Celiac sprue and abdol1linal lyl1lphol1la: Studies on the ...downloads.hindawi.com › journals › cjgh › 1988 › 838210.pdf · human jejunum. Gut 1971; 12: 988-94. 9.0'Donaghuc

CLINICAL GASTROENTEROLOGY

Celiac sprue and abdol1linal lyl1lphol1la: Studies on the

cell--11lediated il1ll1lune response of .. peripheral blood lymphocytes

P. DAVIS, MD, FRCP(C), H.J. FREFMAN, MO, FRCP(C), A.B.R. T11l">MSON, MD, P11D, FRCP(C), FACP

ABSTRACT: The development of primary abdominal lymphoma is a recognized complication of gluten-sensitive enteropachy (GSE). ln five patients with GSE plus lymphoma, the distribution and function of peripheral blood lymphocytes were determined and compared with 13 patients with GSE without lymphoma and with 28 normal control subjects. The percentage ofT cells was lower in patients with GSE and GSE wirh lymphoma than in controls, whereas patients with GSE plus lymphoma had a significantly increased number of peripheral blood B lymphocytes when compared with GSE patients or controls. There was no difference in K cell accivicy or lymphocyte responses co micogens and antigens between controls, GSE or GSE plus lymphoma patients. Prospective studies are needed in patients with GSE co investigate whether this fall in peripheral blood T cells and rise in B lymphocytes is a marker of concurrent lymphoma. Can J Gastroenterol 1988; 2(1):12,14

Key Words: B celb, Celiac s/mH:, ConA , K cells, PHA, Pnmul'\' abdominal l:,,mplwma, T cells, Varidase

Oit"i;ion.1 of Gu1troenwrolog:,, und Rhe11mawlog,, De/J£1rtme111 of Medicme, U111t•ers11" of Al berw, Edmonton, Alberta

Re prims: Dr A.B. R. Thomson, NHtri1ion and M<!wbo/1im Research Gro11p, 519 Roben Neu·ton Research Buildmg, Un1t•cr.1it, of Alberta, Edmonton T6G 2C2

Received for p11blicac1on Occoher 26, 1987. Accepted )anHary JS, 1988

12

G LUlcN-SENSmVE El'fITROPA 11 !Y

(GSE) is a disease characterizecl by an intestinal reaction co gliadin. Although the exact mechanism of inre~cinal mucosa! injury is unknown, there is growing evidence chat it is immunologically mediated (1-3). le is characterized by che presence of increased numbers of lymphocytes in the lamina propria, increased local synthesis of antibody togliadin and, sometimes, increased serum lgA and lgM levels. Boch humeral and cell-mediated sensitizatio n to gluten proteins have been reported in patients with celiac disease (4) .

Impaired fu nctio n of peripheral blood lymphocytes (5-7) and abnormal ities of lymphocyte distributio n (8) have been described in unrreat·

CAN J GASTROlc1'TEROL

ed celiac disease. Although total lymphocyte counts a rc generally normal in untreatcJ patients with celiac sprue, a reduction in rhe number of ci rculat ing thymus-dependent lvmphocytes has been described (9, I 0). However, T cell numbers were normal after treatment with a gluten-free diet (9). lmpaired lymphocyte responses to phyrohemagglutinin (PHA) in untreated celiac disease may improve 1fter treatment with a gluten-free diet (i).

T cell depiction in the peripheral hlood in the untreatetl pacient with celiac disease might explain impaired blast transformation with nonspecifit m1cogens (5-7), and the associat1on of malignancy and ccliac disease ( 11, 12). However, not all studies have shown impaired response of T cells to

mirogens and antigens in these panents (13). lntracpithclial lymphocytes bear the suppressor/cytmoxic T cell marker OKT8 (14), and the wheat protein CX: -gliadin has been shown to induce suppressor T ceHs in human peripheral b lood from patients with ccliac disease (15). Boch ceHular :ind hormonal sensitization to CX: -gliadin occur in this disorder (16,17).

Malignant lymphomas may present with malabsorprion anJ a jejuna! mucosa! lesion similar to that found in celiac patients ( 18). Malignancy may develop in untreated celiac patients (12). The mechanism of this associanon is not clearly understood bur earl y resection of a localized malignant lesion may improve survival (19). Thus, detection of enteropathy-associated T cell lymphoma may have practical implications for management. These lymphomas were formerly called malignant histiocyros1s of the intestine, but it is now considered that the malignant ce ll in these lymphomas is usually ofT cell o rigin (20-22).

