli (AFB) in 29 (25%) biopsies.LimitationsOur study had a retrospective design; we could not compare the lesional age and clinical characteristics of patients with the histological features.ConclusionENL is characterized by dermal infiltrates composed of foamy histiocytes and neutrophils in varying proportions arrayed in different dermal patterns. Extension of dermal infiltrates into the subcutis was frequent but absent in some. Predominant or exclusive involvement of the subcutis was rare. Vasculitis was noted in a small minority, while AFB were demonstrated in about a quarter of cases.

Project description:PurposeTo report a case of Polyarteritis Nodosa (PAN) presenting as bilateral episcleritis and interstitial keratitis along with erythema nodosum and atrial fibrillation and to review the ophthalmic literature on PAN with anterior segment findings.ObservationsA 35-year old man presented with a two-month history of bilateral episcleritis, skin lesions consistent with erythema nodosum, joint effusions and episodes of prolonged diarrhea and atrial fibrillation. Ophthalmic examination was significant for bilateral diffuse episcleral injection and nummular corneal stromal infiltrates. The patient underwent an extensive infectious and inflammatory work-up that was negative except for a very elevated erythrocyte sedimentation rate (123 mm/h, normal < 20 mm/h) and C-reactive protein (51 mg/L, normal < 5 mg/L). In order to rule out inflammatory bowel disease upper endoscopy and colonoscopy were performed. Biopsies of the gastrointestinal mucosa were positive for a small- and medium-vessel necrotizing vasculitis consistent with polyarteritis nodosa. Disease control was achieved with systemic prednisone and azathioprine. Upon self-tapering both medications the patient developed hearing loss and interstitial keratitis recurred, hence the diagnosis of Cogan's syndrome/PAN was made. Intravenous pulse steroids were administered with resolution of his symptoms. The patient continues to be on azathioprine without disease recurrence for 1.5 years. Α review of the ophthalmic literature on PAN with anterior segment findings revealed only 10 cases; of these, 6 had originally presented with ocular manifestations alone (scleritis, peripheral ulcerative keratitis, episcleritis, dacryoadenitis) and 4 of these 6 were lethal due to delay in diagnosis.Conclusion and importanceEarly diagnosis of PAN is crucial, as the five-year mortality rate is close to 90%; upon initiation of systemic immunosuppression the mortality rate drops to 20%. Though PAN manifestations in the anterior segment are rare, a high index of suspicion is warranted in cases of bilateral episcleritis and interstitial keratitis.

Project description:Erythema Nodosum Leprosum (ENL) is an immune reaction in leprosy that aggravates the patient´s clinical condition. ENL presents systemic symptoms of an acute infectious syndrome with high leukocytosis and intense malaise clinically similar to sepsis. The treatment of ENL patients requires immunosuppression and thus needs to be early and efficient to prevent both disabilities and permanent nerve damage. Some patients experience multiple episodes of ENL and prolonged use of immunosuppressive drugs may lead to serious adverse effects. Thalidomide treatment is extremely effective at ameliorating ENL symptoms. Several mechanisms have been proposed to explain the efficacy of thalidomide in ENL, including the inhibition of TNF production. Given its teratogenicity, thalidomide is prohibitive for women of childbearing age. A rational search for molecular targets during ENL episodes is essential to better understand the disease mechanisms involved, which may also lead to the discovery of new drugs and diagnostic tests. Previous studies have demonstrated that IFN-γ and GM-CSF, involved in the induction of CD64 expression, increase during ENL. The aim of the present study was to investigate CD64 expression during ENL and whether thalidomide treatment modulated its expression. Leprosy patients were allocated to one of five groups: (1) Lepromatous leprosy, (2) Borderline leprosy, (3) Reversal reaction, (4) ENL, and (5) ENL 7 days after thalidomide treatment. The present study demonstrated that CD64 mRNA and protein were expressed in ENL lesions and that thalidomide treatment reduced CD64 expression and neutrophil infiltrates-a hallmark of ENL. We also showed that ENL blood neutrophils exclusively expressed CD64 on the cell surface and that thalidomide diminished overall expression. Patient classification based on clinical symptoms found that severe ENL presented high levels of neutrophil CD64. Collectively, these data revealed that ENL neutrophils express CD64, presumably contributing to the immunopathogenesis of the disease.

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Lupus Erythematosus Tumidus Misdiagnosed as Erythema Nodosum from Coccidioidomycosis

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