Imbalance favoring follicular helper T cells over IL10+ regulatory B cells is detrimental for the kidney allograft.

A high frequency of regulatory B (Breg) cells, generally transitional B cells, has been associated with long-term kidney allograft survival and operational tolerance. However, circulating follicular helper T cells (cTfh) correlate with graft rejection. In order to better understand the interplay between these cell subsets and to determine their association with graft outcome we studied transitional and IL10+ Breg cells, as well as cTfh, pre- and post-transplantation in a prospective cohort of 200 kidney transplant recipients and in healthy volunteers. Patients with end-stage kidney disease had higher frequencies of transitional and IL10+ Breg cells compared to controls, and these subsets decreased during the one-year post-transplant follow-up. Higher frequencies of pre-transplant IL10+ Breg cells, and a larger reduction in these cells early post-transplantation, predicted acute rejection and graft failure. Moreover, IL10+ Breg cells correlated with cTfh pre-transplantation, and a post-transplant increase in the cTfh/IL10+Breg ratio preceded acute rejection. Thus, evaluation of pre-transplant IL10+ Breg cells and the regular monitoring of the cTfh/IL10+Breg ratio may be useful to assess post-transplant risk. Hence, our observations suggest the need to develop therapeutic strategies aimed at preserving regulatory B cells, and depleting Tfh, post-transplantation.

De Novo Donor-Specific Antibodies after Heart Transplantation: A Comprehensive Guide for Clinicians.

Antibodies directed against donor-specific human leukocyte antigens (HLAs) can be detected de novo after heart transplantation and play a key role in long-term survival. De novo donor-specific antibodies (dnDSAs) have been associated with cardiac allograft vasculopathy, antibody-mediated rejection, and mortality. Advances in detection methods and international guideline recommendations have encouraged the adoption of screening protocols among heart transplant units. However, there is still a lack of consensus about the correct course of action after dnDSA detection. Treatment is usually started when antibody-mediated rejection is present; however, some dnDSAs appear years before graft failure is detected, and at this point, damage may be irreversible. In particular, class II, anti-HLA-DQ, complement binding, and persistent dnDSAs have been associated with worse outcomes. Growing evidence points towards a more aggressive management of dnDSA. For that purpose, better diagnostic tools are needed in order to identify subclinical graft injury. Cardiac magnetic resonance, strain techniques, or coronary physiology parameters could provide valuable information to identify patients at risk. Treatment of dnDSA usually involves plasmapheresis, intravenous immunoglobulin, immunoadsorption, and ritxumab, but the benefit of these therapies is still controversial. Future efforts should focus on establishing effective treatment protocols in order to improve long-term survival of heart transplant recipients.

Clinical and genetic characteristics in a series of haemophagocytic lymphohistiocytosis patients without perforin defects

Aim: Haemophagocytic lymphohistiocytosis (HLH) is characterised by T cell and macrophage activation and excessive production of inflammatory cytokines. Genetic diagnosis is required to discriminate between primary forms (familial HLH, FHL), due to mutations in genes involved in cytolysis, and secondary forms. We aimed to analyse the genes coding for Munc13-4 (UNC13D) and syntaxin-11 (STX11) proteins in search of mutations that might explain HLH in 5 patients without perforin defects. Materials and methods: Perforin expression was evaluated by flow cytometry, sCD25 was measured by ELISA and NK activity was investigated by the conventional functional assay. Coding regions and exons surroundings were sequenced for PRF1, UNC13D and STX11 genes. Results: P1 and P2 developed severe early-onset HLH, P1 died at 6 months. P3, with a sister who died after HLH, responded well to treatment (HLH-2004), and had a second HLH episode two years later. P2 developed HLH at year 7 while in complete remission after lymphoblastic leukaemia. P4 and P5 were brothers who died at 5 and 6 years old due to an HLH and EBV mononucleosis infection. XLP was discarded because P4 was a girl. P1 and P3 showed mutations in UNC13D previously described as pathogenic. There were no changes in STX11.Conclusions: UNC13D mutations were found in 50% of the HLH families without perforin defects and STX11 defects were not detected. These results agree with published series in which mutations in UNC13D explain up to 50% of FHL without PRF1 mutations, supporting a heterogeneous genetic background for this disease (AU)

Objetivo: La linfohistiocitosis hemofagocítica (HLH) se caracteriza por la activación incontrolada de células T y macrófagos y producción excesiva de citoquinas inflamatorias. El diagnóstico genético es necesario para distinguir entre formas primarias (HLH familiar, FHL),debidas a mutaciones en genes implicados en citolisis, y secundarias. Nuestro objetivo es analizar la presencia de mutaciones en los genes que codifican para Munc13-4 (UNC13D) ysintaxina-11 (STX11) en cinco pacientes con HLH no asociado a defecto de perforina. Materiales y métodos: Se evaluó la expresión de perforina por citometría, CD25s por ELISA y la actividad NK con un ensayo funcional. Se secuenciaron los exones y regiones flanqueantes de los genes PRF1, UNC13D y STX11.Resultados: P1 y P2 desarrollaron HLH severo de inicio temprano, P1 falleció con 6 meses. P3,con una hermana fallecida tras HLH, respondió adecuadamente al tratamiento (HLH-2004),presentando un segundo episodio dos años después. P2 desarrolló HLH a los 7 años de edad estando en remisión completa de una leucemia linfoblástica previa. P4 y P5 son hermanos que fallecieron con 5 y 6 años tras HLH y mononucleosis por infección EBV. Se descartó XLP ya que uno de los pacientes era niña. P1 y P3 presentaron mutaciones en UNC13D previamente descritas como patogénicas. No se encontraron alteraciones en STX11.Conclusiones: Se encontraron mutaciones en UNC13D en el 50% de las familias con HLH sin defectos de perforina y no se detectaron defectos en STX11. Este resultado concuerda con series publicadas en las que mutaciones en UNC13D explican hasta el 50% de la FLH sin mutaciones en PRF1, y apoyan una base genética muy heterogénea para esta enfermedad (AU)