C a se Report Acta Haematol 1992;88:46-49
Joseph Evers Fay Albert Leonard Bazar3 Virginia Sulica Ronald A. Sacher
Autoimmune Hemolytic Anemia Presenting in Sezary Syndrome
a
b
c
3 ' b
Report of a Case and Review of the Literature
Departments of Medicine, Pathology and Dermatology, Georgetown University Medical Center, Washington, D.C., USA
Abstract
A 52-year-old man, who presented with Sezary syndrome with autoimmune hemolytic anemia (AIHA) and was successfully treated with corticosteroids is re ported. Helper function assay determining immunoglobulin confirmed in ducer capability of this clonal population. This patient brings to 4 the number of cases of T cell cutaneous lymphoma and AIHA now reported in the English literature, and is the first case of Sezary syndrome and AIHA thus far.
Introduction
Sezary syndrome is a cutaneous T cell lymphoma asso ciated with circulating lymphocytes exhibiting cerebriform nuclear characteristics and lymphadenopathy. It classi cally presents in the 6th to 7th decades; the median sur vival is of 8-9 years [1], We report a patient with Sezary syndrome who developed an autoimmune hemolytic ane mia (AIHA) 6 years after initial presentation. Since Seza ry syndrome is a clonal disorder of helper T lymphocytes [2], it may be anticipated that autoimmune manifestations may be more frequently noted. Monoclonal gammopathies and multiple myeloma associated with Sezary syn drome have been described; however, this report repre sents the first documentation of hemolytic anemia associ ated with the Sezary syndrome. Case Report A 52-year-old man presented to Georgetown University Medical Hospital in November 1980 with erythroderma. The patient had a 7year history of slowly progressive, scaly diffuse erythematous skin eruption, minimally responsive to topical steroids.
Received: December 4,1991 Accepted: January 27, 1992
Skin biopsy in 1981 showed an atrophic epidermis with a mononu clear cell infiltrate in the dermis and collections of mononuclear cells in the epidermis. Circulating Sézary cells were demonstrated in the peripheral blood buffy coat, constituting between 5 and 10% of the leukocyte differential. Axillary lymph node and liver biopsies at this time were normal. Over the years, he received treatment consisting of topical nitrogen mustard, psoralen and ultraviolet light (PUVA), and systemic antibiotics for recurrent skin infections. In March 1986, while taking oral tetracycline 500 mg q.i.d. for 10 days, hydroxyzine 10 mg for pruritis and Dyazide® for leg edema, he developed shortness of breath, fever, chills, and shaking night sweats and a cough produc tive of white sputum. Two days previously, he had noted profound fa tigue with minimal exertion. Physical examination showed a general ized exfoliative erythroderma, scleral icterus, mild cervical lymphadenopathy and end-expiratory wheezing. Laboratory analysis now revealed a leukocyte count of 6.9 x 10'' cells/1. The differential count showed 74% neutrophils, 2% bands, 16% lymphocytes, 6% monocytes and 2% eosinophils. His hematocrit was 14.5% (hemoglobin 4.5 g/dl) with an MCV at 118 fl. The platelet count was 275 x lO’/l and a reticulocyte count was 24.2%. His periph eral smear showed many spherocytes and a diffuse polychromasia. A buffy coat differential count showed 25% Sézary cells. Additional laboratory data revealed a potassium of 3.4 mg/dl, a total bilirubin of 3.2 mg/dl and a direct bilirubin of 0.2 mg/dl. His serum lactate de hydrogenase was 298 IU/1. Other liver enzymes and electrolytes were normal, as were coagulation studies. Bone marrow aspirate and biopsy showed marked erythroid hyperplasia without a Sézary cell in filtration. Serum protein electrophoresis and immunoelectrophore-
Ronald A. Sacher, MD Division of Hematology Georgetown University Medical Center 38(X) Reservoir Road, N.W. Washington, DC 20007 (USA)
© 1992S.Karger AG.Bascl (XX)l-5792fl2/0881-(XM6 $ 2.75A)
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 6:42:26 AM
Key Words Autoimmune hemolytic anemia Sezary syndrome
sis showed a polyclonal elevation of IgG and IgA with a normal IgM. EBV titer was 1:640 and the mycoplasma complement fixation test, rheumatoid factor, antinuclear antibodies, cold agglutinins, HTLV-1 and urine hemosiderin were negative. A chest x-ray was normal. The patient was treated with prednisone 1 mg/kg day and folate 1 mg/day. He sustained a marked improvement with an increased he matocrit and a reduction in reticulocyte count and bilirubin. No transfusions were given and the patient was discharged after a 2-week hospitalization with a hematocrit of 29% (fig. 1). Six months after this, lymph node biopsy was positive for Sczary cell involvement but the liver biopsy remained negative.
