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Rheumatoid factor and rheumatoid factor isotypes in loiasis with and without accompanying glomerulonephritis
TRANSACTIONS OF THE ROYAL Somn
OF TROPICAL MEDICINE AND
Rheumatoid factor and rheumatoid accompanying glomerulonephritis
HYGIENE (1992)86, 667-669
factor isotypes
667
in loiasis with and without
lRheumatology Research Unit, A. 0. Adebajol*, A. Akinsola’, R. M. Maizels3, T. E. Cawston’ and B. L. HazIernan’ Addenbrooke’s Hospital, Cambridge, UK, 2Department of Medic& Obafemi Awolozoo University, Ile-Ife, Nigeria, 3Department of Biology, Imperial College, London, UK Abstract
We have studied the distribution of rheumatoid factor isotypes amongst patients with loiasis with and without accompanying glomerulonephritis to determine the possible role of rheumatoid factor antiglobulins in this disease. Our findings indicate an increase in both immunoglobulin (Ig) G and IgM rheumatoid factor isotypes in patients with fiariasis alone as well as in patients with accompanying glomerulonephritis. No association with IgA rheumatoid factor was found. The raised IgG and IgM rheumatoid factor levels did not correlate with corresponding IgG and IgM levels. Introduction
Loiasis is a parasitic infection with the tilarial worm Lou loa. associated with considerable morbiditv in Africa, South and Central America, the Middle East and Asia. One aspect of this condition that has received interest in recent times is its association with glomerulonephritis. It has been suggestedthat immunological mechanisms are involved in the pathogenesis of loiasis and possibly in that of the associatedglomerulonephritis (PILLAY et al., 1973). Supporting evidence for this comes from the observation that various autoantibodies are produced in association with L. loa infection (THOMAS et al., 1989). The production of rheumatoid factors (antiglobulins against the Fc region of immunoglobulin (Ig) G) in patients with loiasis is of particular interest as rheumatoid factors have been postulated as being part of the protective immune response (NEMAZEE & SATO, 1983; VAN SNICK & COULIE, 1983). These postulates have led us to determine the distribution of rheumatoid factor (RF) isotypes amongst patients with loiasis and an associated glomerulonephritis, as well as in patients with loiasis alone, with a view to determining the role of RF isotypes in these diseasegroups. Materials and Methods Patient groups
F.our groups of subjects were studied. (i) Loiasis associatedwith glomerulonephritis. Twenty adults, aged 1540 years, who had nephrotic syndrome or significant glomerular proteinuria and a serum creatinine level >3 mg% (265 umol/litre) were selected. All had a history of pruritis associatedwith worms crossing the conjunctiva or transient subcutaneous pruritic swellings (Calabar swellings). In all subjects, microfilaraemia was demonstrated by Knott’s concentration method (KNOTT, 1939).
_
(ii) Idiopathic glomerulonephritis without loiasis. Fourteen adults, aged 15-47 years, with idiopathic nephritis and in whom there was no historical, clinical or laboratory evidence of loaisis were selected. Further identifiable causes of glomerulonephritis such as systemic lupus erythematosus or hepatitis B were excluded using appropriate clinical and laboratory investigations. (iii) Loiasis without glomerulonephritis. Twenty-five adult patients aged 16-50 years with clinical and laboratory evidence of loiasis were selected. These patients had demonstrable L. loa microfilaraemia and had had clinical evidence of the disease for at least 6 months. They had normal urine analyses for albumin, red blood cells and casts, and normal serum electrolytes and urea. (iv) Healthy adults. Twenty-one healthy adults aged l&45 years were selected from hospital workers who had no evidence of loiasis from their history or clinical examination. No microfilaraemia was detected by repeated blood film examination. *Author for correspondence.
