|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
From the Laboratory of Allergic Diseases, National
Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD; Virginia Commonwealth University, Richmond, VA;
and Nichirei Corporation, Tokyo, Japan.
Systemic mastocytosis is a disease of mast cell proliferation that
may be associated with hematologic disorders. There are no features on
examination that allow the diagnosis of systemic disease, and mast
cell-derived mediators, which may be elevated in urine or blood, may
also be elevated in individuals with severe allergic disorders. Thus,
the diagnosis usually depends on results of bone marrow biopsy. To
facilitate evaluation, surrogate markers of the extent and severity of
the disease are needed. Because of the association of mastocytosis with
hematologic disease, plasma levels were measured for soluble KIT (sKIT)
and soluble interleukin-2 receptor alpha chain (sCD25), which are known
to be cleaved in part from the mast cell surface and are elevated in
some hematologic malignancies. Results revealed that levels of
both soluble receptors are increased in systemic mastocytosis. Median
plasma sKIT concentrations as expressed by AU/mL (1 AU = 1.4
ng/mL) were as follows: controls, 176 (n = 60); urticaria pigmentosa
without systemic involvement, 194 (n = 8); systemic indolent
mastocytosis, 511 (n = 30); systemic mastocytosis with an associated
hematologic disorder, 1320 (n = 7); aggressive mastocytosis, 3390 (n = 3). Plasma sCD25 levels were elevated in systemic mastocytosis;
the highest levels were associated with extensive bone marrow
involvement. Levels of sKIT correlated with total tryptase levels,
sCD25 levels, and bone marrow pathology. These results demonstrate that
sKIT and sCD25 are useful surrogate markers of disease severity in
patients with mastocytosis and should aid in diagnosis, in the
selection of those needing a bone marrow biopsy, and in the
documentation of disease progression.
(Blood. 2000;96:1267-1273) Mastocytosis is characterized by an increase
in tissue mast cells, particularly in the skin, bone marrow, lymph
nodes, liver, and spleen. Activating mutations in c-kit, the
receptor for stem cell factor, which is critical for mast cell
proliferation, differentiation, and survival, have been found in both
children and adults with this disease.1,2 The diagnosis
and determination of the extent of disease and the assignment of
prognosis in mastocytosis remain largely within the realm of clinical
judgment influenced by the duration of the disease and tissue biopsy.
Mast cell mediator levels may be elevated in plasma3,4
(tryptases and histamine) and in urine5,6 (prostaglandin
D2 and histamine metabolites). Mediator levels are
generally believed to increase in parallel with an increase in tissue
mast cells7 and thus are diagnostic aids that also may
reflect the extent of disease. Confounding interpretation, levels of
beta-tryptase, histamine, and prostaglandin D2 are also
elevated in patients experiencing a severe systemic allergic reaction
(anaphylaxis).8-10
In some patients, however, the increase in mast cell numbers occurs in
the presence of an identifiable hematologic disorder, particularly
dysmyelopoiesis.11-13 The identification in circulation of
surrogate markers of hematologic disease would facilitate understanding the spectrum of pathologic findings in mastocytosis and also in identifying individuals exhibiting this process. Thus, 2 possible surrogate markers of bone marrow disease appeared promising.
The first of these was soluble KIT (sKIT). KIT is expressed on
primitive hematopoietic cells and on mast cells at all stages of
maturation. The second candidate marker, soluble CD25 (sCD25), is the
alpha chain of interleukin-2 (IL-2) receptor. CD25 is known to be
expressed on bone marrow mast cells in mastocytosis. The soluble forms
of both receptors are elevated in the plasma of patients with certain hematologic malignancies.14-19
As will be shown, both sKIT and sCD25 are increased in the plasma of
patients with mastocytosis. Soluble KIT levels, in particular, seem to
reflect the extent and severity of disease. Both sKIT and sCD25
correlate with plasma total tryptase levels and severity of bone marrow
pathology. Thus, the ability to measure sKIT and sCD25 in the plasma of
patients suspected of having mastocytosis adds insights into the
pathophysiology of mastocytosis and should aid in assessing the
severity of mastocytosis and assigning prognosis.
