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Abnormal Immune Responses of Bloom's Syndrome Lymphocytes in Vitro

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Abnormal Immune Responses of Bloom's Syndrome Lymphocytes in Vitro Abnormal immune responses of Bloom's syndrome lymphocytes in vitro. T H Hütteroth, … , S D Litwin, J German J Clin Invest. 1975;56(1):1-7. https://doi.org/10.1172/JCI108058. Research Article Bloom's syndrome is a rare autosmal recessive disorder, first characterized by growth retardation and asum-sensitive facial telangiectasia and more recently demonstarted to have increased chromosome instability, a predisposition to malignancy, and increased susecptibitily to infection. The present report ocncern the immune function of Bloom's syndrom lymphoctes in vitro. Four affected homozgotes and five heterozygotes were studied. An abnormal serum concentartion of at least one class of immunoglobin was present in three out of four homozgotes. Affected homozgotes were shown capable of both a humoral and cellular response after antigenic challenge, the responses in general being weak but detectable. Blood lymphocytes from Bloom's syndrome individuals were cultured in impaired proliferavite response and synthesized less immunoglobulin at the end of 5 days than did normal controls. In contrast, they had a normal proliferative response to phytohemagglutinin except at highest concentrations of the mitogen. In the mixed lymphocte culture, Bloom's syndrome lymphocytes proved to be poor responder cells but normal stimulator cells. Lmyphoctes from the heterozgotes produced normal responses in these three systems. Distrubed immunity appears to be on of several major consequences of homozygosity for the Bloom's syndrome gene. Although the explanation for this pleiotropism is at present obscure, the idea was advanced that the aberrant immune function is, along with the major clincial feature-small body size, amanifestation of defect in cellular […] Find the latest version: https://jci.me/108058/pdf Abnormal Immune Responses of Bloom's Syndrome Lymphocytes In Vitro T. H. H(;TTEROTH, S. D. LITWIN, and JAMES GERMAN From the Division of Human Genetics, Department of Medicine, Cornell University Medical College, and The New York Blood Center, New York 10021 A B S T R A C T Bloom's syndrome is a rare autosomal and rearrangement are demonstrable in cultured cells and recessive disorder, first characterized by growth retarda- probably occur in vivo as well. tion and a sun-sensitive facial telangiectasia and more Two observations have raised the question of the ade- recently demonstrated to have increased chromosome quacy of host-defense mechanisms in this disorder: (a) instability, a predisposition to malignancy, and increased Most individuals with Bloomn's syndrome present a susceptibility to infection. The present report concerns striking history of infections during early life. This the immune function of Bloom's syndrome lymphocytes may explain the syndrome's relatively recent recognition in vitro. Four affected homozygotes and five heterozy- as a clinical entity, after the advent of antibiotic ther- gotes were studied. All abnormal serum concentration of apy. Infections most often involve the respiratory and at least one class of inmmunoglobulin was present in gastrointestinal tract and are caused by both gram- three out of four homozygotes. Affected hoomozygotes positive and gram-negative bacteria (unpublished ob- were shown capable of both aI humoral and a cellular servations). The severity and frequency of the infec- response after alntigenic challenge, the responses in gell- tions tend to decrease with increasing age. Viral in- eral being weak but detectable. fections appear to be resisted normally. (b) Affected Blood lymphocytes from Bloom's syndrome individu- individuals are at anl increased risk of developing malig- als were cultured in the presence of pokeweed mitogen. nant tumors at an early age; 4 of the first 5 persons The cells had an impaired proliferative response and recognized as having Bloom's syndrome and 8 out of the synthesized less immunoglobulin at the end of 5 days 50 known cases who have survived infancy have devel- than did normal controls. In contrast, they had a normal oped one or more malignant tumors. These observations proliferative response to phytohemagglutinin except at prompted us to investigate immune function in indi- highest concentrations of the mitogen. In the mixed viduals with Bloom's syndrome and their heterozygous lymphocyte culture, Bloom's syndrome lymphocytes parents. proved to be poor responder cells but normal stimulator cells. Lymphocytes from the heterozygotes produced METHODS normal responses in these three systems. Affected homiozygotes, letcrozygotes, and controls. Four Disturbed immunity appears to be one of several unrelated individuals with Bloom's syndrome were studied, major consequences of homozygosity for the Bloom's one female and three males ranging in age from 2 to 23 yr. syndrome gene. Although the explanation for this pleio- They are identified, as in reference 1, as 3 (HoCo), 32 (MiKo), 47 (ArSmi), and 50 (JeBl). The diagnosis was tropism is at present obscure, the idea wvas advanced that made on the basis of the classical clinical features and the the aberrant immune function is, along with the major finding of increased chromosome breakage in dermal fibro- clinical feature-small body size, a manifestation of a blasts, blood lymphocytes, or both. Five parents of three defect in cellular proliferation. of the affected, ranging in age from 21 to 42 yr, were in- cluded in the study and will be referred to as "heterozy- gotes." 