M-LAY van Velthuysen

The pathogenesis of glomerulonephritis is often thought to be immunologically mediated, because in many instance? glomerular changes are seen with im- munoglobulin depositions. It is interesting that the incidence cf the nephrotic syndrome and chronic renal failun.! is much higher in tropical areas than in temperate climates 1. This suggests that parasitic infec- tions such a; malaria might be involved in the patho- genesis of glornerular disease in tropical areas, but probably host-r&ted factors, determining the sus- ceptibility f;or the development of glomerular lesions, are involved as bV*e112J .

Recent advances in the knowledge of the immuno- pathogenesis of glomerular disease show that similar mechanisms may be involved in the pathogenesis of primary (idnopathic) and secondary glomdlrulopathy (infection-associated glomerulopathy).

Malaria Malaria was the first parasitic infection that was

clearly shown to be associated with the nephrotic syndrome lirl tropical areasJ,5. This is especially trL:e for quartan malaria (Plf7srri0rli~rrr7 wdr7rir7e), although renal involvement in falciparum malaria (Plnsrrwdiwr7 fr7lciymw77) P.as also been described’>. Quartan malaria is associated with chronic glomerular disease which is usually not reversible by treating the infectior?. Renal involvement in falciparum malaria is usually transient, and disappears when the infection is brought under contrcl. In some instances, however, persistent glomerular lesions were described. The glomerular lesions associated with P. fdcipw7m infection are thought to be due to general mechanisms such as hypovolemia, ischemia and intravascular co:!gulation. In both infections (1’. rnnlarine and P. f~lcipmrn) histo- logical glomerular lesions are variable, with irregular thickening oi the glomerular capillary wall, and pro- liferative glomerular changes. In quartan malaria, seg- mental sclerosis of the glomerular tuft can be seen as well, sometimes leading to global glomerulosclerosis. Immunofluorescence shows fine and coarse granular mesnngial staining for IgM, IgG and C3 with some extensions along the gl&erular capillary loops. (3n the ultrastructuraI level, electron-dense deposits are seen in the mesangial and subendothelial areas,

Marie-Louisekm Velthwysen is at the Department of Pathology, Un!~l:lslt) of Rotterdam, PO Box 1738, 3000 DR Rotkrdam, The ktherlands. Tel: +3 I IO 408 7924, F%x: +3 l 10 436 6660, e-mail: vanVelthuysen@path.AZR.NL

The glomerular immunoglobulins were initially thought to originate from circulating immune com- plexes as these could be easily detectedYJ(i. To explore the pathogenetic mechanisms involved in the devel- opment of this glomerular disease, animal models were developed. Some research focused on Plns~~~odiz~rr~ infections in monkeys and chicken, but most work was carried out in rodents, especially in mice using Plasmodim~ berghei infection. Mice infected with P. berghci developed a glomerular disease character- ized by mild expansion of the mesangial matrix, and mesangial staining for immunoglobulinsll. Mild tran- sient proteinuria was detected”. Malarial antigen was seen in glomeruli three days after infection, while immunoglobulins were detected only after seven days”, suggesting iit sitar immune-complex formation. Similar results were obtained in a rat modellX As the glomerular disease was only miBd and transient, these experimental models were not a suitable representation of the human counterpart of glomerular involvement in quartan malaria. Similarities with the glomeru- lopathy associated with falciparum malaria, however, were suggested . l~~*J A satisfactory explanation for the persistent glomerular lesions associated with quarta malaria was not found. In later studies, proliferative glomerular changes with overt prottiinuria were ob- ta%ed in rnicelq,‘?. It is not clear whether this differ- ence in occurrence of glomerular disease is due to more-sensitive detection methods or to the use of different parasite or mouse strains. ‘The variation between mouse strains could be relevant co study the differences in host susceptibilitv isee above). Moreover, these studies suggested a role for DNA-binding anti- bodies and cell-mec!iated immune mechanisms in the development of nephritis during murine malaria.

Thus, glomerular lesions can be associated with malaria infection. Murine models have shown that humoral as well as celluEa? immune mechanisms are apparently involved in rke pathogenesis of these lesions. Apart from immunological mecha,~isms, local release of inflammatory mediators and disiurbance 4 the microvasculature by intravascular coagulation could participate by damaging of glomerular endo- thelium. Future studies should elucidate the exact mechanisms involved.