Prednisone q.i.d., mg
Materials and Methods
Helper Function Assay The helper function assay is based on the ability of helper T ceils to induce target B cells to secrete immunoglobulin. Briefly, mononu clear cells from 30 ml of heparinized blood from the patient and from normal donors were isolated by Ficoll-Hypaque® centrifugation [3]. Adherent cells were removed by incubation for 1.5 h at 37 °C/5% C 0 2 in medium consisting of RPMI-1640,10% fetal bovine serum 2 mM L-glutamine, 50 pg/ml gentamicin sulfate and 2.5 pg/ml amphotericin B. The T and B cells were purified by double E rosetting with 2aminocthylisothiouronium bromide hydrobromide (AET)-treated sheep red blood cells. Normal B cells (2 x 105/well and 4 x lOVwell) were incubated in medium for 7 days at 37 °C/5% CO, in 24-well tis sue culture plates in the presence or absence of 4 x lOVwell of the pa tient’s T cells. Control wells included incubation of normal B cells alone, normal B cells plus 4 x lOVwell, normal suppressor T cells (se lected by long-term culture of normal T cells in the presence of ID2) and normal B cells plus 4 x lOVwell normal helper T cells (selected by irradiation of normal T cells to destroy the more radiosensitive sup pressor T cells). Included in all wells was 10% (v/v) human IL-2 (Elec tronucleonics, Md., USA). Duplicate wells also contained 5 pg/ml pokeweed mitogen (PWM) (a B cell activator). At the completion of the incubation, supernatants were assayed for IgG by an ELISA procedure.
Results
Direct AHG testing yielded 3+ agglutination with poly valent antiserum, and 3+ and 2+ agglutination with antiIgG and anti-C3d, respectively. A panreacting antibody with maximal agglutination in the AHG phase was demonstrated by indirect antibody
1986
1987
Fig. 1. Graphic illustration of course of patient’s hemolytic ane mia over 11 months.
screening. When the eluate was applied to the red cell panel, it also showed a panagglutination of 2 to 3+ throughout. The skin biopsy showed a band-like mononuclear infil trate within the dermis and Pautrier microabcesses. Til, a pan-T cell marker, was positive through the infiltrate. T4, a helper T cell marker, had a similar pattern of staining. Scattered T8-positive cells (suppressor T cells) were ad mixed within the dermal infiltrate and found occasionally in the epidermis. Bl, a B cell marker, was negative. Iso lated positive HLA-DR cells were scattered throughout. Immunologic characterization of the buffy coat lym phocytes using OKT4 monoclonal antibody showed 98% of the cells to have positive staining, confirming the helper phenotype. The in vitro helper function of the Sezary cells was determined by coculturing these cells with target B cells from a healthy donor. The results of the helper function assay of the patient’s T cells are shown in table 1. In 3 out of 4 cases, the patient’s T cells caused an increase in IgG secretion by normal B cells (compare sample 1A with 7A, 8A with 11A and 8B with 11B). In one case, the patient’s T cells caused no change, or a slight decrease, in the secretion of IgG by 2 x 105 B cells in the presence of 5 pg/ml PWM (compare sample IB with 7B). However, the patient’s T cells induced IgG secretion by 4 x 105 B cell in the presence of 5 pg/ml PWM (sample 8B versus 11B). Included in the assay as controls, normal helper T cells and normal suppressor T cells respectively augmented and diminished the secretion of IgG by normal B cells.
