[Innate and adaptative immunity of the female genital tract]. / Immunité innée et adaptative du tractus génital féminin.

Most of molecules and cells involved in both types, innate and adaptive immunity are present within the feminine genital tract. This article attempts to list some of the various actors involved in these immunities, essentially at the vaginal level and to illustrate their implications in the most frequent pathologies. Among these molecules: defensins, collectins lysozyme, lactoferrin, calprotectin, SLP1, HSP and many others as well as Toll receptors and immunoglobulins (IgG and IgA) play a major role. Epithelial cells, antigen presenting cells, lymphocytes T, B, NK also contribute efficiently to the defenses in a coordinated way partially under the influence of sex hormones. The therapeutic perspectives, of which vaccines are briefly mentioned.

Duodenal villous atrophy: a cause of chronic diarrhea after solid-organ transplantation.

Persistent diarrhea is commonly observed after solid organ transplantation (SOT). A few cases of mycophenolate mofetil (MMF)-induced duodenal villous atrophy (DVA) have been previously reported in kidney-transplant patients with chronic diarrhea. Herein, we report on the incidence and characteristics of DVA in SOT patients with chronic diarrhea. One hundred thirty-two SOT patients with chronic diarrhea underwent an oesophago-gastroduodenoscopy (OGD) and a duodenal biopsy after classical causes of diarrhea have been ruled out. DVA was diagnosed in 21 patients (15.9%). It was attributed to mycophenolic acid (MPA) therapy in 18 patients (85.7%) (MMF [n = 14] and enteric-coated mycophenolate sodium [n = 4]). MPA withdrawal or dose reduction resulted in diarrhea cessation. The incidence of DVA was significantly higher in patients with chronic diarrhea receiving MPA compared to those who did not (24.6% vs. 5.1%, p = 0.003). DVA was attributed to a Giardia lamblia parasitic infection in two patients (9.5%) and the remaining case was attributed to azathioprine. In these three patients, diarrhea ceased after metronidazole therapy or azathioprine dose reduction. In conclusion, DVA is a frequent cause of chronic diarrhea in SOT recipients. MPA therapy is the most frequent cause of DVA. An OGD should be proposed to all transplant recipients who present with persistent diarrhea.

Incidence and predictive factors for infectious disease after rituximab therapy in kidney-transplant patients.

Rituximab off-label use includes organ transplantation. We review the occurrence of infectious disease and its outcome after rituximab therapy. Between April 2004 and August 2008, 77 kidney-transplant patients received rituximab therapy [2-8 courses (median 4) of 375 mg/m2 each] for various reasons. Their results were compared with a control group (n=902) who had received no rituximab. After a median follow-up of 16.5 (1-55) months for rituximab patients and 60.9 (1.25-142.7) months for control patients, the incidence of infectious disease was 45.45% and 53.9% (ns), respectively. The incidence of bacterial infection was similar between the two groups, whereas the viral-infection rate was significantly lower, and the rate of fungal infection was significantly higher in the rituximab group. Nine out of 77 patients (11.68%) died after rituximab therapy, of which seven deaths (9.09%) were related to an infectious disease, compared to 1.55% in the controls (p=0.0007). In the whole population, the independent predictive factors for infection-induced death were the combined use of rituximab and antithymocyte-globulin given for induction or anti-rejection therapy, recipient age, and bacterial and fungal infections. After kidney transplantation, the use of rituximab is associated with a high risk of infectious disease and death related to infectious disease.

HLA class I antibodies provoke graft arteriosclerosis in human arteries transplanted into SCID/beige mice.

Antibodies toward HLA class I and/or MICA are commonly observed in transplanted patients suffering from allograft arteriosclerosis, also called chronic vascular rejection (CVR). The relative importance of cellular versus humoral alloreactivity for CVR is still disputed. We demonstrate that antibodies toward HLA class I provoke lesions typical for CVR in human arteries in vivo in the absence of cellular immunity. To show this, we grafted segments of human mesenteric arteries from 8 deceased organ donors into 36 immunodeficient SCID/beige mice in the infrarenal aortic position. Three mice died postoperatively. The remaining 33 mice received weekly i.v. injections of either a monoclonal antibody toward HLA class I, toward MICA or an irrelevant monoclonal antibody. At sacrifice after 6 weeks, mice receiving the HLA antibody showed a significant neointimal thickening in the grafted artery due to smooth muscle cell (SMC) proliferation while control mice receiving anti-MICA or irrelevant antibody showed little or no thickening. Whereas antibodies toward HLA class I were mitogenic to SMC in vitro, those directed toward MICA did not have any effect. Humoral alloreactivity toward HLA may thus play a causal role for the development of CVR and this opens new possibilities for the treatment of CVR.

