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Background: Erythema nodosum leprosum (ENL) is a frequent complication of multibacillary leprosy that can result in significant morbidity, including peripheral nerve damage and physical disability. The identification of possible serum markers could be a valuable tool for the early detection of ENL. Aims: The purpose of this study was to evaluate selected serum mediators involved in the innate and adaptive immune responses to identify possible immunomarkers for ENL. Methods: The levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, interleukin-17, interferon-γ, tumor necrosis factor, nitric oxide and anti-phenolic glycolipid-I antibodies were measured in the sera of leprosy patients with ENL [at the beginning of reaction (M0) and 1 month later (M1)], and then compared with the levels of the same markers in patients with untreated multibacillary leprosy without ENL (controls with leprosy: CTRL) and healthy individuals (healthy controls: CTRH). Results: Significantly higher levels of serum interleukin-6 were observed in M0 than in CTRL. In addition, pairwise comparisons showed higher levels of interleukin-6 in M0 compared to M1. Levels of tumor necrosis factor were higher in M0 than in CTRL, with no significant difference between M0 and M1. There were no differences in the levels of interleukin-2, interleukin-4, interleukin-10, interleukin-17 or interferon-γ between groups. The CTRL group had higher levels of nitric oxide compared to M0 and M1. High levels of anti-phenolic glycolipid-I were observed in M0, M1 and CTRL than in CTRH. Limitations: Three patients were not assessed at M1, decreasing the number of evaluated patients from 14 to 11. Conclusion: High-serum levels of interleukin-6 were observed during ENL, primarily in patients with more severe reactions; levels decreased after specific therapy, suggesting a role for this cytokine in pathogenesis and its utility as an ENL biomarker. Further studies should explore whether interleukin-6 could also be used as a predictive marker for ENL or as a specific target for its treatment.

Made available in DSpace on 2021-06-25T10:15:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Despite intense efforts, the number of new cases of leprosy has remained significantly high over the past 20 years. Host genetic background is strongly linked to the pathogenesis of this disease, which is caused by Mycobacterium leprae (M. leprae), and there is a consensus that the most significant genetic association with leprosy is attributed to the major histocompatibility complex (MHC). Here, we investigated the association of human leukocyte antigen (HLA) class I and II genes with leprosy in a Brazilian population encompassing 826 individuals from a hyperendemic area of Brazil; HLA typing of class I (-A, -B, -C) and class II (-DRB1, -DQA1, -DQB1, -DPA1, and -DPB1) loci was conducted. Initially, the associations were tested using the chi-square test, with p-values adjusted using the false discovery rate (FDR) method. Next, statistically significant signals of the associations were submitted to logistic regression analyses to adjust for sex and molecular ancestry data. The results showed that HLA-C*08, -DPB1*04, and -DPB1*18 were associated with protective effects, while HLA-C*12 and -DPB1*105 were associated with susceptibility to leprosy. Thus, our findings reveal new associations between leprosy and the HLA-DPB1 locus and confirm previous associations between the HLA-C locus and leprosy. Lauro de Souza Lima Institute São Paulo State University (UNESP) Medical School Graduate Program in Health Sciences School of Medicine Pontifícia Universidade Católica do Paraná Leprosy Laboratory Oswaldo Cruz Institute-Fiocruz Laboratory of Immunogenetics Department of Basic Health Sciences Maringá State University (UEM) São Paulo State University (UNESP) Medical School

Schwann cells (SCs) critically maintain the plasticity of the peripheral nervous system. Peripheral nerve injuries and infections stimulate SCs in order to retrieve homeostasis in neural tissues. Previous studies indicate that Mycobacterium leprae (ML) regulates the expression of key factors related to SC identity, suggesting that alterations in cell phenotype may be involved in the pathogenesis of neural damage in leprosy. To better understand whether ML restricts the plasticity of peripheral nerves, the present study sought to determine the expression of Krox‐20, Sox‐10, c‐Jun and p75NTR in SC culture and mice sciatic nerves, both infected by ML Thai‐53 strain. Primary SC cultures were stimulated with two different multiplicities of infection (MOI 100:1; MOI 50:1) and assessed after 7 and 14 days. Sciatic nerves of nude mice (NU ‐Foxn1 (nu)) infected with ML were evaluated after 6 and 9 months. In vitro results demonstrate downregulation of Krox‐20 and Sox‐10 along with the increase in p75NTR‐immunolabelled cells. Concurrently, sciatic nerves of infected mice showed a significant decrease in Krox‐20 and increase in p75NTR. Our results corroborate previous findings on the interference of ML in the expression of factors involved in cell maturation, favouring the maintenance of a non‐myelinating phenotype in SCs, with possible implications for the repair of adult peripheral nerves.