47
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Direct anti-human globulin testing (AHG) was performed on the patient’s red blood cells using polyvalent antisera and monospecific anti-IgG and anti-C3d antisera. Indirect antibody screening of his se rum was performed using a commercial erythrocyte panel. An acid elution was performed on his red cells (Gamma Elukit II), and the eluate tested against the same red blood cell panel. A punch skin biopsy was performed and the tissue frozen. Immunophenotyping was done on this tissue, using monoclonal antibodies to T and B cell markers (Coulter Clone®, Coulter Immunology, Hia leah, Fla., USA).
Cells/ well
PWM cone. ng/ml
Normal B cells
2 x 105
Normal E suppressor cells
4 x 10s
Normal T helper cells
4 x l0 5
Patient T cells
4 x 105
Normal B cells + T suppressor cells
2 x 10s 4 x 105
0 5 0 5 0 5 0 5 0
55 ±4.7 169 ±32.6 0 0 0 0 0 0 40.8 ±3.2
Normal B cells + normal T helper cells
2 x l0 5 4 x l0 5
5 0
13.8 ±6.6 62 ±3.9
Normal B cells + patient T cells Normal B cells
2 x 105 4 x 10s 4 x 105
Normal B cells + T suppressor cells Normal B cells + T helper cells
4 x10s 4 x l0 5 4 x l0 5 4 x l0 5
5 0 5 0 5 0 5 0
227 ±22.1 77.2 ±5.4 129 ±23.0 99 ±7.4 456 ±39.2 42.4 ±4.8 34.7 ±4.4 116 ± 8.1
Normal B cells + patient T cells
4 x 105 4 x l0 5
5 0
1,170 ±84.0 160.8 ±12.1
5
1,020 ±92.0
Cells
1A 11 2A B 3A B 4A B 5A B 6A B 7A 8A B 9A 10A B 11A B
IgGa cone. ng/ml
3 Mean ±SD of duplicate wells at 5 serial dilutions in the ELISA assay.
Discussion
AIHA is a syndrome of antibody-mediated shortened red blood cell survival, mostly caused by extravascular se questration. The syndrome may occur as a primary dis order, secondary to an underlying disease or in association with drug exposure [4], Secondary causes of AIHA include rheumatic disorders, infections (notably infectious mono nucleosis and mycoplasma), chronic diseases such as ul cerative colitis, and neoplasms [5]. Fifty percent of the sec ondary causes are lymphoproliférative disorders - notably chronic lymphocytic leukemia and both Hodgkin’s and non-Hodgkin’s lymphomas. AIHA is found in 2% of cases of non-Hodgkin’s lymphoma [6]. Sézary syndrome, described in 1938 by Sézary and Bouvrain, is a cutaneous T cell lymphoma associated with
48
circulating Sezary cells, showing cerebriform nuclei and lymphadenopathy. The Sezary cells were initially thought to be histocytes, but now are recognized as T helper lym phocytes [7], Broder et al. [2], in 1976, were the first to show in vitro helper function of the Sezary cells, noting the augmentation of immunoglobulin production by B lym phocytes. The in vivo helper function of the Sezary cells has also been reported in the literature as the association of Sezary syndrome with monoclonal gammopathies. To date, 13 cases of Sezary syndrome are reported in which monoclonal gammopathies developed [8]. Of these, 2 had multiple myeloma, 1 an IgGic and the other an IgGX. Of this association, Venecie et al. [9] write: ‘The relationship of such a stimulus (Sezary syndrome) to the monoclonal proteins is not clear. One might expect a polyclonal pro tein response.’ Indeed, in our case there was a polyclonal elevation of IgG and IgA. This may imply a polyclonal B cell induction, ordinarily by the Sezary cells, while in the monoclonal gammopathies associated with Sezary syn drome there is a monoclonal B cell induction. However, no in vitro confirmation of monoclonal immunoglobulin synthesis has yet been documented. Cutaneous T cell lymphoma is a more recent classifica tion for which the Sezary syndrome and mycosis fungoides represent a spectrum of disease progression [10], The leu kemic presentation or Sezary