All patients studied were Nigerian. In the patients studied microfilarial infections, other than loiasis, were excluded by the absence of other microtilaraemia on repeated daytime and nocturnal blood film and negative skin snip examinations. Filarial infections were excluded in the 2 control groups not only by the absenceof microfilaria from day and night blood smears and skin snips, but also by the absenceof eosinophilia and low levels of total antirnicrofilarial antibody (optical density <0.4 [see below]). Immunological assays
Seraobtained from these subject groups were stored at -20°C and assayedfor IgM., IgG and IgA RF as well as for total IgM, IgG and IgA unmunoglobulin levels. Rheumatoid factor assays
IgM and IgA RF isotypes were measured using a commercial enzyme-linked immunosorbent assay (Cambridge Life Sciences, Elv, UK), which had nreviouslv beenevaluated in ou; u&i (AD~~BAJOet al., l-991). One hundred ul of each serum samnle diluted 1 in 100 in phosphate-buffered saline plus 0.05% Tween 20@ (PBST) and the standards supplied were incubated at room temperature for 30 min in microtitre plates precoated with human IgG. After washing the wells thrice with PBST, 100 ccl of rabbit antihuman IgM (for IgM RF) or IgA (for IgA RF) peroxidase conjugate diluted 1 in 1000 in PBST were added to each well for 30 min at room temperature. One hundred ~1 of o-phenylenediamine enzyme substrate were then added to each well and incubated in the dark at room temperature for 10 min. The reaction was stopped by the addition of 50 ~1of 2 M HzS04 to all wells. The optical density of each well was then read at 492 run and the results expressed in international units (iu) per ml by reference to a standard curve (based on the World Health Organization reference RF standard). Immunoglobulin assays
IgM, IgA and IgG levels were measured using a nephelometric assay with an automated immunochemistry system (Beckman Instruments, Aylesbury, UK) which generatesa peak rate signal proportional to the increasein light scatter produced when supplied antibody Table 1. Distribution groups
Subjectgroup Loiasis with glomerulonephritis Loiasis alone Glomerulonephritis
of rheumatoid
W
factor
isotypes
in the subject
Rheumatoidfactor times’ kA I.@
20.68 (kO.8) 29.04 (f0.9)
4.84 (k4.8) 4.76 (k2.6)
14.24 (f2.5) 18.80 (k4.0)
4.64 (+0.2) 5.53 (k5.5) 6.31 (f1.5) 2.76 (kO.3) 6.04 (+4.6) 4.80 (f1.6) Healthy controls ‘Expressedas iu/ml (SEMin parentheses);Ig=immunoglobulin. d0ne
668 to human IgM, IgA or IgG is added to the sample seraor supplied standards of IgM, IgA and IgG respectively. The neak rate sienal is a function of the samnle Ia concentration being measuredand, following calibration, the peak rate signal for each Ig assayis converted into concentration units. Statistical analysis
Statistical comparisons between groups of patients were made using the Mann-Witney U test. Correlation coefficients were calculated using the Spearman rank correlation. Results
Table 1 shows the distribution of RF isotypes in the various subject groups. IgM RF was significantly increased in the loiasis patients and in the patients with loiasis and glomerulonephritis combined when compared with the healthy controls and those with glomerulonephritis alone. There was, however, no difference between the mean IgM RF levels of patients with loiasis and glomerulonephritis and those with loiasis alone. With respect to IgA RF, although the mean levels were highest in the patient groups with either loiasis alone or loiasis with glomerulonephritis, the difference was not statistically significant when compared to patients with glomerulonephritis alone or with healthy controls. The mean IgG RF levels were significantly raised in the loiasis group when compared with both the glomerulonephritis patients (P
of immunoglobdin
IEM
subclasses
Immunoglobulin IEA
in the subject
titres” IIG
Lo&is with glomerulonephritis 662.8(t116.8) 436.0(+48.9) 453.6(k48.7) Loiasisalone 681.6 (k71.5) 410.0(k62.5) 444.9(k46.5) Glomerulonephritis alone 309.9 (T81.1) 374.9 (k80.0) 347.8 (k52.0) Healthycontrols 356.6 (k41.1) 344.0 (k60.1) 372.4 (C28.3) ‘Expressed asiuiml (SEM in parentheses). those with loiasis with or without glomerulonephritis (Table 2). The serum IgM levels were higher in the loiasis group than in those with glomerulonephritis alone (P