Microsatellite typing of the human leucocyte antigen region: analytical approach and contribution to rheumatoid arthritis immunogenetic studies.

Within the major histocompatibility complex (MHC), the human leucocyte antigen (HLA)-DRB1 locus is clearly associated with rheumatoid arthritis (RA). Using a microsatellite (MSat) typing approach, we aimed to identify other loci associated with RA susceptibility and/or severity within the MHC. A panel of nine MSat HLA loci [D6S291, D6S2876 (G51152), D6S1666 (DQCAR II), D6S273, D6S2789 (TNFd), D6S2810 (MIB), D6S265, D6S2222, D6S2239], and HLA-A, -B and -DRB1 genes were typed in 170 RA cases and 282 controls. For susceptibility analysis, MSat and HLA allele distribution were compared between cases and controls, before and after stratification on HLA-DRB1*04. Haplotype frequencies were estimated using an expectation-maximization algorithm in a permutation test procedure. For severity analysis, we compared the distribution of structural damage score at onset and after 4 years of follow-up in RA cases carrying susceptibility alleles. Two MSat polymorphisms were positively associated with RA susceptibility: allele*136 of D6S265 [odds ratio, OR (confidence interval, CI) = 1.55 (1.11-2.17), P= 0.007], allele*116 of D6S2239 [OR = 1.34 (1-1.79), P= 0.03] and HLA-A2 [OR = 1.46 (1.08-1.98), P= 0.01]. Two MSat polymorphisms were negatively associated with RA susceptibility: allele*133 of D6S273 [OR = 0.3 (0.1-0.75), P= 0.005] and allele*177 of D6S291 [OR = 0.72 (0.53-0.96), P= 0.02]. The association between allele*136 of D6S265 and RA susceptibility remained unchanged after stratification on HLA-DRB1*04. The haplotypic analysis showed an overrepresentation of D6S265*136/HLA-A*02 haplotype, which suggests an effect independent of HLA-DRB1 locus in RA susceptibility. While HLA-A2 and HLA-DR4 were associated with RA severity, no MSat polymorphism was associated with structural damage score.

Molecular markers of cartilage breakdown and synovitis at baseline as predictors of structural progression of hip osteoarthritis. The ECHODIAH Cohort.

OBJECTIVE: To determine whether systemic markers of bone, cartilage, and synovium can predict structural progression of osteoarthritis (OA). METHODS: Patients with painful hip OA were treated with diacerein or placebo in a multicentre, prospective, double blind, 3 year follow up trial. The following information was collected at entry: demographics, characteristics of hip OA, and 10 markers: N-propeptides of collagen types I and III, cartilage oligomeric matrix protein, YKL-40, hyaluronan (sHA), matrix metalloproteinases-1 and -3, C reactive protein, C-terminal crosslinking telopeptides of collagen types I and II (uCTX-II). Radiographs were obtained at entry and every year. Structural progression was defined as a joint space decrease > or =0.5 mm or requirement for total hip replacement. Grouped survival analysis was performed with time to structural progression as dependent variable, and clinical data, radiographic findings, treatment groups (diacerein versus placebo), and markers as explanatory measures. RESULTS: In the 333 patients in whom all markers were measured, high functional impairment, a joint space width <2 mm, and lateral migration of the femoral head at baseline increased the risk of progression, but diacerein had a protective effect (relative risk = 0.75; 95% confidence interval (CI) 0.54 to 0.96). In addition, patients in whom uCTX-II and sHA were in the upper tertile had a relative risk of progression of 3.73 (95% CI 2.48 to 5.61) compared with patients with markers in the two lower tertiles. CONCLUSION: In this large cohort, combined measurements of uCTX-II and sHA were a new predictor of the structural progression of hip OA.

Long-term evolution of lymphocytes subsets after induction therapy based on continuous versus discontinuous administration of anti-thymocyte globulins in renal-transplant patients.