Schistosomiasis Although schistosomiasis is one of th.: o1dc.k Jm*2

most widespread parasitic infections, its ,&‘& !tion with glomerular disease was established on ,y @I in the 1970s. Mepatosplenic schistosomiasis (induced by Schistoso77n-7 WUKO~Z~), in particular, was shown to be associated with glomerular changes and renal failure16-18. In cases of glomerular disease associated with Schistosom haenratobim infection, concomitant chronic salmonellosis seemed to be involved 18. Overall incidence of glomerular disease with schisto- somiasis was shown to be about 5~6%, whereas in patients with hepatosplenic disease due to S. ~nnnso~i

Copyright @ 1996. Elsevw Science Ltd All qhts resetvcd 0 I69 4758/96/$ I5 00 Parasitology Today. vol. 12, no. 3, I996 102

schistosomiask are ferativc and mem-

tis are occasionally t5sen as welllhJ~,19. t4w1 immunofluorescence, im- munoglobulins (!gM, I&, 1gA and igE) and complement components are observed in the glomerular mesangium with small extensions along the capillary I00ps~~~~~~. On the uhrastructural level, electron- dense deposits (suggesting immune complexes) are seen in tkr mesangium and along the endothe- 1iaB side of the glomerular basement membranel7. Sometimes renal histo- logical changes were found to precede clinical mai-kifestations17.

Fig. I. Changes in experimental African trypanosomiasis as seen by light microscopy. Semi-thin section of a mouse glomerulus six weeks after inoculation of TryL~~nosom~~ brucei brucei (Toluidine blue stain) is shown (a), as is a semi-thin section of a normal mouse glomerulus (Toluidine blue stain) (b). BS, blood space; US, urinary space; CW, capillary wall; arrows point at the mesangium. Scale bars = 20 p,m.

The glomerular disease associated with schistoso- miasis was thought to be a typical example of immune- complex glomerulonephritis. The presence of schistoso- ma1 worm antigens in the glomerular complexes21-24, and the presence of circulating immune complexes con- taining schist~somal antigen, supported this hypoth- esis. Later studies, however, did not show amelioration of the glomerular disease with treatment of the infec- tio$~,I!h and the severity of the glomerular lesions did not seem to depend on the intensity of parasite infest- a tior9. Moreover, l-hllyer and LewcrP found prccipi- tating antibodies to DNA in sera from hamsters infected with s. jnjJ~Ji!iCilrrl. This suggested a role for anti-DNA antibodies, in a context of polyclonal B-cell activation, as in systemic lupus erythematosus. On the other hand, Fujiwara and colleague~~‘~ showed that polyclonal B-cell activation alone was not aw~ig11 to induce glomcrular disease in infected mice. They sugge::ted different, host- dependent factors, which are not yet defined.

Thus, hepathosplenic schistosomiasis is clearly as- sociated with glomerular disease, but a causal relation between glomerular lesions and parasites has been difficult to establish. Beside immune complexes, host- related factors, siclch as hepntic macrophage function, seem to be involved.

Leishmaniasis

Because glomerular changes are seen particularly in hepatosplenic schistosomiasis, portal-systemic shunting was thought to be associated with the development of glomerular !esio&. Experiments in mice, where ligation of the portal vein was performed, showed enhancement of i~l~l~~unt~-cc,ll~plex deposition in the kidncy’J. Glomerular lesions, however, wore more marked and more frequent in hepatosplenic schistosomiasis than in active hepatic cirrhosis?“. Therefore, factors other than shunting of portal blood into the systemic circulation alone had to be involved. The main difference between hcpa tosplenic schistosomiasis and cirrhosis is the presence of circulating schistosomal antigen. In addi- tion, the severity of the glomerular lesions and protein- uria were shown to be correlated with the impairment of hepatic macrophage functiorP. This macrophage function might involve clearance of circulating immune complexes as well as clearance of other nephritogenic factors.

‘TIw glomcrular lesions seen with knla-near consist of mcsangial cxynnsion, somc4imcs with focdl seg- mental prolifer;, ir Ii 1.i 71. Using iilliiltil’lOflLiUrescCI‘1Cd’, IgG, IgM, 1gA and C3 are seen in the mesangium, with some extensions along the cdpiliary l:~p~~~~~. On the ultrastructural level, irregular thickening of the glomerular basement membrane is seen with stub- endothelial and subepithelial electron dense deposit9’. A prospective study has shown that 6W of patients with kala-azar have urinary abnormalities77. Renal biopsies demonstrated imerstitinl changes in all patients, while five out of seven patients had mild glomerular lesions, compatible with the lesions de- scribed earlier. In this study, renal involvement seemed to revert with tile cure of the lcishmnnial infection. Experimental inf~~l:.;ons with L. dowrn~~i in hamsters have resulted in a glomerular disease comparable with its hriman counterpart, although ill hamsters renal amyloidosis was observed 3JJ5. Since L. llolioz~flrri antigens were detected in the glomerular lesions, these antigens were implicated in the pathogcnesis of this glomerular diseascW4.

