W a ld e n is e C o s s e rm e lli-M e s s in a , W ils o n C o s s e rm e lli
Possible m echanism s of chronic leprosy-related arthritis
M ic ro b ia l a g e n ts in d u c e a rth ritis th ro u g h m e c h a n is m s s u c h a s d ire c t in filtra tio n o f tis s u e a n d b y in d u c in g a u to im m u n e p h e n o m e n a . T h e m e c h a n is m s in v o lv e d in th is la s t ty p e o f a rth ritis h a v e b e e n in v e s tig a te d . In e x p e rim e n ta l m o d e ls o f a d ju v a n t a n d re a c tiv e a rth ritis , th e in v o lv e m e n t o f T c e lls a n d in s o m e c a s e s m y c o b a c te ria in th e d e v e lo p m e n t o f a rth ritis h a v e b e e n c o n firm e d . C ro s s -re a c tiv ity b o e tw e e n th e 6 5 k D m y c o b a c te ria l p ro te in a n d c a rtila g e p ro te o g ly c a n s h a s b e e n p o s tu la te d a s a p o s s ib le m e c h a n is m . In th is s tu d y , c h ro n ic p e rip h e ra l a rth ritis w a s o b s e rv e d in p a tie n ts w ith H a n s e n 's d is e a s e , in p a tie n ts w ith re s o lv e d H a n s e n 's a n d in th o s e w ith p a u c ib a c illa ry fo rm s . T h is a rth ritis w a s n o t re la te d to re a c tio n a l s ta te s (e ry th e m a n o d o s u m le p ro s u m a n d re v e rs a l re a c tio n ), in c o n tra s t to s e v e ra l re p o rts in th e lite ra tu re . T h e m e c h a n is m s b y w h ic h m ic ro b e s c o u ld in d u c e c h ro n ic a rth ritis a re d is c u s s e d h e re in .
U N IT E R M S : M y c o b a c te ria , c e llu la r im m u n ity , h u m o ra l im m u n ity , le p ro s y a rth ritis .
E
m y c o b a c te ria lx p e rim e n ta l in fe c tio n sIn o d e ls h a v ec a n trig g e rsu g g e ste da u to im m u n eth a t a rth ritis, m a in ly th ro u g h T -c e ll m e d ia te dre sp o n se s. A d ju v a n t a rth ritis, e x p e rim e n ta lly in d u c e d in
ra ts b y th e in tra d e rm a l in je c tio n o f d e a d m y c o b a c te ria (M .
tuberculosis)
su sp e n d e d in m in e ra l o il, p ro d u c e s c h ro n icin fla m m a tio n o f th e a rtic u la tio n s in g e n e tic a lly
p re d isp o se d a n im a ls.1 In h u m a n s, a rth ritis h a s b e e n
re p o rte d in p a tie n ts su b m itte d to im m u n o th e ra p y w ith B C G .2
T h e ro le o f m y c o b a c te ria in th e p a th o g e n e sis o f rh e u m a to id a rth ritis a n d o th e r ty p e s o f c h ro n ic
in fla m m a tio n h a s b e e n su g g e ste d p re v io u sly .3 In p a rtic u la r, m y c o b a c te rio a l h e a t-sh o c k p ro te in s h a v e b e e n c o n sid e re d
im p o rta n t ta rg e ts o f th e c e llu la r im m u n e re sp o n se in
p a tie n ts w ith ju v e n ile a rth ritis,4 rh e u m a to id a rth ritis,5 a n d
o f a n tib o d y p ro d u c tio n in rh e u m a to id a rth ritis p a tie n ts.6
T h e 6 5 k D h e a t-sh o c k p ro te in is a n iIn p o rta n t ta rg e t fo r
a rth rito g e n ic T -c e ll c lo n e s, m a in ly th e a m in o a c id se q u e n c e 1 8 0 -1 8 8 .7
P e rip h e ra l b lo o d a n d sy n o v ia l flu id T -Iy m p h o c y te s fro m p a tie n ts w ith rh e u m a to id a rth ritis sh o w e d in c re a se d
re a c tiv ity to a m y c o b a c te ria l fra c tio n th a t c ro ss-re a c te d
A d d re s s fo r c o rre s p o n d e n c e :
W a ld e n is e C o s s e rm e lli-M e s s in a
A v . O r. A rn a ld o , 4 5 5 - 3 ºa n d a r R e u m a to lo g ia S ã o P a u lo /S P - B ra s il- C E P : 0 1 2 4 6 -9 0 3
w ith a rtic u la r c a rtila g e c o n stitu e n ts, e sp e c ia lly in p a tie n ts
w ith 1 -1 0 y e a rs o f d ise a se d u ra tio n . x T h e re sp o n se w a s
c o n sid e re d sp e c ific sin c e th e re w a s n o re a c tiv ity to o th e r
m ito g e n s o r stre p to c o c c a l a n tig e n s, su g g e stin g a d ire c t
re la tio n sh ip b e tw e e n th e m y c o b a c te ria l a n tig e n s a n d th e
p a th o g e n e sis o f rh e u m a to id a rth ritis.
