Polyclonal Lymphocyte Activation Research Articles

Toxic Shock Syndrome: A Literature Review.

Toxic shock syndrome (TSS) is a rare, life-threatening, toxin-mediated infectious process linked, in the vast majority of cases, to toxin-producing strains of Staphylococcus aureus or Streptococcus pyogenes. The pathophysiology, epidemiology, clinical presentation, microbiological features, management and outcome of TSS are described in this review. Bacterial superantigenic exotoxins induces unconventional polyclonal lymphocyte activation, which leads to rapid shock, multiple organ failure syndrome, and death. The main described superantigenic exotoxins are toxic shock syndrome toxin-1 (TSST-1) and enterotoxins for Staphylococcus aureus and Streptococcal pyrogenic exotoxins (SpE) A, B, and C and streptococcal superantigen A (SsA) for Streptococcus pyogenes. Staphylococcal TSS can be menstrual or nonmenstrual. Streptococcal TSS is linked to a severe group A streptococcal infection and, most frequently, to a necrotizing soft tissue infection. Management of TSS is a medical emergency and relies on early detection, immediate resuscitation, source control and eradication of toxin production, bactericidal antibiotic treatment, and protein synthesis inhibiting antibiotic administration. The interest of polyclonal intravenous immunoglobulin G administration as an adjunctive treatment for TSS requires further evaluation. Scientific literature on TSS mainly consists of observational studies, clinical cases, and in vitro data; although more data on TSS are required, additional studies will be difficult to conduct due to the low incidence of the disease.

A comparative study of human endogenous retrovirus <i>HERV-E λ 4-1</i> activation in autoimmune pathology

Considering the presence of immunomodulatory properties of human endogenous retroviruses, namely (i) the ability to activate the innate immune response by HERVs nucleic acids; (ii) the antigenicity of transcriptionally competent endogenous retroviruses envelope protein molecule, which causes polyclonal activation of lymphocytes; (iii) the absence of HERVs expression and protein production in the thymus during the immune tolerance formation, which allows us to consider these proteins as autoantigens or neoantigens, it seemed relevant to investigate the association of replication-competent human endogenous retrovirus HERV-E λ 4-1 with course of some of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. The aim of this work was a comparative study of the human endogenous retrovirus HERV-E λ 4-1 activation frequency in blood mononuclear cells in multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, as well as in chronic nervous system non-progressive diseases and the degenerative-dystrophic disease of the musculoskeletal system. The peripheral blood mononuclear cells were isolated by the venous blood centrifugation on Ficoll density gradient of 1.078 g/cm3. Expression of the HERV-E λ 4-1 envelope gene was detected by reverse transcriptase polymerase chain reaction. It was found that the HERV-E λ 4-1 envelope gene expression frequency in the chronic non-progressive diseases of nervous system, as well as in degenerative-dystrophic joint disease, is comparable to the expression frequency in conditionally healthy individuals. However, the HERV-E λ 4-1 envelope gene expression frequency in autoimmune diseases significantly exceeded that in conditionally healthy individuals and in non-inflammatory diseases. The maximum values of expression frequency were observed in active multiple sclerosis, significantly higher than in systemic lupus erythematosus and rheumatoid arthritis in the acute stage. Moreover, the expression frequency in the remission stage of multiple sclerosis was significantly lower than in the acute stage of the relapsing-remitted course, as well as in the progredient course. Estimation of HERV-E λ 4-1 envelope gene expression frequency at different severity levels of multiple sclerosis revealed its maximum rates at III and IV-V severity levels, both in relapsing-remitting and progressive course of multiple sclerosis. Thus, activation of the human endogenous retrovirus HERV-E λ 4-1 is associated with the course of autoimmune diseases, namely multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus; it positively correlates with the activity and severity of multiple sclerosis.

