Immune Derangements in Patients with Myelofibrosis: The Role of Treg, Th17, and sIL2Rα

Abstract

Myelofibrosis (MF), including primary myelofibrosis, post-essential thrombocythemia MF, and post-polycythemia vera MF, has been reported to be associated with autoimmune phenomena. IMiDs have been reported to be effective in some patients with MF, presumably for their immune-modulator effects. We therefore sought to elucidate the immune derangements in patients with MF. We found no differences in T regulatory cells (Treg) and T helper 17 (Th17) cells in MF patients and normal healthy controls. However, we found significantly elevated soluble interleukin 2 alpha (sIL2Rα) in MF patients compared to those with other myeloproliferative neoplasm diseases and normal healthy controls. Our studies with MF patients further revealed that Treg cells were the predominant cells producing sIL2Rα. sIL2Rα and IL2 complex induced the formation of Treg cells but not the formation of Th1 or Th17 cells. sIL2Rα induced CD8+ T cell proliferation in the presence of Treg cells. Monocytes or neutrophils had no effect on the production of sIL2Rα by Treg cells. Furthermore, we found plasma sIL2Rα levels were correlated to the auto-immune serology in MPN patients and ruxolitinib significantly inhibits the sIL2Rα production by the Treg cells in MF patients which may explain the effects of ruxolitinib on the relief of constitutional symptoms. All these findings suggest that sIL2Rα likely plays a significant role in autoimmune phenomena seen in patients with MF. Further studies of immune derangement may elucidate the mechanism of IMiD, and exploration of immune modulators may prove to be important for treating myelofibrosis.

Reduced frequency of circulating CD4+CD25brightCD127lowFOXP3+ regulatory T cells in primary myelofibrosis

“…1 To test this hypothesis, we evaluated the circulating levels of serum interleukin-2 receptor a (sIL2Ra) in 93/202 patients with PMF and 10 normal subjects. As previously reported, 19,[24][25][26] sIL2Ra blood levels were higher (P 5 .014) in patients (median, 1154 pg/mL; range, 276-8968) than in normal subjects (median, 778 pg/mL; range, 272-1177). Although patients with Treg frequency .0.73% (n 5 56; median, 978 pg/mL; range, 275-4891) were comparable to normal subjects, those with Treg frequency ,0.73% had sIL2Ra levels (n 5 37; median, 1413 pg/mL; range, 476-8968) higher (P 5 .004) than normal subjects and inversely correlated to blood Tregs (R 5 20.38; P 5 .009).…”

“…on April 29, 2019. by guest www.bloodjournal.org From evidence of autoimmune diseases, those with at least 1 positive autoimmune serology have significantly elevated sIL2Ra blood levels than those with negative serology. 19 In conclusion, a low frequency of circulating Tregs, a nonclonal component of bone marrow and spleen microenvironment, characterizes patients with PMF. We found that decrease in blood Treg frequency was greatest in subjects with a wild-type JAK2 genotype, and those with a CALR mutation had a Treg frequency significantly associated with advanced disease, higher IPSS/DIPSS score, and lower hemoglobin concentration.…”

“…16 There are contradictory data on numbers of Tregs in persons with PMF. [17][18][19] With the aim of determining whether Tregs were abnormal and interrogating possible associations with clinical and laboratory features, we did a cross-sectional evaluation of 202 consecutive subjects with PMF referred to the Center for the Study of Myelofibrosis, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo of Pavia, Italy, from March 2008 to September 2015 (supplemental Methods, available on the Blood Web site). Sample size was defined by investigating blood Treg frequency in 31 subjects with PMF tested twice within 5 days.…”

Antinuclear antibodies positive patient with splenic infarct a diagnostic dilemma

“…The review of literature showed that ANA positivity is also reported in some sporadic cases of primary myelofibrosis (PMF), such cases were also shown to respond well to steroids [2]. Thus this case demonstrates the difficulty posed due to overlapping features of AIMF and PMF creates possibly indicating an associated etiology.…”

“…However, on bone marrow examination and molecular studies this turned out to be a case of primary myelofibrosis. The autoimmune process is an incidental finding in this case which is reported in literature to be associated with primary myelofibrosis [2]. It is important to diagnose correctly as both conditions have distinct prognosis and course of disease [3].…”