Leprosy remains a health problem in several countries. Current management of patients with leprosy is complex and requires multidrug therapy. Nonetheless, antibiotic treatment is insufficient to prevent nerve disabilities and control Mycobacterium leprae. Successful infectious disease treatment demands an understanding of the host immune response against a pathogen. Immune-based therapy is an effective treatment option for malignancies and infectious diseases. A promising therapeutic approach to improve the clinical outcome of malignancies is the blockade of immune checkpoints. Immune checkpoints refer to a wide range of inhibitory or regulatory pathways that are critical for maintaining self-tolerance and modulating the immune response. Programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, and lymphocyte-activation gene-3 are the most important immune checkpoint molecules. Several pathogens, including M. leprae, are supposed to utilize these mechanisms to evade the host immune response. Regulatory T cells and expression of co-inhibitory molecules on lymphocytes induce specific T-cell anergy/exhaustion, leading to disseminated and progressive disease. From this perspective, we outline how the co-inhibitory molecules PD-1, PD-L1, and Th1/Th17 versus Th2/Treg cells are balanced, how antigen-presenting cell maturation acts at different levels to inhibit T cells and modulate the development of leprosy, and how new interventions interfere with leprosy development.

Submitted by Guilherme Lemeszenski (guilherme@nead.unesp.br) on 2013-08-22T18:48:39Z No. of bitstreams: 1 S0004-282X2012000400012.pdf: 6275055 bytes, checksum: f1da7c7bf148b57ff37227a29524c38c (MD5) Made available in DSpace on 2013-08-22T18:48:39Z (GMT). No. of bitstreams: 1 S0004-282X2012000400012.pdf: 6275055 bytes, checksum: f1da7c7bf148b57ff37227a29524c38c (MD5) Previous issue date: 2012-04-01 Made available in DSpace on 2013-09-30T19:38:39Z (GMT). No. of bitstreams: 2 S0004-282X2012000400012.pdf: 6275055 bytes, checksum: f1da7c7bf148b57ff37227a29524c38c (MD5) S0004-282X2012000400012.pdf.txt: 26569 bytes, checksum: 112a6cf6f0c5a005293149edcd7f43de (MD5) Previous issue date: 2012-04-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T15:10:22Z No. of bitstreams: 2 S0004-282X2012000400012.pdf: 6275055 bytes, checksum: f1da7c7bf148b57ff37227a29524c38c (MD5) S0004-282X2012000400012.pdf.txt: 26569 bytes, checksum: 112a6cf6f0c5a005293149edcd7f43de (MD5) Made available in DSpace on 2014-05-20T15:10:22Z (GMT). No. of bitstreams: 2 S0004-282X2012000400012.pdf: 6275055 bytes, checksum: f1da7c7bf148b57ff37227a29524c38c (MD5) S0004-282X2012000400012.pdf.txt: 26569 bytes, checksum: 112a6cf6f0c5a005293149edcd7f43de (MD5) Previous issue date: 2012-04-01 Neurotrofinas são fatores de crescimento com papel fundamental na fisiopatologia neural. Esses mediadores modulam funcionalmente fibras nociceptivas. Mudanças em sua expressão têm sido relacionadas à perda precoce da nocicepção na hanseníase. Este estudo investigou a expressão de NGF, BDNF e NT3 em nervos dérmicos de pacientes hansenianos. A caracterização de fibras nervosas não mielinizadas foi feita por p75NTR e marcadores axonais NF-L e PGP 9.5. Os parâmetros clínicos de dano neural foram avaliados por monofilamentos Semmes-Wenstein. Nossos achados demonstram diminuição de NGF nos pacientes dimorfos em comparação aos controles. Resultados similares foram observados para PGP 9.5 (dimorfos: p