The production of RF in association with infectious diseases is well reco nized (BONFA et al., 1987; CARVALHOet al., 1983; E REENWOOD et al., 1971; HOUBA& ALISON et ai., 1966; IZUI et al., 1979; SHAPER et al.,
1971). One consequence of this is that the presence of these autoantibodies, commonly associatedwith rheumatoid arthritis, should be interpreted with caution when found in the seraof patients exposed to various infections (GREENWOOD et al., 1971). RFs are produced both in vitro and in vivo following polyclonal B cell activation (DRESSER,1978; IZUI et al., 1979). Proteoglycans, like bacterial hpopolysaccharides, can be B cell polyclonal activators and a filarial proteoglycan bearing an antigenic determinant. ohosohorvlchohne. has been described (PERRY et al.‘, i979): _I ’ Physiological roles for these RFs may include enhancement of IeG antibodv affinitv for its antigen (NEMAZEE & SATO, i983), amplification of IgG complement binding (TANIMOTOet al., 1975; TESAR& SCHMIDT, 1973), augmentation of‘immune complex clearance (VAN SNICK et al., 1978) and immunoregulation (MONESTIERet al., 1986). These mechanisms may enhance immune clearance of antigens and thereby stem their potential pathogenicity (CARVALHOet al., 1983). On the other hand. it has been oostulated that certain autoantibodies may be pathogenetic, particularly in autoimmune diseasesbut also in parasitic infections. Thus autoantibodies binding to double-stranded deoxyrihonucleic acid (DNA) have been implicated in the pathogenesis of both systemic lupus erythematosus (TAN et al., 1966) and malaria nephritis (ZOUALI et al., 1986). In some studies RFs have been identified as possible pathogenetic factors in disease. RF levels in this study were elevated irrespective of the complication of glomerulonephritis, which implies that the filarial infection by itself was the primary inducer of the elevated RF levels. In our study, IgG RF and IgM RF, but not IgA RF, were significantly raised in the loiasis patients with or without accompanying glomerulonephritis, compared with the levels in patients who did not have loiasis. This probably reflects differences in production of the 2 isotvpes as a result of differing mechanisms in their induct& and regulation of synthesis, as has been indicated for IgA RF and IgM RF (ROOPMANetal., 1987). Our finding of an association between IgG RF and loiasis is interesting as MCINTOSHet al. (1971) have previously implicated IgG RF in the pathogenesis of poststreptococcal glomerulonephritis. Similarly AGNELLOet al. (1971) and ROSSEN et aE. (1975) have provided evidence for the presenceof RF in renal deposits of immune complexes. On the other hand, we found that both IgM RF and IaG RF levels were higher in the patients with loiasis alone than in those with-accompanymg glomerulonephritis, although statistical significance was not achieved. This is similar to the findings of CARVALHOet al. (1983) in patients with schistosomiasis, in whom RF levels were lower in those patients with accompanying renal involvement, leading these workers to suggest that RF played a protective role with respect to the development of kidney disease. With regards to pathogenicity, autoantibodies other than RFs are likely to be involved and DNA binding antibodies mav be particularlv important (THOMASet al., 1989). Pathogen&y of any antibodies will also be a fun& tion of such factors as affinitv and fine snecifcitv. Prospective longitudinal studies- may ide&fy any- pathogenetic role for IgM RF and IgA RF in filariasis, but current evidence tends to suggest that they either play a protective role as part of the immune response or are simply epiphenomena. Whether, once produced, these RFs contribute to the disease pathology merits further study. References
Adebajo,A. O., Wright, J. K., Cawston,T. E. & Hazleman,B. L. (1991).Rheumatoidfactor quantitation: a corn tt;;t;c;f ELBA and nephelometric methods. Medical E Sciences, 48,47-51. Agnello, V., Koffler, D., Eisenberg,J. W., Winchester,R. J. & Kunkel, H. G. (1971).Clq precipitins in seraof patients with systemic lupus erythematosusand other hypocom-