Trypanosomiasis Although glomerular disease associated with

TI:1/f7~~zus(~~~~~ brlrcei infection has been described in 103 Purasitology Today, vol. 12, no. 3, I996

glomerulus six weeks after inoculation of Tr$~nosoma brucei brucei. BS, blood space: US, urinary space; CW, capillary wall: arrow points at the mesangium. Scale bar = 20 pm.

Glomerular disease associated with T. i~licci infec- tion has been described in rhesus monkeysJ[‘, rab- bitstTe7H, rat$“-JI and n&t* ‘. 1 I-1 IJ. The glomcrular changes observed vary from mesangioproliferative changes to expansion of the mesangial matrix alone (Fig. 1). With immunofluorcscence IgM, IgG and complement com- ponents are seen in the mesangium, Wiili some exten- sions along the glomerular basement membrane. Occasionally, granular (Fig. 2) and linear staining for igM and IgG are reported as seen along Ihe capillary wc?llsJ~JJ. On the ultrastructural level, large electron- dense deposits are obs~rvf~I in the mesat~~ium and subendothclial as well as subepilhelia!. ;vioreover, striking changes of the glomertrlnr-endothelial cells are seen3HJh (Fig. 3).

Several hypotheses 6x-t the pathogenesis of the glom- erular lesions exist. Most studies postulate a patho- genetic role for immune complexes as with the other parasite-related glomerulopathies. In some studies, 104

these immune complexes consist of trypanosomal antigen and antibodies 37~ but immune complexes comprising autoantibodies ind autoantigens have also been implica teda”sJ7, especially DNA-antiDNA com- plexes, as in lupus nephritis, tog&her with comple- ment activation”“,3”,~“. Othe-; suggested a pathogen- etic role for antibodies directed against glomerular autoantigens-“r-‘Y, in the context of polyclonal B-cell activation. Indeed, antibodies against laminin, as well as various glomerular glycoproteins were detected not only in serum, but also in glomerular eluates. Glomer&ar complement activation was only observed after long-standing infection. Antibodies alone, how- ever, could not account for the development of albu- minuria@. Host-related factors, determined by non- MHC (major histocompatibility complex) genes were shown to be important for the development of glom- erular disease associated with African trypano- somiasis. To delineate which parts of the defence sys- tem (in addition to the B-cell response) were involved in the development of glomerular disease, the partici- pation of thymus, spleen and the mononuclear phago- cytic system (ME) were investigatedJq. It was shown that glomerular disease developed independent of the presence of thymic tissue. Nude mice infected with T. b~~ci parasi:es developed albuminuria, and some glomerular immunoglobulin deposits. Polyclonal B-cell activation, however, was not observed. Auto- antibodies or immune complexes in the context of polyclonal B-cell activation alone, once more, could nol explain the full glomerular disease, ie. histological glomerular changes and albuminuria. In these studies, the spleen was shown to bc a crucial organ; albumin- uria cn111d be prcvcnlcd or significantly lowered, dcpc‘n~~~ng on the moment of splcnectomy. After mocrtryhagc dtplction, infcctcd mice dcvclopcd sig- nificantly higher albuminurin for a period up to two weeks ,Iftcr dcplction. Thcrcforcl, it was concluded hit dct’cloptm9~t of glom~~rul~~p~~~l~y CmociCitcd with Africdn try}~‘~lic,sc,nriasis is incicpend4~nt of thymus- matur& T cc&, whilib macrophagcs have an inhibitory, rather than inducing, cffcct. The spleen cnlargcmcnl during T, III’IIcL~! infection is ncil fully understood. It is, in part, due to an increase in extramedullary hematopoiesis and, in part, due to a proportional increase in CD4” T cells, CDS+ T cells, and B cells. Moreover, a relative increase in null cells (CD4 -, CD8 , lg ) is observedi”. In this respect, the massive increase in splenic $5 T cells is a particularly interesting finding (B. de Geus LB/ [I/., Abstract”), especially so since these y6 T cells seem to be involved in the resistance against T. hwi infection”. Their role in the pathogenesis of this glomerulopathy should be invcstigatcd.

