[The anti-synthetases syndrome: diagnostic and treatments]. / Syndrome des antisynthétases: diagnostic et traitements.

The anti-synthetases syndrome is a rare disease with a specific constellation of clinical symptoms present in a subset of patients with inflammatory myopathy. Besides constitutional symptoms and myositis, it is associated with mechanic's hands, Raynaud phenomenon, and non-erosive arthritis. This syndrome is characterized by the presence of one of eight auto-antibodies to aminoacyl-transfer ribonucleic acid synthetase enzymes in the serum. Interstitial lung disease is more frequent in this subpopulation of inflammatory myopathy and worsens the patient's prognosis.

Risk factors for ICU admission and ICU survival after allogeneic hematopoietic SCT.

A considerable number of patients undergoing allogeneic hematopoietic SCT (HSCT) develop post-transplant complications requiring intensive care unit (ICU) treatment. Whereas the indications and the outcome of ICU admission are well known, the risk factors leading to ICU admission are less well understood. We performed a retrospective single-center study on 250 consecutive HSCT patients analyzing the indications, risk factors and outcome of ICU admission. Of these 250 patients, 33 (13%) were admitted to the ICU. The most common indications for admission to the ICU were pulmonary complications (11, 33%), sepsis (8, 24%), neurological disorders (6, 18%) and cardiovascular problems (2, 6%). Acute GvHD and HLA mismatch were the only significant risk factors for ICU admission in multivariate analysis. Among patients admitted to the ICU, the number of organ failures correlated negatively with survival. Twenty-one (64%) patients died during the ICU stay and the 6-month mortality was 85% (27 out of 33). SAPS II score underestimated the mortality rate. In conclusion, acute GvHD and HLA mismatch were identified as risk factors for ICU admission following allogeneic HSCT. Both, short- and long-term survival of patients admitted to the ICU remains dismal and depends on the number of organ failures.

[Systemic and neurological uses of immunosuppressive agents]. / Immunosuppresseurs: usages systémiques et neurologiques.

Involvement of the central or peripheral nervous system, frequently present in systemic inflammatory immune disorders, has to be considered a severe threat and requires aggressive immunosuppressive treatment to achieve rapid remission. This is usually obtained with high-dose systemic corticosteroids combined with cyclophosphamide. Once remission is obtained, immunosuppressive agents with a more favorable safety profile are needed to exert a corticosteroid-sparing effect and minimize adverse events. New therapeutic approaches are currently developed to treat autoimmune diseases, mostly linked to the definition of new indications for biological agents such as TNF-alpha antagonists and rituximab.

Transplanted human pancreatic islets after long-term insulin independence.

Long-term insulin independence after islets of Langerhans transplantation is rarely achieved. The aims of this study were to identify the histological and immunological features of islets transplanted in a type 1 diabetic patient who died of a cerebral hemorrhage after >13 years insulin independence. Islets were pooled from two donors with respectively one and five HLA mismatches. Insulin-positive islets were found throughout the right and left liver, and absent in the pancreas. Two- and three-dimensional analysis showed that islets lost their initial rounded and compact morphology, had a mean diameter of 136 µm and were constituted of an unfolded epithelial band of 39.1 µm. Leukocyte phenotyping showed no evidence of a tolerogenic environment in the islet-containing portal spaces. Finally, HLA typing of microdissected islets showed HLA from the best matched donor in all 23 microdissection samples, compared to 1/23 for the least matched donor. This case report demonstrates that allogeneic islets can survive over 13 years while maintaining insulin independence. Allogeneic islets had unique morphologic features and implanted in the liver regardless of their size. Finally, our results suggest that, in this case, rejection had been prevalent over autoimmunity, although this hypothesis warrants further investigation.

Changes of circulating antibody levels induced by ABO antibody adsorption for ABO-incompatible kidney transplantation.

