CXCL13 expression in the gut promotes accumulation of IL-22-producing lymphoid tissue-inducer cells, and formation of isolated lymphoid follicles.

The chemokine CXCL13 is overexpressed in the intestine during inflammation. To mimic this condition, we created transgenic mice-expressing CXCL13 in intestinal epithelial cells. CXCL13 expression promoted a marked increase in the number of B cells in the lamina propria and an increase in the size and number of lymphoid follicles in the small intestine. Surprisingly, these changes were associated with a marked increase in the numbers of RORgammat(+)NKp46(-)CD3(-)CD4(+) and RORgammat(+)NKp46(+) cells. The RORgammat(+)NKp46(-)CD3(-)CD4(+) cells expressed CXCR5, the receptor for CXCL13, and other markers of lymphoid tissue-inducer cells, such as LTalpha, LTbeta, and TNF-related activation-induced cytokine (TRANCE). RORgammat(+)NKp46(-)CD3(-)CD4(+) gut LTi cells produced IL-22, a cytokine implicated in epithelial repair; and expressed the IL-23 receptor, a key regulator of IL-22 production. These results suggest that overexpression of CXCL13 in the intestine during inflammatory conditions favors mobilization of B cells and of LTi and NK cells with immunomodulatory and reparative functions.

Most parasite-specific CD8+ cells in Trypanosoma cruzi-infected chronic mice are down-regulated for T-cell receptor-alphabeta and CD8 molecules.

The present study shows that CD8+ T lymphocytes expressing low levels of T-cell receptor (TCR)alphabeta, CD8 and CD3 accumulate in the spleen, blood, peritoneum and liver, but not in the lymph nodes of mice chronically infected with Trypanosoma cruzi. Analysis of spleen lymphocytes reveals that most CD8LOW TCRLOW T cells have an experienced phenotype (CD44HIGH CD62LLOW and CD45RA,B,CLOW). These cells have small size, lack activation markers such as CD69, CD25 and CD11b (Mac-1), and do not spontaneously secrete cytokines, suggesting they are at the resting state. When stimulated in vitro with T. cruzi-infected macrophages, TCRLOW CD8LOW T cells behave as parasite-specific memory cells, readily responding with interferon-gamma (IFN-gamma) production. Indeed, among parasite-activated CD8+ lymphocytes, IFN-gamma production was mostly due to TCRLOW CD8LOW cells. Upon in vitro stimulation with anti-CD3/CD28 monoclonal antibodies, down-regulated cells produce IFN-gamma and tumour necrosis factor-alpha, but not interleukin IL-10 or IL-4. Our results indicate that despite parasite persistence, most T. cruzi-specific experienced CD8+ cells are resting. Nevertheless, when encountering infected macrophages these cells differentiate to Tc1 effectors.

[Physiology of the urethral sphincteric vesico-prostatic complex]. / Fisiologia del complesso sfinterico vescico-prostatico uretrale.

We propose a review of the literature about innervation and physiology of the urethral sphincteric complex. Parasympathetic innervation of the pelvic viscera comes from ventral branches of the sacral nerves (S2-S4). The orthosympathetic component derives from superior hypogastric plexus and runs down the hypogastric nerves to form the right and left pelvic plexus together with the parasympathetic component. The pelvic plexus is situated inferolaterally with respect to the rectum and runs on the surface of the levator ani muscle down to the prostatic apex. The pelvic plexus gives innervation to the rectum, the bladder, the prostate and the urethral sphincteric complex. The pelvic muscular floor is innervated by the somatic component (pudendal nerve) derived from the sacral branches (S2-S4). Bladder neck and smooth muscle urethral sphincter innervation is given mostly by the orthosympathetic component. The rhabdosphincter innervation comes from the pudendal nerve and from the pelvic plexus; its role in the continence mechanism is probably to give steady tonic urethral compression. Levator ani muscle takes part in the sphincteric complex with its anteromedial pubococcygeal portion. It plays its role strengthening the sphincteric tone during increase of the abdominal pressure or during active quick stop cessation of the urinary stream.