UNLABELLED: The aim of our retrospective study was to assess the long-term evolution of lymphocyte subsets after two modes of administration of anti-thymocyte globulin (ATG) after renal transplantation. METHODS: Before 1993, patients (group I, n = 93) received fixed doses of RATG (1 mg/kg per day) for 8 consecutive days. Thereafter, RATG was either continued at the same dose for 15 days, in cases of delayed graft function, or was infused every other day at the same dose until the serum creatinine level became <150 micromol/L. After 1993, patients (group II, n = 66) received RATG at full dose (1 mg/kg per day) during the first 3 days and, thereafter, doses were adapted to target a CD2 T-cell count <50/mm3. RATG cumulative dose was significantly higher among group I than group II (9.7 +/- 4.5 versus 7.4 +/- 3.2 mg/kg, P = .0002). RESULTS: In both groups, total lymphocyte and T lymphocyte subset (CD4, CD8, CD2, CD3) counts decreased significantly during the first month after transplantation, increasing slowly between the first month and the third year posttransplantation. Thereafter it rose rapidly, which was greater in group II. At last follow up, total lymphocyte, T lymphocyte subsets and NK cell counts were similar to those observed before transplantation. At all monitoring times, T lymphocyte, B lymphocyte, and NK cell counts were similar in both group, except for the total lymphocyte count at 6 months and CD4 T lymphocyte count at 1 year, which were significantly higher in group II compared to group I. CONCLUSION: Induction therapy based on continuous or discontinuous administration of ATG is associated with profound depletion of T, B, and NK cells during the first 3 years, followed by a progressive reconstitution of the lymphocyte pool after 5 years.

A third renal transplantation: is it relevant and is it worth it?

INTRODUCTION: The aim of this retrospective study was to determine the outcome of third cadaveric renal transplantations performed between 1989 and 2004 among a cohort of 35 patients whose immunosuppression included induction therapy and calcineurin inhibitors. Most patients were highly sensitized with 1 (0-4) HLA (classes I + II) incompatibility between donor and recipient. RESULTS: The median follow-up time was 57 months (range, 1-190). Fourteen patients experienced delayed graft function that required posttransplantation hemodialysis. The current patient and graft survival rates were 91.4% and 82.8%, respectively. At last follow-up, 6 grafts had been lost: 1 due to primary nonfunction; 1 due to an urinary leak (day 45); 2 deaths with functioning grafts; and 2 chronic allograft nephropathies (CAN) at 85 and 60 months posttransplantation, respectively. Among the 10 patients who experienced acute rejection episodes, half were steroid-sensitive, whereas the others required OKT3 therapy. Overall, when excluding the 2 patients who presented with early loss of their grafts, 13 of 33 patients (39.4%) developed CAN, which led to the graft loss in only 2 cases. The mean creatinine clearance was 57 +/- 23 mL/min at year 5. Of the 35 recipients, 12 (34.3%) developed graft/perigraft complications, among whom 10 (83.3%) required treatment. The most frequent complication was lymphocele (M = 4; 11.4%) or infections that led to rehospitalization (n = 17). CONCLUSION: Results from third transplantations were encouraging. Thus, despite the organ shortage, a third graft was worth it!

[Association between the A2 allele of the HLA system and age at onset of Alzheimer's disease]. / Association entre allèle A2 du système HLA et âge de début de la maladie d'Alzheimer.

OBJECTIVE: Alzheimer is a multifactor disease occurring in a sensitive genetic territory. The e4 allele of the apolipoprotein E (APO E) is a recognised factor of risk. Some studies have suggested an association between the A2 allele of the HLA system and an earlier onset of the disease notably when it appears before the age of 64 or after the age of 75. The aim of our study was to explore this hypothesis in an independent sample of patients. METHODS: We compared the influence of the A2 allele of the HLA system on the age at onset of the disease in two groups of Caucasian patients presenting with Alzheimer's disease: early onset if the disease appeared before the age of 60 (n= 31) and late onset if it had appeared after the age of 75 (n= 44). The influence of the e4 allele of APO E was also taken into account. RESULTS: The comparison of the patients depending on the presence or not of at least one HLA-A2 allele revealed no significant difference, whatever the group of patients studied, in the age at onset of the disease. CONCLUSION: The age at onset of Alzheimer's disease was not influenced in our study by the presence of the HLA-A2 allele.

Use of prick-tests in the screening of immediate allergy to protein: 16 cases.

