Sequential erythema nodosum leprosum and reversal reaction with similar lesional cytokine mRNA patterns in a borderline leprosy patient
ABSTRACT We compare the clinical and histological data with the immunological status of a borderline leprosy patient who experienced an erythema nodosum leprosum (ENL) reaction followed by a reversal reaction (RR) after 12 weeks of anti-inflammatory treatment (pentoxifylline, PTX, 1200 mg daily). Skin biopsies, serum and blood samples were collected sequentially during the reactional episodes. At the outset of RR, the patient's lymphocytes secreted interferon (IFN) -gamma and there was a positive lymphoproliferative test in response to Mycobacterium leprae, which had been absent during ENL. The lepromin reaction reversed from negative (0 mm) at diagnosis, to positive (3 mm) 3 months after the development of RR. Tumour necrosis factor (TNF) -alpha levels in the serum decreased after 1 week of treatment and increased slightly thereafter. The immunohistochemical data for ENL showed a diffuse dermal and hypodermal infiltrate composed of mononuclear cells and neutrophils, while RR was characterized by an epithelioid granulomatous infiltrate with a marked presence of gammadelta T cells. Reverse transcription-polymerase chain reaction showed a mixed cytokine profile characterized by the expression of TNF-alpha, IFN-gamma, interleukin (IL) -6, IL-10 and IL-12 mRNA in the skin, which persisted throughout the development of ENL and RR lesions. IL-4 mRNA, first detected after 7 days of PTX treatment, was still present during RR. The results suggest the emergence of an initial Th0-like cytokine profile in ENL, typical of a state of immunoactivation, before conditions optimal for the appearance of an antigen-specific cell-mediated immune response and gammadelta T-cell migration are created.
SourceAvailable from: Mayara Garcia de Mattos Barbosa[Show abstract] [Hide abstract]
ABSTRACT: Type 1 reaction (T1R) or reversal reaction is the leading cause of physical disabilities and deformities in leprosy. Leprosy patients, even after being considered cured and released from treatment, may suffer from reactional episodes for long periods of time. Early diagnosis is a great challenge for effectively treating and managing T1R. There is an urgent need to identify the most significant biomarkers to prevent recurrent T1R and to differentiate late T1R from relapse. T1R continues to be treated with corticosteroids and complications due to iatrogenic treatment remain frequent. This review aims to provide a framework from which to approach the great challenges that still persist in T1R management and debate key issues in order to reduce the distance between basic research and the clinic.Expert Review of Clinical Immunology 02/2015; 11(3):1-17. DOI:10.1586/1744666X.2015.1012501 · 3.34 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Type-1 (T1R) and Type-2 (T2R) leprosy reactions (LR), which affect up to 50% of leprosy patients, are aggressive inflammatory episodes of sudden onset and highly variable incidence across populations. LR are often diagnosed concurrently with leprosy, but more frequently occur several months after treatment onset. It is not uncommon for leprosy patients to develop recurring reactional episodes; however, they rarely undergo both types of LR. Today, LR are the main cause of permanent disabilities associated with leprosy and represent a major challenge in the clinical management of leprosy patients. Although progress has been made in understanding the immunopathology of LR, the factors that cause a leprosy patient to suffer from LR are largely unknown. Given the impact that ethnic background has on the risk of developing LR, host genetic factors have long been suspected of contributing to LR. Indeed, polymorphisms in seven genes [Toll-like receptors (TLR)1, TLR2, nucleotide-binding oligomerisation domain containing 2, vitamin D receptor, natural resistance-associated macrophage protein 1, C4B and interleukin-6] have been found to be associated with one or more LR outcomes. The identification of host genetic markers with predictive value for LR would have a major impact on nerve damage control in leprosy. In this review, we present the recent advances achieved through genetic studies of LR.Memórias do Instituto Oswaldo Cruz 12/2012; 107:132-142. DOI:10.1590/S0074-02762012000900020 · 1.57 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Leprosy, a chronic disease initiated by Mycobacterium leprae, is often complicated by acute inflammatory reactions. Although such episodes occur in at least 50 % of all leprosy patients and may cause irreversible nerve damage, no laboratory tests are available for early diagnosis or prediction of reactions. Since immune- and genetic host factors are critical in leprosy reactions, we hypothesize that identification of host-derived biomarkers correlated to leprosy reactions can provide the basis for new tests to facilitate timely diagnosis and treatment thereby helping to prevent tissue damage. The longitudinal host response of a leprosy patient, who was affected by a type 1 reaction (T1R) after MDT-treatment, was studied in unprecedented detail, measuring cellular and humoral immunity and gene expression profiles to identify biomarkers specific for T1R. Cytokine analysis in response to M. leprae revealed increased production of IFN-γ, IP-10, CXCL9, IL-17A and VEGF at diagnosis of T1R compared to before T1R, whereas a simultaneous decrease in IL-10 and G-CSF was observed at T1R. Cytokines shifts coincided with a reduction in known regulatory CD39(+)CCL4(+) and CD25(high) T-cell subsets. Moreover, RNA expression profiles revealed that IFN-induced genes, (V)EGF, and genes associated with cytotoxic T-cell responses (GNLY, GZMA/B, PRF1) were upregulated during T1R, whereas expression of T-cell regulation-associated genes were decreased. These data show that increased inflammation, vasculoneogenesis and cytotoxicity, perturbed T-cell regulation as well as IFN-induced genes play an important role in T1R and provide potential T1R-specific host biomarkers.Journal of Clinical Immunology 12/2013; DOI:10.1007/s10875-013-9979-x · 2.65 Impact Factor