Specific Immunosuppressive Therapy Research Articles

High-dimensional profiling of immune responses to kidney transplant reveals heterogeneous T helper 1 and B cell effectors associated with rejection

Rejection is a primary cause of allograft dysfunction after kidney transplantation. The diversity of immune subpopulations involved in the different endotypes of rejection remains to be delineated at single-cell resolution. In a cohort of 76 kidney transplant recipients, we conducted high-dimensional immune phenotyping of blood CD4 T and B cells, single-cell RNA and T/B cell receptor sequencing, and plasma cytokine profiling. Phenotypic, transcriptional, and clonal states of CD4T and B cells could significantly distinguish stable allograft states from rejection. Patients undergoing T cell-mediated rejection displayed accumulation of clonally expanded cytotoxic T helper (Th)1 cells and Th17-like cells, associated with predominant naive B cell responses. In contrast, antibody-mediated rejection was characterized by clonal expansion of Th1-polarized T follicular helper cells and effector T-bet+ memory B cells, both of which strongly expressed interleukin 12 and tumor necrosis factor-signaling pathways. Plasma cytokine analysis confirmed mixed Th1/Th17 and Th1/T follicular helper cell-driven inflammatory profiles distinguishing T cell-mediated rejection and antibody-mediated rejection, respectively. CD4T and B cell subpopulations and signatures were validated using bulk RNA-seq analysis of matched kidney allografts and using an independent single-cell RNA-seq data set. These data improve mechanistic understanding of the immune pathogenesis of rejection and support the development of more specific immunosuppressive therapies to treat allograft rejection.

Pregnancy after kidney and liver transplantation.

Pregnancy in kidney and liver transplant recipients presents unique challenges and risks for both maternal and fetal health. This article examines the management of pregnancy in kidney and liver transplant recipients, focusing on pre-pregnancy counselling, trimester-specific care, the teratogenic effects of immunosuppressive drugs, and the role of the multidisciplinary team. While South African (SA) data on this topic are limited, the Transplant Pregnancy Registry International has provided valuable insights. Despite the increased risk of maternal and fetal complications, the overall risk of graft loss during pregnancy is low. Graft survival rates are comparable between pregnant and non- pregnant transplant recipients, except for pregnancies occurring within 1 year of transplantation. By addressing the complexities of managing pregnant women with kidney or liver transplants, this article underscores the importance of tailored care and the involvement of various medical specialists. It also explores the safety of and potential complications associated with specific immunosuppressive therapies during pregnancy. Further research is needed to enhance our understanding and optimise the management of these high-risk pregnancies in SA.

What the SARS-CoV-2 Pandemic Has Taught Us About Immunosuppression, Vaccinations, and Immune Dysregulation: The Rheumatology Experience.

This review reflects on the impact of the COVID-19 pandemic on the field of rheumatology, emphasizing resulting insights related to the risks of viral infections in immunosuppressed patients, vaccine immunogenicity in immunocompromised patients, and immune dysregulation in the setting of viral infection. During the pandemic, global patient registries provided real-time insights into the risk factors associated with severe COVID-19 outcomes in rheumatology patients. Updated evidence-based recommendations from the American College of Rheumatology (ACR) guided rheumatology practiceduring a time of considerableuncertainty. Studies on COVID-19 vaccines in immunocompromised populations enhanced ourunderstanding of specific immunosuppressive therapies on vaccine efficacy. The immune dysregulation seen in severe COVID-19 underscored a role for immunomodulation in this and other severe infections. Furthermore, novel post-infectious conditions, namely multisystem inflammatory syndrome in children (MIS-C) and Long COVID, reshaped our understanding of post-viral syndromes and revealed novel pathological mechanisms. Lessons from the COVID-19 pandemic demonstrate the power of collaborative research. The scientific revelations from this dreadful time will, nonetheless, benefit the practice of rheumatology for years to come.

Live vaccinations in dermatology for immunosuppressed patients: a narrative review.