BACKGROUND: Allergy to protein hydrolysates seem to be on the rise but screening is difficult because of the wide range of symptoms. The goal of our study was to improve the screening process by skin prick testing infants with an anaphylactic form of allergy to cow's milk. METHODS: We studied 92 infants who were allergic to cow's milk. The diagnosis was based on the results of skin prick tests, specific IgE assays, and oral food challenges. The skin prick tests were performed using a number of protein hydrolysate formulae and a synthetic amino acid-based formula available in France. RESULTS: We detected sensitisation to the hydrolysates in 16 infants (17.3%), 15 by positive skin prick tests and one due to persistent symptoms on protein hydrolysate formulae (gastrointestinal manifestations, atopic dermatitis, and multiple food allergies), which completely receded when the synthetic amino acid formula was used as a substitute. Two infants had a positive hydrolysate oral food challenge test. There were no statistically significant differences in terms of age, sex, breastfeeding, clinical manifestations, family history, skin reaction size, or associated allergies. The infants who were sensitised to the hydrolysates had significantly higher specific IgE levels (whole milk,(_)-lactalbumin, and casein; median = 25.6 kU/L for cow's milk, p = 0.03) than those who were allergic to cow's milk but not sensitised to the hydrolysates. CONCLUSIONS: Skin prick tests can be used to screen for sensitisation to hydrolysates in infants with IgE-mediated cow's milk allergy. They can also be used to determine the most suitable hydrolysate formula for individual infants.

Lack of effect of chronic hepatitis C virus infection on T-cell cytokine production in chronic hemodialysis patients.

It has been shown that chronic hemodialysis modifies, to some extent, the normal immune response by both T and B lymphocytes elicited by antigenic stimulation, e.g. by impairing the T-cell-dependent response after vaccination. A new technique, i.e. flow cytometry, enables to assess intracytoplasmically, at the single cell level, the production of a given cytokine. By using it, we studied in healthy volunteers (HV) and in chronic hemodialysis (CHD) patients, with respect to their hepatitis C virus (HCV) status, the production by the T lymphocytes of type 1, and type 2 cytokines. We studied the following cytokines (CK): IL-2, IL-4, IL-5, IL-6, IL-10, IFN-gamma and TNF-alpha in the T-cell lymphocytes (whole, CD4+ and CD8+). There were 13 HV and 59 CHD patients (36 HCV(-) and 23 HCV(+)). Amongst the latter, there were 32 men and 27 women, aged 59.5 +/- 2 years, undergoing CHD since 70 +/- 9.4 months. We found that: (1) the total number of lymphocytes as well as those expressing CD3, CD4, or CD19 were significantly decreased in CHD patients as compared to those from HV; (2) the total number of lymphocytes as well as their different subsets were similar in HCV(+) and in HCV(-) CHD patients; (3) the frequency of T-cell-expressing IL-5 or IL-10 was always low (<1%) in both HV and CHD groups; (4) overall in CHD patients, the mean percentages of T lymphocytes expressing IL-2, IL-4, IFN-gamma or TNF-alpha were respectively 31 +/- 13, 2.5 +/- 1.3, 28 +/- 12 and 34 +/- 11% and were not statistically different between HCV(+) and HCV(-) patients; (5) IL-2 was mainly produced by CD4+ T cells, whereas IFN-gamma was produced by CD8+ T cells, in both HV and CHD groups, and (6) the lymphocytes of CHD patients produced significantly more IL-2 and IL-4 than those from HV, suggesting an activation of their T lymphocytes. We conclude that using the cytokine flow cytometry assay, our study demonstrated that in HCV(+) CHD patients, as opposed to what has been described for HCV(+) patients with normal renal function, there was no impairment in the production of type 1 cytokines by peripheral blood mononuclear cells when compared to HCV(-) CHD patients. Conversely to HV, T lymphocytes from CHD patients are activated.

[Kidney transplantation. Results and indications]. / Transplantation rénale. Résultats et indications.

Results of renal transplantation are better than those of dialysis. The indications of transplantation are constantly increasing and comprise more and more populations at risk, notably older patients and diabetics. Specific evaluation of such potential recipients can lead to indication for transplantation and registry on the waiting list. The insufficient number of available cadaver kidneys leads to harvesting borderline organs particularly from the elderly or patients with vascular disease. Before definite decision for transplantation is made, case-by-case evaluation has to be made of the potential risks of donor-recipient matching regarding the risk/benefit for the recipient. Only a significant increase in the number of available organs will relieve the constraints of the problem.