General considerations Clinical and epidemiologic studies have established

the existence of glomerular disease associated with parasitic infections. Explanation of the patlmgcnctic mechanism involved, however, remains a difficult challenge. The parasitic infections described above are usually severe chronic infections with fluctuations

___- ---- * Abstract beak of the Xllth meeting of the International Society of iuephrology, I~lvolvemenr of y6 r cells in Tryponosorn,uas-Induced C;bme,u- lopathy, p. 58, 199?

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in antigenemia and therefore fluc‘tu- ations in host immune response. This response consists of several facets that might be nephritogenic.

The antibody response is the most obvious part of the immune system that might act as a ‘pathogen’, be- cause in most instances glomerul;,r immunoglob~rlins are found. Theo- retically these immunoglobulins might accumulate in glomeruli due to passive trapping or specific bind- ing. The variations in antigenemia during these parasitic infections are encountered by a fluctuating host antibody response, resulting in cir- culating immune complexes, which might be trapped in the glomerulus, as the BSA-anti-BSA immune com- plexes in the experiments of Germuth” and Dixon ef ~1.53 Accord- ing to the size and charge of these complexes, this might result in the different glomerular immunofluor- escence staining patterns seen in infected individuals. In experimen- tal malaria infection, however, parasitic antigens were detected in glomeruli before iilllllui~oglobulins. This suggested irr sit11 immune-com- plex formation. Indeed, Fleuren ~1 01 iA showed that alternate perfusion . of isolated kidneys with antigen (BSA) and antibody (anti-BSA) can result in irl sit II formation of glomcrular immune complexes, by binding of antibody to the antigen that was ‘planted’ bcforcl. Roth thco- rics mighl explain the presence of in~mui~oglol,ulins and parasitic anti- gt2ns in glomerl:li as dcscribcd in several parasitic infection5 In many instances, however, parasitic antigen cannot be dctcclcd. This might be due to masking of these antigens by antibodies, or due to the lack of ad- equate dctccqtion methods. Another explanation would be that the glornerular immune complexes con- tain very little or no parasitic antigen, and thus anti- bodii?s with different specificitie., are involved. In this respect, it is of interest that during most of these infections, polyclonal B-cell activation is observedl’),5’1,5f>. The autoantibodies ensuing from this polyclonal activation might form complexes with their antigen and bind in the glomerulus according to the pathways described above. This mechanism was proposed in several papers mentioned 15,?6. Another mechanism involving polyclonal B-cell activation might be direct binding of autoantibodies to glomeru- lar autoantigens, as demonstrated in experimental trypanosomiasisAl,JJ. In these studies, antibodies against parasitic antigens as well as antibodies against known nephritogenic autoantigens, such as !aminin and dipeptidylpeptidase IV, were eluted from the glomerular immune deposits, and were therefore

Par-asrtology Today, vol. 12, no. 3. I996

Fig. 3. Ultrastructural changes in experimental African trypanosomiasis. Electron micrograph of two glomerular capillary loops of a mouse glomerulus six weeks after inoculation of Trypanosoma brucei brucei. BS, blood space: US, urinary space: epi, epithelium; endo, endothelium; EDD, electron-dense deposits in the glomerular mesangium; GBM, glomerular basemcsnc membrane; arrow points at the mesangium. Scale bar = 2.0 km.

thought to 1~~1 pathogenetic. Later studies, however, demons! rated that these ;\ntibodies were neither sufficient nor necessary 18.,+” for the development of proteinuria, one of the parameters of glomerular dysfunction. Similar observations were made in other experimental models for g!omerulonepl~ritis~~~~s. These observations affirmed the importance of other parts of the defence system in the pathogencsis of glomcrular disease.

Although most studies on the pathogenesis of glom- erulonephritis have, uaztil recently, focused on t!re characterization of the glomerular immune deposits, there is now evidence that T cells play a major role in glomerular injury. The potential effect of T cells in glomerular iniury was shown to be twofold?‘. While CD4- T cells ‘Mpere shown to be crucial in the induc- tion of the autoimmune syndrome accompanied by

105

p~ly&l~~l B-41 activation, CDW T cells infiltrating the glomerulus were shown to be directly im:olved in the onset of proteinuria. Therefore, it is of interest that part of the glomerular hypercellularity in murine malaria is due to influx of CDS+ cellsi% Future studies should elucidate the role of T cells in glomerular injury associated with parasitic infections.

