Collagen autoimmunity and arthritis

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					Collagen                                      autoimmunity                                                                     and arthritis
                     JOHN            M. STUART,’                        WILLIAM                      C. WATSON,                 AND      ANDREW              H. KANG
                     Departments of Medicine and Biochemistry,                                                University       of Tennessee, Memphis          and Veterans Administration          Medical      Center,
                     Memphis,   Tennessee 38104, USA

                                                                                                                                 ALTHOUGH           THE ETIOLOGY       OF rheumatoid          arthritis     (RA)
                                              ABSTRACT                                                                           is unknown,       there is substantial         evidence      that immuno-
                                                                                                                                 logically     mediated      inflammation          may be the most im-
   Collagen-induced                       arthritis         in animals                  is an example                     of     portant     factor leading to the characteristic              joint destruc-
   polyarthritis              sufficiently
                              that              resembles       human     rheu-                                                  tion. It has been proposed              that cellular      reactions      in the
   matoid     arthritis     to be used as a model. It is caused               by                                                 synovial tissue surrounding              involved joints and humoral
   immunizing          susceptible      animals      with type II collagen                                                       reactions     within the joint space may produce                   mediators
   isolated from articular           cartilage.    Susceptibility     is genet-                                                  that attract inflammatory              cells and cause the degrada-
   ically determined           and linked to the major histocom-                                                                 tion of cartilage       (1). The initiating         events of the disease
   patibility    locus. It is important             because      some human                                                      and the reasons         why arthritis        persists over many years
   arthritis   is also associated          with major histocompatibil-                                                           in most patients         are unknown.           One possible          explana-
   ity      genes       and         may       be       caused           or       aggravated                  by      the         tion is that the antigens             responsible        for the immune
   presence           of autoimmunity                       to normal                  cartilage         compo-                  reaction      are not eliminated.            One source of antigens
   nents.           Collagen-induced                       arthritis              is     also        important                   that could continuously              fuel an immune             reaction     are
   because           it is an example                   of immunologically                            mediated                   the normal       connective      tissue components.             These could
   joint      destruction,            which             may         share        some           of the       mech-               become       immunogenic,          caused by either alterations                in
   anisms present in human       disease. Although       it is caused                                                            the regulation        of the immune            response,        so that self-
   by autoimmunity       to collagen,     susceptibility      and re-                                                            recognition      becomes aberrant,           or by molecular          mimicry
   sponsiveness   to type II collagen are not completely           cor-                                                          by exogenous             pathogens.       For    several      reasons,      cartilage
   related,          and there             are examples                     of animals               with high                    is of particular            interest       as a source of antigens.                 The
   levels of collagen   immunity   who do not develop                                                        arthri-              structural      elements          of cartilage       are unique to that tissue
   tis. The initial lesion appears   to be the deposition                                                      of an              and could, in part, account                      for the localization            of the
   antibody    on the surface    of articular  cartilage,                                                     which               inflammatory             response         to the joint. Immunity               to car-
   precedes           development                  of overt          arthritis           by several               days.          tilage components                has been described               in patients        who
   Disease          can be readily              transferred                 with specific             antibody.                  have inflammatory                   arthritis      and, in particular,             those
   Arthritogenic                antibodies                  appear               to      have         restricted                 who have RA (2, 3). It has been observed                              that synovec-
   epitope           specificity,            which            may           partially            explain             the         tomy either by physical or chemical                           means is of limited
   disparities   between    responsiveness        to immunization                                                                value in permanently                     reducing        inflammation          in RA.
   with collagen    and susceptibility     to arthritis, but precise                                                             Although          it provides          some relief initially,           after a rela-
   delineation             of the          epitopes           involved                 has   not       yet        been           tively brief interval,               the tissue regrows            and infiltrating
   accomplished.                 Complement     activation   also appears    to                                                  inflammatory            cells return. However,                removal of cartilage
   be intimately               involved since the disease correlates      with                                                   during       joint replacement                 results in the efflux of cells
   the presence               of high levels of complement-binding        IgG                                                    from the surrounding                      synovium         and the cessation           of
   isotypes,           and      passive               transfer           is possible                 only          into          inflammation.
   complement-sufficient                              recipients.           pro-
                                                                               Inflammation                                           To identify         potentially         important         immune        reactions
   gresses rapidly so that cartilage           destruction        and margi-                                                     leading       to inflammatory                 arthritis,      we have studied            a
   nal erosion        develop      over a period            of a few days.                                                       model created by immunizing                          susceptible      animals       with
   Collagen-induced          arthritis  offers a unique          opportunity                                                     the major           structural         component           of cartilage,       type H
   to study    autoimmune-mediated                arthritis    in which        the                                               collagen.       It is now known that rats, mice, and monkeys
   inducing      antigen      is well    characterized          and     readily                                                  are all susceptible             to this form of arthritis.               It has been
   available.    Analysis       of the disease         has permitted           the                                               our objective to determine                    the pathogenetic         mechanisms
   proposal           of a schema for its pathogenesis.                                          -       STUART,                 by which autoimmunity                         to cartilage        collagen       causes
  J.  M.;           WATSON,    W. C.; KANG, A. H. Collagen                                                        auto-          arthritis       in immunized                  animals        and whether            such
   immunity             and arthritis. FASEBJ   2: 2950-2956;                                                     1988.          mechanisms             may be involved in patients                  who have RA.

