Thymic Innervation Impairment in Experimental Autoimmune Encephalomyelitis.

INTRODUCTION: The thymus is the primary lymphoid organ responsible for normal T-cell development. Yet, in abnormal metabolic conditions as well as an acute infection, the organ exhibits morphological and cellular alterations. It is well established that the immune system is in a tidy connection and dependent on the central nervous system (CNS), which regulates thymic function by means of innervation and neurotransmitters. Sympathetic innervation leaves the CNS and spreads through thymic tissue, where nerve endings interact directly or indirectly with thymic cells contributing to their maintenance and development. METHODS: Herein, we hypothesized that brain damage due to an inflammatory process might elicit alterations upon the thymic-CNS neuroimmune axis, altering not just the sympathetic innervation and neurotransmitter release, but also modifying the thymus microenvironment and T-cell development. We used the well-established multiple sclerosis model of experimental autoimmune encephalomyelitis (EAE), to study putative changes in the thymic neural, lymphoid, and microenvironmental compartments. RESULTS: We showed that along with EAE clinical development, thymus morphology, and cellular compartments are affected, altering the peripheric T-cell population and modifying the retrograde thymic communication toward the CNS. CONCLUSION: Altogether, our data suggest that the thymic-CNS neuroimmune bidirectional axis is compromised in EAE. This imbalance may contribute to an increased and uncontrolled auto-immune reaction.

Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis.

The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.

Cytotoxic B Cells in Relapsing-Remitting Multiple Sclerosis Patients.

Background: Emerging evidence of antibody-independent functions, as well as the clinical efficacy of anti-CD20 depleting therapies, helped to reassess the contribution of B cells during multiple sclerosis (MS) pathogenesis. Objective: To investigate whether CD19+ B cells may share expression of the serine-protease granzyme-B (GzmB), resembling classical cytotoxic CD8+ T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients. Methods: In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses. Results: RRMS patients during fingolimod (FTY) and natalizumab (NTZ) treatment showed increased percentage of circulating CD8+GzmB+ T lymphocytes when compared to healthy volunteers. An increase in circulating CD19+GzmB+ B cells was observed in RRMS patients during FTY and NTZ therapies when compared to glatiramer (GA), untreated RRMS patients, and healthy donors but not when compared to interferon-ß (IFN). Moreover, regarding Runx3, the transcriptional factor classically associated with cytotoxicity in CD8+ T lymphocytes, the expression of GzmB was significantly higher in CD19+Runx3+-expressing B cells when compared to CD19+Runx3- counterparts in RRMS patients. Conclusions: CD19+ B cells may exhibit cytotoxic behavior resembling CD8+ T lymphocytes in MS patients during different treatments. In the future, monitoring "cytotoxic" subsets might become an accessible marker for investigating MS pathophysiology and even for the development of new therapeutic interventions.

Decreased Neurofilament L Chain Levels in Cerebrospinal Fluid and Tolerogenic Plasmacytoid Dendritic Cells in Natalizumab-Treated Multiple Sclerosis Patients - Brief Research Report.

BACKGROUND: Neurofilament Light (NfL) chain levels in both cerebrospinal fluid (CSF) and serum have been correlated with the reduction of axonal damage in multiple sclerosis (MS) patients treated with Natalizumab (NTZ). However, little is known about the function of plasmacytoid cells in NTZ-treated MS patients. OBJECTIVE: To evaluate CSF NfL, serum levels of soluble-HLA-G (sHLA-G), and eventual tolerogenic behavior of plasmacytoid dendritic cells (pDCs) in MS patients during NTZ treatment. METHODS: CSF NfL and serum sHLA-G levels were measured using an ELISA assay, while pDCs (BDCA-2+) were accessed through flow cytometry analyses. RESULTS: CSF levels of NfL were significantly reduced during NTZ treatment, while the serum levels of sHLA-G were increased. Moreover, NTZ treatment enhanced tolerogenic (HLA-G+, CD274+, and HLA-DR+) molecules and migratory (CCR7+) functions of pDCs in the peripheral blood. CONCLUSION: These findings suggest that NTZ stimulates the production of molecules with immunoregulatory function such as HLA-G and CD274 programmed death-ligand 1 (PD-L1) which may contribute to the reduction of axonal damage represented by the decrease of NfL levels in patients with MS.