Reactivation of chronic brucellosis infection after COVID-19 (case report)

It has been proven that the SARS-CoV-2 virus, interacting with persistent latent pathogens in the human body, including those living in the ecosystems of the intestine, mouth and lungs, causes dysregulation of the immune system and can contribute to the reactivation of these pathogens. The authors of the article suggested this pathogenic virus can play the role of a superantigen and trigger the phenomenon of polyclonal activation of lymphocytes, due to which various clones of lymphocytes may be activated, thereby giving impetus to the reactivation of a chronic persistent infection. This article describes a clinical case of a patient who had previously undergone an effectively treated form of chronic brucellosis in history, with signs of reactivation of brucellosis infection detected after infection with the SARS-CoV-2 virus, confirmed by clinical laboratory and instrumental studies.

MicroRNA-181 Variants Regulate T Cell Phenotype in the Context of Autoimmune Neuroinflammation.

Recent studies have revealed that multiple sclerosis (MS) lesions have distinct microRNA (miRNA) expression profiles. miR-181 family members show altered expression in MS tissues although their participation in MS pathogenesis remains uncertain. Herein, we investigated the involvement of miR-181a and miR-181b in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). miR-181a and -b levels were measured in the central nervous system (CNS) of patients with MS and mice with EAE as well as relevant leukocyte cultures by real-time RT-PCR. To examine the role of the miRNAs in leukocyte differentiation and function, miR-181a and -b mimic sequences were transfected into cultured primary macrophages and purified CD4+ T cells which were then analyzed by RT-PCR and flow cytometry. Luciferase reporter assays were performed to investigate the interaction of miR-181a and -b with the 3'-UTR of potential target transcripts, and the expression of target genes was measured in the CNS of EAE mice, activated lymphocytes, and macrophages. Expression analyses revealed a significant decrease in miR-181a and -b levels in brain white matter from MS patients as well as in spinal cords of EAE mice during the acute and chronic phases of disease. Suppression of miR-181a was observed following antigen-specific or polyclonal activation of lymphocytes as well as in macrophages following LPS treatment. Overexpression of miR-181a and -b mimic sequences reduced proinflammatory gene expression in macrophages and polarization toward M1 phenotype. miR-181a and -b mimic sequences inhibited Th1 generation in CD4+ T cells and miR-181a mimic sequences also promoted Treg differentiation. Luciferase assays revealed Suppressor of mothers against decapentaplegic 7 (Smad7), as a direct target of miR-181a and -b. Our data highlight the anti-inflammatory actions of miR-181a and -b in the context of autoimmune neuroinflammation. miR-181a and -b influence differentiation of T helper cell and activation of macrophages, providing potential therapeutic options for controlling inflammation in MS.

MECHANISMS OF IMMUNOLOGICAL TOLERANCE DISRUPTION

Autoimmune diseases belong to disorders with an unclear etiology. The spectrum of autoimmune diseases is wide, the most well known of them are type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn’s disease, vitiligo, and others. The key role in the development of autoimmune reactions is played by disturbances of immunological homeostasis. Despite numerous researches, the exact mechanisms of autoimmunity still remain unclear. The analysis of data provided by the literature on the mechanisms of disorders of immunological tolerance is presented in the review. The most discussed theories of pathological autoimmune processes development are described: the theory of hereditary predisposition, the theory of immunological dysregulation and regulatory T-cell dysfunction, the theory of network regulation, the infectious theory of autoimmune diseases development (molecular mimicry, polyclonal activation of lymphocytes). The theory of hereditary predisposition reflects the critical role of hereditary factors in the development of autoimmunity, in particular, the data on relations of autoimmune disorders to human major histocompatibility complex are provided. In addition, the data indicating that the development of autoimmune processes in an organism can be associated with changes in the content and function of regulatory T-lymphocytes are provided in the work. These cells are directly involved in the mechanisms of cellular immune responses in autoimmune diseases and may explain the disorders of immunological tolerance, subsequently leading to the development and progression of immunopathology. The idea of idiotype-anti-idiotype interactions, which can serve as a mechanism ensuring normal autoimmune reactions or lead to the activation of autoreactive clones, is revealed in the description of network regulation theory. The infectious theory of development of autoimmune pathologies presented in the review is based on the results of numerous researches and suggests that the viruses can provoke failures of immunity and lead to autoimmunity.