With the exception of B cells and T cells, monocytes and polymorphonuclear leukocytes have been impli- cated in the pathogenesis of glomerular disease60,h1, especially in acute glomerulonephritis. The increased cellularity of glomeruli in rabbits infected with African trypanosomiasis was shown to be largely due to infil- tration with monocytes and macrophages? As T cells, these components of the primary defence system act through an intricate network of cytokines and other inflammatory mediators such as oxygen radicalsQ,h3. These mediators might be implicated in cases of glomerular disease without cellular influx as well, especially in parasitic infections where levels of these factors can be presumed to be high due to severe chronic infeciion and hepatic failure. Natural killer cells or $5 T cells might prove to be components of the primary defence systemh4,“i and a source of nephrotoxic serum products.

Although the association of parasitic infections with glomerular lesions is clear, several theories on the pathogenesis of these lesions exist. Knowledge on the pathogenetic mechanisms involved has evolved with the knowledge on the pathogenesis of glomerular dis- ease in general. Especially experimental African tryp- anosominsis has shown that immune complcxcs arc involved but can not cxplnin full-blown glomcrular dis- case. Future StUdiC!; should clucidatc the role of other parts of the dcfcncc system in the pathogcncsis of glomcrular discasc associcIted with parasitic inf03ions.

Acknowledgements

Rcfcrences I Chu~h, KS and Snkhuj,l, V. (IOlJO) Glomcrular disease in the

tropics. hr. /. Nqvrwl. IO, 437-450 2 Sl~pcr, ML (1908) Inrmunological stud& in a tropical envi-

ronillcnt. 1M Afr Md. 1. 45, 2lcJ-22P 3 hnning, M.M. Saved Kazura, J.W. (;‘JXd) Genetic linked variation

in susceptibility of mice to schistosomiasis mansoni. IJ~7r*r7sif1*

IltrrrrJrrrrd. 0, 95-103 4 CX$lidi, CL ( llJh2) Malaria and renal disease with special refer-

t\nce to British Guiana. /\,I,I. 7’~)). Mnf. 1+7717sitd. St,, 225-241

5 Kibt~kmrusnkc, I.W., I-lutt, M.S.R. and Wilks, N.E. (1167) The nephrotic syndrome in Uganda and its association with quartan malaria. Q. /, Md. XI, 3Y3-W

(7 Boi)n~~llchna~ig, V. and Sitprijn, V. (1Y7Y) Renal disease in acute ~‘lrlS777Orfi77r77 fi7lcipurm infection in man. Ki[lrt,*~/ lrrf. 16, 44-52

7 ll~b& V. t !‘J7lJ) Immunologic aspects of renai lesions associ- ated with mai,*ria. Kilfrrc,tr /rr/. 16, 3-x

s silprh V. and !~~lony~l~kl~avig, V. ( I1JQ.l) fi~w/ I+7f/r(J/,Jy1~ il~i/j~

cli~k’fll l77td ~11171Vr.Jf717~ ~cJrrd~7/icJr7s (Tishcr, C.C. and &&n~r, B.M., edc;), pp ~%I--~~s~, 1.1’. Lippincott

Y Ward, [‘.A. and Kibukan,llsok~, J.W. ( IYOY) Evidence for so1ub1e immune complexes in the pathogenesis of the glomeru- lonephritis of.quartan malaria. Lnr71-1~t i. 283-285

10 McGregor, 1-A. c’f nl. (1168) Soluble antigens in the blood of African patients with severe ~ln~rodirr~tr fnlc+nrurtl infection in man. Lmwt i, 881-884

11 BoonpllcknaviS, S., Boonpucknavig, V. and Bhamarapravati, N. (1972) lmmunopathological studies of Plasrrzodizrru bcrgllei- infected mice. Arch. Fbfhl. 94, 322-330

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13

14

15

16

17

18

19

211

21

22

23

24

25

21

27

2-i

2’1

30

31

32

33

34

34

34

37

38

39

Parbtani, A. and Cameron, J.S. (1979) Experimental nephritis associated with Plnsrnodirrrn infection in mice. Kidmy lilt. 16, 53-63 Ehrich, J.H. ~‘t 171. (1981) Rat malarial glomerulonephritis. An experimental model of post-infectious glomerular injury. Vi~chil~~ AK/~. 1 Bl37, 343-356 Lloyd, C.M., Wozencraft, A.O. and Williams, D.G. (1993) Cell- mediated pathology during murine malaria-associated neph- ritis. C/ifr. h/J. ~rrrfr77l~ro/. 94, 398-402