ABO-incompatible kidney transplantation using immunoadsorption to remove anti-A/B antibodies has become a successful clinical practice. Since the data on the specificity of the ABO columns are controversial, the present study assessed the efficiency and specificity of the ABO immunoadsorption, the effect on total immunoglobulins and antibodies previously induced by vaccination. Anti-A/B antibodies were measured by agglutination and ABO flow cytometry, total IgG/IgM, carbohydrate- and protein-specific antibodies by nephelometry and ELISA. The first immunoadsorption not only efficiently reduced donor-specific anti-A/B IgM (81%) and IgG (56%) but also reduced compatible anti-A/B IgM (59%) and IgG (34%). The measurements of antidonor A/B antibodies by direct agglutination (IgM) or flow cytometry better represented the effective antibody levels than the indirect agglutination test (IgG). The median reduction of total IgM and total IgG levels after a single immunoadsorption was 34% and 18%, respectively. Antibodies against pneumococcus and haemophilus polysaccharide antigens were significantly reduced, whereas antitetanus and antidiphtheria protein antibodies were not affected. Intravenous immunoglobulin administration restored the protective anticarbohydrate antibody levels. In summary, immunoadsorption efficiently removed antidonor A/B antibodies, but was not specific for A/B antigens. Anti-A/B antibody levels as determined by ABO flow cytometry are useful to establish the minimal number of immunoadsorptions needed for successful ABO-incompatible transplantation.

Natural killer cell receptor repertoire and their ligands, and the risk of CMV infection after kidney transplantation.

Cytomegalovirus (CMV) infection is the most common viral complication after solid organ transplantation (SOT). Whilst current immunosuppression is known to impair antiviral-specific T-cell immunity in SOT, a potential role for natural killer (NK) cells not affected by immunosuppressive therapy remains to be determined. To address this, we compared the genotype of the NK immunoglobulin-like receptor (KIR) genes and their HLA cognate ligands to the rate of CMV infection in 196 kidney transplant recipients. We have shown that the absence of the HLA-C ligand for inhibitory KIR and the presence of activating KIR genes in the recipients were both associated with a lower rate of CMV infection after transplantation. In a cohort of 17 recipients with acute CMV infection, NK cells were phenotyped over a period of time after diagnosis by their expression profile of C-type lectin receptors and capacity to secrete IFN-gamma. The increased expression of the activating C-type lectin receptors NKG2C and NKG2D was paralleled by the decreased IFN-gamma secretion during the early phase of CMV infection. In conclusion, our findings suggest that KIR/HLA genotype and expression of NKG2C and NKG2D might play a significant role in regulating NK cell function and anti-CMV immunity after kidney transplantation.

Cytomegalovirus-associated chorioretinitis after liver transplantation: case report and review of the literature.

A cytomegalovirus (CMV) donor positive/recipient negative liver transplant recipient developed CMV syndrome with presumed colitis 2 weeks after discontinuing the standard 3 months of valganciclovir prophylaxis. Treatment with intravenous ganciclovir (GCV) reduced, but did not clear, CMV replication. A CMV UL97 mutation (M460V) conferring GCV resistance was identified. Reduction of immunosuppression was followed by rapidly rising lymphocyte counts as well as by clearance of CMV viremia and of clinical symptoms. However, bilateral chorioretinitis was diagnosed 2 weeks later and treated with foscarnet and cidofovir. Then, right eye vitritis occurred necessitating vitrectomy due to a partially rhegmatogeneous retinal detachment. Because chorioretinitis-vitritis after rising lymphocyte counts and clearance of CMV viremia was strongly suggestive of an immune reconstitution syndrome (IRS)-like disease, we investigated CMV-specific T-cells in the peripheral blood available during follow-up. We found strong CD8(+) but only low CD4(+) T-cell responses (4.77% vs.<0.1%) to the CMV immediate early pp72, while responses to CMV-lysate or CMV-pp65 (CD4(+) <0.01%; CD8(+)<0.01%) were low. Over 16 weeks of follow-up, pp72-specific CD8(+) responses declined, while responses to pp65 gradually increased (CD4(+) 0.16%; CD8(+) 0.76%) indicating a slowly adapting CMV-specific cellular T-cell response. Review of 12,653 published liver transplant patients identified only 14 (0.1%) reported cases of CMV-associated chorioretinitis at a median 41.7 weeks post transplant. CMV-associated opthalmologic complications late post transplantation may possibly involve 2 different entities of cytopathic retinitis and IRS-like chorioretinitis-vitritis.