Malaria, a difficult diagnosis in a febrile patient with sub-microscopic parasitaemia and polyclonal lymphocyte activation outside the endemic region, in Brazil

A case of autochthonous Plasmodium vivax malaria with sub-microscopic parasitaemia and polyclonal B-cell activation (PBA) (as reflected by positive IgM and IgG serology for toxoplasmosis, cytomegalovirus, and antinuclear and rheumatoid factors) was diagnosed by polymerase chain reaction (PCR) after consecutive negative rapid diagnostic test results and blood films. The patient, a 44-year-old man from Rio de Janeiro state, Brazil, had visited the Atlantic Forest, a tourist, non-malaria-endemic area where no autochthonous cases of ’bromeliad malaria‘ has ever been described. The characteristic pattern of fever, associated with PBA, was the clue to malaria diagnosis, despite consecutive negative thick blood smears. The study highlights a need for changes in clinical and laboratory diagnostic approaches, namely the incorporation of PCR as part of the current routine malaria diagnostic methods in non-endemic areas.

Autoimmunity and infection in Sjögren's syndrome.

To summarize the recent developments concerning the potential viral pathomechanisms and involvement of viruses in Sjögren's syndrome, and to highlight the areas for future research and therapies. Activated IFN-1 pathway plays an important part in the autoimmune disease process of Sjögren's syndrome; therefore, several therapies aiming to reduce or inhibit the IFN-1 production and its effects may be a target for future treatment plans. Activated aryl hydrocarbon receptor may interact with latent Epstein-Barr virus (EBV) infection, which in turn may predispose to the development of Sjögren's syndrome. It is estimated that the population is 95% positive for EBV serology. Microbial factors may incite autoimmune disease. Although this hypothesis is proven in a few illnesses such as rheumatic fever, there is no definitive evidence of an infectious environmental trigger in Sjögren's syndrome. However, there are circumstantial data with regard to viruses and several potential mechanisms of disease. These include antigen mimicry, polyclonal lymphocyte activation, and infection-mediated innate end-organ inflammation. In addition, hepatitis C virus infection clearly causes a Sjögren's-syndrome-like illness. Data continue to implicate viral infection in the cause of Sjögren's syndrome, but there are no definitive studies incriminating a particular virus.

Trypanosoma cruzi infection induces a massive extrafollicular and follicular splenic B-cell response which is a high source of non-parasite-specific antibodies

Acute infection with Trypanosoma cruzi, the aetiological agent of Chagas' disease, results in parasitaemia and polyclonal lymphocyte activation. It has been reported that polyclonal B-cell activation is associated with hypergammaglobulinaemia and delayed parasite-specific antibody response. In the present study we analysed the development of a B-cell response within the different microenvironments of the spleen during acute T. cruzi infection. We observed massive germinal centre (GC) and extrafollicular (EF) responses at the peak of infection. However, the EF foci were evident since day 3 post-infection (p.i.), and, early in the infection, they mainly provided IgM. The EF foci response reached its peak at 11 days p.i. and extended from the red pulp into the periarteriolar lymphatic sheath. The GCs were detected from day 8 p.i. At the peak of parasitaemia, CD138(+) B220(+) plasma cells in EF foci, red pulp and T-cell zone expressed IgM and all the IgG isotypes. Instead of the substantial B-cell response, most of the antibodies produced by splenic cells did not target the parasite, and parasite-specific IgG isotypes could be detected in sera only after 18 days p.i. We also observed that the bone marrow of infected mice presented a strong reduction in CD138(+) B220(+) cells compared with that of normal mice. Hence, in acute infection with T. cruzi, the spleen appears to be the most important lymphoid organ that lodges plasma cells and the main producer of antibodies. The development of a B-cell response during T. cruzi infection shows features that are particular to T. cruzi and other protozoan infection but different to other infections or immunization with model antigens.