Given the higher susceptibility to infectious disease in patients receiving immunosuppressive therapies for inflammatory dermatologic conditions, immunization is important in this population. While live vaccines protect against life-threatening diseases, they can be harmful in immunosuppressed patients given the risk of replication of the attenuated pathogen and adverse reactions. The utilization of live vaccines in immunosuppressed patients depends on multiple factors such as the vaccine and therapy regimen. To provide an overview of evidence-based recommendations for the use of live vaccines in patients receiving immunosuppressive therapies for dermatological conditions. A literature search of the PubMed database was performed using keywords live vaccine, live-attenuated vaccine, dermatology, immunosuppressed, and immunocompromised, and specific immunosuppressive therapies: corticosteroids, glucocorticoids, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, biologics. Relevant articles written in English were included. Using these keywords, 125 articles were reviewed, of which 28 were ultimately selected. Recommendations for live vaccines can be determined on a case-by-case basis. Measles, mumps, rubella, varicella (MMRV) vaccines may be safely administered to patients on low-dose immunosuppressive agents while the yellow fever vaccine is typically contraindicated. It may be safe to administer live MMRV boosters to children on immunosuppressive therapies and the live herpes zoster vaccine to patients on biologics. Given poor adherence to immunization guidelines in immunosuppressed patients, dermatologists have a critical role in educating patients and general practitioners regarding live vaccines. By reviewing a patient's vaccination history and following immunization guidelines prior to initiating immunosuppressive therapies, physicians can mitigate morbidity and mortality from vaccine-preventable diseases.

Organochlorine pesticides disrupt T helper cell regulation and reduce IL-2 and IFN-γ favoring infection and production of autoantibodies among pemphigus patients

The list of environmental factors that trigger autoimmune diseases in genetically susceptible individuals has grown in the recent years and is far from complete. The possible intervention of the environment in triggering these diseases is ever more perceived by the clinicians. This study investigated the effect of environmental factors like organochlorine pesticides (OCPs) on proportions of different T lymphocyte subsets and their cytokine secretion in-vitro among pemphigus patients, before and after specific immunosuppressive therapy. Higher levels of OCPs like β-HCH (isoform of hexachlorohexane), α-endosulfan (a form of endosulfan) and p,p΄-DDE (a metabolite of o,p’-dichlorodiphenyltrichloroethane) were observed in the blood of pemphigus patients as compared to healthy controls. HCH and DDT exposure caused specific reduction in CD8+CD45RA+ and CD4+CD25+ T lymphocyte subpopulations in these patient PBMCs. A strong reduction in Th1 (IL-2 and IFN-γ) cytokines upon exposure to these OCPs in-vitro was also observed. These findings indicate that HCH and DDT have a significant impact on Th1 lymphocytes. Impaired production of these cytokines might favor infections and production of autoantibodies. We therefore speculate that the systemic absorption of the pesticide after the topical contact may be one of the factors triggering the immunological mechanism among pemphigus patients.