Cytotoxic profile of CD3+CD20+ T cells in progressive multiple sclerosis.

Recently, it was shown that highly effective anti-CD20 therapies used for MS patients not only deplete CD20+ B cells, but also a small subset of T cells expressing CD20 surface marker (CD3+CD20+ T cells). Here we demonstrated that, in progressive MS patients, CD3+CD20+ T cells share the ability to express cytotoxic factors such as perforin and serine-protease granzyme-B (GzmB), classically associated with CD8+ T cells functionality. Beyond it, cluster analyses show that a set of activation markers and transcriptional factors related with CD8 effector program are also expressed in CD3+CD20+ T cells. Further characterization of surface and functional markers from CD3+CD20+ T subsets may be helpful for development of new therapeutic strategies mainly for progressive MS patients, as well as for assessing pathophysiological effects of highly effective anti-CD20 therapies.

Clinical variables that help in predicting the presence of autoantibodies in patients with acute encephalitis.

OBJECTIVE: To identify clinical variables that could predict the presence of autoantibodies in patients with acute encephalitis. METHODS: An observational, retrospective study from May 2011 to May 2017. Clinical, EEG, brain MRI data, and antibodies against human neuronal antigens (NMDAR, GABAR, AMPAR, LGI1, CASPR2, and GAD) from 158 patients with criteria for possible autoimmune encephalitis were analyzed to create a predictive model for this disease. RESULTS: We analyzed 158 samples, of which 18 cases were positive for anti-NMDAR, 2 for anti-LGI1, and 2 for anti-GAD. Seven of the 18 positive NMDAR patients were children, and 12 were female. Behavioral disorder, epileptic seizures, movement disorder, and altered level of consciousness were the frequent symptoms with >75 % sensitivity in positive anti-NMDAR patients. Other symptoms, such as language disorder, psychosis, hypoventilation, altered wake and sleep cycle, and cognitive impairment, had a sensitivity >55 %. Abnormal EEG findings had a high sensitivity (99.4 %). Brain MRI suggestive of encephalitis was observed in 7 of the positive cases for NMDAR. Abnormal CSF findings were reported in 12 patients positive for this receptor (sensitivity 70.6 %). With 7 of these symptoms, we obtained a sensitivity of 70 % and specificity of 81 % for the presence of anti-NMDAR antibodies (ROC Area 82 %). However, to predict that a patient with subacute encephalitis may have an autoimmune cause, the patient should include clinical manifestations such as movement disorder, behavioral disorder, hypoventilation, dysautonomia, and alteration of the wake and sleep cycle. Children were significantly more likely than adults with autoimmune encephalitis to experience chorea and status epilepticus (p < 0.05). CONCLUSIONS: Anti-NMDAR encephalitis was more frequent in females and children. The repertoire of autoimmune encephalitis in children is different from adults. The presence of subacute behavioral changes, epileptic seizures, movement disorders, altered consciousness, hypoventilation, dysautonomia, and altered wake and sleep cycle predicted autoimmune encephalitis in our series.

Partial remission in Brazilian children and adolescents with type 1 diabetes. Association with a haplotype of class II human leukocyte antigen and synthesis of autoantibodies.

OBJECTIVE: Characterization of partial remission using the insulin dose-adjusted HbA1c (IDAA1c) ≤ 9 definition in a multiethnic Brazilian population of children and adolescents with type 1 diabetes (T1D), in addition with the determination of both Class II HLA genotype and autoantibodies. METHODS: We analyzed the prevalence of partial remission in 51 new-onset T1D patients with a median time follow-up of 13 months from diagnosis. For this study, anti-GAD65, anti-IA2 and HLA class II genotyping were considered. RESULTS: Partial remission occurred in 41.2% of T1D patients until 3 months after diagnosis, mainly in those aged 5-15 years. We have demonstrated a significant increase in the haplotypes of class II HLA DRB1*0301-DQB1*0201 in children and adolescents with a partial remission phase of the disease (42.9% vs 21.7% in non-remitters, P = .0291). This haplotype was also associated with the reduction of anti-IA2 antibodies production. Homozygote DRB1*03-DQB1*0201/DRB1*03-DQB1*0201 children had the lowest prevalence of IA-2A antibodies (P = .0402). However, this association does not correlate with the time of the remission phase. CONCLUSION: Although the number of patients studied was reduced, our data suggested that the association between genetics and decrease in antibody production to certain islet auto-antigen may contribute, at least in part, to the remission phase of T1D.