syndrome has not previously been described as being associated with AIHA. There are 3 cases of mycosis fungoides occurring in conjunction with AIHA so far documented [11]. There are several reports of autoantibody-mediated syndromes associated with cuta neous T cell lymphomas. These include polyarthritis, viteligo, myasthenia gravis and necrotizing vasculitis [12-15]. There is one report of autoantibody production in asso ciation with Sezary syndrome in an 83-year-old Swedish woman who developed hypogammaglobulinemia where an anti-albumin autoantibody was elucidated [16], In the case under discussion, the peripheral lympho cytes and the skin infiltrate showed helper T cell pheno types. The helper function of these cells was attested to first by the in vivo production of an autoantibody reactive against the patient’s own red cells, and secondly by the in vitro coculturing experiments, whereby augmentation of immunoglobulin production by normal B lymphocytes was achieved. Of further interest is the ‘targeting’ of the pa tient’s red blood cells by this panagglutinin. The associ ation of AIHA with Sezary syndrome in our patient may only be coincidental; however, the in vitro and in vivo evi dence presented attests to the dysfunctional role of these Sezary cells and effect of the clonal expansion of T helper cells characteristic of this disorder.
Evers/Albert/Bazar/Sulica/Sacher
Autoimmune Hemolytic Anemia in Sézary Syndrome
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 6:42:26 AM
Table 1. Helper function assay of patient’s T cells
References 8 Kovary PM, Suter L, Macher E, et al: Mono clonal gammophatics in Sézary syndrome. Can cer 1981;48:788-792. 9 Venecie PY, Winkclmann RK, Puissant A, Kyle RA: Monoclonal gammopathy in Sézary syn drome. Arch Dermatol 1984;120:605-608. 10 Sausville EA, Eddy JL, Makuch RW: Histo pathologic staging at initial diagnosis of myco sis fungoides and the Sézary syndrome. Ann In tern Med 1988;109:372-382. 11 Palavic-Knox J, Massa MC, Gradini R: Au toimmune hemolytic anemia in a patient with mycosis fungoides. Cutis 1990;45:52-59. 12 Gottlieb M, Hoppe RT, Calin A: Arthritis in a patient with mycosis fungoides: Complete re mission after radiotherapy. Arthritis Rheuma 1979;22:424-425.
13 Alcalay J, David M, Shohat B: Generalized viti ligo following Sézary syndrome. Br J Dermatol 1987;116:851-855. 14 Manigand G: Association between mycosis fungoides and myasthenia gravis (abstract). Se maine Hôp Paris 57:1426-1428, Sep 18-25 1981. 15 Granstein RD: Necrotizing vasculitis within cu taneous lesions of mycosis fungoides. J Am Acad Dermatol 1983;9:128-133. 16 Iliescu V, Lindholm L, Ehrnst A: Erythroder mia Sézary with immunological deficiency and antibodies against human albumin. Acta Med Scand 1975;197:141-144.
49
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1 Broder S, Bunn P: Cutaneous T cell lympho mas. Semin Oncol 1980;7:310-327. 2 Jaffe E: Surgical Pathology of Lymph Nodes and Related Organs. Philadelphia, Saunders, chapt 13,1985. 3 Gootenbcrg JE, Ruscctti FW, Gallo RC: A bio chemical variant of human T cell growth factor produced by a cutaneous T cell lymphoma cell line. J Immunol 1982;129:1499-1505. 4 Williams WJ, et al: Hematology. Maidenhead, McGraw-Hill, cd 4, chapt 67,1990. 5 Rubenstein I, Langevitz P, Hirsch R, Bcrkowicz M, Licberman Y, Shibi G: Autoimmune hemolytic anemia as the presenting manifesta tion of malignant thymoma. Acta Haematol 1985;74:40-42. 6 Joncs SE: Autoimmune disorders/malignant lymphoma. Cancer 1973;31:1092-1098. 7 Broder S, Edelson RL, Lutzner MA. et al.: The Sézary syndrome: A malignant proliferation of helper T cells. J Clin Invest 1976;58:1297-1306.