#2776 KIDNEY INVOLVEMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS

Abstract Background and Aims In rheumatoid arthritis (RA) kidney is commonly affected organ with clinical presentation characterized by proteinuria and microalbuminuria, followed by chronic renal failure. RA is associated with reduced kidney function, possibly due to chronic inflammation or the use of nephrotoxic therapies. Renal diseases occurring in patients with RA may have a variable clinicopathological picture. Little is known about the effects of using the novel biological agents on the risk of kidney diseases. The aim of this study was to determine the relationship between effect of therapy and kidney involvement in patients with RA and evaluated the histopathological findings and associated clinical manifestation. Method In this retrospective study 275 patients with diagnosis of RA were included. In 48 patients renal biopsy was performed. The patients were divided in three groups according to changes in management of RA: 1991-2001, 2002-2011 and 2012-2022 year. Data of demographic characteristics, clinical symptoms and pathological diagnosis were extracted from medical records and pathological reports. Results In our study amyloidosis was the most common histologic pattern, followed by chronic glomerulonephritis (GN) and tubulointerstitial nephritis. Renal amyloidosis was diagnosed in 13 patients, membranous GN – in 9, mesangioproliferative GN – in 7 patients, focal segmental necrotizing GN – in 5, focal segmental sclerosis – in 4, minimal change disease – in 3, tubulointerstitial nephritis – in 7 patients. Between 1991 and 2001 year the most common clinical manifestation was nephrotic syndrome and the most common histopathological findings – renal amyloidosis, followed by membranous GN and focal segmental necrotizing GN. The membranous GN was related to the use of gold and its frequency decreased after 2001. The mesangioproliferative GN was the leading cause of kidney disease between 2002–2011 years and focal segmental sclerosis – between 2012–2022. In our study 68 patients had a decrease of glomerular filtration rate (GFR) < 60 mL/min/m2. No kidney biopsies were performed in these cases because no urine abnormalities were detected. We found that age, duration of the disease, arterial hypertension, C-reactive protein were significant risk factors for GFR decline in patients with RA. Patients with RA who are treated with biologic agents are less likely to experience progressive decline in kidney function than those not receiving biologic treatment (hazard ratios {HRs] [95% CI], 0,84 [0,68-1,02]}. Conclusion In all patients with RA, renal function should be monitored and in the case of pathologic results, renal biopsy should be performed. In RA patients with renal disorder, suspected causal drug should be removed from the treatment and specific immunosuppressive therapy initiated. Improved pain management associated with biologic treatment may help to reduce the need for potentially nephrotoxic anti-inflammatory agents such as NSAIDs and certain types of non-biologic DMARDs, which could consequently reduce the risk of drug-induced nephrotoxicity and thereby contribute to the lower risk of renal diseases.

THE CLINICAL CASE OF GENERALIZED CONGENITAL HERPESVIRUS INFECTION IN NEWBORNS, AS A RESULT OF PRIMARY ASYMPTOMATIC INFECTION OF THE MOTHER WITH HSV TYPE 2 DURING PREGNANCY

The article presents a clinical case of generalized congenital herpesvirus infection with manifestation on the fourth day of life due to asymptomatic primary infection of the mother with HSV type 2 during pregnancy, complicated by early neonatal bacterial sepsis. The features of the clinic, diagnostics, principles of treatment and follow-up data of the child are presented. Clinical manifestation of congenital herpes infection took place on the 4th day of life. Laboratory confirmed by the detection of DNA of the herpes simplex virus type 2 in the blood, followed by determination of the quantitative level of this indicator and subsequent clinical and laboratory dynamics. Cancellation of specific therapy after 21 days due to the end of the course. Continuation up to 1 year 2 months of a course of specific mmunosuppressive therapy with acyclovir with increased therapy in case of recurrence of local manifestations. At the age of 1 year and 2 months, the withdrawal of specific immunosuppressive therapy. During the next year of life, 4 episodes of recurrence of herpes infection, in the form of local skin lesions. The child was vaccinated according to the calendar, additional vaccination against chickenpox, hepatitis A, pneumococcus, rotavirus infection, seasonal flu. Now the child is 2.4 years old. The child's condition is satisfactory. Development by age. The publication of materials was agreed with the Bioethics Commission of the National Bohomolets Medical University. All anamnestic data, examination results and photo materials were published upon written consent of the parents of the newborn child.Conclusions. Neonatal herpes infection can lead to significant morbidity, mortality, and adverse long-term outcomes. Despiteadequate therapy, vesicular rash recurrences in the first years of life are very common. Given the high rate of herpes simplex virus infection in the population, especially in pregnant women, all children should be considered potentially prone to herpes infection. Determination of maternal immune status, early diagnosis of clinical signs with verification of the causative agent, and timely and adequate specific antiviral therapy are essential to improve prognosis and reduce disability in later years of life.

Pulmonary hypertension in connective tissue diseases: epidemiology, pathogenesis, and treatment.