A lte ra tio n in th e a g a la c to sy l im ln u n o g lo b u lin G (Ig G )
m o le c u le w a s o b se rv e d in p a tie n ts w ith tu b e rc u lo sis,
e ry th e m a n o d o su m le p ro su m ,9 C ro h n 's d ise a se , a n d
rh e u ln a to id a rth ritis.lO A g a la c to sy l Ig G is a sso c ia te d w ith
c y to k in e p ro d u c tio n , a c u te p h a se re sp o n se a n d tissu e
in ju ry . lO E le v a tio n o f th is im m u n o g lo b u lin p a ra lle ls w ith
in c re a se d b in d in g o f m y c o b a c te ria l p ro te in s to
im m u n o g lo b u lin s.ll
C h ro n ic a rth ritis h a s b e e n d e sc rib e d in H a n se n 's d ise a se
b u t n o t a sso c ia te d w ith th e p re se n c e o f b a c illi w ith in th e jo in t o r to re a c tio n a l sta te s.1 2 .1 3 .1 4In a p re v io u s stu d y b y o u r g ro u p , 1 5
p e rip h e ra l a rth ritis w a s o b se rv e d in se v e ra l p a tie n ts w ith
H a n se n 's d ise a se . In th e In a jo rity , th e a rth ritis fo llo w e d a
c h ro n ic p a tte rn a n d w a s n o t a sso c ia te d w ith le p ro sy re a c tio n s.
A rth ritis w a s id e n tifie d in p a tie n ts w ith n e g a tiv e b a c illo sc o p y
a n d w ith re so lv e d H a n se n 's d ise a se . P a tie n ts w ith d iffe re n t
fo rm s o f H a n se n 's d ise a se (in d e te rm in a te , d im o rp h o u s,
tu b e rc u lo id a n d le p ro m a to u s) h a d a rth ritis. T h e se d a ta
c o n tra ste d w ith stu d ie s w h e re a rth ritis w a s re la te d a n d
c o n fin e d to e ry th e m a n o d o su m re a c tio n s.
W e h y p o th e siz e d th e p o ssib le m e c h a n ism s in v o lv e d
in th e g e n e ra tio n o f a rth ritis in p a tie n ts w ith p a u c ib a c illa ry
form s, w ith resolved H ansen's disease and w ithout
reaction. In addition, the long duration of the articular
m anifestation suggested that som ehow it has been
.perpetuated.
Pathogenic m echanism s sim ilar to those of adjuvant
arthritis m ay be involved in the chronic articular
phenom ena in H ansen's disease, particularly if the
hom ology betw een M . leprae and M . tuberculosis is
considered. In adjuvant arthritis, the ceIlular im m une
response to m ycobacterial antigens has been detected, and
is probably involved in the developm ent of arthritis.16The
identification of the 65 kD a protein as the m ain target of
T-ceIl m ediated responses,I7.IX its cross-reaetivity to
purified cartilage proteoglycans, 19including in rheum atoid .
arthritis,20 has em phasized its im portanee in arthritis during
m ycobacterial infections, and possibly in chronic
leprosy-related arthritis. The 65 kD a protein is an im m unodom inant
target for T-celI responses in H ansen's disease, and shares
hom ology w ith the hum an 60 kD a protein.21 The response
to bacterial antigens stim ulates T-eell clones that m ay cross
react w ith intrinsic com ponents ofthe joints in susceptible
individuaIs.
