Rafael Bojalil

Shift from an early protective Th1-type immune response to a late permissive Th2-type response in murine cysticercosis (Taenia crassiceps).

In early stages of experimental murine cysticercosis caused by Taenia crassiceps, there is a clear but transient Th1-type immune response (characterized by high levels of interleukin [IL]-2, interferon-gamma, concanavalin A, and antigen specific response, delayed-type hypersensitivity, and immunoglobulin [Ig]G2a antibodies) that associates with a low rate of parasite reproduction. As time of infection progresses an energic and more permanent Th2-type response follows (characterized by high levels of IL-4, IL-6, IL-10, IgG2b, and IgG1 antibodies) that in turn associates with an increment in the rate of parasite reproduction. The sequential activation of Th1-type and Th2-type responses in murine cysticercosis would appear to favor progressively parasite reproduction, explaining the long time residence and the massive parasite intensity reached in chronic infections.

Chronic Helminth Infection Induces Alternatively Activated Macrophages Expressing High Levels of CCR5 with Low Interleukin-12 Production and Th2-Biasing Ability

ABSTRACT Helminth infections induce Th2-type biased immune responses. Although the mechanisms involved in this phenomenon are not yet clearly defined, antigen-presenting cells (APC) could play an important role in this process. Here, we have used peritoneal macrophages (F4/80+) recruited at different times after challenge with Taenia crassiceps as APC and tested their ability to regulate Th1/Th2 differentiation. Macrophages from acute infections produced high levels of interleukin-12 (IL-12) and nitric oxide (NO), paralleled with low levels of IL-6 and prostaglandin E2 (PGE2) and with the ability to induce strong antigen-specific CD4+ T-cell proliferation in response to nonrelated antigens. In contrast, macrophages from chronic infections produced higher levels of IL-6 and PGE2 and had suppressed production of IL-12 and NO, associated with a poor ability to induce antigen-specific proliferation in CD4+ T cells. Failure to induce proliferation was not due to a deficient expression of accessory molecules, since major histocompatibility complex class II, CD40, and B7-2 were up-regulated, together with CD23 and CCR5 as infection progressed. These macrophages from chronic infections were able to bias CD4+ T cells to produce IL-4 but not gamma interferon (IFN-γ), contrary to macrophages from acute infections. Blockade of B7-2 and IL-6 and inhibition of PGE2 failed to restore the proliferative response in CD4+ T cells. Furthermore, studies using STAT6−/− mice revealed that STAT6-mediated signaling was essential for the expansion of these alternatively activated macrophages. These data demonstrate that helminth infections can induce different macrophage populations that have Th2-biasing properties.

Variations in circulating cytokine levels during 52 week course of treatment with SSRI for major depressive disorder

Major depressive disorder (MDD) is a psychiatric condition characterized by hypercortisolism and variations in circulatory cytokines. Previously it has been reported that administration of selective serotonin reuptake inhibitors (SSRI) in MDD patients modify cortisol and cytokine levels but these studies only evaluated changes over a short time period. This work reports the long-term effects of administration of SSRI on the cortisol levels and pro-/anti-inflammatory cytokine profile in a group of MDD patients treated for 52 weeks. A total of 31 patients diagnosed with MDD received anti depressant treatment with SSRI. HDRS and BDI were administered over a year, and levels of interleukin IL-1beta, IL-10, IL-2, IFN-gamma, IL-4, IL-13, and 24-h urine cortisol were determined at weeks (W) 0, 5, 20, 36 and 52 of treatment. Before treatment we found high levels of cortisol, IL-4, IL-13 (Th2) and IL-10 in MDD patients when compared with healthy volunteers. At W20 psychiatric scales indicated a remission of the depressive episode concomitantly with increments in IL-2 and IL-1beta but without changes in cortisol. Towards the end of the treatment (W52) we observed a significant reduction (p<0.01) in cortisol levels, with an increment in IL-1beta and IFN-gamma and a decrease in Th2 cytokines. Our results suggest that depressed patients only reach a partial reestablishment of HPA axis function after the long-term administration of SSRI.