Pulmonary hypertension (PH) is a clinical condition characterized by increased pulmonary arterial pressure arising from a heterogeneous range of diseases that has a deteriorating effect on the quality of life and may cause early mortality if left untreated. Connective tissue disorders (CTD)-associated PH is the second most common cause of pulmonary arterial hypertension (PAH), after the idiopathic form, categorized as group I. Systemic scleroderma (SSc) accounts for 75% of CTD-associated PH cases. Although SSc ranks first place for CTD-associated PH, SSc is followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), having a lesser frequency of PH occurrence, while it occurs as a rare complication in cases with rheumatoid arthritis (RA) and inflammatory myositis. PH may also occur during non-SSc CTDs and even other rheumatic diseases, including Behcet's disease and adult-onset Still's disease, albeit to a lesser extent. The prognosis of CTD-associated PH is worse than the other forms of PH. Although, as in idiopathic pulmonary arterial hypertension (IPAH), the mechanism of CTD-related PH is associated with an increase in vasoconstrictors like endothelin-1 and a decrease in vasodilators like prostacyclin and nitric oxide production, inflammation, and autoimmune mechanisms also play a role in the development and progression of PH. This may lead to the involvement of more than one mechanism in CTD-associated PH. Knowing which mechanism is dominant is very important in determining the treatment option. This review will primarily focus on the epidemiology, risk factors, and prognosis of PH that develops during rheumatic diseases; the pathogenesis and treatment will be briefly mentioned in light of the newly published guidelines. Key Points • Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) in Western countries is the second most common type of PAH after idiopathic PAH (IPAH). • CTD-PH can be seen most often in systemic scleroderma (SSc), less in systemic lupus erythematosus (SLE), mixed CTD (MCTD), and rarely in other CTDs. • While current guidelines recommend annual transthoracic echocardiography as a screening test for asymptomatic SSc patients, screening for PH is not advised in the absence of symptoms suggestive of PH in other CTDs. • CTD-PH treatment can be divided into specific vasodilator PH treatments and immunosuppressive therapy. Current treatment guidelines recommend the same treatment algorithm for patients with CTD-associated PH as for patients with IPAH. Several case series have shown the beneficial effect of immunosuppressive agents in patients with SLE-PH and MCTD-PH.

SYSTEMIC LUPUS ERYTHEMATOSUS AND DENTISTRY

Introduction: Systemic lupus erythematosus (SLE) can be described as a heterogeneous, multisystemic autoimmune disease characterized by the production of autoantibodies against several cell constituents. Objective: To characterize the relationship between systemic lupus erythematosus and dentistry, explaining the means for its diagnosis and treatment. Method: For the composition of this work, we use the investigation method based on a bibliographic survey of sources (physical and digital) relevant to the theme addressed here. Conclusion: When early detection of SLE by the dentist, it is possible to institute, case by case, a specific immunosuppressive therapy that enables a better prognosis.

Everolimus Reduces Cancer Incidence and Improves Patient and Graft Survival Rates after Kidney Transplantation: A Multi-Center Study.

Kidney transplantation can prevent renal failure and associated complications in patients with end-stage renal disease. Despite the good quality of life, de novo cancers after kidney transplantation are a major complication impacting survival and there is an urgent need to establish immunosuppressive protocols to prevent de novo cancers. We conducted a multi-center retrospective study of 2002 patients who underwent kidney transplantation between 1965 and 2020 to examine patient and graft survival rates and cumulative cancer incidence in the following groups categorized based on specific induction immunosuppressive therapies: group 1, antiproliferative agents and steroids; group 2, calcineurin inhibitors (CNIs), antiproliferative agents and steroids; group 3, CNIs, mycophenolate mofetil, and steroids; and group 4, mammalian target of rapamycin inhibitors including everolimus, CNIs, mycophenolate mofetil, and steroids. The patient and graft survival rates were significantly higher in groups 3 and 4. The cumulative cancer incidence rate significantly increased with the use of more potent immunosuppressants, and the time to develop cancer was shorter. Only one patient in group 4 developed de novo cancer. Potent immunosuppressants might improve graft survival rate while inducing de novo cancer after kidney transplantation. Our data also suggest that everolimus might suppress cancer development after kidney transplantation.