12 normal persons ranging in age from 2 to 47 yr INTRODUCTION served as controls. All subjects were clinically well and Bloom's syndrome ( 1-3) is a rare autosonmal recessive were not receiving medication at the time of the study. Lyniphocyte cultures. Leukocytes were isolated from disorder the major clinical features of which are severe venous blood by Ficoll-Hypaque gradient centrifugation growth retardation and a sun-sensitive telangiectatic (4); the preparations contained more than 85%o small mono- erythema of the face. Increased chromosome breakage nuclear cells. Cell yield was similar in persons with Bloom's syndrome, heterozygotes, and controls. For immunofluores- Received for publication 29 August 1973 and in revised cent studies, leukocytes were purified further by incubation form 10 March 1975. at 37'C for 30 min with poly-L-lysine-coated carbonyl-iron The Journal of Clinical Investigation Volume 56 july 1975 1-7 I in dextran (Technicon Instruments Corp., Tarrytown, N. Y.); phagocytic cells and free iron were removed with A 78-HOUR INCUBATION a magnet. Lymphocyte cultures were performed in triplicate in 0.2-ml volumes in flat bottom microtiter plates (Linbro, New Haven, Conn.). The culture medium was RPMI 1640 0 containing 100 U penicillin/ml, 100 ug streptomycin/ml, 2 0 2I0 mM glutamine/ml (Grand Island Biological Co., Grand 0 0 0 Island, N. Y.), and 10%o pooled human AB serum. For mitogenic stimulation, 1.5X 105 cells/0.2 ml were used; the 0 P. 00 -0- concentration of mitogen was added in a volume to 0 appropriate : L:j .p4 ** ' of 10 ,ul. Mixed lymphocyte cultures (MLC) contained 0 0 11 A. O" 00 I - 0 00 1.5 X 105 responder cells and 3.0X 10' irradiated (3,000 rad) x E.0 0 stimulator cells in a volume of 0.2 ml. Included in each E experiment were cultures without mitogen and cultures B 126-HOUR INCUBATION with autologous irradiated cells. Pokeweedmitogen (PWM) 0 6 was purchased from Grand Island Biological Co., purified Co am phytohemagglutinin (PHA) from Burroughs Wellcome Research Triangle Park, N. C. PWM concentrations Co., 4 were expressed as dilutions of the manufacturer's stock solution, PHA concentrations as gg/0.2 ml. Cultures con- taining mitogen were incubated in a 370C humidified incu- 2 bator (5% C02-95%7c air mixture) for either 78 or 126 h; MLCs were incubated for 126 h. 6 h before termination of the cultures, 1 MCi [methl-3H]thymidine (sp act 2 Ci/ 5i PWM 5XI 0 510 5x1 5xk 5 mmol, New England Nuclear, Boston, Mass.) in a volume 5Xd 4Xif of 2 IAI was added to each well. Cell cultures were processed BLOOM'S HETEROZYGOTES CONTROLS for liquid scintillation counting as previously described (5, 6). FIGURE 1 Lymphocyte stimulation by PWM. Lymphocytes from 4 persons with Bloom's syndrome In vitro immunioglobdlin synthesis after PWM stimula- (Bl), 5 heterozygotes (Hz), and 12 normal controls (Nl) were cultured with three tion. 5 X 106 lymphocytes were cultured in 5 ml of medium different concentrations of PWM. [3H]thymidine uptake was RPMI with 10% human AB serum. The final con- 1640 measured after incubation for 78 h (A) and 126 h (B). Bars centration of PWM was 1:100 of the stock solution. After denote mean±1 SD. Note different scales for ordinates in 5 days the cells were washed three times in minimal essen- A and B. PWM concentrations are expressed as dilutions of tial medium (MEM) without leucine, suspended in 1 ml stock solution. MEM without leucine containing 5%o fetal calf serum and Statistical comparison of experimental groups: 20 /LCi [3H]leucine (sp act 30-50 Ci/mmol, New England Nuclear), and incubated for 4 h at 370C. The cells were Fig. IA then centrifuged for 10 min at 1,500 g; the supernatant BI vs. NI PWM 5 X 10-4 p <0.05 medium was removed and retained for further analysis. The PWM 5 X 10-3 P <0.05 cell pellet was lysed by addition of 1 ml of 0.5% Triton-X PWM 5 X 10-2 P <0.025 in phosphate-buffered saline (PBS), pH 7.2. The super- Bl vs. Hz PWM 5 X 10-2 P < 0.025 natant medium and cell pellet lysate were each centrifuged for 1 h at 20,000 g, and insoluble material discarded. Im- Other comparisons, including Hz vs. Nl, nonsignificant. munoglobulin (Ig) synthesis was determined by specific Ig Fig. lB of radiolabeled proteins (7, 8).
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