Joseph Evers Fay Albert Leonard Bazar3 Virginia Sulica Ronald A. Sacher
Autoimmune Hemolytic Anemia Presenting in Sezary Syndrome
a
b
c
3 ' b
Report of a Case and Review of the Literature
Departments of Medicine, Pathology and Dermatology, Georgetown University Medical Center, Washington, D.C., USA
Abstract
A 52-year-old man, who presented with Sezary syndrome with autoimmune hemolytic anemia (AIHA) and was successfully treated with corticosteroids is re ported. Helper function assay determining immunoglobulin confirmed in ducer capability of this clonal population. This patient brings to 4 the number of cases of T cell cutaneous lymphoma and AIHA now reported in the English literature, and is the first case of Sezary syndrome and AIHA thus far.
Introduction
Sezary syndrome is a cutaneous T cell lymphoma asso ciated with circulating lymphocytes exhibiting cerebriform nuclear characteristics and lymphadenopathy. It classi cally presents in the 6th to 7th decades; the median sur vival is of 8-9 years [1], We report a patient with Sezary syndrome who developed an autoimmune hemolytic ane mia (AIHA) 6 years after initial presentation. Since Seza ry syndrome is a clonal disorder of helper T lymphocytes [2], it may be anticipated that autoimmune manifestations may be more frequently noted. Monoclonal gammopathies and multiple myeloma associated with Sezary syn drome have been described; however, this report repre sents the first documentation of hemolytic anemia associ ated with the Sezary syndrome. Case Report A 52-year-old man presented to Georgetown University Medical Hospital in November 1980 with erythroderma. The patient had a 7year history of slowly progressive, scaly diffuse erythematous skin eruption, minimally responsive to topical steroids.
Received: December 4,1991 Accepted: January 27, 1992
Skin biopsy in 1981 showed an atrophic epidermis with a mononu clear cell infiltrate in the dermis and collections of mononuclear cells in the epidermis. Circulating Sézary cells were demonstrated in the peripheral blood buffy coat, constituting between 5 and 10% of the leukocyte differential. Axillary lymph node and liver biopsies at this time were normal. Over the years, he received treatment consisting of topical nitrogen mustard, psoralen and ultraviolet light (PUVA), and systemic antibiotics for recurrent skin infections. In March 1986, while taking oral tetracycline 500 mg q.i.d. for 10 days, hydroxyzine 10 mg for pruritis and Dyazide® for leg edema, he developed shortness of breath, fever, chills, and shaking night sweats and a cough produc tive of white sputum. Two days previously, he had noted profound fa tigue with minimal exertion. Physical examination showed a general ized exfoliative erythroderma, scleral icterus, mild cervical lymphadenopathy and end-expiratory wheezing. Laboratory analysis now revealed a leukocyte count of 6.9 x 10'' cells/1. The differential count showed 74% neutrophils, 2% bands, 16% lymphocytes, 6% monocytes and 2% eosinophils. His hematocrit was 14.5% (hemoglobin 4.5 g/dl) with an MCV at 118 fl. The platelet count was 275 x lO’/l and a reticulocyte count was 24.2%. His periph eral smear showed many spherocytes and a diffuse polychromasia. A buffy coat differential count showed 25% Sézary cells. Additional laboratory data revealed a potassium of 3.4 mg/dl, a total bilirubin of 3.2 mg/dl and a direct bilirubin of 0.2 mg/dl. His serum lactate de hydrogenase was 298 IU/1. Other liver enzymes and electrolytes were normal, as were coagulation studies. Bone marrow aspirate and biopsy showed marked erythroid hyperplasia without a Sézary cell in filtration. Serum protein electrophoresis and immunoelectrophore-