Increased Risk of Secondary Malignancy Associated with the Use of Azathioprine for Chronic Graft-Versus-Host Disease Treatment

Background Secondary malignancies (SM) are a recognized complication following allogeneic hematopoietic stem cell transplant (HCT). It is unclear whether specific immunosuppressive therapies (IST) may contribute to this risk. We have reported that Azathioprine (AZP) is a relevant option as a steroid-sparing agent in chronic graft versus host disease (cGvHD) treatment (Uhm et al BMT 2018) by evaluating its failure-free survival and overall survival. AZP is known to increase the risk of SM in patients with inflammatory bowel disease or autoimmune disease. Also, cGvHD in of itself increases the risk of SM. However, SM risk was not extensively investigated in patients treated with AZP for cGvHD. Thus, we performed a retrospective chart review to evaluate IST and analyze for correlations with SM risk and whether treatment with distinct IST, including AZP, may be associated with added risk for SM development. Patients and methods A total of 502 patients who received HCT from Jan 2000 to Dec 2012 and had a diagnosis of cGvHD according to NIH criteria after HCT, treated from April 2000 to Mar 2013, at Princess Margaret Cancer Center, Canada, were enrolled in the retrospective study. Patients and disease characteristics are as follows: median age of 48 years; male 289 (57.6%), classical 217 (43.6%), overlap syndrome 281 (56.4%). Of note, 394 patients (78.6%) had a previous history of acute GvHD. Subtype, severity and organ involvement of cGvHD were assessed at initial presentation of cGvHD. The most common treatment used for cGvHD was systemic corticosteroid (82.7%) followed by AZP (40.8%), cyclosporine (CSA) (40.1%) and mycophenolate mofetil (MMF) (26.5%). The incidence of SM was calculated from HCT to the first day of confirmed diagnosis of SM using cumulative incidence method considering competing events such as relapse or death. Risk factors for SM development were compared using Gray model. Survival after diagnosis of SM was calculated using Kaplan-Meier estimates and compared using log-rank test. For multivariate analysis, Fine-Gray regression model and Cox proportional hazard model were used to analyze the effects of variables on SM risk and survival (OS), respectively. Results With a median follow-up duration of 12.3 years, 101 patients were diagnosed with SM with a median onset of 5.7 years (range 0.3-18.3 years). The most common types of SM were basal cell skin cancer (n=29), followed by squamous cell skin cancer (n=22) and head & neck cancer (n=17). The overall incidence of SM was 19.5% (95% CI, 15.9-23.4%) at 12 years. We evaluated multiple risk factors for the risk of SM, and the following variables were not statistically significant: the use of fludarabine, total body irradiation, stem cell source, donor type, previous acute GvHD, use of T-cell depletion, subtype and severity of cGvHD, organ involvement of mouth, eye, liver, gut, lung, musculoskeletal system at initial presentation. In addition, we evaluated the use of systemic IST including corticosteroid, CSA, tacrolimus, MMF and ECP but with no effect on SM risk. Of interest, the use of AZP was found to increase the risk of SM: The cumulative incidence of SM was 22.7% (16.9-29.1%) at 12 years in the AZP group, whereas it was 16.9% (12.5-21.9%) in those treated without AZP (p=0.023) (Fig A). Exposure duration of AZP showed good correlation with increased risk of SM: patients treated with AZP for 5.85 years or longer showed 46% higher risk of SM development than those not (HR 1.46 [1.11-1.91], p=0.007). Multivariate analysis confirmed the following factors as risk factor for SM: exposure to AZP (HR 1.65, p=0.012), age at transplant >60 years (HR 2.40, p=0.007), male sex (HR 1.56, p=0.039) and skin involvement at cGvHD presentation (HR 1.59, p=0.018) (Fig B). A refined SM risk score was developed, giving a point each for age over 60 years, male sex, skin involvement at cGvHD presentation, and exposure to AZP. The summed scores were grouped 0-1 (n=244), low risk of 13.3%; 2 (n=174), intermediate risk of 19.9% (HR 1.614); above 2 (n=80), high risk for SM, 38.1% at 12 years (HR 3.502; p<0.001) (Fig C). Median survival duration was 3.9 years after SM diagnosis, while 5 year survival rate was 43.6% (33.8-52.9%) (Fig D). The use of AZP does not appear to affect survival after diagnosis of SM. Conclusions The present study suggests that the use of AZP correlates with the risk of SM after adjustment of other confounding covariates such as skin involvement of GVHD, patient age or sex. Figure 1 Disclosures Lipton: Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria. Mattsson:Jazz Pharmaceuticals: Honoraria; ITB: Honoraria; Gilead: Honoraria; Mallinkrodt: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Azathioprine is being used to treat chronic gvhd