669 plementemic states: characterization of high and low molecular ty es. Journal of Experimental Medicine, 134,228-241. Llovet, R., Scheinborg, M., Souza, J. M. & Elkon, Bonfa, i K. B. (i987). Comparison between autoantibodies in malaria and leprosy with lupus. Clinical and Experimental Zmmunology, 70,529-537. Carvalho, E. M., Andrews, B. S., Martinelli, R., Dutra, M. & Rocha, H. (1983). Circulating immune complexes and rheumatoid factor in schistosomiasis and visceral leishrnaniasis. AmericanJournal of Tropical Medicine and Hygiene, 32,61-68. Dresser, D. W. (1978). Most IgM-producing cells in the mouse secrete autoantibodies (rheumatoid factor). Nature, 244,480483. Greenwood, B. M., Muller, A. S. & Valkenburg, H. A. (1971). Rheumatoid factor in Nigerian sera. Clinical and Experimental Immunology, 9, 163-173. Houba, V. & Allison, A. (1966). M-antiglobulins (rheumatoid factor-like globulins) and immunoglobulins in relation to tropical parasitic infections. Lancet, i, 848-852. Izui, S., Lambert, I’. H., Foumie, G. J. Turler, H. & Mierscher, I’. A. (1979). Features of systemic lupus erythematosus in mice injected with bacterial lipopolysaccharides: identification of circulating DNA and renal localisation of DNA-anti DNA complexes. Journal of Experimental Medicine, 145, 1115-1130. Knott, J. (1939). Method for making rnicrotilarial surveys on day blood. Transactions of the Royal So&e& of Tropical Medicine and Hygiene, 33,191-196. Koopman, W. J., Schrohenloher, R. E. & Czerkinsky, C. (1987). Differential expression of IgA and IgM rheumatoid factors in human disease: evidence for independent regulation of RF isotype production. Advances in Experimental Medicine andBiolonv. 216.1627-1639. McIntosh, R.‘N. M., Kulvinskas, C. & Kaufman, D. B. (1971). Cryoglobulins. II. The biological and chemical properties of cryoproteins in acute post-streptoccal glomerulonepbritis. Znternational Archives of Allergy and Applied Zmmunology, 41,
__ __
7rML715
Nemazze, D. A. & Sato, V. L. (1983). Induction of rheumatoid antibodies in the mouse: regulated Droduction of autoantibody in the secondary humoral response. Journal of ExwrimentalMedicine. 158.529-545. Perry, I’., Petit, A., Poulain, J. & Luffau, G. (1979). Phospho-
rylchohne bearing components in homogenates of nematodes. Journal of Zmmunolr, 4,637-639. Pillay, V. K., Kirch, & Kurtzman, N. A. (1973). Glomerulovathv associated with iilariasis. ‘iournal of the American Medi. ;alAssociation, 22!,179-181. Rossen, R. D., Reisberg, M. A., Sharp, T., Suki, W. N., Schloeder, F. X., Hill, L. & Ekroyer, G. (1975). Antiglobulins and glomerulonephritis. Journal of Clinical Znvestigation. 56.427-%37. Shaper, A. G., Kaplan, M. H., Moby, N. J. & McIntyre, P. A. (1968). Malaria autoantibodies and autoantibodies to heart and other tissues in the immigrant and indigenous peoples of Unanda. Lance& i. 1342-1346. Tan;E. M., Schur,-P. H., Carr, R. I. & Kunkel, H. G. (1966). Deoxyribonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. Journal ofClinicalZnvestiaations. 45. 1732-1740. Tanimoto, K., Cooper, N: R:, Johnson, J. S. & Vaughan, J. H. (1975). Complement fixation by rheumatoid factor.yournal of ClinicalZnvestigationn, 55,437-$45. Tesar, J. T. & Schmidt. F. R. (1973). Heteroeeneitv amone rheumatoid factors for complement fixation. f&nal if Zmmu: nology, 110,993-1002. Thomas, M. A. B., Frampton, G., Isaenberg, D. A., Shoenfield, Y ., Akinsola, A., Maizels, R. M., Lillywhite, J. E. 81 Williams, D. G. (1989). A common anti-DNA antibody idiotype and anti-phospholipid antibody in sera from patients with schistosonuasis and filariasis with and without nephritis. Journal ofAutoimmunity, 2,803-811. Van Snick, J. & Coulie, P. (1983). Rheumatoid factors and secondary immune responses in the mouse. I. Frequent occurrence of hvbridomas secreting IaM-anti-It& antibodies after immunization with protein antigen. European Journal of Zmmunologv, 13,890-894. Zouali, M., Druilhe, P. & Equem, A. (1986). IgG subclass expression of anti-DNA and anti-ribonucleoprotein autoantibodies in human malaria. Clinical and Experimental Immunology, 66,273-278.
