Differential Regulation of Granuloma Size and Hepatic Fibrosis in Schistosome Infections

Differential Regulation of Granuloma Size and Hepatic Fibrosis in Schistosome Infections

Vol. 92(5): 689-692

Allen W Cheever

Biomedical Research Institute, 12111 Parklawn Drive, Rockville, MD 20852 USA and Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-0425 USA

Granuloma size is the variable most frequently used to evaluate the immunopathogenesis of schistosome infections. However, hepatic fibrosis is at the least an equally relevant variable. Hepatic fibrosis and the size of circumoval granulomas are frequently dissociated in experimental murine Schistosoma mansoni and S. japonicum infections. Virtually nothing is known of the immunoregulation of schistosomal hepatic fibrosis. This review notes many of the studies which have found discrepancies in granuloma volume and hepatic fibrosis, attempts to put them in perspective and to evaluate different methods of calculating changes in collagen synthesis or content.

Key words: schistosomiasis - granulomatous inflammation - fibrosis

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In experimental schistosomiasis the degree of hepatic fibrosis often correlates with volume of hepatic granulomas, but there are numerous exceptions to this and the regulation of hepatic fibrosis and granuloma size are clearly at least partly independent.

It is clear that when comparing granuloma size and fibrosis that one should consider only those situations in which the duration of infection is the same in the groups being considered and in which only newly formed granulomas are measured, i.e. reactions around eggs containing mature, viable embryos.

It is less clear how one should quantify fibrosis. We have generally used the total increase above normal levels of hepatic collagen (determined as the increase in hydroxyproline per liver per egg). This gives a measure of the cumulative increase in total collagen (synthesis minus destruction) at any given time point, but different time points cannot be rigorously compared and rates of synthesis and destruction at specific times after infection are not determined. Collagen synthetic rates should give a better picture at any given moment, but one does not generally know the rate of collagen destruction at that moment. Even if the level of collagenases is known, should one in any case consider constitutive or latent collagenases, besides needing to consider at least type I and type III collagenases?

The frequent dissociation of granuloma size and collagen content or synthetic rates is evident in the Table. I find the interpretation difficult when granulomas decrease in size and the collagen or synthetic rate per g granuloma does not change, i.e. the collagen or synthetic enzymes in the granulomas are perhaps decreased but compacted into a smaller volume (Fig.). However, when the granulomas remain the same size and the collagen and synthetic rates per g granuloma decrease (Olds et al. 1989) or when different treatments have different effects (Olds & Kresina 1989), the results seem unequivocal. Similarly the results seem clearly interpretable when total hepatic collagen is considered in relation to egg numbers.

Illustration of an instance in which the interpretation of dissociation of granuloma size and hepatic fibrosis is equivocal. The box represents a gram of granulomatous tissue.

Since the number of granulomas per gram has increased and the hydroxyproline per gram granuloma has remained constant, the hydroxyproline per granuloma must have decreased. The number of granulomas per liver will not have changed and the hydroxyproline per liver must have also decreased.

There are dissociations between granuloma size and fibrosis in addition to the treatments and comparisons noted in the Table. For example, in Schistosoma mansoni-infected mice granuloma volume does not change with intensity of infection (expressed as worm pairs or total liver eggs) while the fibrosis per egg decreases as infection intensity increases (Cheever 1986).

We know nothing of the kinetics of collagen deposition in relation to granuloma size in humans. We do know that in many cases of "active" Symmers' fibrosis that downregulatory anti-idiotypic T cells are absent and proliferation of peripheral blood mononuclear cells is greater than that in asymptomatic hepato-intestinal cases (Montesano et al. 1990). Similar anti-idiotypic T cells downregulate the size of in vitro granulomas formed around schistosome eggs by PMBC of infected patients (Parra et al. 1991). Obviously, it will be important to have surrogate variables of hepatic fibrosis and collagenolysis to follow in infected humans. Past studies suggest that serum procollagen III (Zwingenberger et al. 1988, Mincis et al. 1990, Fayol et al 1991, Shahin et al. 1992) or other serum precursors (Tanabe et al. 1989, Parise & Rosa 1992, Shahin et al. 1995) or in vitro responses of liver from infected patients (Dunn et al. 1979, Monteiro & Borojevic 1995) may be of interest in this regard. Collagen production by in vitro granulomas (Parra et al. 1991) has apparently not yet been examined.