Massive activity of cytotoxic cells during refractory Neuromyelitis Optica spectrum disorder.

Our group is interested in the cytotoxic mechanism during autoimmune neuroinflammation. Unexpectedly, we come across a case that presents a massive enhancement of cytotoxic behavior in lymphocytes, either in peripheral blood and cerebrospinal fluid. Interestingly, this specific patient was refractory to Methylprednisolone treatment. Hypothetically, the cytotoxic activity could represent a novel and complementary effector mechanism to NMOSD pathogenesis. Nevertheless, further investigation is needed to evaluate the extension and the clinical relevance of our finds.

From Charcot's descriptions to the current understanding of neuropsychiatric symptoms in multiple sclerosis.

Neuropsychiatric disorders in multiple sclerosis have been known since the original clinicopathological description by Charcot in the late nineteenth century. Charcot, in the last decades of his life, became involved in the field of neuropsychiatry. This produced a battle between rival schools in the era that still echoes to this day. Charcot's intuition, including the line of thought of Babinski, one of his most famous disciples, was that there was a connection between mood disorders and many of the diseases of the nervous system. Medicine's concern with establishing a relationship between mood disorders and disease stems from the ancient and middle ages with references found in the Hippocratic doctrine. However, it was only in the second half of the nineteenth and early twentieth century, with Charcot's discoveries, that this discussion was established in a structured way, laying the foundations of neuropsychiatry.

From Charcot's descriptions to the current understanding of neuropsychiatric symptoms in multiple sclerosis / Das descrições de Charcot à compreensão atual dos sintomas neuropsiquiátricos na esclerose múltipla

ABSTRACT Neuropsychiatric disorders in multiple sclerosis have been known since the original clinicopathological description by Charcot in the late nineteenth century. Charcot, in the last decades of his life, became involved in the field of neuropsychiatry. This produced a battle between rival schools in the era that still echoes to this day. Charcot's intuition, including the line of thought of Babinski, one of his most famous disciples, was that there was a connection between mood disorders and many of the diseases of the nervous system. Medicine's concern with establishing a relationship between mood disorders and disease stems from the ancient and middle ages with references found in the Hippocratic doctrine. However, it was only in the second half of the nineteenth and early twentieth century, with Charcot's discoveries, that this discussion was established in a structured way, laying the foundations of neuropsychiatry.

RESUMO Os distúrbios neuropsiquiátricos na esclerose múltipla são conhecidos desde a descrição clínico-patológica original de Charcot no final do século XIX. Charcot nas últimas décadas de sua vida se envolveu no campo da neuropsiquiatria. Isso produziu uma batalha de escolas rivais na época que ainda ecoa até hoje. A intuição de Charcot, incluindo a linha de pensamento de Babinski, um de seus discípulos mais famosos, foi a teoria correta da conexão entre os transtornos do humor e muitas das doenças do sistema nervoso. A preocupação da Medicina em estabelecer uma relação entre transtornos do humor e doenças vem das idades antiga e média, com referências encontradas na doutrina hipocrática. No entanto, foi apenas na segunda metade do século XIX e início do século XX que, com as descobertas de Charcot essa discussão foi realizada de maneira estruturada, estabelecendo os fundamentos da neuropsiquiatria.

Dimethyl fumarate downregulates the immune response through the HCA2/GPR109A pathway: Implications for the treatment of multiple sclerosis.