Patients
Determination of sKIT
Determinations of SCF, sCD25, and IL-2 Plasma levels of SCF, sCD25, and IL-2 were determined by commercially available ELISA kits (R&D Systems, Minneapolis, MN) according to the manufacturer's instructions. The SCF ELISA detects free SCF as well as SCF in complex with KIT. The optical density was read at 450 nm with correction at 570 nm. All samples were assayed in duplicate.Determination of tryptase Tryptase in serum or plasma was measured by means of sandwich immunoassays.3 Beta-tryptase levels were measured with the use of mAbs B12 for capture and biotin-G5 for detection. Total tryptase levels (alpha-tryptases plus beta-tryptases, primarily alpha-protryptase at baseline) were measured on the UniCAP system (Pharmacia-Upjohn, Peapack, NJ) with the use of mAbs B12 for capture and beta-galactosidase-G4 for detection.Statistical analysis Comparisons for statistical significance were performed with the use of the Wilcoxon rank sum (Mann-Whitney U) test. Correlations between observations were assessed by Spearman's rank correlation coefficient. Contingency table analyses were performed by Fisher's exact test. A P value of < .05 was considered statistically significant.
Plasma sKIT levels in mastocytosis and systemic anaphylaxis To determine if sKIT is elevated in mastocytosis and systemic anaphylaxis, we determined the plasma sKIT levels in 48 patients with mastocytosis and 11 patients with systemic anaphylaxis and compared the levels with those found in healthy controls. The control group had a median plasma sKIT level of 176 AU/mL (range, 81-322 AU/mL; n = 60) (Figure 1). These data are consistent with reported levels of sKIT in healthy adults.21 There was a statistically significant increase of sKIT in anaphylaxis serum when compared with healthy controls (median, 260 AU/mL; range, 55-356 AU/mL; P < .05). Plasma sKIT levels were also found to be significantly elevated in patients with mastocytosis, where the median value was considerably higher (median, 513 AU/mL; range, 112-5055 AU/mL; P < .00001 vs healthy controls and P < .005 vs anaphylaxis).
Correlation of plasma sKIT with disease category Because plasma sKIT levels were observed over a broad range in patients with mastocytosis, we determined whether this variation correlated with clinical patterns of disease. As can be seen in Figure 2A, plasma sKIT levels were not significantly elevated in those with skin involvement only when compared with normal subjects (category Ia: median, 194 AU/mL; range, 148-377 AU/mL; statistically insignificant when compared with control group). However, levels were significantly elevated in systemic mastocytosis (ie, categories Ib, II, and III), and the level of elevation was greatest in those with more severe forms of disease. Thus, patients with systemic indolent disease (Ib) had a median level of 511 AU/mL (range, 112-4755 AU/mL; P < .00001 vs healthy controls and P < .002 vs category Ia). The median sKIT level for patients with an associated hematologic disorder was 1320 AU/mL (range, 506-3195 AU/mL; P < .00005 vs healthy controls, P < .002 vs category Ia, and P < .05 vs category Ib). Patients with aggressive mastocytosis who presented with lymphadenopathy and exhibited a rapidly progressive course (category III) had the highest median plasma level of sKIT (3390 AU/mL; range, 2910-3605 AU/mL; P < .005 vs healthy controls, P < .02 vs categories Ia and Ib, P < .05 vs category II).