Treatment of bleeding in a patient with immune coagulopathy (acquired haemophilia A)

Objective. We are representing the case of acquired haemophilia A and analyze the timeliness and adequacy of treatment.
 Materials and methods. The subject of the study was immune coagulopathy with a factor VIII (FVIII) inhibitor – acquired haemophilia A.
 Results and discussion. Female, 33 years old, pregnancy II, urgent delivery. There was excessive bleeding in the early postpartum period, hemostatic therapy was provided. She hospitalized three times with recurrences of uterine bleeding. Vacuum aspiration of the walls of the uterine cavity was performed twice. After the third recurrence, blood loss of 1200 ml and ineffectiveness of conservative treatment, laparotomy and extirpation of the uterus was performed. Despite intensive care, the bleeding continued, the patient was transferred to the regional clinical hospital, where she was diagnosed with DIC syndrome, stage III, severe anemia. Three relaparotomies were performed, the source of bleeding was not found, there was excessive bleeding from the operating field. The total blood loss was 24,447 ml. Intensive infusion-transfusion therapy was continued, which gave unstable hemostasis. The patient received 12,060 ml of fresh-frozen plasma (FFP), 15,130 ml of erythrocytes, 600 ml of albumin 10 %, 20 doses of cryoprecipitate (CP), 16,000 U of activated prothrombin complex (APCC), 8 mg of recombinant activated factor VII (rVIIa), 8,000 U of prothrombin complex (PC). 16.1 BU/ml of inhibitor FVIII, FVIII <1.0 %, activated partial thromboplastin time (APTT) – 146.1 s was detected on day 37. Within 30 days, blood loss was 10,608 ml; patient received 23,420 ml of FFP, 2,080 ml of erythrocytes, 17 mg of rVIIa, 19,000 U of APCC, 6000 U of PC, 61 dose of CP, 50,000 IU of FVIII. Immunosuppressive therapy (prednisolone 1-1.5 mg/kg/day) was started on day 67 and lasted for 12 months. Bleeding stopped completely 10 months after delivery, and after 14 months the inhibitor was not detected, factor levels and APTT returned to normal. Scheduled reconstructive surgery on the urinary tract was performed without the use of transfusion replacement therapy.
 Conclusions. Recurrent postpartum hemorrhage requires early diagnosis of coagulation factors inhibitors, which will ensure specific transfusion and immunosuppressive therapy, avoidance of serious consequences, including extirpation of the uterus and reduce the economic costs of treatment.

How to Monitor Cardiac Complications of Immune Checkpoint Inhibitor Therapy.

Immune-checkpoint inhibitors (ICIs) represent a successful paradigm in the treatment of cancer. ICIs elicit an immune response directed against cancer cells, by targeting the so-called immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Such response, however, is not entirely tumor-specific and may result in immune-related adverse events (irAEs), involving a number of organs and systems. Cardiovascular (CV) irAEs are rare, although potentially severe. In particular, several cases of ICI-related myocarditis with life-threatening course have been reported: the possibility of fulminant cases, thus, requires a high level of awareness among both oncologists and cardiologists. Aggressive work-up and management of symptomatic patients taking ICIs is fundamental for early recognition and initiation of specific immunosuppressive therapies. Notably, myocarditis occurs within few weeks from ICIs initiation, offering opportunity for a targeted screening. Troponin testing is the cornerstone of this screening, yet uncertainties remain regarding timing and candidates. Moreover, troponins positivity should be carefully interpreted. We herein review the main aspects of ICI-related myocarditis and suggest a practical approach. In particular, we focus on the opportunities that a baseline CV evaluation offers for subsequent management by collecting clinical and instrumental data, essential for the interpretation of troponin results, for differential diagnosis and for the formulation of a diagnostic and therapeutic workup.

