Neutrophil extracellular traps contribute to the pathogenesis of leprosy type 2 reactions.

Up to 50% of patients with the multibacillary form of leprosy are expected to develop acute systemic inflammatory episodes known as type 2 reactions (T2R), thus aggravating their clinical status. Thalidomide rapidly improves T2R symptoms. But, due to its restricted use worldwide, novel alternative therapies are urgently needed. The T2R triggering mechanisms and immune-inflammatory pathways involved in its pathology remain ill defined. In a recent report, we defined the recognition of nucleic acids by TLR9 as a major innate immunity pathway that is activated during T2R. DNA recognition has been described as a major inflammatory pathway in several autoimmune diseases, and neutrophil DNA extracellular traps (NETs) have been shown to be a prime source of endogenous DNA. Considering that neutrophil abundance is a marked characteristic of T2R lesions, the objective of this study was to investigate NETs production in T2R patients based on the hypothesis that the excessive NETs formation would play a major role in T2R pathogenesis. Abundant NETs were found in T2R skin lesions, and increased spontaneous NETs formation was observed in T2R peripheral neutrophils. Both the M. leprae whole-cell sonicate and the CpG-Hlp complex, mimicking a mycobacterial TLR9 ligand, were able to induce NETs production in vitro. Moreover, TLR9 expression was shown to be higher in T2R neutrophils, suggesting that DNA recognition via TLR9 may be one of the pathways triggering this process during T2R. Finally, treatment of T2R patients with thalidomide for 7 consecutive days resulted in a decrease in all of the evaluated in vivo and ex vivo NETosis parameters. Altogether, our findings shed light on the pathogenesis of T2R, which, it is hoped, will contribute to the emergence of novel alternative therapies and the identification of prognostic reactional markers in the near future.

Increased CD5+ B-cells are associated with autoimmune phenomena in lepromatous leprosy patients.

BACKGROUND AND OBJECTIVE: Leprosy is a chronic slowly progressive infection caused by Mycobacterium leprae that primarily affects the skin and peripheral nerves. Lepromatous leprosy is characterized by absence of T-cell responses to M. leprae and advanced clinical disease. It is frequently associated with the presence of autoantibodies, which might be related to CD19+CD5+ and CD19+CD5- B lymphocyte percentages. Therefore, the aim of this study was to evaluate the percentages of CD19+CD5+ and CD19+CD5- B cell subsets as well as the total B cells in lepromatous leprosy patients. MATERIALS AND METHODS: Twenty lepromatous leprosy patients and ten healthy subjects served as control were included in this study. Venous blood samples were analyzed by flow cytometry to determine the B cell subsets and total B cell percentages. RESULTS: Compared to healthy controls, the percentages of CD19+CD5+ B cell subset and total B cells were found to be significantly higher in the patient group. While, the percentage of CD19+CD5- B cell subset was found to be higher in the patient group than the control without any significantly difference. Regarding the eye affection, the percentage of total B cells was observed to be significantly higher in affected patients compared to the non-affected group. CONCLUSION: The observed significant increases in CD19+CD5+ and total B cell percentages in patients with lepromatous leprosy suggests a possible role of these cells in the disorganized protective immune response as well as the development of eye complications in these patients.

M. paratuberculosis and Parkinson's disease--is this a trigger.

Genetic linkage studies and genome wide analysis have provided insights into complex medical diseases. Mycobacterium avium ss. paratuberculosis (MAP) causes Johne's disease, an important enteric inflammatory disease mostly studied in ruminant animals. MAP is also the putative cause of Crohn's disease. Moreover, MAP has been linked to other inflammatory diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis and multiple sclerosis. Genetic studies reveal an association between Parkinson's disease (PD), leprosy and Crohn's disease and since discovered, these findings have been considered "surprising". Autophagy and ubiquitin-proteosome systems are cellular systems that both fight intracellular pathogens (xenophagy) and maintain cellular protein quality control. PD is a common neurodegenerative disease that manifests clinically as a profound movement disorder. The recognized genetic defects of PD create disruption of cellular homeostasis that result in protein folding abnormalities of PD called Lewy bodies. Those same genetic defects are associated with susceptibility to intracellular pathogens, including mycobacteria. It is now understood that PD Lewy body pathology starts in the enteric nervous system and "spreads" to the brain in a retrograde fashion via the vagus nerve. This is the same process by which prions affect the brain. Lewy body pathology of the enteric nervous system predates the Lewy body pathology of the central nervous system (CNS) by years or even decades. This article proposes that genetic defects associated with PD also result in a permissive environment for MAP infection--ineffective xenophagy. It postulates that beginning as an enteric infection, MAP--via the vagus nerve--initiates a pathologic process that results in a targeted neuroinvasion of the CNS. The article proposes that MAP infection and resultant PD pathology are due, in the genetically at-risk and age dependant, to the consumptive exhaustion of the protein quality control systems.

Slow bacterial infections or autoimmunity?

In this article, Graham Rook and John Stanford propose that a group of idiopathic diseases that are often associated with a degree of autoimmunity and arthritis, including rheumatoid arthritis, inflammatory bowel disease, sarcoidosis and psoriasis, are caused by extremely slow-growing bacteria. They suggest that these diseases are one end of a continuous spectrum caused by related slow-growing genera, which ranges from rheumatoid arthritis, through Takayasu's arteritis and Whipple's disease, to reach the conventional mycobacterioses such as tuberculosis and leprosy.

The experimental inoculation with Mycobacterium leprae in autoimmune mice: results of MRL/lpr mice inoculated into the right hind foot (continued).

Using MRL/lpr, NOD and Crj:CD-1 (ICR) mice, inoculations of M. leprae were made into the right hind foot at a dose of 5.8 x 10(6) bacilli per foot in order to study the influence of the immunobiological characteristics of their mice on the growth of M. leprae. To summarize of the results, MRL/lpr mice showed the high susceptibility to M. leprae, while that of NOD mice were poor. In conclusion, the immunobiological characteristics of MRL/lpr, autoimmune mice bearing lpr gene had effect on the multiplication of M. leprae, this mouse is a suitable multibacillary model for the study of leprosy.