Leprosy is a complex infectious disease influenced by genetic and environmental factors. The genetic contributing factors are considered heterogeneous and several genes have been consistently associated with susceptibility like PARK2, tumor necrosis factor (TNF), lymphotoxin-alpha (LTA) and vitamin-D receptor (VDR). Here, we combined a case-control study (374 patients and 380 controls), with meta-analysis (5 studies; 2702 individuals) and biological study to test the epidemiological and physiological relevance of the interleukin-10 (IL-10) genetic markers in leprosy. We observed that the -819T allele is associated with leprosy susceptibility either in the case-control or in the meta-analysis studies. Haplotypes combining promoter single-nucleotide polymorphisms also implicated a haplotype carrying the -819T allele in leprosy susceptibility (odds ratio (OR)=1.40; P=0.01). Finally, we tested IL-10 production in peripheral blood mononuclear cells stimulated with Mycobacterium leprae antigens and found that -819T carriers produced lower levels of IL-10 when compared with non-carriers. Taken together, these data suggest that low levels of IL-10 during the disease outcome can drive patients to a chronic and unprotective response that culminates with leprosy.

Submitted by Priscila Medeiros (pribio0912@gmail.com) on 2022-04-08T19:06:47Z No. of bitstreams: 1 j.meegid.2016.01.015.pdf: 726803 bytes, checksum: e916615e7bde4e864ce9b94fe1bfaf37 (MD5) Approved for entry into archive by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br) on 2022-04-19T12:50:24Z (GMT) No. of bitstreams: 1 medeiros_p_posprint_bot_thegata.pdf: 726803 bytes, checksum: e916615e7bde4e864ce9b94fe1bfaf37 (MD5) Made available in DSpace on 2022-04-19T12:50:24Z (GMT). No. of bitstreams: 1 medeiros_p_posprint_bot_thegata.pdf: 726803 bytes, checksum: e916615e7bde4e864ce9b94fe1bfaf37 (MD5) Previous issue date: 2016-04 Outra Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Leprosy outcome is a complex trait and the host-pathogen-environment interaction defines the emergence of the disease. Host genetic risk factors have been successfully associated to leprosy. The 10p13 chromosomal region was linked to leprosy in familial studies and GATA3 gene is a strong candidate to be part of this association. Here, we tested tag single nucleotide polymorphisms at GATA3 in two case-control samples from Brazil comprising a total of 1633 individuals using stepwise strategy. The A allele of rs10905284 marker was associated with leprosy resistance. Then, a functional analysis was conducted and showed that individuals carrying AA genotype express higher levels of GATA-3 protein in lymphocytes. So, we confirmed that the rs10905284 is a locus associated to leprosy and influences the levels of this transcription factor in the Brazilian population. Versão final do editor Instituto Lauro de Souza Lima Faculdade de Medicina de Botucatu - FMB FAPESP: 2009/16873-8 FAPESP: 576051/2008-0 FAPESP: 2014/04143-3

Made available in DSpace on 2018-11-26T16:16:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-08-01. Added 1 bitstream(s) on 2019-10-09T18:25:36Z : No. of bitstreams: 1 S0074-02762015000500655.pdf: 1108367 bytes, checksum: 138ebf10244ef2d71fb00581b96ff2c9 (MD5) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) AMC-UvA Dendritic cells (DCs) play a pivotal role in the connection of innate and adaptive immunity of hosts to mycobacterial infection. Studies on the interaction of monocyte-derived DCs (MO-DCs) using Mycobacterium leprae in leprosy patients are rare. The present study demonstrated that the differentiation of MOs to DCs was similar in all forms of leprosy compared to normal healthy individuals. In vitro stimulation of immature MO-DCs with sonicated M. leprae induced variable degrees of DC maturation as determined by the increased expression of HLA-DR, CD40, CD80 and CD86, but not CD83, in all studied groups. The production of different cytokines by the MO-DCs appeared similar in all of the studied groups under similar conditions. However, the production of interleukin (IL)-12p70 by MO-DCs from lepromatous (LL) leprosy patients after in vitro stimulation with M. leprae was lower than tuberculoid leprosy patients and healthy individuals, even after CD40 ligation with CD40 ligand-transfected cells. The present cumulative findings suggest that the MO-DCs of LL patients are generally a weak producer of IL-12p70 despite the moderate activating properties of M. leprae. These results may explain the poor M. leprae-specific cell-mediated immunity in the LL type of leprosy. Univ Estadual Paulista, Fac Med Botucatu, Programa Posgrad Doencas Trop, Botucatu, SP, Brazil Univ Santo Amaro, Sao Paulo, SP, Brazil Fac Anhanguera Bauru, Bauru, SP, Brazil Inst Lauro Souza Lima, Equipe Tecn Imunol, Bauru, SP, Brazil Univ Sao Paulo, Fac Odontol Bauru, Dept Microbiol & Imunol, Bauru, SP, Brazil Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1105 AZ Amsterdam, North Holland, Netherlands Univ Birmingham, Sch Immun & Infect, Birmingham, W Midlands, England Univ Estadual Paulista, Fac Med Botucatu, Programa Posgrad Doencas Trop, Botucatu, SP, Brazil FAPESP: 2009/01436-1