Haemophagocytic lymphohistiocytosis in adult critical care

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune dysregulation, characterised by extreme inflammation, fever, cytopaenias and organ dysfunction. HLH can be triggered by conditions such as infection, autoimmune disease and malignancy, among others. Both a familial and a secondary form have been described, the latter being increasingly recognised in adult patients with critical illness. HLH is difficult to diagnose, often under-recognised and carries a high mortality. Patients can present in a very similar fashion to sepsis and the two syndromes can co-exist and overlap, yet HLH requires specific immunosuppressive therapy. HLH should be actively excluded in patients with presumed sepsis who either lack a clear focus of infection or who are not responding to energetic infection management. Elevated serum ferritin is a key biomarker that may indicate the need for further investigations for HLH and can guide treatment. Early diagnosis and a multidisciplinary approach to HLH management may save lives.

Acetylcholine receptor-specific immunosuppressive therapy of experimental autoimmune myasthenia gravis and myasthenia gravis.

Experimental autoimmune myasthenia gravis (EAMG) and myasthenia gravis (MG) are caused by autoantibodies to the extracellular domain of muscle nicotinic acetylcholine receptors (AChRs). Autoantibodies to the cytoplasmic domain of AChRs do not cause EAMG because they cannot bind AChRs in vivo. The ideal MG therapy would quickly and permanently suppress only the pathological autoimmune response to AChRs. We have developed a specific immunosuppressive therapy for EAMG that involves immunizing rats with bacterially expressed cytoplasmic domains of human muscle AChRs. Therapy prevents onset of chronic EAMG, rapidly suppresses ongoing EAMG, and is potent, robust, long lasting, and safe, because the therapeutic antigen cannot induce EAMG. The therapy was developed using incomplete Freund's adjuvant, but is likely to work equally well with alum adjuvants routinely used for human immunizations. Therapeutic mechanisms may involve a combination of antibody-mediated feedback suppression and regulatory T and/or B lymphocytes.

Anticardiolipin antibodies and 12-month graft function in kidney transplant recipients: a prognosis cohort survey.

In kidney transplant recipients, anticardiolipin (ACL) antibodies without antiphospholipid syndrome (APS) are found in up to 38% of patients and could be associated with thrombotic events (TEs). However, the prognostic role of ACL regarding kidney transplant and patients outcomes have still not been well defined. We conducted an observational, monocentric, retrospective cohort study including 446 kidney transplant recipients and standardized follow-up: 36-month allograft and patient survival, 12-month estimated glomerular filtration rate (eGFR) and 3- and 12-month screening biopsies. ACL tests were run on 247 patients, 101 were positive (ACL+ group, 41%) and 146 were negative (ACL- group, 59%). Allografts and patient survival within 36 months as TE were similar between both groups [hazard ratio (HR) = 1.18 and HR = 0.98, respectively]. The 12-month eGFR was significantly lower in the ACL+ group [median (95% confidence interval) 48.5 (35.1-60.3) versus 51.9 (39.1-65.0) mL/min/1.73 m2, P= 0.042]. ACL+ was independently associated with eGFR decrease (P = 0.04). In 12-month screening biopsies, tubular atrophy was significantly more severe in the ACL+ group compared with the ACL- group (P = 0.02). ACL without APS before kidney transplantation is an independent risk factor of eGFR decline within the first year post-transplant without over-incidence of TEs. Specific immunosuppressive therapy including mammalian target of rapamycin inhibitors should be discussed in the future.

Significant Associations of Neurological Complications of Herpes Zoster With Stroke in Rheumatoid Arthritis Patients