Wozencraft, A.O. ct 171. (IYYO) Role of DNA-binding antibodies in kidney pathology associated with murine malaria infec- tions. lufipcf. lrrrrrl~rrl. 58,2156-2164 Andrade, Z.A., Andrade, S.G. and Sadigurskv, M. (1971) Rena! changes in patients with hepatosplenic schistosomiasis. Am. 1. h/J. Md. H!yx. 20, 77-83 Rocha, H. cf al. (lY76) Renal involvement in patients with hepatosplenic schistosomiasis mansoni. AN. 1. Trq~. Md. H!yg. 25,108-l 15 Barsoum, R.S. ~‘t 171. (1977) Renal disease in hepatosplenic schisto- somiasis: a clinicopathological study. Tn7rzs. R. Svc. Tw/J. Mctf. Hyg. 71, 387-39 1 Barsoum, R.S. (lYY3) Schistosomal glomerulopathies. Kilfrwy Id. 4&l-12 Andrade, Z.A. and h&a, tl. (lY7Y) Schistosomal glomerulo- pathy. Ki~fwy Irrt. 16, 23-29 Sobh, M.A. ct 171. (lYH7) Schistosomal specific nephropathy lead- ing to end-stage renal failure. Kicfrry Irlf. 31, 1006-1011 Hoshino-Shilnizu, S. of nl. (1976) Human schistosomiasis: Sclristosmrn rrrcr~sorri antigen detection in renal glomeruli. Tu7r75. K. !GlC. Trap MClf. t@/S. 70, 4Y2-4Y6 van Marck, E.A.E., Dccldcr, A.M. and Gigasc, P.L.J. (lY77) Effect of portal vein ligation on immune glomerular deposits in Scllisto- SOWI rtrn~sorti infected mice. Br. /. E.vp Pr7tlrd. 5X,412-417 Houba, V. U‘J7Y) Experimental renal disease due to schisto- somiasis. Kicfrrq !rrt. 16, 30-43 Mnrtinclli, R. P\ r7l ( IYXY) Schistosor7t~~ rrrnflsorli-induced mesangiocapillary glomerulonephritis: influence of therapy. h’ihq Irrt. 3S, 1227-1233 S&h, M.A. ct r7l. (IYSX) Effect of anti-schistosomal treatment on schistosomal-specific nephropathy. N@wI~/. KG7/. ‘I’r*r7rrs~J/r7rr/. 3,

7-11-7s 1 C,lvallo, 1’. (I/ rll. (lU74) The ncphropathy of cxperimcntal hep~itosplcnic schi:~tosominsis. Alrr. /, I’r7//rr~/. 70, 433-450 I lillycr, C;.V, dnd I.~*wcrt, I4.M. (1074) Studies on renal pathol- ogy on hamsters infcctcd with Sc/risfosorrrct IIIIUISOU~ and s. ~crp”/ilwrrL /\rrr* 1, ‘I’rry,, rklrd, ill/,$ 23, -104 4 I I Ihjiwcw,l, M., M,\hino, M. c~~~~l WC~l(,~~~,llx~, I I. (IYX8) Sc~lrislrwrrrtr IIIIIJIBOU~: induction of severe glomcrnloncphritis in f’cmalc BXSB mice following chronic infection. I:\)L l’l7rr7dtd. 6,

214-211 lJL~rso~m~, R.S. 1’1 al. ( IcJHX) Hepatic macrophage flmction in s&is= tosomal glomcrulopathy. N~~rlrr~c~l. FJirl/. ‘l’n7rr.~pl17rr~. 3, h12-4~10 dct Urito, ‘I’. (I/ nl. (lY75) Glomerular involvcnrent in human kala- azar: A light, immunofluorescent and electron microscopic study based on kidney biopsies. Arrr. I. Trctl~ Mc[f. Hy,v. 24, Y-18 Sarhwi, A. 1’1 171. (lYY1) Immune complex glomerulonephritis in experimental kala-azar II: Detection and characterization of parasite antigens and antibodies eluted from kidneys of Lcisl777rm7ir7 rfoaoz,rrrrf-infected hamsters. Clirr. E.v~J, lrrrrrrrrrr~~l. X7, 3Nl-302 Dutm M. ct I!/. (lYH5) Renal involvement in visceral leishman- iasis. ,lrrr. 1. Kirfrwy Dis. h, 22-27 Olivcira, A.V. ct r7l. (lYH5) Mesangial proliferative glomeru- lonephritis associated with progressive amyloid deposition in hamsters experimentally infected with Leislrrrrmti~~ ~OUOZUW~. hr. 1. 1’~71hJ/. 120, ZSh-262