The examples cited above and in the Table indicate that granuloma size and hepatic fibrosis are frequently regulated independently. The factors relevant to immune-modulation of granuloma size include CD8⁺ suppressor effector cells, CD4⁺ suppressor inducer and effector cells, macrophages, cross-regulation of Th1 and Th2 cells, anti-idiotypic antibodies (S. japonicum) and anti-idiotypic t cells (S. mansoni and S. japonicum). Immunoregulation of schistosomal hepatic fibrosis has been less examined and might affect pathways involved in collagen synthesis, cross-linking or collagenase activity. All of these pathways determining granuloma size and fibrosis are presumably affected by the balance of cytokines which may affect reaction size and fibrosis in different ways or to different degrees. For example, cytokines affecting cell recruitment might be expected to affect primarily the size of granulomas. Some treatments noted in the Table, i.e. anti-IL-4 treatment (Cheever et al. 1994), may act directly on enzymes affecting collagen (Postlewaite et al. 1992) as well as through immunoregulatory pathways.

REFERENCES

• Cheever AW 1986. The intensity of experimental schistosome infections modulates hepatic pathology.

  Am J Trop Med Hyg

  35

  : 124-133.

• Cheever AW, Duvall RH, Hallack Jr TA 1984. Differences in hepatic fibrosis and granuloma size in several strains of mice infected with

  Schistosoma japonicum

  .

  Am J Trop Med Hyg

  33

  : 602-607.

• Cheever AW, Duvall RH, Hallack Jr TA, Minker RG, Malley JD, Malley KG 1987. Variation of hepatic fibrosis and granuloma size among mouse strains infected with

  Schistosoma mansoni

  .

  Am J Trop Med Hyg

  37

  : 85-97.

• Cheever AW, Finkelman FD, Caspar P, Heiny S, Macedonia JG, Sher A 1992. Treatment with anti-IL-2 antibodies reduces hepatic pathology and eosinophilia in

  Schistosoma mansoni

  -infected mice while selectively inhibiting T cell IL-5 production.

  J Immunol

  148

  : 3244-3248.

• Cheever AW, Finkelman FD, Cox TM 1995. Anti-interleukin-4 treatment diminishes secretion of Th2 cytokines and inhibits hepatic fibrosis in murine schistosomiasis japonica.

  Parasite Immunol

  17

  : 103-109.

• Cheever AW, Xu Y, Sher A, Finkelman FD, Cox TM, Macedonia JG 1993.

  Schistosoma japonicum

  -infected mice show reduced hepatic fibrosis and eosinophilia and selective inhibition of IL-5 secretion by CD4

  ⁺

  cells after treatment with anti-IL-2 antibodies.

  Infect Immunity

  61

  : 1288-1292.

• Cheever AW, Williams ME, Wynn TA, Finkelman FD, Seder RA, Cox TM, Hieny S, Caspar P, Sher A 1994. Anti-IL-4 treatment of

  Schistosoma mansoni

  -infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis.

  J Immunol

  153

  : 753-759.

• Dunn MA, Kamel R, Kamel IA, Biempica I, El Kholy A, Hait PK, Rojkind M, Warren KS, Mahmoud AAF 1979. Liver collagen synthesis in schistosomiasis mansoni.

  Gastroenterol

  76

  : 978-982.

• Fayol V, Hassanein HI, El-Badrawy N, Ville G, Hartmann DJ 1991. Aminoterminal propeptide of type III procollagen: a marker of disease activity in schistosomal patients.

  Eur J Clin Chem Clin Biochem

  9

  : 737-741.

• Hirata M, Kage M, Takushima M, Fukuma T 1993. Different courses of granulomatous reactions around

  S. japonicum

  eggs in three strains of mice.

  J Parasitol

  79

  : 266-273.

• Hood AT, Boros DL 1980. The effect of splenectomy on the pathophysiology and egg-specific immune response of

  Schistosoma mansoni

  -infected mice.

  Am J Trop Med Hyg

  29

  : 586-591.