BACKGROUND: The mechanisms of action of dimethyl fumarate (DMF), and its metabolite, monomethyl fumarate (MMF), for the treatment of multiple sclerosis are not completely elucidated. OBJECTIVES: To discuss the role of DMF/MMF-induced hydroxycarboxylic acid receptor 2 (HCA2/GPR109A) pathway activation in the immune response and treatment of MS. METHODS: A narrative (traditional) review of the current literature. RESULTS: Studies have shown that binding of DMF/MMF to HCA2 on dendritic cells inhibits the production of pro-inflammatory cytokines in vitro and in MS murine models. Evidence suggests that activation of HCA2 expressed in immune cells and gut epithelial cells by DMF/MMF, may induce anti-inflammatory responses in the intestinal mucosa. CONCLUSION: Although the DMF/MMF mechanism of action remains unclear, evidence suggests that the activation of HCA2/GPR109A pathway downregulates the immune response and may activate anti-inflammatory response in the intestinal mucosa, possibly leading to reduction in CNS tissue damage in MS patients.

Immunization with the MAEBL M2 Domain Protects against Lethal Plasmodium yoelii Infection.

Malaria remains a world-threatening disease largely because of the lack of a long-lasting and fully effective vaccine. MAEBL is a type 1 transmembrane molecule with a chimeric cysteine-rich ectodomain homologous to regions of the Duffy binding-like erythrocyte binding protein and apical membrane antigen 1 (AMA1) antigens. Although MAEBL does not appear to be essential for the survival of blood-stage forms, ectodomains M1 and M2, homologous to AMA1, seem to be involved in parasite attachment to erythrocytes, especially M2. MAEBL is necessary for sporozoite infection of mosquito salivary glands and is expressed in liver stages. Here, the Plasmodium yoelii MAEBL-M2 domain was expressed in a prokaryotic vector. C57BL/6J mice were immunized with doses of P. yoelii recombinant protein rPyM2-MAEBL. High levels of antibodies, with balanced IgG1 and IgG2c subclasses, were achieved. rPyM2-MAEBL antisera were capable of recognizing the native antigen. Anti-MAEBL antibodies recognized different MAEBL fragments expressed in CHO cells, showing stronger IgM and IgG responses to the M2 domain and repeat region, respectively. After a challenge with P. yoelii YM (lethal strain)-infected erythrocytes (IE), up to 90% of the immunized animals survived and a reduction of parasitemia was observed. Moreover, splenocytes harvested from immunized animals proliferated in a dose-dependent manner in the presence of rPyM2-MAEBL. Protection was highly dependent on CD4(+), but not CD8(+), T cells toward Th1. rPyM2-MAEBL antisera were also able to significantly inhibit parasite development, as observed in ex vivo P. yoelii erythrocyte invasion assays. Collectively, these findings support the use of MAEBL as a vaccine candidate and open perspectives to understand the mechanisms involved in protection.

Clinical predictors of cognitive impairment and psychiatric complications in Parkinson's disease.

OBJECTIVE: To estimate the clinical and demographics aspects that may contribute to cognitive impairment and psychiatric symptoms in Parkinson's disease (PD). METHOD: All patients answered a structured standardized clinical questionnaire. Two movement disorders specialists performed the following scale: Unified Parkinson's disease rating score (UPDRS), the modified Hoehn and Yahr staging, Schwab and England Scale, SCOPA cognition (SCOPA-COG), SCOPA-Psychiatric complications (SCOPA-PC) and Non-Motor Symptoms Scale (NMSS). We built a generalized linear model to assess predictors for the SCOPA-COG and SCOPA-PC scores. RESULTS: Almost 37% of our patients were demented as per SCOPA-COG scores. Level of education and the UPDRS-Subscale III were predictors of cognitive impairment. Higher scores in domain 3 of NMSS and male gender were associated with psychiatric complications as assessed per the SCOPA-PC. CONCLUSION: Level of education and disease severity are predictors of dementia in PD. Psychiatric complications are more commonly observed in men.

How can proteomics elucidate the complexity of multiple sclerosis?