Correlation of sKIT with bone marrow pathology Mastocytosis may be associated with dysmyelopoiesis. Soluble KIT shed from mast cells and other KIT-bearing hematopoietic cells might be expected to increase as hematopoiesis becomes more disordered. We thus correlated the plasma sKIT concentrations with the extent of bone marrow pathology. Pathological findings in bone marrow biopsies from patients with mastocytosis were divided into 3 groups: (1) normocellular bone marrow with no evidence of increased mast cells (n = 8); (2) normocellular bone marrow with diagnostic focal increases in mast cell numbers (n = 20); and (3) focal or diffuse mast cell aggregates and hypercellular bone marrow or evidence of an associated hematologic disorder such as myelodysplasia or myeloproliferative state (n = 20). In the last patient group, 7 deaths occurred over a 2- to 42-month follow-up. No disease-related deaths were reported in groups 1 and 2 over a 1- to 11-year follow-up.Elevations in sKIT were found to correlate with the extent of bone marrow involvement (Figure 2B), with the highest levels observed in group 3 (median levels: 193.5 AU/mL in group 1; 421.5 AU/mL in group 2; 1418 AU/mL in group 3). Soluble KIT levels in patients in groups 2 and 3 were significantly higher than in healthy controls and in group 1. Thus, the higher the levels of sKIT, the greater the likelihood that the patient will have an abnormal bone marrow at the time of the measurement. Correlation of sKIT levels with detectability of c-kit mutation The detectability of the somatic c-kit mutations at the amino acid position D816 (single-letter amino acid code) by restriction fragment length polymorphism analysis following reverse transcription polymerase chain reaction in the peripheral blood white cells has been shown to correlate with disease severity and a poorer prognosis.22 We therefore compared sKIT levels in patients who carried this molecular marker with those who did not. Results revealed a statistically significant increase in sKIT levels in patients who exhibited the D816 c-kit mutation in the peripheral blood (median levels of 421.5 AU/mL vs 1320 AU/mL, P < .005). This is consistent with the correlation found in categorizations based on clinical presentation and bone marrow pathology.Correlation of plasma sKIT levels with plasma tryptase Because plasma levels of tryptase have been shown to be elevated in mastocytosis, and proposed as an indicator of total body mast cell burden,3 we next determined tryptase levels in plasma samples from the same group of 48 patients with mastocytosis. Prior work suggested that total tryptase levels of 20 ng/mL or more in association with a total tryptase to beta-tryptase ratio of 20 or more identifies patients with systemic mastocytosis.3,7 The median total tryptase plasma level in healthy controls was 5.0 ng/mL. Statistically significant elevations in total tryptase were found in patients with all forms of the disease when compared with healthy controls: median tryptase levels (ng/mL) were 13 (range, 4-35) for category Ia; 61 (range, 16-400) for category Ib; 159 (range, 59-347) for category II; and 219 (range, 26-670) for category III. The beta form of tryptase was undetectable (ie, below 1 ng/mL) in 23 out of 48 patients and ranged from 1 through 53 ng/mL in the remaining patients. Such detectable levels of beta-tryptase are thought to reflect concurrent mast cell activation and cross-reactivity with alpha-protryptase in patients with biopsy-confirmed mastocytosis. There was no statistically significant difference in total tryptase levels or total tryptase/beta-tryptase ratios among categories Ib, II, and III. These data are consistent with previous reports.3When plasma sKIT and total tryptase levels were compared within each
disease category (Figure 3), a highly
significant overall correlation was found between plasma sKIT and total
tryptase levels (Spearman's r = 0.77
P < .0001) and in patients with systemic indolent disease (category Ib) (r = 0.81, P < .0001).
This correlation was not evident for patients with the mildest (Ia) or
more extensive (II and III) categories of disease. Of 8 patients in
category Ia, 3 had total tryptase levels exceeding 20 ng/mL, the cutoff value suggestive of a diagnosis of systemic mastocytosis, whereas only
1 patient in this category had an sKIT value greater than the highest
normal control. Of the 30 patients classified as category Ib, 8 had an
sKIT level lower than the highest normal control, whereas 2 had a total
tryptase level below 20. This suggests that total tryptase levels are a
more sensitive indicator than sKIT of an increased mast cell burden. On
the other hand, sKIT elevations were not observed to be paralleled to
the same extent by total tryptase values in advanced categories of
disease (ie, II and III), although the levels of both proteins were
increased. These data suggest that as the bone marrow pathology
increases, it may not be accompanied by a parallel increase in total
tryptase, but is better reflected by sKIT levels.