Unlike patients with celiac disease , patients with enteropathy-associated T cell lymphoma do not have raised levels of CX:-gli adin antibody (23). As part of an ongoing study of cell-mediated immune responses in patients with bowel diseases che authors h ad cheopportunity to study ceH-mcdiaced immune reponses in patients with GSE

Vol. 2 No. l. Mard1 1988

TABLE 1 Numbers and function of lymphocytes

Controls (28)

E rosettes I% I 50:!:5 EA rosettes (%) 25± 5 EAC rosettes ( 0 o) 22±'1 K cell act1v1ly '15:!: 13 PHA 50 3 04:!: 1 21

100 3 29:!: 1 35 ConA 50 2 46:!: 1 18

100 2 23 :!: 1 51 Variclase 50 1 18:!: 1 13

100 1 10:!: I 12

Celiac sprue. lymphoma and CMI

GSE (13)

3:i:!: 12· 30:!: 11 2'1±2 49:!:26

2 83:!: 2 22 2 98:!: 2 18 1 94 :!: 2 18 1 36:!: 2 34 1 82:!: l 26 1 04:!: 1 26

GSE plus lymphoma (5)

38:!: 12' 29:!:<J 42:t[)· [17 :!: 23

2 71 :!: 1 34 285:!:l 49 2 75:!: 1 43 2 8'1:!: 1 54 1 30:!: 1 11 1 39 :!: 1 98

• P <O 00 I lcatculmed /or pa1,enr groups when compared to normal cor)f{o/s/ R1•s11// l!Xf'rt" sed "·' mean:tS£M PHA Phvtohem<19glu1mm

and in patients who had developed an associated lymphoma. The cell-mediated immune responsiveness of peripheral hlooJ lymphotytes obtained from patients with teli::ic sprue o r ccliat sprue associated with abdomtnal lymphoma were examined and compared.

PATIENTS AND METHODS The clinical details of the five pa

tients with gluccn-sensicive enteropathy plus lymphomas studied here have been reported (24). In each patient with lymphoma, the diagnosis o(

GSE was established on the basis of typical small bowel biopsies prior to treatment and a clinical, biochemical and histologic small bowel response co gluten restriction (24) . Also, 13 patients, rangi ng in age from l 7 to 58 years, with GSE but no clinical or radiological evidence of abdominal lymphoma were studied. All these patients were adhering to a gluten-free diet.

Distributio n o f peripheral blood lymphocytes were determined using Erosetting (T cells), EAS rosetting (B cells) and EA rosetting (K cells). In additio n, K cell activity and lymphocyte transformation responses to PHA, ConA and Varidase were studied using previously reported techniques (25). The results of the patients with GSE and the patients with GSE complicated with lymphom::i were compared with 28 control subjects.

Statistical analysi~ of data was calculated ustng unpaired t test.

RESULTS The absolute numbers of peripheral

blood lymphocytes were no rmal in all groups but the percentage of T cells was significantly lower in patients with treateJ GSE without known lymphoma and patients with GSE plus lymphoma when c.ompared co contro l subjects (Table 1) . In the case of B cells, patients with GSE and lymphoma had a significantly increased number of peripheral blood B lymphocytes when compared to controls and patients with uncomplitaceJ GSE (P <0.001). The ratio of T :B cells fe ll fro m 2.27 in no rmal subjects to 0.9 1 in GSE with lymphoma. The numbers of K cells were not significantly different between the three groups. There was no signiCicant differente in K cell activity o r peripheral blood lymphocyte responses to mitogens and antigens between patients with or without lymphoma and contro ls.

DISCUSSION Decreased numbers of T ce lls have

been Jescribed in untreated patients with celiac disease but these return to normal with gluten withdrawal (7). In the present study, treated patients with GSE claimed to be strictly adhering co the gluten-free diet, therefore, their reduced number of peripheral b lood T cells was mexplicable. However, m agreement with previous studies, T cell fu nctio n was normal in patients with treated GSE (Table 1). This supports the previous suggestio n chat peripheral blood cell-mediarc<l immune responses do not play a major role in the

13

DAVIS ec al

pathogenesis of GSE as assessed by

peripheral blood lymphocyte crans

formacion responses and K cell

activity. The present study <lemonstrated

that the percentage rather than the number of peripheral blood T lympho

cytes was lower in patients with GSE (with or without lymphoma) when

compared co normal controls, and that patients with lymphoma had a signifi

cantly increased number of peripheral

R EFEREN CES l. Marsh MN. The small intestine:

mechanisms of local immun1t y anc.J gluten sensitivity. Clin Sci l98l; 61 :497-503.

2.Strober W. An immunological theory of gluten-sensitive cnteropathy. In: McNkholl B, McCarthy CF, Fottrcll PF, cc.ls. Perspccnvcs 111 Celiac Disease. Lancaster: MTP Press, JL)78: 169.

3. Lam CWE, Thomson ABR. Upc.late in Small Bowel Disease. Chicago: Year Book Medical Publishers, 1986: 63-97.

4. Cole SO, Kagnoff MF. Celiac disease. Ann Rev Nutr 1985; 5:241-66.

5. Blechcr TE, Brzcchwa-Ajdukiewicz A, McC?""thy CF, et al. Serum immunoglobulins and lymphocyte transformation studies in cocliac c.Jiscasc. Gut 1969; 10:57-62.