Sartwi, A. ct r7l. ( I YX7) Immune complex glomerulonephri tis in experimental kala-azar. /Jmxd~~ Irrrrrt~rrol. 9, ‘J3-103 Nagl~, K.B. II! r7l. (lY74) Experimental infections with African tryp anosomes. VI Glomerulonephritis involving the alternative path- way of complement activation. Am 1. T7qJ. Maf. ?f!/s. 23,15-26 Facer, CA. 1” nl. (1973 Tr~~~uoso~II~ bnrcei: renal pathology in rabbits. Eqt. Pmsitol. 44,249-261 Nagle, R.B. l*t 01. (1982) Glomerular accumulation of monocytes and macrophages in experimental glomerulonephritis associ- ated with Trypwosom rlrodcsierrse infection. Lnb. 177wsf. 46, 356-376 Lindsley, H-B. ~‘t 171. (1980) Variable severity of glomeruloneph- ritis in inbred rats infected with Trymzosoma rhodesierrse.

Parmtology Today, vol. 12, no. 3, I996

Correlation with immunoglobulin class-specific antibody responses to trypanosomal antigens and total IgM levels. An?. 1. Trof~. Md. HI/~. 29,348-357

40 Rickman, W.J‘and Cox, H.W. (1979) Association of autoanti- bodies with anemia, splenomegaly, and glomerulonephritis in experimental African trppmosomiasis. /. Prrrnsitnl. 65,65-73

41 Bruijn, J.A. et nl. (1987) An&basement membrane glomerulo- pathy in experimental trypanosonriasis. 1. /r~r~~no/. 139, 2482-2488

42 van Marck, E.A.E. ct nl. (1981) Renal disease in chronic experi- mental ~n~pnnosotm gmrbiense infections. AHI. 5. Trap. Mnf. H!/g. 30,780-789

43 van Velthuysen, M-L.F. et nl. (1992) Pathogenesis of trypano- somiasis-induced glomerulonephritis in mice. Nq~hrol. Did. Trmzsf~/flr~t. 7, 507-515

44 Barrett-Connor, E., Ugoretz, R.G. and Braude, A.L. (1973) Dis- seminated intravascular coagulation in trypanosomiasis. Arch. lnkw. Md. 131, 574-577

45 Costa, R.S. ~‘t nl. (1991) Immune complex-mediated glomeru- lopathy in experimental Chagas’ disease. C/ill. /l~n~lno/. I/flrlIfrnOfJ~rh[,1. 58, 102-l 14

16 van Velthuysen, M-L.F. ct nl. (1994) Phagocytosis by glomeru- lar endoihelial cells in infection-related glomerulopathy. Nep/m/. Did. ~l?7flS~Jhlf. 9, 1077-1083

47 Lindsley, H.B., Nagle, R.B. and Stechschulte, D.J. (1478) Prolifer- ative glomerulonephritis, hypocomplementemia, and nucleic acid antibodies in rats infected with T’~J/JII~IOSOI~~~I rhodesierrsc.

hr. 1. Trap. Mctl. Hyg 27, 865-872 48 van Velthuysen, M-L.F. cf rj/. (1993) Susceptibility for infection-

related glomerulopathy depends on non-MHC genes. Kilfrlq lr~f. 43,623-629

49 van Velthuysen, M-L.F. et n! (1994) T cells and macrophages in T~!IVIIIIOSOII~~ brrrcei-related glomerulopathy. /f$c!. /r~rnr~l. 62, 3230-3235

SO Makumyaviri, A.M. I*! r?/. (1988~ S)lsteme lymphocytaire et resistance relative de la souris consanguine a Tr~~pmtosm~u~ brrrcei brrrcei. A~rl. /rl$!. f&crrr /rrllfrrrrrc?/. 139, .545-556

51 Flvnn, J.N. and Sileghem, M.R. (1994) Involvement of gamma- dhlta T cells in immunity to trypanosomiasis. /~rrrrrrrr~o/o,q~ 83, 86-92

52 Gcrrn. ,h, F.G. (1953) A comparative histologic and immuno-

-

ecent articles in other Trends journals

The role of nuclear import and export in influenza virus infection, by G. Whittaker, M. Bui and A. Helenius ( I 996) Trends in Cell Biology 6, 67-7 I

