Vessel permeability by Interleukin 2 causes anasarca, hypoalbuminemia.
Case 264
【Discussion】
Interleukin 2 (IL2) is released from helper T cell following acceptance from antigen information from dendritic cells differentiated from macrophages. Helper T cell is the center of immune system. It functions stimulation of innate and adaptive immune system. In short, IL2 stimulate macrophages and natural killer cell as innate immune system. Further, it activates naïve T cell into helper T cell, memory T cell, cytotoxic T cell (natural killer T cell) and repressive (regulatory) T cell. Furthermore, it activates B cell for antibody production. Furthermore, IL2 is reported to increase of vascular permeability on tumor vessels and brain blood barrier (1, 2).
Interleukin 6 (IL6) is released from various cells not just from leukocytes of macrophages, monocytes, lymphocytes but also from endothelial cells, epidermal cells, mesenchymal cells. It functions production of neutrophils, platelets, antibody, CRP, fibrinogen, stimulation of osteoclasts and new vessel formation (3). IL6 released from endothelial cell promotes vascular endothelial growth factor (VEGF) expression, forming new vessels (3). IL6 looks to be released for coping with stress and resistance to pathogen. IL6 is released from various sites probably for different aims responded to different require. It might be natural that there are various degrees of strength of IL6 function depending on IL6 releasing sites.
VEGF which is the same as vascular permeability factor (VPF) is released from endothelial cells and platelets. It increases permeability of vessel and produces new vessels.
TAFRO indicates thrombocytopenia, anasarca, fever, reticular fibrosis and organomegaly (5-7). Thrombocytopenia occurs in destruction of platelets or consumption of platelets. In our case, platelets count decreased instantly corresponded to elevation of D dimer, indicating that thrombocytopenia occurs in consumption of platelets.
Anasarca occurs by increasing vascular permeability of vessels or by loss of intravascular albumin. Albumin production disorder from liver, nephrotic syndrome and protein loosing gastroenteropathy were not reported in TAFRO syndrome. Then, albumin instant loss is considered to occur by vascular permeability. Increasing vascular permeability occur by VPF releasing probably from endothelial cells irrespective of stimulation of IL6 (3).
Fever comes from IL6 release mainly from leukocytes including macrophages or endothelial cells.
Reticular fibrosis in TAFRO is controversial: a report says bone marrow biopsied suspicious TAFRO syndrome revealed no evidence of reticular fibrosis. Hyperplasia of megakaryocyte is simultaneously known to occur in TAFRO syndrome, indicative compensatory response of platelets loss.
Organomegaly occurs by increasing vessel permeability due to VPF. Hepatomegaly, splenomegaly, renal hypertrophy, adrenal enlargement are probably due to vessel permeability.
In our case, thrombocytopenia, hypoalbuminemia, increasing count of neutrophils and D dimer values advanced with worsening of anasarca. Further, IL2R increased, while IgG4 was within normal limits. Histologically, hyperplasia of mantle zone which produces antibody (Ig G) and hyalinized vessel formation related with VEGF is found in TAFRO as well as Castleman disease (8) although histologic examination was not conducted in the present case. In TAFRO, IgG4 is normal and no marked enlargement of lymph node indicate that elevation of IL2 was not purposed of producing antibody. IL2 increases permeability of vessels, not always no relation with VPF (3).
There are contrast cases which some cases are effective using tocilizumab that is antagonist to IL6 and others are effective with rituximab that is antagonist to IL2 (9, 10).
【Summary】
We presented a sixty-year-old female for mild fever. At first, she was expected relapse of eosinophilic pneumonia because her medicine was in the process of steroid decrease. During hospital stay, edema of the whole body including ascites and pleural effusion worsened associated with thrombocytopenia, hypoalbuminemia, CRP elevation, increase of neutrophils count and D dimer value. IL2R 787 U/mL (> 496). It is borne in mind that IL2 itself works vascular permeability, thrombocytopenia occurs by consumption of platelets causing thrombotic angiopathy, anasarca and hypoalbuminemia are caused by increasing vascular permeability factor, fever is caused by IL 6 releasing probably from macrophages and/or endothelial cells. Reticulin fibrosis of bone marrow arises from unknown origin. Organomegaly including hepato-splenomegaly ,adrenal hypertrophy is probably due to edematous change. Imaging diagnosis might be able to contribute to clinical diagnosis of TAFRO by figuring ascites, pleural effusion, swollen adrenal gland and skin edema without cardiac failure, and then by checking thrombocytopenia and hypoalbuminemia.
【References】
1.Heslan JM, et al. Differentiation between vascular permeability factor and IL-2 in lymphocyte supernatants from patients with minimal-change nephrotic syndrome. Clin Exp Immunol.1991 Oct;86(1):157-62
2.Ballmer-Weber BK, et al. Interleukin 2-induced increase of vascular permeability without decrease of the intravascular albumin pool. British Journal of Cancer 1995; 71:78–82
3.Huang SP, et al. Interleukin-6 increases vascular endothelial growth factor and angiogenesis in gastric carcinoma. J Biomed Sci 2004;11(4):517-27
4.Takai K, et al. Thrombocytopenia with mild bone marrow fibrosis accompanied by fever, pleural effusion, ascites and hepatosplenomegaly. Rinsho Ketsueki 2010; 51:320–325
5.Kawabata H, et al. Castleman-Kojima disease (TAFRO syndrome): a novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly: a status report and summary of Fukushima (6 June, 2012) and Nagoya meetings (22 September, 2012). J Clin Exp Hematop 2013; 53:57–61
6.Sakashita K, et al. TAFRO syndrome: current perspectives. J Blood Med. 2018; 9: 15–23.
7.Konishi Y, et al. Successful Treatment of TAFRO Syndrome, a Variant of Multicentric Castleman's Disease, with Cyclosporine A: Possible Pathogenetic Contribution of Interleukin-2. Tohoku J Exp Med. 2015 Aug;236(4):289-95.
8.Frizzera G, et al. A systemic lymphoproliferative disorder with morphologic features of Castleman's disease: clinical findings and clinicopathologic correlations in 15 patients. J Clin Oncol 1985; 3: 1202–1216
9.Konishi Y, et al. Successful Treatment of TAFRO Syndrome, a Variant of Multicentric Castleman's Disease, with Cyclosporine A: Possible Pathogenetic Contribution of Interleukin-2. Tohoku J Exp Med. 2015 Aug;236(4):289-95
10.Tanaka H, et al. TAFRO syndrome with a rapid fatal course despite corticosteroid and tocilizumab therapy. Journal of Hematopathology. 2016; 9:167–171
2022.4.21