Multiple sclerosis affects more than 2.5 million people worldwide. Although multiple sclerosis was described almost 150 years ago, there are many knowledge gaps regarding its etiology, diagnosis, prognosis, and pathogenesis. Multiple sclerosis is an inflammatory, demyelinating, neurodegenerative disease of the CNS. During the last several decades, experimental models of multiple sclerosis have contributed to our understanding of the inflammatory disease mechanisms and have aided drug testing and development. However, little is known about the neurodegenerative mechanisms that operate during the evolution of the disease. Currently, all therapeutic approaches are primarily based on the inflammatory aspect of the disease. During the last decade, proteomics has emerged as a promising tool for revealing molecular pathways as well as identifying and quantifying differentially expressed proteins. Therefore, proteomics may be used for the discovery of biomarkers, potential drug targets, and new regulatory mechanisms. To date, a considerable number of proteomics studies have been conducted on samples from experimental models and patients with multiple sclerosis. These data form a solid base for further careful analysis and validation.

Clinical predictors of cognitive impairment and psychiatric complications in Parkinson’s disease / Preditores clínicos de transtorno cognitivo e complicações psiquiátricas na doença de Parkinson

Objective To estimate the clinical and demographics aspects that may contribute to cognitive impairment and psychiatric symptoms in Parkinson’s disease (PD). Method All patients answered a structured standardized clinical questionnaire. Two movement disorders specialists performed the following scale: Unified Parkinson’s disease rating score (UPDRS), the modified Hoehn and Yahr staging, Schwab and England Scale, SCOPA cognition (SCOPA-COG), SCOPA-Psychiatric complications (SCOPA-PC) and Non-Motor Symptoms Scale (NMSS). We built a generalized linear model to assess predictors for the SCOPA-COG and SCOPA-PC scores. Results Almost 37% of our patients were demented as per SCOPA-COG scores. Level of education and the UPDRS-Subscale III were predictors of cognitive impairment. Higher scores in domain 3 of NMSS and male gender were associated with psychiatric complications as assessed per the SCOPA-PC. Conclusion Level of education and disease severity are predictors of dementia in PD. Psychiatric complications are more commonly observed in men. .

Objetivo Estimar aspectos clínicos e demográficos que podem contribuir para o comprometimento cognitivo e sintomas psiquiátricos na doença de Parkinson (DP). Método Todos pacientes responderam questionário clínico padrão. Duas especialistas em distúrbios do movimento aplicaram as seguintes escalas: Unified Parkinson’s disease rating score (UPDRS), Hoehn and Yahr estágios, Schwab and England Scale, SCOPA cognição (SCOPA-COG), SCOPA-Complicações psiquiátricas (SCOPA-CP) e Escala de sintomas não motores (NMSS). Utilizamos análise multivariada, para avaliar os preditores relacionados ao SCOPA-COG e SCOPA CP. Resultados Aproximadamente 37% dos nossos pacientes foram classificados como dementes utilizando-se os valores obtidos no SCOPA-COG. Nível educacional e a parte III do UPDRS foram preditores de comprometimento cognitivo. Escores elevados no domínio 3 do NMSS e sexo masculino associaram-se com complicações psiquiátricas quando acessadas pelo SCOPA-CP. Conclusão Nível educacional e gravidade de doença são preditores de demência na DP. Complicações psiquiátricas são mais comumente observadas em homens. .

Impact of pregabalin treatment on synaptic plasticity and glial reactivity during the course of experimental autoimmune encephalomyelitis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease that affects young adults. It is characterized by generating a chronic demyelinating autoimmune inflammation in the central nervous system. An experimental model for studying MS is the experimental autoimmune encephalomyelitis (EAE), induced by immunization with antigenic proteins from myelin. AIMS: The present study investigated the evolution of EAE in pregabalin treated animals up to the remission phase. METHODS AND RESULTS: The results demonstrated a delay in the onset of the disease with statistical differences at the 10th and the 16th day after immunization. Additionally, the walking track test (CatWalk) was used to evaluate different parameters related to motor function. Although no difference between groups was obtained for the foot print pressure, the regularity index was improved post treatment, indicating a better motor coordination. The immunohistochemical analysis of putative synapse preservation and glial reactivity revealed that pregabalin treatment improved the overall morphology of the spinal cord. A preservation of circuits was depicted and the glial reaction was downregulated during the course of the disease. qRT-PCR data did not show immunomodulatory effects of pregabalin, indicating that the positive effects were restricted to the CNS environment. CONCLUSIONS: Overall, the present data indicate that pregabalin is efficient for reducing the seriousness of EAE, delaying its course as well as reducing synaptic loss and astroglial reaction.