The contrasting roles of CD4+ T cells in intracellular infections in humans: leishmaniasis as an example, by M. Kemp, T.G. Theander and A. Kharazmi (1996) immunology Today 17, I 3- I6

Rhodococcus equi: an emerging opportunistic pathogen, by D.M. Mosser and M.K. Hondalus ( 1996) Trends in Microbiology 4, 29-33

Programmed DNA deletions in Tetrqhymena: mecha- nisms and implications, by M-C. Yao (1996) Trends in Genetic 12, 26-30

Sacrifice in the face of foes: pathogen-induced programmed cell death in plants, by R. Mittler and E. Lam ( 1996) Trends in Microbiology 4, IO- I 5

Communicate your science! Super seminar slides, by B.S. Brown (I 996) Trends in Cell Siology 6.74-76

logic study in rabbits of induced hypersensitivity of the serum sickness type. 1. Exp. Ma-f. 97,257-282

53 Dixon, F.J., Feldman. J.D. and Vazquez, J.J. (1961) Experimental glomeruloneplrrttis. The pathogenesis of a labti.atory model resembling tht spectrum of human glomerulonephritis. I. Eql. Md. 113,899-920

54 Fleuren, G.J., Grond, J. and Hoedemaeker, P.J. (1980) Zrr s&r for- mation of subepithelizl glomerular immune complexes in passive serum sickness. Kid~q ht. 17,613-637

S5 Kobayakawa, T. [‘t a/. (1979) Autoimmune responses to DNA, red blood cells, and thymocyte antigens in association with polyclonal antibody sythesis during experimental African tryp- anosomiasis. 1. I~nm~rnc~l. 122, 296-301

56 Hentati, B. cf n/. (1994) Beneficial effect of polyclonal immuno- globulins from malari;-infected BALB/c mice on the lupus- like syndrome of (NZB X NZW)Fl mice. EUV. 1. Im~unol. 24, 8-l 5

57 Aten, J. ct 17/. (1988) Cyclosporin A induces long-term unrespon- siveness in mercuric chloride-induced autoimmune glomeru- lonephritis. C/ill. E.c/?. I~ra~a~rrol. 73, 307-311

58 Kawasaki, K. ct nl. (1992) Depletion of CD8 positive cells in nephrotoxic serum nephritis of WKY rats. Kifncy hf. 41, 1517-l 526

59 Florquin, S. and Goldman, M. (1994) T cell subsets in glomeru- lar diseases. S/Jriqrr Snrri~. ltrlrrrlrnofmf/m/. 16, 71-80

60 Cattell, V. (1994) Macrophages in acute glomerular inflam- mation. Ki~11q Irll. 45,945-952

61 Schrijver, G. cf nl. (1990) Anti-GBM nephritis in the mouse: role of granulocytes in the heterologous phase. Ki[frzq hf. 38,86-95

62 Benigni, A. and Remuzzi, G. (1994) Inflammation and glomeru- lar injury. S/jrirl,q*r Scrrri~. /rirrn~rrrl,/w~/Jt,1. 16, 39-51

63 Diamond, J.R. (1992) The role of reactive oxygen species in animal models of glomerular disease. Am. /. Kifncy Dis. 19, 292-300

64 Scharton, T.M. and Scott, P. (1993) Naturai killer cells are a source of interferon gamma that drives differentiation of CD4. T cell subsets and induces early resistance to Leisltrrrntrin tnnjor

in mice. 1. Esp. Mnf. 178, 567-577 65 Hiromatsu, K. II/ a/. (1992) A protective role of gamma-delta T

cells in primary infection with Listerin rrrorrocytogertrs in mice. /. Es/l. Mt:f. 175, 4%S6

DNA replication in the malaria parasite, by J.H. White and B.J. Kilbey

Genomic repetitive elements of Try~anosoma cruzi, by J.M. Requena, L.C. Lopez and C. Alonso

Modulation of host cell intracellular Cal+ , by M. Olivier

Lymphatic filariasis: what mice can tell us, by R.A. Lawrence

Currently available molluscicides, by S. Perrett and P.J. Whitfield

y/S T cells In malaria infections, by J. Langhorn

Cryptosporidium parvum and our water supply, by G. Widmer, M. Carraway and S. Tzipori

Mosquitocidal toxins, genes and bacteria: the hit squad, by A.G. Porter

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