Paracoccidioidomycosis (PCM) is the most prevalent human mycosis in Latin America. The infection is thought to take place firstly in the lungs and then may disseminate to other organs and tissues. Treatment by currently available antifungals is lengthy, the drugs may have undesirable side effects, and some are costly. Occasional resistant strains of Paracoccidioides brasiliensis, the causative agent of PCM, have been reported. So, the search for more efficient treatments or adjuvant therapies has to be continued. In this work, we evaluated the effects of HeNe laser irradiation on cutaneous inflammatory lesions caused by the inoculation of 5 x 10(6)/0.1ml yeasts cells into the back footpad of Balb/c mice. HeNe irradiation (lambda=632.8nm, 3mW, incident energy of 3J/cm(2)) was applied at days 7, 8 and 9 post-infection and histological and immunohistochemical analysis were done. Unirradiated animals were used as controls. The results showed that laser-treated mice presented reduction of footpad edema, faster cutaneous wound healing, confluent granuloma, diffuse- and more loosely distributed immunolabeling for TNF-alpha, enhanced labeling of IFN-gamma and any P. brasiliensis form detected, whereas multiple viable fungi were seen in diffuse widespread granulomas obtained from non-treated mice foot-pad. Fungi that were harvested from laser-treated animals presented no capability of growth in vitro as compared to those obtained from non-treated mice. We conclude that HeNe laser irradiation was able to inhibit the progress of inflammatory local reaction produced by P. brasiliensis infection and influence local cytokines production. We suggest that this treatment modality can be a useful coadjuvant tool to be combined with antifungal agents in the treatment of PCM ulcerations. The mechanisms involved in laser therapy of PCM lesions need further investigation.

Conflicting findings about the association between leprosy and TLR1 variants N248S and I602S have been reported. Here, we performed case-control and family based studies, followed by replication in 2 case-control populations from Brazil, involving 3162 individuals. Results indicated an association between TLR1 248S and leprosy in the case-control study (SS genotype odds ratio [OR], 1.81; P = .004) and the family based study (z = 2.02; P = .05). This association was consistently replicated in other populations (combined OR, 1.51; P < .001), corroborating the finding that 248S is a susceptibility factor for leprosy. Additionally, we demonstrated that peripheral blood mononuclear cells (PBMCs) carrying 248S produce a lower tumor necrosis factor/interleukin-10 ratio when stimulated with Mycobacterium leprae but not with lipopolysaccharide or PAM3cysK4. The same effect was observed after infection of PBMCs with the Moreau strain of bacillus Calmette-Guerin but not after infection with other strains. Finally, molecular dynamics simulations indicated that the Toll-like receptor 1 structure containing 248S amino acid is different from the structure containing 248N. Our results suggest that TLR1 248S is associated with an increased risk for leprosy, consistent with its hypoimmune regulatory function.

The immunosuppression observed in systemic mycosis can be related to primary lymphoid organs damage. Thus, our laboratory has studied the effects of the Paracoccidioides brasiliensis infection on the thymus of mice. Here, thymuses of susceptible and resistant mice were evaluated after inoculation with highly and slightly virulent isolates of the fungus. All groups presented thymic atrophy, loss of corticomedullary delimitation and increase of apoptotic index. However, mice inoculated with high virulent strain showed earlier and stronger alterations suggesting that thymic atrophy can be directly related to the fungal virulence and to the immunosuppression.A imunossupressão observada em micoses sistêmicas pode estar relacionada a danos nos órgãos linfóides primários. Assim, nosso laboratório tem estudado uma possível ação do Paracoccidioides brasiliensis sobre o timo de camundongos. Neste estudo, analisamos o timo de camundongos susceptíveis e resistentes ao fungo utilizando cepas de alta e baixa virulência. Todos os grupos apresentaram atrofia tímica, perda de delimitação corticomedular e aumento da taxa de apoptose. Entretanto, as alterações foram mais precoces e pronunciadas em camundongos inoculados com a cepa virulenta do fungo, sugerindo que a virulência fúngica pode estar diretamente ligada à atrofia tímica e indução de imunossupressão.

