IL-33 reflects dynamics of disease activity in patients with autoimmune hemolytic anemia by regulating autoantibody production

Abstract

Background Autoimmune hemolytic anemia (AIHA), a life-threatening anemia with rapid onset, is caused by autoantibody directed to self red blood cells (RBCs). Currently, mechanisms underlying AIHA pathogenesis are largely undefined. Here we explored the correlation of IL-33 with AIHA disease activity and evaluated IL-33 based therapeutics in AIHA treatment.Methods Thirty patients diagnosed with AIHA of warm-type autoantibodies without treatment were enrolled and followed up for 6 months. Levels of cytokines including IL-33, IL-4, IL-6 and IL-13 was determined with ELISA. AIHA disease activity was presented by levels of reticulocyte count, hemoglobin and lactate dehydrogenase. Serum RBC-bound IgG autoantibody was detected using anti-IgG antibody with flow cytometry. To evaluate the effect of IL-33 blockade on AIHA development, groups of B6 mice were immunized with rat RBCs plus recombinant IL-33 protein or IL-33 neutralizing antibody respectively and detected for levels of anti-RBC antibody, frequency of reticulocytes and destruction of transfused syngeneic mouse RBCs.ResultsSerum level of IL-33 was higher in AIHA patients compared with healthy individuals. Of interest, serum IL-33 was positively correlated with AIHA disease activity and sensitive to their changes in AIHA patients under clinical management. Mechanistically, IL-33 could promote the production of anti-RBC autoantibody. Serum IL-33 was closely associated with serum anti-RBC autoantibody and sensitive to their changes in AIHA patients. Accordingly, blockade of IL-33 interfered with AIHA incidence and ameliorated disease activity. Vice vasa, enforced IL-33 promoted AIHA incidence and disease activity.ConclusionsIL-33 was a potential biomarker for monitoring disease activity and therapeutic response in AIHA patients. Targeting IL-33 was a promising strategy for controlling autoantibody production in AIHA patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0745-0) contains supplementary material, which is available to authorized users.

C-Reactive Protein Enhances IgG-Mediated Cellular Destruction Through IgG-Fc Receptors in vitro

“…Besides some case studies, CRP levels have never been systematically studied in AIHA or HDFN patients. Especially AIHA patients are likely to have episodes of elevated CRP levels and FcγRIa expression since AIHA is often secondary to a broad range of inflammatory conditions and IL-33 levels are reportedly elevated ( 41 , 42 ). Moreover, autoimmune diseases are generally known to initiate, exacerbate or relapse upon bacterial or viral infections which inflict CRP upregulation.…”

“…Recent work of Meinderts et al ( 40 ) suggests that basically all types of splenic myeloid cells (monocytes, macrophages, and polymorphonuclear leukocytes (PMNs; consisting mostly of neutrophils but also eosinophils and basophils)] play a role in the phagocytosis of IgG-opsonized erythrocytes. In AIHA, this tends to occur under inflammatory conditions (e.g., elevated IL-33, a positive regulator of IL-6 expression) ( 41 , 42 ) which often result in episodes of increased CRP levels ( 43 – 47 ), although the causal link has not been established. Nevertheless, a recent case study of AIHA suggested CRP elevation to aggravate the anemia ( 48 ).…”

IL‐33 induces production of autoantibody against autologous respiratory epithelial cells: a potential mechanism for the pathogenesis of COPD

“…5,23 IL-33, mainly produced by airways epithelial cells, fibroblasts and endothelial cells as well as activated immune cells, 24 plays important roles in a range of autoimmune diseases. [25][26][27][28] In an attempt to link these findings, and in particular to provide a possible explanation for why lung function impairment and particularly alveolar damage may persist and progress despite apparent removal of the provoking stimulus, we hypothesized that the respiratory epithelial alarmin IL-33, known to be produced in response to inhaled environmental insults such as cigarette smoke, triggers a humoral autoimmune response directed against alveolar epithelial cells. Our aim was to explore whether antibodies can be induced in mice immunized with autologous (syngeneic) normal lung tissue while exposed to exogenous IL-33 delivered topically to the airways or systemically, and to examine their specificity in mice as well as their cross-specificity for human alveolar epithelial cells.…”

“…It has also been shown that COPD is characterized by elevated production of the alarmin cytokine IL‐33, particularly with continued cigarette smoke exposure, to a degree that correlates with the rate of progression of the disease . IL‐33, mainly produced by airways epithelial cells, fibroblasts and endothelial cells as well as activated immune cells, plays important roles in a range of autoimmune diseases …”

Immune Checkpoint Inhibitors Induced Autoimmune Haemolytic Anemia: Case Series and Literature Review

“…Enforced IL-33 promoted AIHA incidence and accelerated disease activity, while blockade of IL-33 interfered with AIHA incidence and ameliorated disease activity. (Bu et al, 2015) In our report (Table 3), three patients previously with anemia were treated with three different anti-PD-1 antibodies, which were pembrolizumab, camrelizumab, and nivolumab. Their anemia was all successively exacerbated and developed AIHA.…”