Th1-type cytokines improve resistance to murine cysticercosis caused by Taenia crassiceps

Abstract Resistance and susceptibility to different parasitic diseases have been associated with the predominance of Th1- or Th2-type immune responses. In experimental murine cysticercosis a Th1 response seems to be involved in resistance, whereas Th2 activity is associated with heavy parasite intensities. To test this notion the roles of Th1- and Th2-type cytokines in infected mice were studied after treatment with anticytokine monoclonal antibodies or with recombinant murine cytokines during early stages of infection. Mice receiving anti-interleukin 10 (IL-10) carried lower parasite intensities than did control mice and developed a strong Th1-type response, whereas mice receiving anti-interferon gamma (IFN-γ) showed a dramatic increase in susceptibility. Treatment with recombinant cytokines confirmed these results; mice receiving IFN-γ and IL-2 showed low parasite numbers, whereas IL-10 induced a significant increase in parasite loads. Thus, the Th1-type immune response plays a fundamental role in protection against Taenia crassiceps cysticercosis, whereas Th2, at least through IL-10, favors parasite establishment.

Macrophage Migration Inhibitory Factor Plays a Critical Role in Mediating Protection against the Helminth Parasite Taenia crassiceps

ABSTRACT To determine the role of endogenous migration inhibitory factor (MIF) in regulation of immune response during murine cysticercosis caused by the helminth parasite Taenia crassiceps, we analyzed the course of T. crassiceps infection in MIF−/− BALB/c mice. MIF−/− mice were highly susceptible to T. crassiceps and developed significantly higher parasite loads compared to similarly infected MIF+/+ mice. Throughout the course of infection, Taenia crassiceps soluble antigen-stimulated spleen cells from both MIF+/+ and MIF−/− mice produced significant and comparable levels of interleukin-4 (IL-4), but those from MIF−/− mice produced significantly more IL-13, as well as gamma interferon (IFN-γ), suggesting that the susceptibility of MIF−/− mice to T. crassiceps was not due to the lack of IFN-γ production. Interestingly, low levels of both total and specific immunoglobulin G2a were observed in MIF−/− cysticercotic mice despite the high IFN-γ levels; in addition, peritoneal macrophages obtained from T. crassiceps-infected MIF−/− mice at different time points failed to respond efficiently to stimulation in vitro with lipopolysaccharide plus IFN-γ and produced significantly lower levels of IL-12, tumor necrosis factor alpha, and NO compared to those from MIF+/+ mice. These findings demonstrate that MIF plays a critical role in mediating protection against T. crassiceps in vivo. Moreover, these findings also suggest that impaired macrophage function rather than the lack of Th1 development may be responsible for mediating susceptibility to T. crassiceps.

Cutting Edge: Susceptibility to the Larval Stage of the Helminth Parasite Taenia crassiceps Is Mediated by Th2 Response Induced Via STAT6 Signaling

Using STAT6−/− BALB/c mice, we analyzed the role of STAT6-induced Th2 response in determining the outcome of murine cysticercosis caused by the helminth parasite Taenia crassiceps. After T. crassiceps infection, wild-type BALB/c mice developed a strong Th2-like response; produced high levels of IgG1, IgE, IL-4, as well as IL-13; and remained susceptible to T. crassiceps. In contrast, similarly infected STAT6−/− mice mounted a strong Th1-like response; produced high levels of IgG2a, IL-12, IFN-γ, as well as nitric oxide; and efficiently controlled T. crassiceps infection. These findings demonstrate that Th2-like response induced via STAT6-mediated signaling pathway mediates susceptibility to T. crassiceps and, furthermore, that unlike the case in most helminths, immunity against T. crassiceps is mediated by a Th1-like rather than Th2-like response.

A role for 17-beta-estradiol in immunoendocrine regulation of murine cysticercosis (Taenia crassiceps).

In experimental murine cysticercosis caused by Taenia crassiceps, parasite reproduction is favored by thymectomy or by orchidectomy, and restricted by ovariectomy. Hormonal reconstitution experiments showed that 17-beta-estradiol increases parasite numbers whereas 5-alpha-dihydrotestosterone was ineffective. Parasite numbers decreased with increments in cellular immunity but were insensitive to antibody levels. A possible immunoendocrinological interaction involving estrogen as a depressor of cellular immunity is envisaged in the control of cysticercosis.