   Key Words:    collagen-induced arthritis . cartilage                                                    autoim-
   munity . type II collagen . IgG antibody                                                                                        ‘To whom all correspondence should be addressed: Research
                                                                                                                                 Service151, Medical Center,lO30Jefferson
                                                                                                                                             VA                           Ave., Memphis, TN
                                                                                                                                 38104, USA.

2950                                                                                                                                                                   0892-6638/88/0002-2950/SO          1.50. © FASEB
INDUCTION                OF     ARTHRITIS                                                  proteoglycan        depletion       to be an early event (Fig. 2),
                                                                                           but one that occurred           concomitantly         with synovial pro-
We discovered          that outbred            Wistar      rats developed                  liferation.    Although       the significance        of this loss of pro-
inflammatory        polyarthritis       2-4 wk after immunization                          teoglycan     is unknown,         it is potentially       reversible,    since
with purified     type II collagen          (Fig. 1) (4). Type I colla-                    it is seen in passively         transferred      arthritis,     which heals
gen and type III collagen,              which are closely related to                       without     sequellae.     The loss of proteoglycan              is probably
type II collagen         structurally,        were isolated        from skin               enzyme      mediated,       but the source of the enzymes                   re-
and used for immunization                  via an identical          protocol,             sponsible     has not yet been identified.                  Since it occurs
but they did not induce                arthritis.     Disease      developed               early in the disease, it seems unlikely that inflammatory
rapidly   over a period          of 2-3 days after an interval                 of          cells recruited      from the circulation            are responsible.
latency    and gradually            subsided        over several        weeks.
Radiographs        demonstrated           a marked        loss of bone oc-
                                                                                           MULTISYSTEM                INVOLVEMENT
curred without        apparent       attempts       at repair in the joint
but with extensive        periostitis     and reactive new bone for-                       Lesions in type II collagen-immunized                   animals     are not
mation    in adjacent        bones. Histologically,            the arthritis               limited to the joints. We have also found inflammation
was characterized          by synovial         hyperplasia      (infiltration              in the pinna of the ear (9). This abnormality                     seems to
of inflammatory          cells into the subsynovial               connective               be confined to certain strains of rats and has never been
tissue),   pannus       formation         (erosion      of cartilage         and           described      in other species.        It begins as a localized        area
bone),    and ultimately            by ankylosis          of the involved                  of inflammation           beneath     the perichondrium           and pro-
joints.  These changes resemble                 those seen in RA. Ab-                      ceeds centrifugally.         In advanced        stages the entire pinna
 sent from collagen-induced                 arthritis     (CIA)      was evi-              can be involved.           Because      of this finding,      it has been
dence     of vasculitis         in   synovial      blood      vessels,     a lesion        suggested     that CIA may in fact be a model for relapsing
characteristic        of RA. Another             finding not characteristic                polychondritis        in humans.         Relapsing     polychondritis       is
of RA was the marked               periostitis.       The finding        that pen-         an episodic       disease characterized            by severe inflamma-
ostitis does not occur in monkeys                     that are also suscepti-              tion of cartilage       in various     parts of the body, most often
ble to CIA suggests                that the periostitis              might        be a     in the nasal septum and pinnae of the ear. It can be ac-
peculiarity       of rodents       and not intrinsic             to CIA (5).               companied        by arthritis.     The most striking         lesions are a
    Caulfield      and co-workers            (6) have analyzed              in detail      saddle nose deformity              resulting      from collapse       of the
the pathologic           changes     seen in knee joints of arthritic                      nasal septum         and stridor,       which results from laryngo-
rats. The earliest change was the deposition                           of fibrin in        tracheal    collapse.      Neither     laryngotracheal       collapse nor
the synovium          by the fifth day after immunization.                         The     nasal deformity     has been noted    in CIA.  When                   labeled
next change          noted was synovial               hyperplasia,          followed       antibodies   to type II collagen  were administered                  to nor-
over a period           of several days by infiltration                  of mono-          mal mice, localization            to both ears and lungs could be
nuclear       and polymorphonuclear                    cells. Klareskog            and     demonstrated         (10). In addition,         immunohistologic            ex-
colleagues        (7) characterized               the infiltrating           cells by      amination        revealed        deposition       of antibody        in the
using rabbit and mouse monoclonal                          antibodies        reactive      trachea     but not in the cartilage           plate of the ear, except
with cell surface            markers       of rat immunocytes.                   Early     for the localized       lesions     noted earlier (unpublished             ob-
infiltrates     were comprised           largely of Ia positive cells. In                  servations).      Despite       the presence        of antibody       in the
studies      concentrating         on the articular             cartilage,       Desi-     trachea,     there was an absence of inflammation.                   CIA is
mone       and co-workers           noted       a loss of proteoglycan                as   thus an imperfect           model for this human            disease.
being the earliest            detectable         lesion (8). We have also                      Many animals         have hearing       loss. By measuring          brain
noted the loss of safranin                0 staining,          which       indicates       stem-evoked        potential      in response       to sound      of graded