Lack of correlation between plasma sKIT and SCF Soluble receptors may in some instances influence the circulating levels of their ligands by accelerating their metabolic clearance or by competing for binding to the cell-surface receptors.23 We therefore determined the plasma levels of SCF. The median SCF level in control samples was 983 pg/mL (range, 440-1838 pg/mL). Patients with mastocytosis had significantly higher plasma SCF levels than healthy controls (median, 1335; range, 272-2256, P < .00005). Analysis of SCF levels in different categories of disease revealed a significant increase only in category Ib (P < .00001). Patients with mastocytosis in categories Ia, Ib, II, and III had median SCF levels of 1211, 1615, 1312, and 553 pg/mL, respectively. There was no significant correlation between SCF and sKIT levels. All 10 patients in advanced categories (ie, II and III) had SCF levels below 1500 pg/mL, whereas only 16 of 38 patients (42%) with indolent disease had similar levels (Fisher's exact probability P < .001).Correlation of hematologic parameters with plasma sKIT and SCF Abnormalities in the numbers of circulating blood cells are encountered in systemic mastocytosis. In addition to the presence of a hematologic disorder,12 the presence of anemia, thrombocytopenia, and a hypercellular bone marrow implies more extensive disease and a poorer prognosis.24 However, we found no significant correlation between sKIT and hemoglobin levels, total white blood cell (WBC) count, and platelet count. Analysis of differential WBC counts for neutrophils, monocytes, and lymphocytes similarly failed to yield a significant correlation (data not shown). There was a marginal negative correlation between SCF levels and total WBC counts (Spearman's r = 0.30, P < .05) as well as
lymphocyte counts (r = 0.33, P < .05). Because sKIT
correlates with bone marrow pathology but not peripheral blood
abnormalities, sKIT may indicate bone marrow disease prior to its
reflection in peripheral blood counts.
Soluble CD25 in mastocytosis Demonstration of the elevation of sKIT in mastocytosis suggests that soluble forms of the membrane proteins highly or preferentially expressed by mast cells may be useful surrogate markers of disease activity and prognosis. This prompted an investigation of the plasma levels of sCD25. Because CD25 is reported to be expressed by the bone marrow mast cells of patients with systemic mastocytosis but not healthy individuals,25 we determined plasma sCD25 and IL-2 levels in a representative subset of 29 patients with mastocytosis and those with anaphylaxis. Results revealed an overall elevation of plasma sCD25 both in mastocytosis (median, 955 pg/mL; range, 138-2829 in controls, vs median, 2491; range, 310-15 020 in mastocytosis; P < .00001) and in anaphylaxis (median, 1361 pg/mL; P < .05 vs controls). Soluble CD25 was also significantly elevated in each category of systemic mastocytosis (categories Ib, II, and III) (Figure 4) when compared with controls (Ia median, 1092 pg/mL; range, 671-1933; Ib median, 1866; range, 310-5757; II median, 6589; range, 2677-12 566; III median, 6852; range, 4411-15 020). The elevations were more pronounced in categories II and III, both of which were significantly higher than categories Ia and Ib, although there was no significant difference between categories Ia vs Ib and II vs III. Analysis of sCD25 levels according to bone marrow pathology revealed that patients with hypercellular bone marrows had significantly higher levels than those with less or no significant pathology (P < .005 and P < .0001 when bone marrow pathology group 3 is compared with groups 1 and 2, respectively; data not shown). Patients who had detectable levels of D816V (single-letter amino acid code) messenger RNA in peripheral blood white cells similarly had significantly higher sCD25 levels than those who did not (P < .05). Plasma IL-2 levels in all patients were below the detection limit of the assay (ie, below 7 pg/mL) (data not shown).