The auto-antibodies generated in H ansen's dIsease
are considered natural antibodies w ith low affinity, and
therefore their possible participation in the pathogenic
m echanislTIS of chronic leprosy-related 'arthritis is
im probable. In our study, no correlation w as found betw een
auto-antibodies and arthritis.
A Ithough the hum oral response w as not considered
an im portant m echanism for defense or for the clinicaI
m anifestations ofH ansen's disease, it m ay indicate that B ceIls had been activated as part of the netw ork of im m une
aIterations occurring during m ycobacteria recognition. In
H ansen's disease, auto-antibodies are low -affinity
antibodies and m ay only be im portant w hen form ing im m unocom plexes. Tubercle bacilli have been considered
potentadjuvants for induction of polyclonal B lym phocytes acti vation. 22 In addition, no cross-reaction w as observed
betw een the 70 kD a m ycobacterial protein and hum an
structures.23 The polyclonal B -cell activation in
leprom atous leprosy is probably a consequence of cytokine
production by T lym phocytes.
Perpetuation of arthritis m ay be due to the persistence of antigens' inside the joints or to the hom ing of the
continually activated T lym phocytes,24 as dem onstrated in
adjuvant arthritis and inflam m atory arthritis. In particular,
1407
it has been show n that w hen 65 kD a specific- T
lym phocytes m igrate to the joint, articular lym phocytes
are responsible for the continuation of the im m une
response, m ainly because these celIs are m em ory cells. 17.24
M astocytes m ay also be able to am plify the response w ithin
the joint in chronic arthritis.25 In reactive arthritis, an
augm ented T-cell response w as detected in
synovial-derived cells w hen com pared to peripheral blood ceIls
responses, dem onstrating a local activation of T celIs, IXor
m igration of chronically activated ceIls.
Several patients w ith H ansen's disease and chronic
arthritis required specific treatlTIent for the articular
m anifestations, such as chloroquine or sulfasalazine.'5
Therapeutic resuIts w ere very good and in m any patients,
sym ptom s disappeared even after drug use had been
interrupted. Inhibition of the antigen presentation by
chloroquine m ay be one of the possible m echanism s by
w hich this drug am eliorates M . leprae-induced arthritis.
The presence of arthritis in all types of H ansen's
disease and in patients w ithout reactions em phasizes that
the contact w ith the bacilli m ay trigger chronic
im m unological responses' in genetically.predisposed
individuaIs. Indeed, chronic synovitis w as den10nstrated
in biopsies of patients w ith active H ansen's disease and
during reaction, indicating that chronic inflam m ation m ay
occur parallel to acute m anifestations.26 PO W ELL and
SW A N 27 also deteeted chronic inflam m atory infiltrates and
fibrom atous' reaction in bone tissue of H ansen's disease
patients.
R O O K clarified the im m unological pathw ays by
w hich slow -grow ing bacteria m ay induce and perpetuate
chronic arthritis, such as m ycobacterial infections.2X In
brief, invading bacteria activate T lym phocytes w hich
release IY lTIphokines chronically. Those lym phokines
activate B lym phocytes to produce agalactosyl
im m unoglobulins. In addition, bacterial antigens stim ulate
autoreactive clones that m ay induce im m une responses
m ediated by antibodies or by T-cells. It is believed that
local im m une responses also occur in addition to the
hom ing of sensitized T lym phocytes to the joint.
Studies of the m echanism s involved in arthritic
m anifestation in infectious diseases m ay clarify the
possible pathw ays by w hich chronic inflam m atory diseases
are induced, and suggest new therapeutical options, such
as peptide-based im m unotherapy.29
M E S S IN A , W .C .; C O S S E R M E L L I, W . - P o s s ib le m e c h a n is m s o f c h r o n ic le p r o s y - r e la te d a r th r itis
1408
REFERENCES
1 . P earso n C M . D ev elo p m en t o f arth ritis, p eriarth ritis an d
p erio stitis in rats g iv en ad ju v an ts. P ro c S o c E x p B io l N ew
Y o rk 1 9 5 6 ;9 5 -1 0 1 .
2 . T o risu M , M iy ah ara T , S h in o h ara N , O h sato K , S o n o zak i H .
