The effects of a human IgM monoclonal anticardiolipin antibody on pregnancy in a transgenic mouse model

Abstract

The clinical features of antiphospholipid (or Hughes') syndrome (APS) are most commonly seen in individuals who have raised levels of IgG anticardiolipin antibodies. Most murine models of the syndrome have involved the administration of such antibodies to normal mice. However, APS can occur in the presence of raised levels of serum IgM anticardiolipin antibodies alone. The present study was designed to see if an IgM monoclonal antibody can induce changes in mice similar to those seen in human APS. This antibody, BH1, has previously been derived from a patient with primary APS. In its ligand-binding and idiotypic characteristics it is representative of antiphospholipid antibodies (aPL) found in the serum of patients with APS.

In order to minimise the immune response to human IgM, we used transgenic mice (F₁₅) which express, and are predicted to be tolerant of, human immunoglobulin m chains. The features of APS may develop more readily in individuals who have an existing autoimmune disorder, such as systemic lupus erythematosus (SLE). We therefore crossed these transgenic mice with New Zealand Black (NZB, SLE-prone) mice, and used the progeny (F₁₅ × NZB/F₁) in our experiments. Twenty-four F₁₅ × NZB/F₁ mice were given BH1, or a control IgM antibody, (A5566) immediately preceding and then three times during pregnancy

There was a reduction in the mean number of foetuses in animals given BH1 compared with those given A5566 (8.6 vs 11.0; P 0.05), and a similar reduction in mean total foetal weight per pregnancy (9.05 vs 12.73 g; P 0.05). Two mice showed a marked reduction in platelet count. No evidence of thrombosis was detected macroscopically or histologically.

Our results show a lower incidence of APS-type features compared to previous studies in which mice have been administered aPL. This may be because BH1 is an IgM antibody. Nevertheless, the data support the concept that IgM aPL of particular ligand-binding specificities may have a direct pathogenetic role in certain cases of human APS.

Keywords

antiphospholipid syndrome Hughes' syndrome antiphospholipid antibody animal model transgenic mice

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References

Khamashta MA , Asherson RA . Hughes' syndrome: antiphospholipid antibodies move closer to thrombosis in 1994 . Br J Rheumatol 1995; 34: 493–497 .

Rai RS , Clifford K , Cohen H , Regan L . High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies . Hum Reprod 1995; 10: 3301–3304 .

Lockshin MD . Pathogenesis of the antiphospholipid syndrome . Lupus 1996; 5: 404–408 .

Harris EN , Chan JKH , Asherson RA et al. Thrombosis, recurrent fetal loss, thombocytopenia: predictive value of IgG anticardiolipin antibodies . Arch Intern Med 1986; 146: 2153-2153 .

Alarcon-Segovia D , Deleze M , Oria CV et al. Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus, erythematosus. A prospective analysis of 500 consecutive patients . Medicine 1989; 68: 353–365 .

Cervera R , Font J , Lopez-Soto A et al. Isotype distribution of anticardiolipin antibodies in systemic lupus erythematosus: prospective analysis of a series of 100 patients . Ann Rheum Dis 1990; 49: 109–113 .

Out HJ , Bruinse HW , Christiaens GCML et al. A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies . Am J Obstet Gynecol 1992; 167: 26–32 .

Mackworth-Young CG , Andreotti F , Harmer IJ et al. Endotheliumderived haemostatic factors and the antiphospholipid syndrome . Br J Rheumatol 1995; 34: 201–206 .

Harris EN , Pierangeli SS . Functional effects of anticardiolipin antibodies . Lupus 1996; 5: 372–377 .

10.

Kandiah DA , Sali A , Sheng Y et al. Current insights into the ‘antiphospholipid’ syndrome: clinical, immunological and molecular aspects . Adv Immunol 1998; 70: 507–563 .

11.

Radway-Bright EL , Inanc M , Isenberg DA . Animal models of the ‘antiphospholipid’ syndrome . Rheumatology 1999; 38: 591–601 .

12.

Blank M , Cohen J , Toder V , Shoenfeld Y . Induction of antiphospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies . Proc Natl Acad Sci USA 1991; 88: 3069–3073 .

13.

Blank M , Tincani A , Shoenfeld Y . Induction of antiphospholipid syndrome in naive mice with purified IgG antiphosphatidylserine antibodies . J Rheumatol 1994; 21: 100–104 .

14.

Piona A , La Rosa L , Tincani A et al. Placental thrombosis and fetal loss after passive transfer of mouse lupus monoclonal or human polyclonal anti-cardiolipin antibodies in pregnant naive BALB/c mice . Scand J Immunol 1995; 41: 427–432 .

15.

Ikematsu W , Luan F-L , La Rosa L et al. Human anticardiolipin monoclonal autoantibodies cause placental necrosis and fetal loss in BALB/c mice . Arthritis Rheum 1998; 41: 1026–1039 .