Ronald A. Sacher, MD Division of Hematology Georgetown University Medical Center 38(X) Reservoir Road, N.W. Washington, DC 20007 (USA)
© 1992S.Karger AG.Bascl (XX)l-5792fl2/0881-(XM6 $ 2.75A)
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 6:42:26 AM
Key Words Autoimmune hemolytic anemia Sezary syndrome
sis showed a polyclonal elevation of IgG and IgA with a normal IgM. EBV titer was 1:640 and the mycoplasma complement fixation test, rheumatoid factor, antinuclear antibodies, cold agglutinins, HTLV-1 and urine hemosiderin were negative. A chest x-ray was normal. The patient was treated with prednisone 1 mg/kg day and folate 1 mg/day. He sustained a marked improvement with an increased he matocrit and a reduction in reticulocyte count and bilirubin. No transfusions were given and the patient was discharged after a 2-week hospitalization with a hematocrit of 29% (fig. 1). Six months after this, lymph node biopsy was positive for Sczary cell involvement but the liver biopsy remained negative.
Prednisone q.i.d., mg
Materials and Methods
Helper Function Assay The helper function assay is based on the ability of helper T ceils to induce target B cells to secrete immunoglobulin. Briefly, mononu clear cells from 30 ml of heparinized blood from the patient and from normal donors were isolated by Ficoll-Hypaque® centrifugation [3]. Adherent cells were removed by incubation for 1.5 h at 37 °C/5% C 0 2 in medium consisting of RPMI-1640,10% fetal bovine serum 2 mM L-glutamine, 50 pg/ml gentamicin sulfate and 2.5 pg/ml amphotericin B. The T and B cells were purified by double E rosetting with 2aminocthylisothiouronium bromide hydrobromide (AET)-treated sheep red blood cells. Normal B cells (2 x 105/well and 4 x lOVwell) were incubated in medium for 7 days at 37 °C/5% CO, in 24-well tis sue culture plates in the presence or absence of 4 x lOVwell of the pa tient’s T cells. Control wells included incubation of normal B cells alone, normal B cells plus 4 x lOVwell, normal suppressor T cells (se lected by long-term culture of normal T cells in the presence of ID2) and normal B cells plus 4 x lOVwell normal helper T cells (selected by irradiation of normal T cells to destroy the more radiosensitive sup pressor T cells). Included in all wells was 10% (v/v) human IL-2 (Elec tronucleonics, Md., USA). Duplicate wells also contained 5 pg/ml pokeweed mitogen (PWM) (a B cell activator). At the completion of the incubation, supernatants were assayed for IgG by an ELISA procedure.
Results
Direct AHG testing yielded 3+ agglutination with poly valent antiserum, and 3+ and 2+ agglutination with antiIgG and anti-C3d, respectively. A panreacting antibody with maximal agglutination in the AHG phase was demonstrated by indirect antibody
1986
1987
Fig. 1. Graphic illustration of course of patient’s hemolytic ane mia over 11 months.