A n ew sid e effect o f B C G im m u n o th erap y : B C G in d u ced
arth ritis in m an o C an cer Im m u n o I 1 9 7 8 ;5 :7 7 -8 3 .
3 . L y d y ard P M , R o o k G A W , T so u lfa G ,. S h arifM , S m ith M . Is
th ere a ro le fo r m y co b acteria in th e etio p ath o g en esis o f
rh eu m ato id arth ritis? Im m u n o l R ev iew s 1 9 9 1 ; 1 2 1 : 1 3 7 -5 4 .
4 . D e G raeff-M eed er E r, V an D er Z ee R , R ijk ers G T , et aI.
R eco g n itio n o f h u m an 6 0 k D h eat sh o ck p ro tein b y
m o n o n u clear cells fro m p atien ts w ith ju v en ile ch ro n ic
arth ritis. L an cet 1 9 9 1 ;3 3 7 : 1 3 6 8 -7 2 .
5 . L i S G , Q u ay le A J, S h en Y , et aI. M y co b acteria an d h u m an
h eat sh o ck p ro tein -sp ecific cy to to x ic T Iy m p h o cy tes in
rh eu m at< ?id sy n o v ial in flam m atio n . A rth r R h eu m
1 9 9 2 ;3 5 :2 7 0 -8 1 .
6 . B ah r G m M R o o k G A W , A I-S affar M , V an E m b d en JD A ,
S tan fo rd JL , B eh b eh an i K . A n an aly sis o f an tib o d y lev eis to
m y co b acteria in relatio n to H L A ty p e: E v id en ce fo r n o n
-H L A -lin k ed h ig h lev eIs o f an tib o d y to th e 6 5 k D h eat sh o ck
p ro tein o f M . tu b ercu lo sis in rh eu m ato id arth ritis. C lin E x p Im m u n o I 1 9 8 9 ;7 4 :2 1 1 -5 .
7 . V an E d en W , T h o le Jer, V an D er Z ee R , et aI. C lo n in g o f th e m y co b acteriaI ep ito p e reco g n ized b y T ly m p h o cy tes in
ad ju v an t arth ritis. N atu re 1 9 8 8 ;3 3 1 : 1 7 1 -3 .
8 . H o lo sh itz J, K lajm an A , D ru ck er I, et aI. T Iy m p h o cy tes o f
rh eu m ato id arth ritis p atien ts sh o w au g m en ted reactiv ity to a
fractio n o f m y co b acteria cro ss-reactiv e w ith cartilag e. L an cet
1 9 8 6 ;9 :3 0 5 -9 .
9 . F illey E , A n d reo li A , S teele J, et aI. A tran sien t rise in
ag alacto sy l Ig G co rrelatin g w ith free IL -2 recep to rs d u rin g
ep iso d es o f ery th em a n o d o su m lep ro su m . C lin E x p Im m u n o l
1 9 8 9 ;7 6 :3 4 3 -7 .
1 0 . R o o k G . R h eu m ato id arth ritis, m y co b acterial an tig en s an d
ag alacto sy l Ig G . S can d J Im m u n o l 1 9 8 8 ;2 8 :4 8 7 -9 3 ".
1 1 . R o o k G , L y d y ard P , S tan fo rd JL . M y co b acteria an d
rh eu m ato id arth ritis. A rth R h eu m 1 9 9 0 ;3 3 (3 ):4 3 1 -5 .
1 2 . A tk in S L , E I-G h o b arey A , K am el M , O w en Jp , D ick W C .
C lin icaI an d lab o rato ry stu d ies o f arth ritis in H an sen 's
d isease. B rit M ed J 1 9 8 9 ;2 9 8 : 1 4 2 3 -5 .
1 3 . A tk in S L , E I-G h o b arey A , K am eI M , O w en Jp , D ick W C .
C lin icai an d lab o rato ry stu d ies in p atien ts w ith Iep ro sy an d
en th esitis. A n n R h eu m D is 1 9 9 0 ;4 9 :7 1 5 -7 .
1 4 . A tk in S L , W elb u ry R R , S tan field E , B eav is D , Iw ais B , D ick
W C . C lin icaI an d lab o rato ry stu d ies o f in flam m ato ry
p o ly arth ritis in p atien ts w ith Iep ro sy in P ap u a N ew G u in ea.