Specific Humoral Immunity versus Polyclonal B Cell Activation in Trypanosoma cruzi Infection of Susceptible and Resistant Mice

BackgroundThe etiologic agent of Chagas Disease is Trypanosoma cruzi. Acute infection results in patent parasitemia and polyclonal lymphocyte activation. Polyclonal B cell activation associated with hypergammaglobulinemia and delayed specific humoral immunity has been reported during T. cruzi infection in experimental mouse models. Based on preliminary data from our laboratory we hypothesized that variances in susceptibility to T. cruzi infections in murine strains is related to differences in the ability to mount parasite-specific humoral responses rather than polyclonal B cell activation during acute infection.Methodology/Principal FindingsRelatively susceptible Balb/c and resistant C57Bl/6 mice were inoculated with doses of parasite that led to similar timing and magnitude of initial parasitemia. Longitudinal analysis of parasite-specific and total circulating antibody levels during acute infection demonstrated that C57Bl/6 mice developed parasite-specific antibody responses by 2 weeks post-infection with little evidence of polyclonal B cell activation. The humoral response in C57Bl/6 mice was associated with differential activation of B cells and expansion of splenic CD21highCD23low Marginal Zone (MZ) like B cells that coincided with parasite-specific antibody secreting cell (ASC) development in the spleen. In contrast, susceptible Balb/c mice demonstrated early activation of B cells and early expansion of MZ B cells that preceded high levels of ASC without apparent parasite-specific ASC formation. Cytokine analysis demonstrated that the specific humoral response in the resistant C57Bl/6 mice was associated with early T-cell helper type 1 (Th1) cytokine response, whereas polyclonal B cell activation in the susceptible Balb/c mice was associated with sustained Th2 responses and delayed Th1 cytokine production. The effect of Th cell bias was further demonstrated by differential total and parasite-specific antibody isotype responses in susceptible versus resistant mice. T cell activation and expansion were associated with parasite-specific humoral responses in the resistant C57Bl/6 mice.Conclusions/SignificanceThe results of this study indicate that resistant C57Bl/6 mice had improved parasite-specific humoral responses that were associated with decreased polyclonal B cell activation. In general, Th2 cytokine responses are associated with improved antibody response. But in the context of parasite infection, this study shows that Th2 cytokine responses were associated with amplified polyclonal B cell activation and diminished specific humoral immunity. These results demonstrate that polyclonal B cell activation during acute experimental Chagas disease is not a generalized response and suggest that the nature of humoral immunity during T. cruzi infection contributes to host susceptibility.

Warm Autoimmune Hemolytic Anemia: Recent Progress in Understanding the Immunobiology and the Treatment

Autoimmune hemolytic anemia (AIHA) is defined as a condition associated with the increased destruction of red blood cells (RBCs) associated with the presence of IgG anti-RBC autoantibodies. The etiology underlying the pathogenesis of such autoantibodies is still uncertain. In the present article, we will discuss the postulated mechanisms that produce a breakdown of immunologic tolerance leading to warm AIHA including the possible roles of RBC autoantigens and the complement system, the lack of effective presentation of autoantigens, functional abnormalities of B and T cells resulting in polyclonal lymphocyte activation and alteration of cytokine production, and the role of immunoregulatory T cells. Because warm AIHA is a relatively rare clinical entity, current recommended therapeutic strategies for patients with warm AIHA are mainly based on results from small cohort studies. Clinicians must also balance the risk of withholding RBC transfusions against the possible benefit of ameliorating the hemoglobin level with such transfusions particularly in critically ill patients with warm AIHA. Glucocorticoids are the first-line treatment for patients with warm AIHA resulting in an 80% clinical response after 3 weeks of treatment. The latter, however, also may cause adverse events such as excessive weight gain, neuropsychiatric disorders, endocrine, or cardiovascular events. Splenectomy should be considered for patients who do not show a satisfactory response to glucocorticoids and may offer a success rate of up to 70% in patients with idiopathic warm AIHA. Rituximab treatment in patients with refractory warm AIHA has been well tolerated with an overall median response rate of approximately 60%. Danazol, intravenous immunoglobulin, alemtuzumab, as well as other immunosuppressive drugs have also been successfully used in patients with warm AIHA, refractory to glucocorticoids, splenectomy, and rituximab.