Received 9 January 1992; revised I April 1992; accepted for publication 2 April I992
OF TROPICAL MEDICINE AND
Rheumatoid factor and rheumatoid accompanying glomerulonephritis
HYGIENE (1992)86, 667-669
factor isotypes
667
in loiasis with and without
lRheumatology Research Unit, A. 0. Adebajol*, A. Akinsola’, R. M. Maizels3, T. E. Cawston’ and B. L. HazIernan’ Addenbrooke’s Hospital, Cambridge, UK, 2Department of Medic& Obafemi Awolozoo University, Ile-Ife, Nigeria, 3Department of Biology, Imperial College, London, UK Abstract
We have studied the distribution of rheumatoid factor isotypes amongst patients with loiasis with and without accompanying glomerulonephritis to determine the possible role of rheumatoid factor antiglobulins in this disease. Our findings indicate an increase in both immunoglobulin (Ig) G and IgM rheumatoid factor isotypes in patients with fiariasis alone as well as in patients with accompanying glomerulonephritis. No association with IgA rheumatoid factor was found. The raised IgG and IgM rheumatoid factor levels did not correlate with corresponding IgG and IgM levels. Introduction
Loiasis is a parasitic infection with the tilarial worm Lou loa. associated with considerable morbiditv in Africa, South and Central America, the Middle East and Asia. One aspect of this condition that has received interest in recent times is its association with glomerulonephritis. It has been suggestedthat immunological mechanisms are involved in the pathogenesis of loiasis and possibly in that of the associatedglomerulonephritis (PILLAY et al., 1973). Supporting evidence for this comes from the observation that various autoantibodies are produced in association with L. loa infection (THOMAS et al., 1989). The production of rheumatoid factors (antiglobulins against the Fc region of immunoglobulin (Ig) G) in patients with loiasis is of particular interest as rheumatoid factors have been postulated as being part of the protective immune response (NEMAZEE & SATO, 1983; VAN SNICK & COULIE, 1983). These postulates have led us to determine the distribution of rheumatoid factor (RF) isotypes amongst patients with loiasis and an associated glomerulonephritis, as well as in patients with loiasis alone, with a view to determining the role of RF isotypes in these diseasegroups. Materials and Methods Patient groups
F.our groups of subjects were studied. (i) Loiasis associatedwith glomerulonephritis. Twenty adults, aged 1540 years, who had nephrotic syndrome or significant glomerular proteinuria and a serum creatinine level >3 mg% (265 umol/litre) were selected. All had a history of pruritis associatedwith worms crossing the conjunctiva or transient subcutaneous pruritic swellings (Calabar swellings). In all subjects, microfilaraemia was demonstrated by Knott’s concentration method (KNOTT, 1939).