Isotype-specific detection of ABO blood group antibodies using a novel flow cytometric method.

Several methods to detect anti-A/B antibodies based on haemagglutination and haemolysis have been described. These methods measure predominantly anti-A/B immunoglobulin (Ig)M, whereas anti-A/B IgG and IgG subclasses are less well examined. We established a flow cytometry method (ABO-fluorescence-activated cell sorting; ABO-FACS) to quantify binding of anti-A/B IgM, IgG and IgG subclasses to human A or B red blood cells. Anti-A/B IgM were present in the majority of 120 blood donors, as expected from blood group typing. The sensitivity and specificity of anti-A/B IgM to predict the blood group was 93% and 96% respectively. Anti-A/B IgG was found in 34/38 blood group O samples (89%). Anti-B IgG in blood group A or anti-A IgG in blood group B was present in 4/28 (14%) and 1/28 (4%) samples, respectively, and absent in 26 AB sera. IgG2 was the predominant IgG subclass. The correlation of anti-A/B IgM and IgG in the ABO-FACS with haemagglutination titres was 0.870 and 0.783, respectively (n = 240; P < 0.001) whereas the comparison of ABO-FACS with ABO-enzyme-linked immunosorbent assay was less significant. In conclusion, ABO-FACS is a valid method to quantify anti-A/B IgM, IgG and IgG subclasses. It opens the possibility of isotype-specific monitoring of anti-A/B antibodies levels after ABO-incompatible solid organ and stem cell transplantation.

Levels of anti-A/B antibodies after ABO-incompatible hematopoietic stem cell transplantation.

In contrast to solid organ transplantation, ABO incompatibility is generally not associated with survival differences in hematopoietic stem cell transplantation. Therefore, patients receiving ABO-incompatible stem cell transplantation can be analyzed to study the mechanism of tolerance induction after antigen-mismatched transplantation. The goal of this study was to analyze the levels of anti-A/B antibodies after ABO-incompatible transplantation. Host-derived antidonor antibodies disappeared rapidly after transplantation and did not reappear in the further posttransplant course. Donor-derived antihost antibodies did not significantly increase and compatible anti-A/B antibodies remained positive after hematopoietic stem cell transplantation. Thus, there is no evidence for stimulation of donor B lymphocytes to produce antirecipient antibodies suggesting a potential B cell tolerance.

Deadly carousel or difficult interpretation of new diagnostic tools for Whipple's disease: case report and review of the literature.

Whipple's disease is a rare systemic disorder classically presenting with weight loss, arthralgias, and diarrhea, which was first described in 1907. The causative bacterium Tropheryma whipplei, is a fastidious organism not growing on conventional media. Before the introduction of polymerase chain reaction (PCR)-based methods, the diagnostic gold standard was histological detection of diastase-resistant periodic acid Schiff (PAS)-positive macrophages or electron microscopy. As in the present case, contradictory results between the former and new diagnostic methods may obscure the correct diagnosis. We critically summarize the performance of the different diagnostic methods and discuss their impact on the clinical management of patients with suspected Whipple's disease.

Aerococcus urinae endocarditis: case report and review of the literature.

Aerococcus urinae is a rare cause of urinary tract infections, mainly in elderly men with underlying urinary tract pathologies. In addition, it has been described as a pathogen in balanitis, soft tissue infections, septicemia and endocarditis. To date ten cases of A. urinae endocarditis have been reported in the literature with a high rate of mortality (7/10) and morbidity, as two out of three survivors suffered from neurovascular complications. Here we present the case of an additional patient who was successfully treated with surgical valve replacement and antibiotic therapy consisting of ceftriaxone and netilmicin for 6 weeks. Furthermore, we review all reported cases of A. urinae endocarditis with emphasis on predisposing factors and therapeutic options.