screening. When the eluate was applied to the red cell panel, it also showed a panagglutination of 2 to 3+ throughout. The skin biopsy showed a band-like mononuclear infil trate within the dermis and Pautrier microabcesses. Til, a pan-T cell marker, was positive through the infiltrate. T4, a helper T cell marker, had a similar pattern of staining. Scattered T8-positive cells (suppressor T cells) were ad mixed within the dermal infiltrate and found occasionally in the epidermis. Bl, a B cell marker, was negative. Iso lated positive HLA-DR cells were scattered throughout. Immunologic characterization of the buffy coat lym phocytes using OKT4 monoclonal antibody showed 98% of the cells to have positive staining, confirming the helper phenotype. The in vitro helper function of the Sezary cells was determined by coculturing these cells with target B cells from a healthy donor. The results of the helper function assay of the patient’s T cells are shown in table 1. In 3 out of 4 cases, the patient’s T cells caused an increase in IgG secretion by normal B cells (compare sample 1A with 7A, 8A with 11A and 8B with 11B). In one case, the patient’s T cells caused no change, or a slight decrease, in the secretion of IgG by 2 x 105 B cells in the presence of 5 pg/ml PWM (compare sample IB with 7B). However, the patient’s T cells induced IgG secretion by 4 x 105 B cell in the presence of 5 pg/ml PWM (sample 8B versus 11B). Included in the assay as controls, normal helper T cells and normal suppressor T cells respectively augmented and diminished the secretion of IgG by normal B cells.
47
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 6:42:26 AM
Direct anti-human globulin testing (AHG) was performed on the patient’s red blood cells using polyvalent antisera and monospecific anti-IgG and anti-C3d antisera. Indirect antibody screening of his se rum was performed using a commercial erythrocyte panel. An acid elution was performed on his red cells (Gamma Elukit II), and the eluate tested against the same red blood cell panel. A punch skin biopsy was performed and the tissue frozen. Immunophenotyping was done on this tissue, using monoclonal antibodies to T and B cell markers (Coulter Clone®, Coulter Immunology, Hia leah, Fla., USA).