[Personal research: reconstruction of the urethral striated sphincter]. / Ricerca personale: la ricostruzione dello sfintere striato uretrale.

OBJECTIVE: Incontinence is one of the drawbacks of radical prostatectomy. The causes of post-operative incontinence are sphincter deficiency (SD) and bladder dysfunction (BD). SD seems to be the main cause of incontinence and long time to continence. We present a surgical modification of the anatomical radical retropubic prostatectomy consisting in the reconstruction of the posterior aspect of the striated urethral sphincter in order to obtain a quick recovery of continence postoperatively. MATERIALS AND METHODS: Caudal retraction of the urethro-sphincteric complex after apical dissection of the prostate often occurs. Furthermore posterior fibrous raphe interruption can cause shortening of anatomical and functional urethral length and affect continence. In order to avoid caudal retraction of the sphincteric complex, after completing vesico-urethral anastomosis, the posterior emicircumference of the striated sphincter is fixed to the posterior aspect of the bladder one centimeter cranially and posteriorly to the urethro-vesical anastomosis. The rabdosphincter is sutured separately from the urethro-vesical suturing. This technical modification makes it possible to obtain an anatomical length of the urethra of about a centimeter more than with the standard technique, replacing it in a more anatomical position. Furthermore, this technique provides the new posterior platform for the urethro-sphincteric complex. Twenty-four patients with clinical organ confined disease and age range 54-74 years (mean 64 years) underwent Walsh's anatomical radical retropubic prostatectomy with reconstruction of the rabdosphincter (group A). Catheter was removed 7 to 11 days postoperatively. Early continence was assessed objectively with the number of pads per day as follows: 0-1 mini pad = continent; 1-2 pads per day = mild incontinence; 2 or more pads per day = severe incontinence. Continence was evaluated at 3 days and one month after catheter removal. Group A compared to 21 patients (group B) who underwent standard anatomical RPP (historical control group). RESULTS: In group A 16/24 patients (66.7%) and 19/24 patients (79.2%) were continent respectively at three days after removal of the catheter and after one month; mild incontinence (1-2 pads/day) was present in 6/24 patients (25%) and 3/24 (12.5%) respectively, 2/24 patients (8.3%) suffered from severe incontinence after 3 days and one month. In group B 7/21 patients (33%) were continent at hospital discharge, 11/21 (52%) after one month. CONCLUSIONS: Careful reconstruction of the posterior aspects of the rabdosphincter shortens time to continence after RRP.

Influence of acute-phase parasite load on pathology, parasitism, and activation of the immune system at the late chronic phase of Chagas' disease.

To obtain low and high parasite loads in the acute phase of Chagas' disease, A/J mice were infected with 10(3) or 10(5) Trypanosoma cruzi trypomastigotes of the Y strain and treated on day 6 with benznidazol. One year later, chronically infected mice were screened for subpatent parasitemias, tissue pathology, and immune response. Mice infected with the high parasite inoculum showed higher levels of chronic parasitemias, heart and striated muscle inflammation, and activation of the immune system than did mice infected with the low inoculum. Concerning the activation of the immune system, the main findings for high-dose-infected mice were (i) increased numbers of splenocytes, with preferential expansion of CD8(+) and B220(-) CD5(-) cells, many of them bearing a macrophage phenotype; (ii) higher frequencies of B (B220(+)), CD4(+), and CD8(+) large lymphocytes; (iii) a shift of CD4(+) cells towards a CD45RBLow phenotype; (iv) increased frequencies of both CD45RBLow and CD45RBHigh large CD4(+) cells; (v) augmented numbers of total immunoglobulin (Ig)-secreting cells, with predominance of IgG2a-producing cells; and (vi) increased production of gamma interferon and interleukin 4. In addition, these mice presented lower IgM and higher IgG2a and IgG1 parasite-specific serum antibody levels. Our results indicate that the parasite load at the acute phase of T. cruzi infection influences the activation of the immune system and development of Chagas' disease pathology at the late chronic phase of the disease.