6. Asquith P. Cell mediatec.1 immunity in cocli:ic c.Jisease. In: Hekkcns WMJ, Pena AS, eds. Coeliac Disease. Second International Codiac Symposium, LciJen. Stcnfcrr Koresc Leiden, 1974: 242-62.

7.Scott BB, Lo~owsky MS. Depressed cell-mediated immunity in coeliac disease. Gut 1976; 17:900-5.

8. Ferguson A, Murray D. Quantitation of intraepithclial lymphocytes 1t1

human jejunum. Gut 1971; 12: 988-94. 9.0'Donaghuc DP, Lancaster-Smith M,

Lavmierc P, ct al. T cell depletion in untreated adult coeliac disease. Gut

blood B cells.

No single immunological process is likely to account for all th e path ologi

cal changes and cl inical features

c h aracteristic of the entire natural h is

tory of celiac sprue. Celiac disease

nevertheless appears to represent a dis

turbance of normal protective mechanisms in the intestine, allowing sensi

t izat ion to a d ietary staple and the

development of host damage. The relevance of this observat ion of a

1976; 17:328-3 l. IO. Bullen AW, Losowsky MS. Lympho

cyte subpopulations in adult cocliac disease. Gut 1978; 19:892-7.

11. Austad WI, Cornes JS, Gough KR, et al. Steatorrhca and malignant lymphoma. Am J Dig Dis 1967; [2:475-90.

12. Harris DD, Cooke WT, Thompson H, et al. Malignancy in adult coeliac disease and idiopmhil steacorrhea. Am J Med 1967; 42:899-912.

I 3. Scrobcr W. The pathogenesis of gluten sensitive enteropathy. Ann Intern Med 1975; 83:242.

14.Selby WS, Janossy G, Bofill M, Jewell DP. Lymphocyte subpopulations in the human small intestine. The findings in normal mucosa and in the mucosa of patients with adult cehac disease. Clin Exp lmmunol 1983; 52:219-28.

15.0'Farrelly C, Whelan CA, Fe1ghery CF, Weir DO. Suppressor-cell activity in ccliac disea,e inc.lucec.l by alphagliadin, a dietary antigen. Lancet 1984; ii:1305-7.

16.0'Farrclly C, Feighcry C, Grcally J, Wier DO. Cellular response co alpha gliadin in untreated celiac disease. Gut !982; 23:83-7.

17.0'Farrclly C, Kelly J, Hekkens W, et al. Alpha gliadin antibody levels: a serological test for cocliac disease. Br MedJ 1983; 286;2007-10.

decreased percentage ofT cells and in

creased percentage of B cells to the

development of lymphoma in GSE rema ins to be determi ned. Prospective

s tudies are needed to investigate

w h ether th is rise in peripheral blood B cell populations is a marker of concur

rent lymphoma, or if it is of use to d is

tinguish between patients with uncom

plicated celiac disease versus those

with enteropathy-associated T cell

lymphoma.

18.lsaacson P, Wright DH. lntc:,tinal lymphoma associated with m:ilabsorption . Lancet 1978; i:67-70.

19.Swinson CM, Coles EC. Salvin G, Booth CC. Cocliac c.li,ease and malignancy. Lancet 1983; i: 111-5.

20. Isaacson PG, Spencer J, Connolly CE, ct al. Malignant hi,tiocytosis of the intestine: a T-cell lymphoma. L:incer 1985; i:688-91.

21. Loughran TP, Kadin ME, Deeg HJ. T-cell intestinal lymphoma associated with ccliac sprue. Ann lnrern MeJ 1986; 104:44-7.

22.Salter OM, Krajewski AS, Dewer AE. lmmunophenotype analysis of malignant histiocytosts of the intestine. J Clin Pathol 1986; 39:8-15.

23. O'Farrelly C, Feighcry C, O'Bnan OS, ct al. Humeral response to wheat protcm in patients with ccliac disease and enteropathy-associated T cell lymphoma. Br Med J 1986; 293:908-10.

24.Frecman HJ, Weinstein WM, Shnitb TK, er nl. Primary ahdommal lymphoma. Presenting manifestation of celiac sprue, or complicating dermatitis hcrpcriformis. Am J Med 1977; 63:585-94.

25. Lyanga J, Davi:, P, Thomson ABR. In vitro testing of immunorcsponsiveness in patiencs with inOammarory bowel disease. Clin Exp lmmunol 1979; 37: 120-5.

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Celiac sprue and abdol1linal lyl1lphol1la: Studies on the ...downloads.hindawi.com › journals › cjgh › 1988 › 838210.pdf · human jejunum. Gut 1971; 12: 988-94. 9.0'Donaghuc