Iron is essential for all organisms and its availability can control the growth of microorganisms; therefore, we examined the role of iron metabolism in multibacillary (MB) leprosy, focusing on the involvement of hepcidin. Erythrograms, iron metabolism parameters, pro-inflammatory cytokines and urinary hepcidin levels were evaluated in patients with MB and matched control subjects. Hepcidin expression in MB lesions was evaluated by quantitative polymerase chain reaction. The expression of ferroportin and hepcidin was evaluated by immunofluorescence in paucibacillary and MB lesions. Analysis of hepcidin protein levels in urine and of hepcidin mRNA and protein levels in leprosy lesions and skin biopsies from healthy control subjects showed elevated hepcidin levels in MB patients. Decreases in haematologic parameters and total iron binding capacity were observed in patients with MB leprosy. Moreover, interleukin-1 beta, ferritin, soluble transferrin receptor and soluble transferrin receptor/log ferritin index values were increased in leprosy patients. Hepcidin was elevated in lepromatous lesions, whereas ferroportin was more abundant in tuberculoid lesions. In addition, hepcidin and ferroportin were not colocalised in the biopsies from leprosy lesions. Anaemia was not commonly observed in patients with MB; however, the observed changes in haematologic parameters indicating altered iron metabolism appeared to result from a mixture of anaemia of inflammation and iron deficiency. Thus, iron sequestration inside host cells might play a role in leprosy by providing an optimal environment for the bacillus.

Leprosy is an infectious disease caused by Mycobacterium leprae. Tumor necrosis factor (TNF) plays a key role in the host response. Some association studies have implicated the single nucleotide polymorphism TNF -308G>A in leprosy susceptibility, but these results are still controversial. We first conducted 4 association studies (2639 individuals) that showed a protective effect of the -308A allele (odds ratio [OR] = 0.77; P = .005). Next, results of a meta-analysis reinforced this association after inclusion of our new data (OR = 0.74; P = .04). Furthermore, a subgroup analysis including only Brazilian studies suggested that the association is specific to this population (OR = 0.63; P = .005). Finally, functional analyses using whole blood cultures showed that patients carrying the -308A allele produced higher TNF levels after lipopolysaccharide (LPS) (6 hours) and M. leprae (3 hours) stimulation. These results reinforce the association between TNF and leprosy and suggest the -308A allele as a marker of disease resistance, especially among Brazilians.

Apoptosis eliminates pathogen-infected cells. Its modulation can influence the course of infections, permitting the survival of intracellular pathogens. In leprosy, which presents several clinical manifestations related to bacillary burden and host immune status, the mechanisms responsible for the persistence of the bacillus are unknown. Few studies have focused on apoptosis over the disease spectrum and as a defense mechanism against Mycobacterium leprae. We evaluated apoptosis using terminal transferase dUTP nick end labeling and the expression of Bcl-2 by immunohistochemistry in skin lesions from 11 tuberculoid and 15 lepromatous leprosy patients. Each specimen was evaluated by determining the number of positive cells in 10 fields at × 400 magnification. We observed a higher number of apoptotic cells in tuberculoid lesions in comparison with lepromatous leprosy (42.5 cells per 10 fields vs. 11.5 cells per 10 fields, P

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, a low virulence mycobacterium, and the outcome of disease is dependent on the host genetics for either susceptibility per se or severity. The IFNG gene codes for interferon-γ (IFN-γ), a cytokine that plays a key role in host defense against intracellular pathogens. Indeed, single nucleotide polymorphisms (SNPs) in IFNG have been evaluated in several genetic epidemiological studies, and the SNP +874T>A, the +874T allele, more specifically, has been associated with protection against infectious diseases, especially tuberculosis. Here, we evaluated the association of the IFNG locus with leprosy enrolling 2,125 Brazilian subjects. First, we conducted a case–control study with subjects recruited from the state of Sao Paulo, using the +874 T>A (rs2430561), +2109 A>G (rs1861494) and rs2069727 SNPs. Then, a second study including 1,370 individuals from Rio de Janeiro was conducted. Results of the case–control studies have shown a protective effect for +874T carriers (ORadjusted = 0.75; p = 0.005 for both studies combined), which was corroborated when these studies were compared with literature data. No association was found between the SNP +874T>A and the quantitative Mitsuda response. Nevertheless, the spontaneous IFN-γ release by peripheral blood mononuclear cells was higher among +874T carriers. The results shown here along with a previously reported meta-analysis of tuberculosis studies indicate that the SNP +874T>A plays a role in resistance to mycobacterial diseases.

