The Functional State of the Complement System in Leprosy

Gomes, Gabriela I.; Junior, Edilbert Pellegrini Nahn; Santos, Rose K. R. G.; Silva, Wilmar D. da; Kipnis, Thereza Liberman

doi:10.4269/ajtmh.2008.78.605

Cited by 17 publications

(16 citation statements)

References 18 publications

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“…The increased levels of C4d in the patients supports activation of the lectin and/or classical pathway of complement, while elevated Bb supports a significant involvement of the alternative pathway in leprosy patients. Earlier studies had already suggested a role for the classical pathway of the complement system in leprosy across the spectrum by measuring the ability of circulating immune complexes isolated from sera of leprosy patients to activate complement, but none of these studies measured pathway-specific activation products [23,24,37].…”

Section: Discussionmentioning

confidence: 99%

“…In support of the involvement of the lectin pathway in MB leprosy patients, one study found that MBL serum levels were increased significantly in the LL form of leprosy compared to other leprosy types [23]. However, it should be noted that the association of MBL with leprosy pathophysiology is controversial, because some investigators found increased levels of MBL in the patients undergoing reaction.…”

Section: Discussionmentioning

confidence: 99%

“…Because nerve damage is prominent in reactional episodes, it is rational to speculate that complement activation and formation of TCC or MAC can be valuable in diagnosing leprosy patients without reaction from those with reactions. There have been only a few studies reported in the literature on the serology of complement activation in leprosy [20][21][22][23]. Previous serological studies showed (1) reduced complement hemolytic activity and reduced levels of C4 in LL patients, suggesting consumption of complement in the circulation via activation of the classical or lectin pathway [23,24]; (2) an increased C1q binding activity (the initiator of classical pathway activation) in LL patients with ENL reactions, suggesting involvement of the classical pathway in these patients, and increased C3d levels in 70% of patients with ENL and 18% of patients with uncomplicated LL.…”

Section: Introductionmentioning

confidence: 99%

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Complement activation in leprosy: a retrospective study shows elevated circulating terminal complement complex in reactional leprosy

Idrissi

Hakobyan

Ramaglia

et al. 2016

Clinical and Experimental Immunology

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SummaryMycobacterium leprae infection gives rise to the immunologically and histopathologically classified spectrum of leprosy. At present, several tools for the stratification of patients are based on acquired immunity markers. However, the role of innate immunity, particularly the complement system, is largely unexplored. The present retrospective study was undertaken to explore whether the systemic levels of complement activation components and regulators can stratify leprosy patients, particularly in reference to the reactional state of the disease. Serum samples from two cohorts were analysed. The cohort from Bangladesh included multi-bacillary (MB) patients with (n 5 12) or without (n 5 46) reaction (R) at intake and endemic controls (n 5 20). The cohort from Ethiopia included paucibacillary (PB) (n 5 7) and MB (n 5 23) patients without reaction and MB (n 5 15) patients with reaction. The results showed that the activation products terminal complement complex (TCC) (P 0Á01), C4d (P 0Á05) and iC3b (P 0Á05) were specifically elevated in Bangladeshi patients with reaction at intake compared to endemic controls. In addition, levels of the regulator clusterin (P 0Á001 without R; P < 0Á05 with R) were also elevated in MB patients, irrespective of a reaction. Similar analysis of the Ethiopian cohort confirmed that, irrespective of a reaction, serum TCC levels were increased significantly in patients with reactions compared to patients without reactions (P 0Á05). Our findings suggests that serum TCC levels may prove to be a valuable tool in diagnosing patients at risk of developing reactions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Complement activation in leprosy: a retrospective study shows elevated circulating terminal complement complex in reactional leprosy

Idrissi

Hakobyan

Ramaglia

et al. 2016

Clinical and Experimental Immunology

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“…Previous studies have indicated an important role for complement in leprosy, showing increased levels of complement components by serological and pathological studies [5–11]. Another study showed deposits of the MAC in cutaneous sensory nerves of leprosy patients, suggesting a possible role for MAC in leprosy pathology [10, 12]. We have shown that formation of the MAC contributes to early demyelination and axonal damage after traumatic injury of the peripheral nerve [13, 14], and that inhibition of MAC formation reduces nerve damage [15] and improves regeneration and functional recovery [16].…”