Value of investigation in the diagnosis of allergic fungal rhinosinusitis: results of a prospective study.

The authors report a prospective study in which the aim was to analyse the usefulness of different criteria in optimizing the diagnosis of allergic fungal rhinosinusitis. From 1995 to 1998, 165 patients were operated on for chronic rhinosinusitis. Investigations used in this study for the diagnosis of allergic Aspergillus rhinosinusitis consisted of an analysis of clinical, radiological, immuno-allergic criteria. Fourteen patients presented with allergic Aspergillus rhinosinusitis. One hundred and fifty-one patients did not present any of the necessary criteria for the diagnosis of allergic Aspergillus rhinosinusitis. The results show that the characteristic macroscopic appearance, the maxillary sinus localization, and the presence of positive specific IgE to Aspergillus fumigatus are arguments that reinforce the diagnostic certitude of allergic fungal sinusitis. No specific clinical or radiological criteria orients a diagnosis of chronic rhinosinusitis toward that of allergic fungal rhinosinusitis. The other immuno-allergic tests do not contribute to the diagnosis of allergic fungal rhinosinusitis. pathological, mycological, and

Interferon gamma gene polymorphism and susceptibility to, and severity of, rheumatoid arthritis.

A strong association between an interferon gamma (IFN-gamma) gene polymorphism and rheumatoid arthritis susceptibility and severity has been reported in a case-control study. We investigated this polymorphism in 103 patients with early rheumatoid arthritis and 130 controls. Severity of rheumatoid arthritis was measured after 4-year follow-up with a validated radiographic score. The median radiographic score in patients increased from 1 (IQR 0-4) to 11.5 (2-35) over the 4-year follow up. The distribution of IFN-gamma alleles did not differ between patients and controls, and the distribution of radiographic scores did not differ among patients carrying the different IFN-gamma alleles. We have failed to confirm the association between the IFN-gamma gene polymorphism and rheumatoid arthritis susceptibility or severity.

Study of host- and virus-related factors associated with spontaneous hepatitis C virus clearance.

Epidemiologic parameters, virologic characteristics and frequency of HLA class II DR and DQ antigens were compared between 63 subjects with spontaneous hepatitis C virus clearance (group 1) and 282 patients with chronic active hepatitis C virus infection (group 2). DRB1*1101 and moreover DQB1*0301 alleles were more frequent in group 1 than in group 2 (33.8% vs. 14.7% and 64.4% vs. 28.6%; P=0.012 and P=0.003, respectively). The frequency of DQB1*02 was lower in group 1 than in group 2 (25.4% vs. 49%; P=0.04). No difference was observed in viral genotype distribution between group 1 and group 2. Univariate analysis showed that female sex and contamination by intravenous drug use were associated with self limited infection. However, by multivariate analysis, the only independent factor associated with hepatitis C virus RNA clearance was female sex (P=0.004). In conclusion, spontaneous hepatitis C virus RNA clearance is determined by class II antigens (mainly DQB1*0301) and female sex, while viral genotype plays no role.

Relationship between the fatty acid composition of rat lymphocytes and immune functions.

The effects of dietary lipids on the fatty acid composition, activation and proliferation of lymphocytes were investigated. Weanling male Wistar rats were fed for 8 weeks on one of two low-fat diets which contained 50 g lipid/kg, or one of two high-fat diets containing 200 g lipid/kg, from either coconut oil or soyabean oil. The fatty acid composition of phospholipids from splenocyte membranes was affected by dietary lipid manipulation, and these differences influenced lymphocyte functions. Increased levels of linoleic acid in spleen lymphocytes correlated negatively with interleukin-2 receptor alpha-chain expression determined either by measuring the mean fluorescence or by the proportion of cells staining positive for CD25, and with the cell proliferation index. However, we found a positive correlation between interleukin-2 receptor alpha-chain expression determined by measuring the mean fluorescence and the cell proliferation index with the oleic acid concentration of spleen lymphocytes. Since phospholipid hydrolysis occurs early in lymphocyte activation, immunosuppressive effects induced by polyunsaturated fatty acids, described in the literature, could be due to an increase of linoleic acid or a decrease of oleic acid affecting many components of plasma-membrane-associated events involved in lymphocyte activation.