_
(ii) Idiopathic glomerulonephritis without loiasis. Fourteen adults, aged 15-47 years, with idiopathic nephritis and in whom there was no historical, clinical or laboratory evidence of loaisis were selected. Further identifiable causes of glomerulonephritis such as systemic lupus erythematosus or hepatitis B were excluded using appropriate clinical and laboratory investigations. (iii) Loiasis without glomerulonephritis. Twenty-five adult patients aged 16-50 years with clinical and laboratory evidence of loiasis were selected. These patients had demonstrable L. loa microfilaraemia and had had clinical evidence of the disease for at least 6 months. They had normal urine analyses for albumin, red blood cells and casts, and normal serum electrolytes and urea. (iv) Healthy adults. Twenty-one healthy adults aged l&45 years were selected from hospital workers who had no evidence of loiasis from their history or clinical examination. No microfilaraemia was detected by repeated blood film examination. *Author for correspondence.
All patients studied were Nigerian. In the patients studied microfilarial infections, other than loiasis, were excluded by the absence of other microtilaraemia on repeated daytime and nocturnal blood film and negative skin snip examinations. Filarial infections were excluded in the 2 control groups not only by the absenceof microfilaria from day and night blood smears and skin snips, but also by the absenceof eosinophilia and low levels of total antirnicrofilarial antibody (optical density <0.4 [see below]). Immunological assays
Seraobtained from these subject groups were stored at -20°C and assayedfor IgM., IgG and IgA RF as well as for total IgM, IgG and IgA unmunoglobulin levels. Rheumatoid factor assays
IgM and IgA RF isotypes were measured using a commercial enzyme-linked immunosorbent assay (Cambridge Life Sciences, Elv, UK), which had nreviouslv beenevaluated in ou; u&i (AD~~BAJOet al., l-991). One hundred ul of each serum samnle diluted 1 in 100 in phosphate-buffered saline plus 0.05% Tween 20@ (PBST) and the standards supplied were incubated at room temperature for 30 min in microtitre plates precoated with human IgG. After washing the wells thrice with PBST, 100 ccl of rabbit antihuman IgM (for IgM RF) or IgA (for IgA RF) peroxidase conjugate diluted 1 in 1000 in PBST were added to each well for 30 min at room temperature. One hundred ~1 of o-phenylenediamine enzyme substrate were then added to each well and incubated in the dark at room temperature for 10 min. The reaction was stopped by the addition of 50 ~1of 2 M HzS04 to all wells. The optical density of each well was then read at 492 run and the results expressed in international units (iu) per ml by reference to a standard curve (based on the World Health Organization reference RF standard). Immunoglobulin assays
IgM, IgA and IgG levels were measured using a nephelometric assay with an automated immunochemistry system (Beckman Instruments, Aylesbury, UK) which generatesa peak rate signal proportional to the increasein light scatter produced when supplied antibody Table 1. Distribution groups
Subjectgroup Loiasis with glomerulonephritis Loiasis alone Glomerulonephritis
of rheumatoid
W
factor
isotypes
in the subject
Rheumatoidfactor times’ kA I.@
20.68 (kO.8) 29.04 (f0.9)
4.84 (k4.8) 4.76 (k2.6)
14.24 (f2.5) 18.80 (k4.0)
4.64 (+0.2) 5.53 (k5.5) 6.31 (f1.5) 2.76 (kO.3) 6.04 (+4.6) 4.80 (f1.6) Healthy controls ‘Expressedas iu/ml (SEMin parentheses);Ig=immunoglobulin. d0ne
668 to human IgM, IgA or IgG is added to the sample seraor supplied standards of IgM, IgA and IgG respectively. The neak rate sienal is a function of the samnle Ia concentration being measuredand, following calibration, the peak rate signal for each Ig assayis converted into concentration units. Statistical analysis
Statistical comparisons between groups of patients were made using the Mann-Witney U test. Correlation coefficients were calculated using the Spearman rank correlation. Results