Section: Introductionmentioning

confidence: 99%

In Situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on leprosy lesional skin

et al. 2017

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Mycobacterium leprae (M. leprae) infection causes nerve damage and the condition worsens often during and long after treatment. Clearance of bacterial antigens including lipoarabinomannan (LAM) during and after treatment in leprosy patients is slow. We previously demonstrated that M. leprae LAM damages peripheral nerves by in situ generation of the membrane attack complex (MAC). Investigating the role of complement activation in skin lesions of leprosy patients might provide insight into the dynamics of in situ immune reactivity and the destructive pathology of M. leprae. In this study, we analyzed in skin lesions of leprosy patients, whether M. leprae antigen LAM deposition correlates with the deposition of complement activation products MAC and C3d on nerves and cells in the surrounding tissue. Skin biopsies of paucibacillary (n = 7), multibacillary leprosy patients (n = 7), and patients with erythema nodosum leprosum (ENL) (n = 6) or reversal reaction (RR) (n = 4) and controls (n = 5) were analyzed. The percentage of C3d, MAC and LAM deposition was significantly higher in the skin biopsies of multibacillary compared to paucibacillary patients (p = <0.05, p = <0.001 and p = <0.001 respectively), with a significant association between LAM and C3d or MAC in the skin biopsies of leprosy patients (r = 0.9578, p< 0.0001 and r = 0.8585, p<0.0001 respectively). In skin lesions of multibacillary patients, MAC deposition was found on axons and co-localizing with LAM. In skin lesions of paucibacillary patients, we found C3d positive T-cells in and surrounding granulomas, but hardly any MAC deposition. In addition, MAC immunoreactivity was increased in both ENL and RR skin lesions compared to non-reactional leprosy patients (p = <0.01 and p = <0.01 respectively). The present findings demonstrate that complement is deposited in skin lesions of leprosy patients, suggesting that inflammation driven by complement activation might contribute to nerve damage in the lesions of these patients. This should be regarded as an important factor in M. leprae nerve damage pathology.

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“…on May 10, 2018 by guest http://mmbr.asm.org/ (105,112), while frank MBL deficiency (defined as serum levels Ͻ100 ng/ml or ϳ10-fold lower than average) is associated with protection from lepromatous leprosy (76,105,112). Those studies measured MBL levels in patients with active disease, an approach vulnerable to confounding if MBL levels are modulated by leprosy-associated inflammation (105,324).…”

Section: Innate Immune Effector Molecules and Serum Proteinsmentioning

confidence: 99%

Leprosy and the Human Genome

Misch¹,

Berrington²,

Vary

et al. 2010

Microbiol Mol Biol Rev

116

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SUMMARY Despite the availability of effective treatment for several decades, leprosy remains an important medical problem in many regions of the world. Infection with Mycobacterium leprae can produce paucibacillary disease, characterized by well-formed granulomas and a Th1 T-cell response, or multibacillary disease, characterized by poorly organized cellular infiltrates and Th2 cytokines. These diametric immune responses confer states of relative resistance or susceptibility to leprosy, respectively, and have well-defined clinical manifestations. As a result, leprosy provides a unique opportunity to dissect the genetic basis of human in vivo immunity. A series of studies over the past 40 years suggests that host genes influence the risk of leprosy acquisition and the predilection for different clinical forms of the disease. However, a comprehensive, cellular, and molecular view of the genes and variants involved is still being assembled. In this article, we review several decades of human genetic studies of leprosy, including a number of recent investigations. We emphasize genetic analyses that are validated by the replication of the same phenotype in independent studies or supported by functional experiments demonstrating biological mechanisms of action for specific polymorphisms. Identifying and functionally exploring the genetic and immunological factors that underlie human susceptibility to leprosy have yielded important insights into M. leprae pathogenesis and are likely to advance our understanding of the immune response to other pathogenic mycobacteria. This knowledge may inform new treatment or vaccine strategies for leprosy or tuberculosis.

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The Functional State of the Complement System in Leprosy

Cited by 17 publications

References 18 publications

Complement activation in leprosy: a retrospective study shows elevated circulating terminal complement complex in reactional leprosy

Complement activation in leprosy: a retrospective study shows elevated circulating terminal complement complex in reactional leprosy

In Situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on leprosy lesional skin

Leprosy and the Human Genome

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