• Mincis M, Braga LLC, Russo EMK, Novo NF, Juliano Y 1990. Serum type III procollagen peptides in patients with hepatointestinal and compensated hepatoesplenic schistosomiasis forms.

  Arq Gastroenterol São Paulo

  27

  : 24-29.

• Monteiro A, Borojevic R 1995. Complement-dependent induction of DNA-synthesis and cell-proliferation in human liver connective-tissue cells

  in-vitro. In Vitro Cellular Dev Biol-Animal

  31

  : 149-155.

• Montesano MA, Freeman GL, Gazzinelli G, Colley DG 1990. Immune responses during human

  Schistosoma mansoni

  . XVII. Recognition by monoclonal anti-idiotypic antibodies of several idiotypes on a monoclonal anti-soluble schistosomal egg antigen antibody and anti-soluble schistosomal egg antigen antibodies from patients with different clinical forms of infection.

  J Immunol

  145

  : 3095-3099.

• Olds GR, Kresina TF 1989. Immunoregulation of hepatic fibrosis in murine schistosomiasis japonica.

  J Infect Dis

  159

  : 798-801.

• Olds GR, Meneza S el, Mahmoud AAF, Kresina TF 1989. Differential immunoregulation of granulomatous inflammation, portal hypertension, and hepatic fibrosis in murine schistosomiasis mansoni.

  J Immunol

  142

  : 3605-3611.

• Parise ER, Rosa H 1992. Serum laminin in hepatic schistosomiasis.

  Trans R Soc Trop Med Hyg

  86

  : 179-181.

• Parra JC, Gazzinelli G, Goes AM, Moyes RB, Rocha R, Colley DG, Doughty BL 1991. Granulomatous hypersensitivity to

  Schistosoma mansoni

  egg antigens in human schistosomiasis. II.

  In vitro

  granuloma modulation induced by polyclonal idiotypic antibodies.

  J Immunol

  147

  : 3949-3954.

• Postlewaite AE, Holness MA, Kitai H, Raghow R 1992. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4.

  J Clin Invest

  90

  : 1479-1485.

• Shahin M, Schuppan D, Waldherr R, Risteli J, Tisteli L, Savolainen E-R, Oesterling C, Abdel Rahman HM, El Sahly AM, Abdel Razek SM, El Ruby O, Koch A, Seitz HK 1992. Serum procollagen peptides and collagen type VI for the assessment of activity and degree of hepatic fibrosis in schistosomiasis and alcoholic liver disease.

  Hepatology

  15

  : 637-644.

• Shahin M, Schuppan D, Waldherr R, Zalpur F, Rahman HM, Elsahly AM, Razek SMA, Elruby O, Seitz HK 1995.

  Hepato-Gastroenterology

  42

  : 22-26.

• Tanabe M, Sekiguchi T, Kaneko N, Kobayashi S, Takeuchi T, Coutinho A, Tateno S, Maruyama K, Okazaki I 1989. Elevation of laminin and beta-subunit prolyl 4-hydroxylase in the sera of human subjects with

  Schistosoma mansoni

  .

  Japan J Exp Med

  39

  : 109-119.

• Weinstock JV, Ehrinpreis MN, Boros DL, Gee JB 1981. Effect of SQ 14225, an inhibitor of angiotensin I-converting enzyme, on the granulomatous response to

  Schistosoma mansoni

  eggs in mice.

  J Clin Invest

  67

  : 931-936.

• Wynn TA, Cheever AW, Jankovic, D, Poindexter RW, Caspar P, Lewis FA, Sher A 1995. An Il-12 based vaccination method for preventing fibrosis induced by schistosome infection.

  Nature

  376

  : 594-596.

• Zwingenberger KG, Harms H, Feldmeier O, Muller A, Steiner A, Bienzle U 1988. Liver involvement in human schistosomiasis mansoni. Regression of immunological and biochemical disease markers after specific treatment.

  Acta Tropica

  45

  : 263-275.

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Received 16 April 1997

Accepted 30 June 1997

Publication Dates

• Publication in this collection
  14 Oct 1998
• Date of issue
  Sept 1997

History

• Accepted
  30 June 1997
• Received
  16 Apr 1997