16.

Branch DW , Dudley DJ , Mitchell MD et al. Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss . Am J Obstet Gynecol 1990; 163: 210–216 .

17.

Sthoeger ZM , Mozes E , Tartakovsky B . Anti-cardiolipin antibodies induce pregnancy failure by impairing embryonic implantation . Proc Natl Acad Sci USA 1993; 90: 6464–6467 .

18.

Suzuki T , Takabayashi K , Ichikawa K et al. Effects of monoclonal anticardiolipin antibodies on pregnant mice . J Rheumatol 1996; 23: 83–86 .

19.

Bakimer R , Fishman P , Blank M , Sredni B , Djaldetti M , Shoenfeld Y . Induction of primary antiphospholipid syndrome in mice by immunisation with a human monoclonal anticardiolipin antibody (H3) . J Clin Invest 1992; 89: 1558–1563 .

20.

Pierangeli SS , Barker JH , Stikovac D et al. Effect of human IgG antiphospholipid antibodies on an in vivo thrombosis model in mice . Thromb Haemostas 1994; 71: 670–674 .

21.

Olee T , Pierangeli SS , Handley HH et al. A monoclonal IgG anticardiolipin antibody from a patient with the antiphospholipid syndrome is thrombogenic in mice . Proc Natl Acad Sci USA 1996; 93: 8606–8611 .

22.

Alarcon-Segovia D , Cabral AR . The antiphospholipid/cofactor syndromes . J Rheumatol 1996; 23: 1319–1322 .

23.

Loizou S , Mackworth-Young CG , Cofiner C , Walport MJ . Heterogeneity of binding reactivity to different phospholipids of antibodies from patients with systemic lupus erythematosus (SLE) and with syphilis . Clin Exp Immunol 1990; 80: 171–176 .

24.

Matsuura E , Igarashi Y , Fujimoto M et al. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor . J Immunol 1992; 148: 3885–3891 .

25.

Roubey RAS . Immunology of the antiphospholipid antibody syndrome . Arthritis Rheum 1996; 39: 1444–1454 .

26.

Harmer IJ , Loizou S , Thompson K , So AKL , Walport MJ , Mackworth-Young CG . A human monoclonal anti-phospholipid antibody that is representative of serum antibodies and is germline encoded . Arthritis Rheum 1995; 38: 1068–1076 .

27.

Mackworth-Young CG , Loizou S , Walport MJ . Primary antiphospholipid syndrome: features of patients with raised anticardiolipin antibodies but with no other disorder . Ann Rheum Dis 1989; 48: 362–367 .

28.

Asherson R , Khamashta MA , Ordi-Ros J et al. The ‘primary antiphospholipid syndrome’: major clinical and serological features . Medicine (Baltimore) 1989; 68: 366–374 .

29.

Mason AN , Harmer IJ , Mageed RA , Mackworth-Young CG . The BH1 idiotype defines a population of anticardiolipin antibodies closely associated with the antiphospholipid syndrome . Lupus 1999; 8: 234–239 .

30.

Bruggemann M , Spicer C , Buluwela L et al. Human antibody production in transgenic mice: expression from 100 kb of the human IgH locus . Eur J Immunol 1991; 21: 1323–1326 .

31.

Shoenfeld Y , Isenberg DA . The mosaic of autoimmunity . Immunol Today 1989; 10: 123–128 .

32.

Theofilopoulos AN , Kofler R , Singer PA , Dixon FJ . Molecular genetics of murine lupus models . Adv Immunol 1989; 46: 61–109 .

33.

Johnstone A , Thorpe R . Immunochemistry in Practice. Blackwell Scientific: Oxford , 1982.

34.

Harmer IJ , Mageed RA , Kaminski A , Charles P , Bruggemann M , Mackworth-Young CG . Chimaeric monoclonal antibodies encoded by the human VH26 gene from naive transgenic mice display a wide range of antigen binding specificities . Immunology 1996; 88: 174–182 .

35.

George J , Blank M , Levy Y et al. Differential effects of anti-beta2-glycoprotein I antibodies on endothelial cells and on the manifestations of experimental antiphospholipid syndrome . Circulation 1998; 97: 900–906 .

36.

Alarcon-Segovia D , Cabral AR . The anti-phospholipid syndrome: clinical and serological aspects . Clin Rheumatol 2000; 14: 139–150 .

37.

Lockshin MD . Why do patients with antiphospholipid antibody clot? Lupus 1997; 6: 351–352 .

38.

Hayem G , Kassis N , Nicaise P et a1. Systemic lupus erythematosusassociated catastrophic antiphospholipid syndrome occurring after typhoid fever . Arthritis Rheum 1999; 42: 1056–1061 .