Soluble CD25 plasma levels strongly correlated with those of sKIT and
total tryptase in patients with mastocytosis (Spearman's r = 0.72,
P < .0001, and r = 0.67, P < .0001,
respectively) (Figure 5). A slight
negative correlation was observed between sCD25 and SCF levels
(r =
This study documents that sKIT and sCD25 levels are significantly elevated in systemic forms of mastocytosis when compared with healthy controls and patients with suspected systemic anaphylaxis. There was overlap between normal values and those obtained from patients with milder forms of the disease and among systemic disease categories. The sKIT value corresponding to the mean + 2 SD in the normal population was 312 AU/mL. Soluble KIT levels in 9 of 11 patients with anaphylaxis were within healthy normal range (Figure 1). Out of 8 patients in category Ia, 7 (88%) had levels below this value. This overlap was less apparent (8 out of 30 or 27%) for patients with systemic indolent disease (category Ib) and did not exist for categories II and III. While half of the patients with an sKIT value below 300 AU/mL lacked systemic involvement, sKIT levels higher than 400 AU/mL were exclusively associated with systemic forms of the disease. All 3 patients in category III had sKIT levels exceeding 2900 AU/mL. Such high levels of sKIT have not been reported in other diseases. Similarly, there was a significant difference in median sCD25 levels in systemic mastocytosis when compared with controls, although some values in healthy individuals overlapped with the values in indolent forms of the disease. Soluble CD25 levels in aggressive forms of the disease did not display this overlap. Thus, all the normal controls and patients without systemic involvement had sCD25 levels below 3000 pg/mL, while 8 of 9 patients (88%) with an associated hematologic disorder or aggressive disease had levels above this value. Soluble KIT and sCD25 levels correlated not only with the classification based on clinical presentation but also with bone marrow pathology and detectability of the D816V mutation in blood. Because both sKIT and sCD25 are thought to be generated by the proteolytic cleavage of the membrane-bound receptors,26 it is possible that the increased levels in mastocytosis in part reflect increased mast cell numbers. This is supported by the finding that sKIT and sCD25 levels highly correlated with total tryptase levels, a proposed marker of mast cell burden. Comparison of the diagnostic value of plasma sKIT measurements with that of total tryptase (primarily alpha-protryptase) shows that these 2 assays may be complementary in assessment of the disease status in mastocytosis and its differential diagnosis from idiopathic anaphylaxis. It appears that total tryptase is a more sensitive indicator of increased mast cell burden in early stages of the disease, because 5 out of 8 patients with category Ia and 28 of 30 patients with systemic disease had total tryptase levels greater than the suggested cutoff value of 20 ng/mL. On the other hand, there was considerable overlap of total tryptase measurements between patients with category Ia, Ib, and II forms of systemic disease. Therefore, it appears that total tryptase levels may best reflect the total body burden of mast cells, but not necessarily the bone marrow pathology of the underlying disease. In patients with aggressive disease, non-mast cell lineages that express KIT but not tryptase may be involved. Also, it is possible that mast cells in lesions of category III mastocytosis produce less tryptase and more KIT per cell than those associated with less aggressive disease. Soluble KIT levels have been determined in a number of other clinical conditions. Among the hematopoietic neoplasms examined, acute myeloid leukemia subtypes M1 and M2 were associated with modest increases in sKIT levels.14 One study found increased levels of sKIT in chronic myeloid leukemia (CML) in acute myeloid blast crisis and advanced myelodysplastic syndromes,15 although another study showed no statistically significant difference in these disease groups.14 The highest level of sKIT in these studies was 1470 AU/mL, using the same ELISA system as ours, and was reported in a patient with CML in myeloid blast crisis. Similar to mastocytosis, elevated levels of sKIT in these malignancies are thought to be related to the higher surface expression