 Figure 1.    Appearance         of early collagen-induced       arthritis  in a rat immunized                                  (a)
                                                                                                     with nativetype II collagen and unimmunized control
 (6). Photograph      was     taken 2 days after onset        of inflammation.

 COLLAGEN AUTOIMMUNITY                 AND ARTHRITIS                                                                                                                  2951

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Figure  2. Demonstration   of the striking loss of proteoglycan from articular cartilage in early arthritis.Histologic appearance   of the
cartilagestained with safranin 0 from a rat 48 h afteronset of arthritis. Normal cartilage(a) stains are uniformly red (seen as dark grey
in thisphotograph); cartilagefrom an arthritic  joint (b) has an unstained band (between the arrows) extending about one-half the depth
of the cartilage.

intensity,   it was possible to demonstrate        that rats sus-                         alter the severity of arthritis       without    apparent    affect on
ceptible   to CIA also had marked       elevation    of the hear-                         the levels of collagen immunity           (19, 20). Thus, intrinsic
ing threshold     (11). The loss was more pronounced             at                       inflammatory      potential    that in some way contributes           to
higher frequencies.     As with arthritis,     this abnormality                           the development       of disease     and arthritis    is the result of
was    demonstrable          in other      species,      including       mice     and     the quality and quantity         of the immune      response     to col-
monkeys,        as well as in guinea             pigs,    a species       resistant       lagen          in a predisposed       host.
to arthritis      (12).
                                                                                           ROLE            OF         AUTOIMMUNITY
                                                                                          Although        the precise mechanism                by which CIA develops
It is well established that collagen-induced      arthritis  is                           is not clear and the host attributes                  that determine          suscep-
linked to the major histocompatibility      locus (MHC)     in                            tibility are only partially             understood,         several lines of evi-
both rats (13) and mice (14). H-2 linkage varies with the                                 dence     suggest that autoimmunity                     to type II collagen            is
species    of collagen       used    for immunization.               For example,         intimately       involved. All susceptible               animals develop high
DBA/1       mice, which are H-2,                 are highly          susceptible          levels of immunity              to type II collagen.          Within a suscep-
when immunized              with chick or bovine type II collagen,                        tible strain a general correlation                   exists between         the level
are less susceptible         when immunized            with porcine type II               of immunity           and arthritis          (21). Direct evidence              of the
collagen.      B10.RIII,      which are H2T, are most susceptible                         role of autoimmunity                was provided           by transfer       studies,
when immunized             with bovine or porcine            type II collagen             which demonstrated                 that arthritis        could be transferred
and less susceptible           when immunized            with chick type II               with either immune                 cells (22) or serum             (23).
collagen       (15). An interesting             anomaly          is the SWR                    Several      years ago Trentham                    and co-workers             (22)
strain,     which      is H-2?        but nevertheless             resistant        to    administered           cells from type II collagen-immunized
arthritis     (16). Immunization              of this strain with chick                   rats to syngeneic            unimmunized             recipients      and induced
type    II collagen      results    in antibody       levels equal to those               a transient          arthritis.        Later,      this group          (24) devel-
of susceptible      DBA/1 mice, but arthritis              does not develop.              oped      T cell lines reactive                    with     type     II collagen.