Structural brain abnormalities are related to retinal nerve fiber layer thinning and disease duration in neuromyelitis optica spectrum disorders.

BACKGROUND: Although aquaporin-4 (AQP4) is widely expressed in the human brain cortex, lesions are rare in neuromyelitis optica (NMO) spectrum disorders (NMOSD). Recently, however, several studies have demonstrated occult structural brain atrophy in NMO. OBJECTIVE: This study aims to investigate magnetic resonance imaging (MRI) patterns of gray matter (GM) and white matter (WM) abnormalities in patients with NMOSD and to assess the visual pathway integrity during disease duration correlation of the retinal nerve fiber layer (RNFL) and pericalcarine cortex thickness. METHODS: Twenty-one patients with NMOSD and 34 matched healthy controls underwent both high-field MRI (3T) high-resolution T1-weighted and diffusion-tensor MRI. Voxel-based morphometry, cortical analyses (Freesurfer) and diffusion-tensor imaging (DTI) analyses (TBSS-FSL) were used to investigate brain abnormalities. In addition, RNFL measurement by optic-coherence tomography (OCT) was performed. RESULTS: We demonstrate that NMOSD is associated with GM and WM atrophy, encompassing more frequently the motor, sensory and visual pathways, and that the extent of GM atrophy correlates with disease duration. Furthermore, we demonstrate for the first time a correlation between RNFL and pericalcarine cortical thickness, with cortical atrophy evolving over the course of disease. CONCLUSIONS: Our findings indicate a role for retrograde and anterograde neurodegeneration in GM atrophy in NMOSD. However, the presence atrophy encompassing almost all lobes suggests that additional pathomechanisms might also be involved.

Ten years of proteomics in multiple sclerosis.

Multiple sclerosis, which is the most common cause of chronic neurological disability in young adults, is an inflammatory, demyelinating, and neurodegenerative disease of the CNS, which leads to the formation of multiple foci of demyelinated lesions in the white matter. The diagnosis is based currently on magnetic resonance image and evidence of dissemination in time and space. However, this could be facilitated if biomarkers were available to rule out other disorders with similar symptoms as well as to avoid cerebrospinal fluid analysis, which requires an invasive collection. Additionally, the molecular mechanisms of the disease are not completely elucidated, especially those related to the neurodegenerative aspects of the disease. The identification of biomarker candidates and molecular mechanisms of multiple sclerosis may be approached by proteomics. In the last 10 years, proteomic techniques have been applied in different biological samples (CNS tissue, cerebrospinal fluid, and blood) from multiple sclerosis patients and in its experimental model. In this review, we summarize these data, presenting their value to the current knowledge of the disease mechanisms, as well as their importance in identifying biomarkers or treatment targets.

Lymphocyte activation in silica-exposed workers.

Exposure to silica dust has been examined as a possible risk factor for autoimmune diseases, including systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and ANCA-associated vasculitis. However, the underlying cellular and molecular mechanisms resulting in the increased prevalence of autoimmunity remain elusive. To clarify these mechanisms, we studied various markers of immune activation in individuals occupationally exposed to silica dust, i.e., serum levels of soluble IL-2 receptor (sIL-2R), levels of IL-2, other pro- and anti-inflammatory cytokines and lymphoproliferation. Our results demonstrate that silica-exposed individuals present important alterations in their immune response when compared to controls, as shown by increased serum sIL-2R levels, decreased production of IL-2 and increased levels of the pro-inflammatory (IFN-γ, IL-1α, TNF-α, IL-6) as well as anti-inflammatory (IL-10 and TGF-ß) cytokines. Furthermore, silica-exposed individuals presented enhanced lymphoproliferative responses. Our findings provide evidence that the maintenance of immune homeostasis may be disturbed in silica-exposed individuals, possibly resulting in autoimmune disorders.