of KIT in the immature neoplastic cells. Mild yet statistically significant increases have also been reported in chronic renal failure with a median value of 244 AU/mL.27 In contrast, low levels of sKIT were associated with graft-vs-host reaction,28 delayed engraftment after bone marrow transplantation,29 and systemic lupus erythematosus.21 In contrast to the relatively few clinical conditions in which sKIT is known to be elevated, sCD25 is elevated in a number of hematologic malignancies,16-19 solid tumors,30 rheumatic disorders,31-34 and infectious diseases.35-37 These elevations may reflect the numbers of activated T cells or neoplastic cells displaying CD25 on their surface. Indeed, changes in sCD25 levels correspond to clinical response to therapy in hematologic neoplasms such as hairy cell leukemia and adult T-cell leukemia.18,38 Monitoring of sCD25 levels could similarly be used as a predictor of response to therapy in mastocytosis. A modest increase in sCD25 similar to that of sKIT was found in patients with anaphylaxis in this study. This finding is consistent with an earlier report of elevated sCD25 in children with a history of anaphylactic reaction to food or atopic eczema.39 The cellular source of sCD25 in these patients is likely to be activated T lymphocytes, in line with the demonstration of activated T cells in hymenoptera hypersensitivity40 and down-regulation of their surface IL-2 receptors following rush hyposensitization.41 The levels of SCF were found to be elevated in patients with systemic indolent mastocytosis although they did not correlate with those of sKIT or the patterns of disease. There was a mild inverse correlation between SCF levels and WBC and lymphocyte numbers. A similar inverse correlation was observed in patients with renal failure, which was thought to reflect a physiological response to stimulate the bone marrow in cases of inefficient hematopoiesis.27 Other studies, however, failed to yield a similar negative correlation in other bone marrow failure states, such as aplastic anemias and myelodysplastic syndromes.42-44 Whether the high levels of sKIT in mastocytosis have a pathophysiological relevance is unknown. Soluble KIT circulates in approximately 30-fold molar excess of its ligand SCF under physiologic circumstances.45 According to simple dissociation kinetics, it is predicted that about 85% of SCF exists bound to sKIT. Since sKIT can compete with the membrane-bound KIT for binding of SCF, a negative regulatory role is proposed for this soluble receptor.26 In advanced mastocytosis, where plasma levels of sKIT are increased 10-fold or more, approximately 98% of SCF may be predicted to exist in complex with sKIT. Therefore, high levels of sKIT may contribute to the impaired hematopoiesis in patients with advanced categories of disease. In conclusion, we have demonstrated that plasma sKIT and sCD25 levels are elevated in mastocytosis and that the level of elevation correlates with the severity of cellular and molecular parameters of pathology of the disease. Assessment of these markers together with tryptase levels provides valuable information relating to the probable severity of mastocytosis, may help determine which individuals should undergo a bone marrow biopsy, and will facilitate the differential diagnosis of patients evaluated after anaphylactic episodes. Finally, determination of the plasma levels of these receptors may help identify patient subpopulations that may be predicted to respond to biological therapies targeting these receptors on the neoplastic mast cells.
Submitted November 23, 1999; accepted April 14, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Cem Akin, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11C205, 10 Center Drive, MSC 1881, Bethesda, MD 20892-1881; e-mail: cakin{at}niaid.nih.gov.