PTPN22 Deficiency Cooperates with the CD45 E613R Allele to Break Tolerance on a Non-Autoimmune Background

Pep and CD45 are tyrosine phosphatases whose targets include the Src-family kinases, critical mediators of Ag receptor signaling. A polymorphism in PTPN22, the gene that encodes the human Pep orthologue Lyp, confers susceptibility to multiple human autoimmune diseases in the context of complex genetic backgrounds. However, the functional significance of the R620W risk allele is not clear. We report that misexpression of wild-type or R620W Pep/Lyp in Jurkat cells, in the context of its binding partner Csk, unmasks the risk allele as a hypomorph. It has been shown previously that although Pep-deficient mice on the B6 background have hyperresponsive memory T cells, autoimmunity does not develop. Mice containing a point mutation in the CD45 juxtamembrane wedge domain (E613R) develop a B cell-driven, lupus-like disease on the mixed 129/B6 background, but not on the B6 background. We studied the ability of Pep deficiency to act as a genetic modifier of the CD45 E613R mutation on the nonautoimmune B6 background to understand how complex susceptibility loci might interact in autoimmunity. In this study we report that double mutant mice develop a lupus-like disease as well as lymphadenopathy, polyclonal lymphocyte activation, and accelerated memory T cell formation. Following Ag receptor stimulation, peripheral B cells in the double mutant mice phenocopy hyperresponsive CD45 E613R B cells, whereas peripheral T cells respond like Pep(-/-) T cells. These studies suggest that Pep(-/-) T cells in the context of a susceptible microenvironment can drive hyperresponsive CD45 E613R B cells to break tolerance.

Viral Commensalism in Humans?

Viral Commensalism in Humans?

A Leishmania infantum cytosolic tryparedoxin activates B cells to secrete interleukin‐10 and specific immunoglobulin

The immune evasion mechanisms of pathogenic trypanosomatids involve a multitude of phenomena such as the polyclonal activation of lymphocytes, cytokine modulation and the enhanced detoxification of oxygen reactive species. A trypanothione cascade seems to be involved in the detoxification process. It was recently described and characterized a tryparedoxin (LiTXN1) involved in Leishmania infantum cytoplasmatic hydroperoxide metabolism. LiTXN1 is a secreted protein that is up-regulated in the infectious form of the parasite, suggesting that it may play an important role during infection. In the present study, we investigated whether recombinant LiTXN1 (rLiTXN1) affects T- and B-cell functions in a murine model. We observed a significant increase in the CD69 surface marker on the B-cell population in total spleen cells and on isolated B cells from BALB/c mice after in vitro rLiTXN1 stimulus. Activated B-cells underwent further proliferation, as indicated by increased [(3)H]thymidine incorporation. Cytokine quantification showed a dose-dependent up-regulation of interleukin (IL)-10 secretion. B cells were identified as a source of this secretion. Furthermore, intraperitoneal injection of rLiTXN1 into BALB/c mice triggered the production of elevated levels of rLiTXN1-specific antibodies, predominantly of the immunoglobulin M (IgM), IgG1 and IgG3 isotypes, with a minimum reactivity against other heterologous antigens. Taken together, our data suggest that rLiTXN1 may participate in immunopathological processes by targeting B-cell effector functions, leading to IL-10 secretion and production of specific antibodies.

Autoantibodies in patients treated for active pulmonary tuberculosis

The genesis of auto-immune antibodies directed against the own tissue antigens of a host may be due to the host's immune response to mycobacteria. The prospective study included 110 patients treated for active pulmonary tuberculosis and the control group of 60 healthy subjects, volontary blood donors. Applying the method of indirect immnunofluorescence and cryostat sections of rat organs and human larynx cancer epithelial cell line (HEp-2 cells), the prescence of the following autoantibodies in the serum of the examined patients was examined: anti,nclear (ANA), anticardiac (ACA), antimitochondrial (AMA), antiparietal (APA), anti smooth muscular (ASMA), antithyroidal (ATA), rheumnatoid factor (RF). These autoantibodies were determined in the course oftreatment and five years later. Low levels of some examined autoantibodies were detected in the serum of a number of the examined patients. No significant difference in the presence of the analysed antibodies was registered between the sexes. In the course of the treatment a reversible hyper-gammaglobulinemia developed, which was at least partially due to the presence of autoantibodies in the patients blood serum. Besides possibly involved mechanisms of molecular mimicry and polyclonal lymphocyte activation, the presence of antinuclear antibodies in the patient's serum is at least partially due to isoniazide treatment. The finding of other autoantibodies is nonspecific and not related to the mycobacterial infection or antituberculosis drug administration.

