Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple autoantibody types, some of which are produced by long-lived plasma cells (LLPC). Active SLE generates increased ...circulating antibody-secreting cells (ASC). Here, we examine the phenotypic, molecular, structural, and functional features of ASC in SLE. Relative to post-vaccination ASC in healthy controls, circulating blood ASC from patients with active SLE are enriched with newly generated mature CD19
CD138
ASC, similar to bone marrow LLPC. ASC from patients with SLE displayed morphological features of premature maturation and a transcriptome epigenetically initiated in SLE B cells. ASC from patients with SLE exhibited elevated protein levels of CXCR4, CXCR3 and CD138, along with molecular programs that promote survival. Furthermore, they demonstrate autocrine production of APRIL and IL-10, which contributed to their prolonged in vitro survival. Our work provides insight into the mechanisms of generation, expansion, maturation and survival of SLE ASC.
Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory ...molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell- but not B cell-dependent because PDL1-specific antibody treatment caused fetal rejection in B cell-deficient but not in RAG-1-deficient females. Blockade of PDL1 also resulted in a significant increase in the frequency of IFN-gamma-producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-gamma levels in placental homogenates by ELISA. Finally, PDL1-deficient females exhibited decreased allogeneic fetal survival rates as compared with littermate and heterozygote controls and showed evidence of expansion of T helper type 1 immune responses in vivo. These results provide the first evidence that PDL1 is involved in fetomaternal tolerance.
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. ...Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19
+
B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE).
Methods
The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries.
Planned Outcomes
The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue.
Trial Registration
NCT04540497.
IgG4-related disease is an immune-mediated fibroinflammatory condition with a diverse spectrum of organ involvement, commonly in the pancreas and bile ducts among other organs such as salivary and ...lacrimal glands. Classic histopathologic findings are the gold standard for confirmation of diagnosis, although diagnosis remains challenging, as biomarkers to date are neither sufficient nor necessary. Glucocorticoids are the most effective initial treatment, generally having a dramatic response, although limited clinical evidence exists regarding effective maintenance therapy. This review summarizes key GI manifestations of this condition for the practicing gastroenterologist and addresses the pathology, disease mechanism, and current therapeutic recommendations.
Autoimmune pancreatitis frequently mimics adeno carcinoma of the pancreas by causing painless jaundice, and has been diagnosed in 27% of patients undergoing the Whipple procedure.1 IgG4-related ...systemic disease can affect various organs and anatomical sites, including the pancreas, biliary tract, salivary glands, retroperito neum, aorta, kidney, lung, and prostate.2,3 Most patients have marked increase of serum IgG4 concentrations. Tumorous swelling, diffuse lymphoplasmacytic infiltration, and obliterative phlebitis are common and have been reported in the setting of inflammatory abdominal aortic aneurysm.4 The disease occurs predominantly in older men, is frequently associated with lymphadenopathy, and responds well to glucocorticoid therapy.
Immunoglobulin G4-related disease (IgG4-RD) is a heterogeneous fibroinflammatory condition. The 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification ...Criteria for IgG4-RD were published to provide unified classification criteria in clinical research. The purpose of this study was to characterize demographics, disease manifestations, and treatments of patients with IgG4-RD and assess performance of the Classification Criteria in a heterogeneous cohort with a large population of Black patients.
This was a medical records review of all patients referred to a specialized IgG4-RD clinic. Demographics, serology, histopathology, disease manifestations, and treatment information were collected and analyzed. An ACR/EULAR Classification Criteria score for IgG4-RD was calculated to compare performance in definite diagnosis, probable diagnosis, and mimicker groups.
A total of 198 patients were evaluated. Eighty-five (43%) were mimickers. Of the remaining 114, 58 (51%) were classified as definite, and 56 (49%) as probable cases by treating clinicians. Pancreatitis was the most common presentation (37%) among 28 different organ manifestations of IgG4-RD. In patients with definite clinical diagnosis of IgG4-RD, 84% met the IgG4-RD Classification Criteria (i.e., score ≥20) with mean score of 29. Only 9% of the probable cases met this threshold with an average score of 8. None of the mimickers met the Classification Criteria.
This study highlights the broad spectrum of IgG4-RD and validates the use of the ACR/EULAR Classification Criteria for IgG4-RD, including a large proportion of Black patients. As shown in this study, IgG4-RD is a heterogeneous disease and continues to represent a diagnostic challenge to clinicians.
Patients with IgG4-related disease (IgG4-RD) share histopathological characteristics that are similar across affected organs. The finding of infiltration with IgG4+ plasma cells in the proper ...clinical and histopathological contexts connects a large number of clinical entities that were viewed previously as separate conditions. The renal involvement in IgG4-RD is usually characterized by tubulointerstitial nephritis, but membranous nephropathy has also been reported to be one of the renal complications of IgG4-RD. The recent discovery that a high proportion of patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies to the M-type phospholipase A2 receptor (PLA2R) in the circulation and glomerular immune deposits, together with the profound IgG4 hypergammaglobulinemia and occasional reports of membranous nephropathy in IgG4-RD, raised the question of a common antigen. To assess the presence of anti-PLA2R antibody in patients with IgG4-RD, we screened sera from 28 IgG4-RD patients by immunoblot. None of the patients in this cohort had detectable circulating anti-PLA2R antibodies. This study suggests that despite some clinical and serological overlaps between IgG4-RD and IMN,anti-PLA2R antibodies do not play a role in the pathogenesis of IgG4-RD. Additional studies of IgG4-RD with evidence of membranous nephropathy are important to exclude any definite relationship.
PDF