1. Nagata H, Worobec AS, Oh CK, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A. 1995;92:10560-10564. 2. Longley BJ Jr, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci U S A. 1999;96:1609-1614. 3. Schwartz LB, Sakai K, Bradford TR, et al. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest. 1995;96:2702-2710. 4. Friedman BS, Steinberg SC, Meggs WJ, Kaliner MA, Frieri M, Metcalfe DD. Analysis of plasma histamine levels in patients with mast cell disorders. Am J Med. 1989;87:649-654. 5. Roberts LJ II, Sweetman BJ, Lewis RA, Austen KF, Oates JA. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med. 1980;303:1400-1404. 6. Granerus G, Roupe G. Increased urinary methylimidazoleacetic acid (MelmAA) as an indicator of systemic mastocytosis. Agents Actions. 1982;12:29-31. 7. Kanthawatana S, Carias K, Arnaout R, Hu J, Irani AM, Schwartz LB. The potential clinical utility of serum alpha-protryptase levels. J Allergy Clin Immunol. 1999;103:1092-1099. 8. Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987;316:1622-1626. 9. Lieberman P, Taylor WW Jr. Recurrent idiopathic anaphylaxis. Arch Intern Med. 1979;139:1032-1034. 10. Awad JA, Morrow JD, Roberts LJ II. Detection of the major urinary metabolite of prostaglandin D2 in the circulation: demonstration of elevated levels in patients with disorders of systemic mast cell activation. J Allergy Clin Immunol. 1994;93:817-824. 11. Horny HP, Parwaresch MR, Lennert K. Bone marrow findings in systemic mastocytosis. Hum Pathol. 1985;16:808-814. 12. Travis WD, Li CY, Yam LT, Bergstralh EJ, Swee RG. Significance of systemic mast cell disease with associated hematologic disorders. Cancer. 1988;62:965-972. 13. Lawrence JB, Friedman BS, Travis WD, Chinchilli VM, Metcalfe DD, Gralnick HR. Hematologic manifestations of systemic mast cell disease: a prospective study of laboratory and morphologic features and their relation to prognosis. Am J Med. 1991;91:612-624. 14. Tajima F, Kawatani T, Ishiga K, Nanba E, Kawasaki H. Serum soluble c-kit receptor and expression of c-kit protein and mRNA in acute myeloid leukemia. Eur J Haematol. 1998;60:289-296. 15. Kawakita M, Yonemura Y, Miyake H, et al. Soluble c-kit molecule in serum from healthy individuals and patients with haemopoietic disorders. Br J Haematol. 1995;91:23-29. 16. Pizzolo G, Chilosi M, Vinante F, et al. Soluble interleukin-2 receptors in the serum of patients with Hodgkin's disease. Br J Cancer. 1987;55:427-428. 17. Wagner DK, Kiwanuka J, Edwards BK, Rubin LA, Nelson DL, Magrath IT. Soluble interleukin-2 receptor levels in patients with undifferentiated and lymphoblastic lymphomas: correlation with survival. J Clin Oncol. 1987;5:1262-1274. 18. Marcon L, Rubin LA, Kurman CC, et al. Elevated serum levels of soluble Tac peptide in adult T-cell leukemia: correlation with clinical status during chemotherapy. Ann Intern Med. 1988;109:274-279. 19. Motoi T, Uchiyama T, Hori T, Itoh K, Uchino H, Ueda R. Elevated serum-soluble interleukin-2 receptor (Tac antigen) levels in chronic myelogenous leukemia patients with blastic crisis. Blood. 1989;74:1052-1057. 20. Metcalfe DD. Conclusions. J Invest Dermatol. 1991;96(suppl):64S. 21. Kitoh T, Ishikawa H, Sawada S, et al. Significance of stem cell factor and soluble KIT in patients with systemic lupus erythematosus. Clin Rheumatol. 1998;17:293-300. 22. Worobec AS, Semere T, Nagata H, Metcalfe DD. Clinical correlates of the presence of the Asp816Val c-kit mutation in the peripheral blood mononuclear cells of patients with mastocytosis. Cancer. 1998;83:2120-2129. 23. Heaney ML, Golde DW. Soluble receptors in human disease. J Leukoc Biol. 1998;64:135-146. 24. Travis WD, Li CY, Bergstralh EJ, Yam LT, Swee RG. Systemic mast cell disease: analysis of 58 cases and literature review [published correction appears in Medicine (Baltimore). 1990;69:34]. Medicine (Baltimore). 1988;67:345-368. 25. Escribano L, Orfao A, Diaz-Agustin B, et al. Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood. 1998;91:2731-2736. 26. Turner AM, Bennett LG, Lin NL, et al. Identification and characterization of a soluble c-kit receptor produced by human hematopoietic cell lines. Blood. 1995;85:2052-2058. 27. Kitoh T, Ishikawa H, Ishii T, Nakagawa S. Elevated SCF levels in the serum of patients with chronic renal failure. Br J Haematol. 1998;102:1151-1156. 28. Hashino S, Imamura M, Kobayashi S, et al. Soluble c-kit levels in acute GVHD after allogeneic bone marrow transplantation. Br J Haematol. 1995;89:897-899. 29. Hashino S, Imamura M, Tanaka J, et al. Low levels of serum soluble c-kit relates to delayed engraftment after bone marrow transplantation. Leuk Lymphoma. 1997;25:327-331. 30. Barton DP, Blanchard DK, Michelini-Norris B, Nicosia SV, Cavanagh D, Djeu JY. High serum and ascitic soluble interleukin-2 receptor alpha levels in advanced epithelial ovarian cancer [see comment in Blood 1993;82:326]. Blood. 1993;81:424-429. 