Influence of Linseed and Fish Oil on Metabolic and Immunological Indicators of Laying Hens

The metabolic and immunological indicators were determined in the blood of laying hens of ISA BROWN hybrid divided into three groups, the control group and two experimental groups. The administration of n-3 polyunsaturated fatty acids (PUFA) in the form of linseed (Group 1) and fish oil (Group 2) and α-tocopherol as antioxidant to laying hens resulted in a significant increase in concentrations of high density lipoproteins (HDL) cholesterol (P < 0.05), eicosapentaenoic (EPA), docosahexaenoic (DHA) and α-linolenic acids (AA) in blood in comparison to the control group. Significantly lower levels of cholesterol (CHOL) were determined in both experimental groups at the third sampling (P < 0.05) and arachidonic acid (AA) in the fish group (P < 0.01). The metabolic activity of phagocytes and polyclonal activation of lymphocytes showed no significant differences and remained within the physiological range. Oral administration of n-3 PUFA showed no significant increase of the immune response of experimental animals.

A B lymphocyte mitogen is aBrucella abortusvirulence factor required for persistent infection

Microbial pathogens with the ability to establish chronic infections have evolved strategies to actively modulate the host immune response. Brucellosis is a disease caused by a Gram-negative intracellular pathogen that if not treated during the initial phase of the infection becomes chronic as the bacteria persist for the lifespan of the host. How this pathogen and others achieve this action is a largely unanswered question. We report here the identification of a Brucella abortus gene (prpA) directly involved in the immune modulation of the host. PrpA belongs to the proline-racemase family and elicits a B lymphocyte polyclonal activation that depends on the integrity of its proline-racemase catalytic site. Stimulation of splenocytes with PrpA also results in IL-10 secretion. Construction of a B. abortus-prpA mutant allowed us to assess the contribution of PrpA to the infection process. Mice infected with B. abortus induced an early and transient nonresponsive status of splenocytes to both Escherichia coli LPS and ConA. This phenomenon was not observed when mice were infected with a B. abortus-prpA mutant. Moreover, the B. abortus-prpA mutant had a reduced capacity to establish a chronic infection in mice. We propose that an early and transient nonresponsive immune condition of the host mediated by this B cell polyclonal activator is required for establishing a successful chronic infection by Brucella.

Atrophy of mesenteric lymph nodes in experimental Chagas’ disease: differential role of Fas/Fas-L and TNFRI/TNF pathways

It is currently accepted that experimental acute infection by Trypanosoma cruzi promotes changes in secondary lymphoid organs, with general T and B lymphocyte polyclonal activation. Here we show that mesenteric lymph nodes (MLN) of acutely infected mice show severe atrophy due to extensive lymphocyte apoptosis. Accordingly, clusters of apoptotic cells are detected in the initial phase of infection in MLN but not in subcutaneous nodes. Moreover, such atrophy is independent of the infection route, parasite load or the mouse strain used. Studies in Fas-L deficient (BAL B gld/gld +/+ ) and in TNF type 1 receptor (p55 –/– ) knockout mice indicate that both molecules are involved in MLN atrophy: Fas-L participates in cell death of CD4 + as well as B lymphocytes, whereas the TNF type 1 receptor is important for the apoptosis of CD4 + and CD8 + T lymphocytes. In contrast, perforin does not play a role, as lymph nodes from perforin-deficient mice do not behave differently from the corresponding wild types. Our data support the concept that, even in a systemic infection, differential (even opposing) responses can be found in different lymph node chains.