Table 1 shows the distribution of RF isotypes in the various subject groups. IgM RF was significantly increased in the loiasis patients and in the patients with loiasis and glomerulonephritis combined when compared with the healthy controls and those with glomerulonephritis alone. There was, however, no difference between the mean IgM RF levels of patients with loiasis and glomerulonephritis and those with loiasis alone. With respect to IgA RF, although the mean levels were highest in the patient groups with either loiasis alone or loiasis with glomerulonephritis, the difference was not statistically significant when compared to patients with glomerulonephritis alone or with healthy controls. The mean IgG RF levels were significantly raised in the loiasis group when compared with both the glomerulonephritis patients (P
of immunoglobdin
IEM
subclasses
Immunoglobulin IEA
in the subject
titres” IIG
Lo&is with glomerulonephritis 662.8(t116.8) 436.0(+48.9) 453.6(k48.7) Loiasisalone 681.6 (k71.5) 410.0(k62.5) 444.9(k46.5) Glomerulonephritis alone 309.9 (T81.1) 374.9 (k80.0) 347.8 (k52.0) Healthycontrols 356.6 (k41.1) 344.0 (k60.1) 372.4 (C28.3) ‘Expressed asiuiml (SEM in parentheses). those with loiasis with or without glomerulonephritis (Table 2). The serum IgM levels were higher in the loiasis group than in those with glomerulonephritis alone (P
The production of RF in association with infectious diseases is well reco nized (BONFA et al., 1987; CARVALHOet al., 1983; E REENWOOD et al., 1971; HOUBA& ALISON et ai., 1966; IZUI et al., 1979; SHAPER et al.,
1971). One consequence of this is that the presence of these autoantibodies, commonly associatedwith rheumatoid arthritis, should be interpreted with caution when found in the seraof patients exposed to various infections (GREENWOOD et al., 1971). RFs are produced both in vitro and in vivo following polyclonal B cell activation (DRESSER,1978; IZUI et al., 1979). Proteoglycans, like bacterial hpopolysaccharides, can be B cell polyclonal activators and a filarial proteoglycan bearing an antigenic determinant. ohosohorvlchohne. has been described (PERRY et al.‘, i979): _I ’ Physiological roles for these RFs may include enhancement of IeG antibodv affinitv for its antigen (NEMAZEE & SATO, i983), amplification of IgG complement binding (TANIMOTOet al., 1975; TESAR& SCHMIDT, 1973), augmentation of‘immune complex clearance (VAN SNICK et al., 1978) and immunoregulation (MONESTIERet al., 1986). These mechanisms may enhance immune clearance of antigens and thereby stem their potential pathogenicity (CARVALHOet al., 1983). On the other hand. it has been oostulated that certain autoantibodies may be pathogenetic, particularly in autoimmune diseasesbut also in parasitic infections. Thus autoantibodies binding to double-stranded deoxyrihonucleic acid (DNA) have been implicated in the pathogenesis of both systemic lupus erythematosus (TAN et al., 1966) and malaria nephritis (ZOUALI et al., 1986). In some studies RFs have been identified as possible pathogenetic factors in disease. RF levels in this study were elevated irrespective of the complication of glomerulonephritis, which implies that the filarial infection by itself was the primary inducer of the elevated RF levels. In our study, IgG RF and IgM RF, but not IgA RF, were significantly raised in the loiasis patients with or without accompanying glomerulonephritis, compared with the levels in patients who did not have loiasis. This probably reflects differences in production of the 2 isotvpes as a result of differing mechanisms in their induct& and regulation of synthesis, as has been indicated for IgA RF and IgM RF (ROOPMANetal., 1987). Our finding of an association between IgG RF and loiasis is interesting as MCINTOSHet al. (1971) have previously implicated IgG RF in the pathogenesis of poststreptococcal glomerulonephritis. Similarly AGNELLOet