31. Campen DH, Horwitz DA, Quismorio FP Jr, Ehresmann GR, Martin WJ. Serum levels of interleukin-2 receptor and activity of rheumatic diseases characterized by immune system activation. Arthritis Rheum. 1988;31:1358-1364. 32. Keystone EC, Snow KM, Bombardier C, Chang CH, Nelson DL, Rubin LA. Elevated soluble interleukin-2 receptor levels in the sera and synovial fluids of patients with rheumatoid arthritis. Arthritis Rheum. 1988;31:844-849. 33. Semenzato G, Bambara LM, Biasi D, et al. Increased serum levels of soluble interleukin-2 receptor in patients with systemic lupus erythematosus and rheumatoid arthritis. J Clin Immunol. 1988;8:447-452. 34. Symons JA, Wood NC, Di Giovine FS, Duff GW. Soluble IL-2 receptor in rheumatoid arthritis: correlation with disease activity, IL-1 and IL-2 inhibition. J Immunol. 1988;141:2612-2618. 35. Brown AE, Rieder KT, Webster HK. Prolonged elevations of soluble interleukin-2 receptors in tuberculosis. Am Rev Respir Dis. 1989;139:1036-1038. 36. Chu CM, Liaw YF. Serum levels of soluble Tac peptide in acute and chronic hepatitis B virus infection. Clin Immunol Immunopathol. 1989;53:52-58. 37. Honda M, Kitamura K, Matsuda K, et al. Soluble IL-2 receptor in AIDS: correlation of its serum level with the classification of HIV-induced diseases and its characterization. J Immunol. 1989;142:4248-4255. 38. Chilosi M, Semenzato G, Cetto G, et al. Soluble interleukin-2 receptors in the sera of patients with hairy cell leukemia: relationship with the effect of recombinant alpha-interferon therapy on clinical parameters and natural killer in vitro activity. Blood. 1987;70:1530-1535. 39. Matsumoto T, Miike T, Yamaguchi K, Murakami M, Kawabe T, Yodoi J. Serum levels of IL-2 receptor, IL-4 and IgE-binding factors in childhood allergic diseases. Clin Exp Immunol. 1991;85:288-292. 40. Bonay M, Echchakir H, Lecossier D, et al. Characterization of proliferative responses and cytokine mRNA profiles induced by Vespula venom in patients with severe reactions to wasp stings. Clin Exp Immunol. 1997;109:342-350. 41. Tilmant L, Dessaint JP, Tsicopoulos A, Tonnel AB, Capron A. Concomitant augmentation of CD4+ CD45R+ suppressor/inducer subset and diminution of CD4+ CDw29+ helper/inducer subset during rush hyposensitization in hymenoptera venom allergy. Clin Exp Immunol. 1989;76:13-18. 42. Nimer SD, Leung DH, Wolin MJ, Golde DW. Serum stem cell factor levels in patients with aplastic anemia. Int J Hematol. 1994;60:185-189. 43. Wodnar-Filipowicz A, Yancik S, Moser Y, et al. Levels of soluble stem cell factor in serum of patients with aplastic anemia. Blood. 1993;81:3259-3264. 44. Bowen D, Yancik S, Bennett L, Culligan D, Resser K. Serum stem cell factor concentration in patients with myelodysplastic syndromes. Br J Haematol. 1993;85:63-66. 45. Wypych J, Bennett LG, Schwartz MG, et al. Soluble kit receptor in human serum. Blood. 1995;85:66-73.
© 2000 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  A. C. Cruz, B. T. Frank, S. T. Edwards, P. F. Dazin, J. J. Peschon, and K. C. Fang Tumor Necrosis Factor-{alpha}-converting Enzyme Controls Surface Expression of c-Kit and Survival of Embryonic Stem Cell-derived Mast Cells J. Biol. Chem., February 13, 2004; 279(7): 5612 - 5620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Schwartz, H.-K. Min, S. Ren, H.-Z. Xia, J. Hu, W. Zhao, G. Moxley, and Y. Fukuoka Tryptase Precursors Are Preferentially and Spontaneously Released, Whereas Mature Tryptase Is Retained by HMC-1 Cells, Mono-Mac-6 Cells, and Human Skin-Derived Mast Cells J. Immunol., June 1, 2003; 170(11): 5667 - 5673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Yavuz, P. E. Lipsky, S. Yavuz, D. D. Metcalfe, and C. Akin Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene Blood, June 28, 2002; 100(2): 661 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M C Carter and D D Metcalfe Paediatric mastocytosis Arch. Dis. Child., May 1, 2002; 86(5): 315 - 319. [Full Text] [PDF]
|
|
|
|
|
|
T. Daley, D. D. Metcalfe, and C. Akin Association of the Q576R polymorphism in the interleukin-4 receptor {alpha} chain with indolent mastocytosis limited to the skin Blood, August 1, 2001; 98(3): 880 - 882. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2000 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
indicates category Ia; 
, category Ib; 
, category II; and 
,
category III. Dashed lines represent suggested cutoff
values.