Cells/ well
PWM cone. ng/ml
Normal B cells
2 x 105
Normal E suppressor cells
4 x 10s
Normal T helper cells
4 x l0 5
Patient T cells
4 x 105
Normal B cells + T suppressor cells
2 x 10s 4 x 105
0 5 0 5 0 5 0 5 0
55 ±4.7 169 ±32.6 0 0 0 0 0 0 40.8 ±3.2
Normal B cells + normal T helper cells
2 x l0 5 4 x l0 5
5 0
13.8 ±6.6 62 ±3.9
Normal B cells + patient T cells Normal B cells
2 x 105 4 x 10s 4 x 105
Normal B cells + T suppressor cells Normal B cells + T helper cells
4 x10s 4 x l0 5 4 x l0 5 4 x l0 5
5 0 5 0 5 0 5 0
227 ±22.1 77.2 ±5.4 129 ±23.0 99 ±7.4 456 ±39.2 42.4 ±4.8 34.7 ±4.4 116 ± 8.1
Normal B cells + patient T cells
4 x 105 4 x l0 5
5 0
1,170 ±84.0 160.8 ±12.1
5
1,020 ±92.0
Cells
1A 11 2A B 3A B 4A B 5A B 6A B 7A 8A B 9A 10A B 11A B
IgGa cone. ng/ml
3 Mean ±SD of duplicate wells at 5 serial dilutions in the ELISA assay.
Discussion
AIHA is a syndrome of antibody-mediated shortened red blood cell survival, mostly caused by extravascular se questration. The syndrome may occur as a primary dis order, secondary to an underlying disease or in association with drug exposure [4], Secondary causes of AIHA include rheumatic disorders, infections (notably infectious mono nucleosis and mycoplasma), chronic diseases such as ul cerative colitis, and neoplasms [5]. Fifty percent of the sec ondary causes are lymphoproliférative disorders - notably chronic lymphocytic leukemia and both Hodgkin’s and non-Hodgkin’s lymphomas. AIHA is found in 2% of cases of non-Hodgkin’s lymphoma [6]. Sézary syndrome, described in 1938 by Sézary and Bouvrain, is a cutaneous T cell lymphoma associated with
48
circulating Sezary cells, showing cerebriform nuclei and lymphadenopathy. The Sezary cells were initially thought to be histocytes, but now are recognized as T helper lym phocytes [7], Broder et al. [2], in 1976, were the first to show in vitro helper function of the Sezary cells, noting the augmentation of immunoglobulin production by B lym phocytes. The in vivo helper function of the Sezary cells has also been reported in the literature as the association of Sezary syndrome with monoclonal gammopathies. To date, 13 cases of Sezary syndrome are reported in which monoclonal gammopathies developed [8]. Of these, 2 had multiple myeloma, 1 an IgGic and the other an IgGX. Of this association, Venecie et al. [9] write: ‘The relationship of such a stimulus (Sezary syndrome) to the monoclonal proteins is not clear. One might expect a polyclonal pro tein response.’ Indeed, in our case there was a polyclonal elevation of IgG and IgA. This may imply a polyclonal B cell induction, ordinarily by the Sezary cells, while in the monoclonal gammopathies associated with Sezary syn drome there is a monoclonal B cell induction. However, no in vitro confirmation of monoclonal immunoglobulin synthesis has yet been documented. Cutaneous T cell lymphoma is a more recent classifica tion for which the Sezary syndrome and mycosis fungoides represent a spectrum of disease progression [10], The leu kemic presentation or Sezary syndrome has not previously been described as being associated with AIHA. There are 3 cases of mycosis fungoides occurring in conjunction with AIHA so far documented [11]. There are several reports of autoantibody-mediated syndromes associated with cuta neous T cell lymphomas. These include polyarthritis, viteligo, myasthenia gravis and necrotizing vasculitis [12-15]. There is one report of autoantibody production in asso ciation with Sezary syndrome in an 83-year-old Swedish woman who developed hypogammaglobulinemia where an anti-albumin autoantibody was elucidated [16], In the case under discussion, the peripheral lympho cytes and the skin infiltrate showed helper T cell pheno types. The helper function of these cells was attested to first by the in vivo production of an autoantibody reactive against the patient’s own red cells, and secondly by the in vitro coculturing experiments, whereby augmentation of immunoglobulin production by normal B lymphocytes was achieved. Of further interest is the ‘targeting’ of the pa tient’s red blood cells by this panagglutinin. The associ ation of AIHA with Sezary syndrome in our patient may only be coincidental; however, the in vitro and in vivo evi dence presented attests to the dysfunctional role of these Sezary cells and effect of the clonal expansion of T helper cells characteristic of this disorder.
Evers/Albert/Bazar/Sulica/Sacher
Autoimmune Hemolytic Anemia in Sézary Syndrome
Downloaded by: Nagoya University 133.6.82.173 - 1/13/2019 6:42:26 AM
Table 1. Helper function assay of patient’s T cells
References 8 Kovary PM, Suter L, Macher E, et al: Mono clonal gammophatics in Sézary syndrome. Can cer 1981;48:788-792. 9 Venecie PY, Winkclmann RK, Puissant A, Kyle RA: Monoclonal gammopathy in Sézary syn drome. Arch Dermatol 1984;120:605-608. 10 Sausville EA, Eddy JL, Makuch RW: Histo pathologic staging at initial diagnosis of myco sis fungoides and the Sézary syndrome. Ann In tern Med 1988;109:372-382. 11 Palavic-Knox J, Massa MC, Gradini R: Au toimmune hemolytic anemia in a patient with mycosis fungoides. Cutis 1990;45:52-59. 12 Gottlieb M, Hoppe RT, Calin A: Arthritis in a patient with mycosis fungoides: Complete re mission after radiotherapy. Arthritis Rheuma 1979;22:424-425.
13 Alcalay J, David M, Shohat B: Generalized viti ligo following Sézary syndrome. Br J Dermatol 1987;116:851-855. 14 Manigand G: Association between mycosis fungoides and myasthenia gravis (abstract). Se maine Hôp Paris 57:1426-1428, Sep 18-25 1981. 15 Granstein RD: Necrotizing vasculitis within cu taneous lesions of mycosis fungoides. J Am Acad Dermatol 1983;9:128-133. 16 Iliescu V, Lindholm L, Ehrnst A: Erythroder mia Sézary with immunological deficiency and antibodies against human albumin. Acta Med Scand 1975;197:141-144.
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