BackgroundAccumulating evidence suggests an increased risk of stroke after herpes zoster (HZ). This risk is elevated in immunocompromised patients. The incidence of HZ in Asia is higher than in Western countries. However, the epidemiology of HZ and HZ‐related stroke among rheumatoid arthritis (RA) patients in Asia remains unclear.Methods and ResultsWe conducted a retrospective cohort study using a population‐based database to investigate the epidemiology of HZ in RA patients in Taiwan during the period of 2000‐2011. A total of 27 609 newly diagnosed and eligible RA cases were identified, and 110 436 non‐RA cases were matched for age and sex at a ratio of 4:1. HZ risk increased by 2.53‐fold (P<0.0001) in RA patients compared with the general population. Exposure to corticosteroids (adjusted odds ratio=1.73, P<0.0001), adalimumab (adjusted odds ratio=1.61, P=0.002), and rituximab (adjusted odds ratio=2.06, P=0.008) was associated with an increased risk of HZ in RA patients. A significant association between the use of methotrexate or corticosteroids and HZ risk was dose‐dependent (P trend<0.0001). Elevated risk of stroke was observed in RA patients with HZ (adjusted hazard ratio=1.27, P=0.047), particularly in those with neurological complications (adjusted hazard ratio=1.54, P=0.015). A 2.30‐fold significantly increased risk of stroke within 90 days after HZ occurrence was observed in RA patients compared with those without HZ (P=0.02). Furthermore, death risk increased in RA patients with HZ (adjusted hazard ratio=1.18, P=0.026).ConclusionsThe risk of HZ and HZ‐related stroke has increased in RA patients. Monitoring the occurrence of HZ in RA patients and preventing HZ‐related stroke or mortality during a specific immunosuppressive therapy are important.

Risk and severity of herpes zoster in patients with rheumatoid arthritis receiving different immunosuppressive medications: a case–control study in Asia

ObjectiveIncreasing evidence indicates that the risk of herpes zoster (HZ) is elevated in rheumatoid arthritis (RA). Little is known about the epidemiology of HZ in patients with RA in Asia....

Immune pathophysiology of acquired aplastic anemia.

Acquired aplastic anemia (AA) is a hematopoietic dyscrasia characterized by pancytopenia and bone marrow hypoplasia. AA is considered to be caused mainly by T-cell attacks on hematopoietic stem cells, as assumption based on good responses to T-cell specific immunosuppressive therapy (IST). Several markers, such as HLA-DRB1(*)1501 and an increase in the percentage of paroxysmal nocturnal hemoglobinuria (PNH) phenotype cells, have been shown to represent the immune pathophysiology of AA. However, little is known about the pathogenesis of AA. This review article focuses on immune mechanisms underlying the development of AA and the roles of the aforementioned markers in the management of bone marrow failure.

Wharton’s jelly mesenchymal stem cells differentiation into hepatocyte-like cells: functional characterization and expression of immunomodulatory molecules

Mesenchymal stem cells derived from Wharton’s jelly (WJ-MSCs) recently emerged as promising tools for cellular therapy due to their ability to differentiate into diverse cell types and their immunomodulatory features. Little is known on the expression of immunomodulatory molecules in mature cells differentiated from WJ-MSCs, therefore we aimed to characterize the extent of maintenance of the naive traits of these cells also in a highly specialized differentiated counterpart. WJ-MSCs were differentiated into hepatocyte-like cells (HLCs) with a four weeks protocol. RT-PCR, flow cytometry, IHC and ICC were performed to assess expression of key markers in both undifferentiated and differentiated cells. Hepatocyte specific assays such as PAS staining, CYP3A4 induction and activity, G6Pase activity, were performed to demonstrate the acquisition of traits of the mature hepatocyte phenotype. WJ-MSCs were successfully differentiated into HLCs using a multi-step protocol. These cells were able to store glycogen, incorporate specific live cells stains, perform enzymatic reactions and metabolic activities which are usually featured by mature hepatocytes. In addition, WJ-MSCs did express several immune-related molecules, for which an immunomodulatory role has been demonstrated both in vitro and in vivo. We demonstrated for the first time that key molecules as HLA-E and B7-H3 are expressed also by HLCs derived from WJ-MSCs. Our data showed for the first time that HLCs mostly maintain the expression of immune-modulating molecules, together with new markers and functional features of mature cells. In multiple pathologic conditions the intrinsic immunomodulatory ability of differentiated cells may help survive the interaction with the host immune system, even in the absence of a specific immunosuppressive therapy. This, together with the acquisition of key mature hepatocyte functions, may render WJ-MSCs promising in cell therapy applications for liver diseases.