The effect of HeNe laser on the extracellular matrix deposition, chemokine expression and angiogenesis in experimental paracoccidioidomycotic lesions was investigated. At days 7, 8 and 9 postinfection the wound of each animal was treated with a 632.8 nm HeNe laser at a dose of 3 J cm(-2). At day 10 postinfection, the wounds were examined by using histologic and immunohistochemical methods. Results revealed that laser-treated lesions were lesser extensive than untreated ones, and composed mainly by macrophages and lymphocytes. High IL-1beta expression was shown in the untreated group whereas in laser-treated animals the expression was scarce. On the other hand, the expression of CXCL-10 was found to be reduced in untreated animals and quite intensive and well distributed in the laser-treated ones. Also, untreated lesions presented vascular endothelial growth factor (VEGF) in a small area near the center of the lesion and high immunoreactivity for hypoxia-inducible factor-1 (HIF-1), whereas laser-treated lesions expressed VEGF surrounding blood vessels and little immunoreactivity for HIF-1. Laser-treated lesions presented much more reticular fibers and collagen deposition when compared with the untreated lesion. Our results show that laser was efficient in minimizing the local effects observed in paracoccidioidomycosis and can be an efficient tool in the treatment of this infection, accelerating the healing process.

The immunosuppression observed in systemic mycosis can be related to primary lymphoid organs damage. Thus, our laboratory has studied the effects of the Paracoccidioides brasiliensis infection on the thymus of mice. Here, thymuses of susceptible and resistant mice were evaluated after inoculation with highly and slightly virulent isolates of the fungus. All groups presented thymic atrophy, loss of corticomedullary delimitation and increase of apoptotic index. However, mice inoculated with high virulent strain showed earlier and stronger alterations suggesting that thymic atrophy can be directly related to the fungal virulence and to the immunosuppression. A imunossupressão observada em micoses sistêmicas pode estar relacionada a danos nos órgãos linfóides primários. Assim, nosso laboratório tem estudado uma possível ação do Paracoccidioides brasiliensis sobre o timo de camundongos. Neste estudo, analisamos o timo de camundongos susceptíveis e resistentes ao fungo utilizando cepas de alta e baixa virulência. Todos os grupos apresentaram atrofia tímica, perda de delimitação corticomedular e aumento da taxa de apoptose. Entretanto, as alterações foram mais precoces e pronunciadas em camundongos inoculados com a cepa virulenta do fungo, sugerindo que a virulência fúngica pode estar diretamente ligada à atrofia tímica e indução de imunossupressão.

Literature has shown that immunosuppression observed in systemic mycosis can be related to damage in primary lymphoid organs. We have studied the immunopathological alterations induced experimentally by Paracoccidioides brasiliensis in these organs. In this work, thymic alterations induced in BALB/c mice during acute and chronic stages of infection are described. It was observed that P. brasiliensis is able to invade the thymic microenvironment, inducing severe atrophy characterized by degeneration of the cortical area, organ weight decrease, loss of corticomedullary delimitation and increase in histiocyte number. Occurrence of polymorphonuclear infiltration in the subcapsular area was also observed. Our results demonstrate that P. brasiliensis induces profound thymic atrophy and raises the question of whether this could be a fungal strategy to achieve successful establishment in the host over the long term.

Many works have shown that immunosuppressive effects induced by systemic mycosis can be related to primary lymphoid organ damage. Previous studies in our laboratory showed that Paracoccidioides brasiliensis was able to invade the thymus, inducing a severe atrophy with significant reduction of cortical area along with a loss of cortico-medullary boundary. The objective of the present study was to investigate whether thymic atrophy is caused by programmed cell death (PCD) and to examine the ultrastructural characteristics of the thymus in experimentally infected BALB/c mice. The results revealed an eightfold increase in the apoptotic index occurring by day 5 post infection, i.e., during early stages of the infection, shown by immunohistochemistry. In addition, typical cell alterations of autophagic PCD were observed by transmission electron microscopy. Taken together, these results reinforce the idea that thymic alterations may be involved in the immunosuppressive phenomenon frequently associated with paracoccidioidomycotic infection.