Trypanosoma cruzi proline racemases are involved in parasite differentiation and infectivity

Polyclonal lymphocyte activation is one of the major immunological disturbances observed after microbial infections and among the primary strategies used by the parasite Trypanosoma cruzi to avoid specific immune responses and ensure survival. T. cruzi is the insect-transmitted protozoan responsible for Chagas' disease, the third public health problem in Latin America. During infection of its mammalian host, the parasite secretes a proline racemase that contributes to parasite immune evasion by acting as a B-cell mitogen. This enzyme is the first described eukaryotic amino acid racemase and is encoded by two paralogous genes per parasite haploid genome, TcPRACA and TcPRACB that give rise, respectively, to secreted and intracellular protein isoforms. While TcPRACB encodes an intracellular enzyme, analysis of TcPRACA paralogue revealed putative signals allowing the generation of an additional, non-secreted isoform of proline racemase by an alternative trans-splicing mechanism. Here, we demonstrate that overexpression of TcPRAC leads to an increase in parasite differentiation into infective forms and in its subsequent penetration into host cells. Furthermore, a critical impairment of parasite viability was observed in functional knock-down parasites. These results strongly emphasize that TcPRAC is a potential target for drug design as well as for immunomodulation of parasite-induced B-cell polyclonal activation.

IL-10 and the Cytokine Network in the Pathogenesis of Human Autoimmune Hemolytic Anemia

In animal and human autoimmune hemolytic anemia (AIHA) immunologic tolerance loss against RBC self-antigens could be originated by several mechanisms: ignored self-antigens' epitopes, polyclonal lymphocyte activation, molecular mimicry between self- and foreign antigens, central or peripheral tolerance errors, or immunoregulatory disturbances including the alteration of a cytokine network. To identify the immunologic factors contributing to autoimmune onset and maintenance, several murine strains (such as NZB and NZB/NZW) that spontaneously develop a complex autoimmune syndrome, including AIHA, have been extensively studied. In human AIHA, the respective roles of IL-2, IL-4, IFN-gamma, IL-10, and IL-12 were investigated by examining the spontaneous and mitogen-induced (OKT3 or LPS) production of these cytokines. ELISA methods were used in PBMCs to evaluate whether the manipulation of IL-10/IL-12 balance can have an effect on the incidence of autoimmune diseases and whether this might be useful for the control of AIHA. Results affirmed that AIHA is a disease that exhibits an increased basal synthesis of IL-4 and decreased levels of IFN-gamma by AIHA PBMCs compared with controls and that there is a basal increase of Th2 cytokines. Th1-type cytokine decrease in the basal state occurred in parallel with an increase of constitutive IL-10 production and an IL-12 decrease. In conclusion, decreased production of Th1-type cytokines and the production of autoantibodies in AIHA may be secondary to the imbalance between IL-10 and IL-12, and the neutralization of IL-10 may be efficacious in diminishing the clinical pathology associated with Th2 subset prevalence. In the same way, the treatment with IL-12 could offer a second and independent level of blockade against the consequences of the overstimulation of B cells associated with AIHA.

Differential infectivity and immunopathology in murine experimental infections by two natural clones belonging to theTrypanosoma cruziI lineage

Immunopathology of Chagas' disease in Balb/c mice infected with 2 Trypanosoma cruzi clones, belonging to the T. cruzi I lineage and presenting different in vitro virulence (P/209 cl1 > SO34 c14) was compared. In the acute phase, evading mechanisms such as parasite-induced lymphocyte polyclonal activation and T cell immunosuppression were higher in mice infected with the clone giving a higher parasitaemia (P/209 cl1). A similar increase of non-specific isotypes was observed in both infections with IgG2a prevalence. Interestingly, CD8+ cell hypercellularity and lymphocyte immunosuppression were observed during the chronic phase (245 days post-infection) in mice infected by the most virulent clone. In the same way, the parasite-specific antibody response was more intense in P/209 cl1-infected mice over the acute phase. During the chronic phase this response remarkably dropped down in SO34 cl4-infected mice exclusively. Finally, P/209 cl1-infected mice presented a more severe inflammation and tissue damage in heart and quadriceps than SO34 cl4-infected mice. This comparative study showed differences between the two clones: a higher virulence in vivo being clearly associated with a greater ability to induce evasion mechanisms and severe tissue damage.