al. (1971) and ROSSEN et aE. (1975) have provided evidence for the presenceof RF in renal deposits of immune complexes. On the other hand, we found that both IgM RF and IaG RF levels were higher in the patients with loiasis alone than in those with-accompanymg glomerulonephritis, although statistical significance was not achieved. This is similar to the findings of CARVALHOet al. (1983) in patients with schistosomiasis, in whom RF levels were lower in those patients with accompanying renal involvement, leading these workers to suggest that RF played a protective role with respect to the development of kidney disease. With regards to pathogenicity, autoantibodies other than RFs are likely to be involved and DNA binding antibodies mav be particularlv important (THOMASet al., 1989). Pathogen&y of any antibodies will also be a fun& tion of such factors as affinitv and fine snecifcitv. Prospective longitudinal studies- may ide&fy any- pathogenetic role for IgM RF and IgA RF in filariasis, but current evidence tends to suggest that they either play a protective role as part of the immune response or are simply epiphenomena. Whether, once produced, these RFs contribute to the disease pathology merits further study. References
Adebajo,A. O., Wright, J. K., Cawston,T. E. & Hazleman,B. L. (1991).Rheumatoidfactor quantitation: a corn tt;;t;c;f ELBA and nephelometric methods. Medical E Sciences, 48,47-51. Agnello, V., Koffler, D., Eisenberg,J. W., Winchester,R. J. & Kunkel, H. G. (1971).Clq precipitins in seraof patients with systemic lupus erythematosusand other hypocom-
669 plementemic states: characterization of high and low molecular ty es. Journal of Experimental Medicine, 134,228-241. Llovet, R., Scheinborg, M., Souza, J. M. & Elkon, Bonfa, i K. B. (i987). Comparison between autoantibodies in malaria and leprosy with lupus. Clinical and Experimental Zmmunology, 70,529-537. Carvalho, E. M., Andrews, B. S., Martinelli, R., Dutra, M. & Rocha, H. (1983). Circulating immune complexes and rheumatoid factor in schistosomiasis and visceral leishrnaniasis. AmericanJournal of Tropical Medicine and Hygiene, 32,61-68. Dresser, D. W. (1978). Most IgM-producing cells in the mouse secrete autoantibodies (rheumatoid factor). Nature, 244,480483. Greenwood, B. M., Muller, A. S. & Valkenburg, H. A. (1971). Rheumatoid factor in Nigerian sera. Clinical and Experimental Immunology, 9, 163-173. Houba, V. & Allison, A. (1966). M-antiglobulins (rheumatoid factor-like globulins) and immunoglobulins in relation to tropical parasitic infections. Lancet, i, 848-852. Izui, S., Lambert, I’. H., Foumie, G. J. Turler, H. & Mierscher, I’. A. (1979). Features of systemic lupus erythematosus in mice injected with bacterial lipopolysaccharides: identification of circulating DNA and renal localisation of DNA-anti DNA complexes. Journal of Experimental Medicine, 145, 1115-1130. Knott, J. (1939). Method for making rnicrotilarial surveys on day blood. Transactions of the Royal So&e& of Tropical Medicine and Hygiene, 33,191-196. Koopman, W. J., Schrohenloher, R. E. & Czerkinsky, C. (1987). Differential expression of IgA and IgM rheumatoid factors in human disease: evidence for independent regulation of RF isotype production. Advances in Experimental Medicine andBiolonv. 216.1627-1639. McIntosh, R.‘N. M., Kulvinskas, C. & Kaufman, D. B. (1971). Cryoglobulins. II. The biological and chemical properties of cryoproteins in acute post-streptoccal glomerulonepbritis. Znternational Archives of Allergy and Applied Zmmunology, 41,
__ __
7rML715
Nemazze, D. A. & Sato, V. L. (1983). Induction of rheumatoid antibodies in the mouse: regulated Droduction of autoantibody in the secondary humoral response. Journal of ExwrimentalMedicine. 158.529-545. Perry, I’., Petit, A., Poulain, J. & Luffau, G. (1979). Phospho-
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Received 9 January 1992; revised I April 1992; accepted for publication 2 April I992