A n n R h eu m D is 1 9 8 7 ;4 6 :6 8 8 -9 0 .
1 5 . C o sserm eIli-M essin a W . A b o rd ag em reu m ato ló g ica n a
h an sen íase - D issertação d e M estrad o , F acu ld ad e d e M ed icin a
d a U S P , 1 9 9 2 .
1 6 . W h iteh o u se M W . R at p o ly arth ritis: In d u ctio n w ith ad ju v an ts
co n stitu ted w ith m y co b acteria (an d o iIs) fro m th e
en v iro n m en t. J R h eu m ato I 1 9 9 2 ;9 :4 9 4 -5 0 1 .
1 7 . G asto n JS H , L ife P F , B ailey L C , B aco n P A . In v itro resp o n ses
to a 6 5 k ilo d alto n m y co b acteriaI p ro tein b y sy n o v iaI T cells
fro m in flam m ato ry arth ritis p atien ts. J Im m u n o l
1 9 8 9 ; 1 4 3 (8 ):2 4 9 4 -5 0 0 .
1 8 . G asto n JS H , L ife P A , G ran fo rs K , et aI. S y n o v ial T
ly m p h o cy te reco g n itio n o f o rg an ism s th at trig g er reactiv e
arth ritis. J E x p M ed 1 9 8 9 ;7 6 :3 4 8 -5 3 .
1 9 . V an E d en W , H o lo sh itz J, N ev o Z , F ren k eI A , K lajm an ,
C o h en IR . A rth ritis in d u ced b y a T -Iy m p h o cy te clo n e th at
resp o n d s to m y co b acteriu m tu b ercu lo sis an d to cartilag e
p ro teo g ly can s. P ro c N atI A cad S ci U S A 1 9 8 5 ;8 2 :5 1 1 7 -2 0 .
2 0 . Q u ay le A J, W ilso n K B , L i S G , et aI. P ep tid e reco g n itio n , T
-cell recep to r u sag e an d H L A restrictio n elem en ts o f h u m an
1409
heat-shock protein (hsp) 60 and mycobacterial 65-kDa
hsp-reactive T'-cell clones from rheumatoid synovial fluido Eur J
Immunol 1992;22: 1315-1322.
21. McuIloch J, Lydard PM, Rook GAW. Rheumatoid arthritis:
How do the theories fit the evidence. Clin Exp Immunol
1993;92: 1-6.
22. Winfield JB. Stress proteins, arthritis, and autoimmunity.
Arthr Rheum 1989;32:1497-1504.
23. Davenport MP, McKenzie KR, Basten A, Britton WJ. The
variable C-terminal region of the mycobacterium leprae
70-kilodalton heat shock protein is the target for humoral
immune responses. Infect Immunity 1992;60(3): 1170-7.
24. Dejoy SQ, 'Perguson-Chanowitz K, Oronsky AL, Zabriskie
JB, Kerwar SS. Studies on the homing of
mycobacterium-sensitized T-Iymphocytes to the synovium during passive
adjuvant arthritis. Cell Immunol 1990; 130: 195-203.
25. Mican JA, Metcalfe DD. Arthritis and mast cell activation. J
Allergy Clin Immunol 1990;86(4):677-83.
26. Holla VV, Kenetkar MV, Kolhatkar MK, Kulkarin CN.
Leprous synovitis: A study offifty cases. Int J Lepr Mycobact
Dis 1983;5:29-32.
27. Powell CS, Swan LL. Leprosy pathologic changes observed in
fifty consecutive necropsies. Am J PathoI1955;31:1131-47.
28. Rook G, Stanford JL. Slow bacterial infections or
autoimmunity? Immunol Today 1992; 13(5): 160-4.
29. Yang XD, Gasser J, Peige U. Prevention of adjuvant arthritis
in rats by a nonapeptide from the 65 kD mycobacterial
heat-shock protein. Clin Exp Immunol 1990;81: 189-194.
M E S S I N A , W . C . ; C O S S E R M E L L I , w . -P o s s ib le m e c h a n is m s o f c h r o n ic le p r o s y - r e la t e d a r t h r it is