Thymus-related cellular immune mechanisms in sex-associated resistance to experimental murine cysticercosis (Taenia crassiceps)

The role of sex, thymus, and cellular immune mechanisms in mouse resistance to experimental cysticercosis with Taenia crassiceps was studied in male and female susceptible mice treated with cyclophosphamide, as well as in mice neonatally thymectomized and passively transferred with T-enriched lymphoid cells. High doses of cyclophosphamide increased delayed hypersensitivity and resistance of mice of both sexes without affecting antibody production. Neonatal thymectomy diminished resistance in both sexes but depressed delayed hypersensitivity in females only, without significantly affecting antibody response in either sex. Passive transfer of T-enriched lymphoid cells to thymectomized mice restored resistance to control levels without greatly affecting delayed hypersensitivity. Thus, our results indicate that cell-associated immune mechanisms are implicated in resistance to murine cysticercosis with T. crassiceps. Because neonatal thymectomy nearly equalized the intensity of infection of female and male mice, it is argued that the thymus is importantly involved in the interaction between gonads and the immune system in the control of this cysticercosis.

Susceptibility to Trypanosoma cruzi is modified by a previous non‐related infection

Helminth infections are frequently massive, chronic and strong inductors of Th2‐type cytokines. This implies that infection by such parasites could alter the susceptibility to subsequent infections by other pathogens, particularly intracellular parasites. We therefore explored whether a persistent infection, caused by Taenia crassiceps cysticerci, in BALB/c mice could affect susceptibility to a later infection by Trypanosoma cruzi. We found that the presence of the cysticerci indeed modified the immune response and the susceptibility to T. cruzi, and that these modifications depended on the time‐course evolution of the initial infection. Coinfection with the protozoan in the early stages of the helminth infection, induced a delay on the onset of parasitaemia, early specific production of IFN‐γ and high specific production of IL‐4. A significant increase in susceptibility to T. cruzi was observed only when mice were coinfected in late stages when the helminth load is greater and a Th2 type response against it is predominant. The in vitro specific response to T. cruzi antigens was then characterized by low levels of both IFN‐γ and IL‐4. These findings suggest that chronic helminth infections could potentially have a significant influence over the immune response and hence susceptibility to other pathogens.

Transcript levels of Toll-Like receptors 5, 8 and 9 correlate with inflammatory activity in Ulcerative Colitis

BackgroundDysregulation of innate immune response by Toll-Like Receptors (TLRs) is a key feature in Ulcerative Colitis (UC). Most studies have focused on TLR2, TLR3, and TLR4 participation in UC. However, few studies have explored other TLRs. Therefore, the aim of this study was to evaluate the mRNA profiles of TLR1 to 9 in colonic mucosa of UC patients, according to disease activity.MethodsColonic biopsies were taken from colon during colonoscopy in 51 patients with Ulcerative Colitis and 36 healthy controls. mRNA levels of TLR1 to 9, Tollip, inflammatory cytokines IL6 and TNF were assessed by RT-qPCR with hydrolysis probes. Characterization of TLR9 protein expression was performed by Immunohistochemistry.ResultsToll-like receptors TLR8, TLR9, and IL6 mRNA levels were significantly higher in the colonic mucosa from UC patients (both quiescent and active) as compared to healthy individuals (p < 0.04). In the UC patients group the TLR2, TLR4, TLR8 and TLR9 mRNA levels were found to be significantly lower in patients with quiescent disease, as compared to those with active disease (p < 0.05), whereas TLR5 showed a trend (p = 0.06). IL6 and TNF mRNA levels were significantly higher in the presence of active disease and help to discriminate between quiescent and active disease (p < 0.05). Also, IL6 and TNF mRNA positively correlate with TLRs mRNA with the exception for TLR3, with stronger correlations for TLR5, TLR8, and TLR9 (p < 0.0001). TLR9 protein expression was mainly in the lamina propria infiltrate.ConclusionsThis study demonstrates that TLR2, TLR4, TLR8, and TLR9 expression increases in active UC patients, and that the mRNA levels positively correlate with the severity of intestinal inflammation as well as with inflammatory cytokines.