Banerjee       and co-workers          (17) have found this strain to                     They found           that these line cells will induce                      arthritis
have a unique         defect in the gene coding for the j3 chain                          when       injected       directly       into the joint           but were not
of the T cell receptor           for antigen.      Thus, although             some        active when given systemically.                         In addition,          culture
haplotypes       are clearly susceptible,         incidence        and severity           supernatants           also induced              arthritis      when       adminis-
of the arthritis       that develops         are not easily predictable                   tered      directly       into the joint.              It has been             known
and probably         involve non-MHC                genes (16).                           for many          years that lymphokine-rich                     culture        super-
     Not only is susceptibility              to arthritis       linked to the             natants      can induce arthritis               when administered                local-
major histocompatibility                gene complex,            but so is re-            ly into the joint               (25), and it has been shown                        that
sponsiveness        to immunization              with type II collagen                    purified       IL 1 is similarly               active (26). However,                the
(18). And whereas             responsiveness         is a prerequisite            for     active principal          described        by Trentham           et al. eluted as
susceptibility,      the converse         is not true. Several             strains        a discrete       peak on molecular              sieve columns          with an ap-
develop      high levels of autoimmunity                  in the absence           of     parent      molecular         weight that was different                 from IL 1.
arthritis.    There are also examples             of manipulations              that      This factor could also be isolated                      on a type II collagen

2952      Vol. 2      Nov. 1988                                                 The FASEB Journal                                                              STUART ET AL.
affinity column.            Because       it seems to have antigen                   spe-    tributions      of each major arm of the immune                             system be
cificity,     it is distinct         from the generally                   recognized         identified     to understand            clearly the pathogenesis                  of dis-
T cell effector molecules.                  The precise            identity      of this     ease and ultimately               relate it to human               arthritis.
factor remains             to be determined.                Holmdahl          and co-            Circumstantial             evidence         favors the idea that the
workers       reported       that mouse T cell lines reactive                       with     initial lesion is caused                by an antibody.               Morgan         and
type II collagen            would also induce mild joint swelling                            co-workers        found that administration                      of cobra venom
and histologic            evidence       of cellular          infiltration       in the      factor to deplete            complement             prevented          the develop-
synovium          (27).                                                                      ment of disease until complement                       levels returned           toward
    Our own studies have focused on the role of antibody                                     normal      (28). In acutely arthritic                 joints,      both antibody
in the generation             of disease.        We were able to transfer                    and C3 are present,              as determined           by immunohistologic
disease      with concentrated                immunoglobulin                from im-         staining     (29). We have found deposition                        of antibody         on
munized         rats or DBA/1 mice to unimmunized                           recipients       the articular       surface to precede the development                          of overt
(23). The active element                  in this case was identified                   as   arthritis.    Antibody          is deposited         in mouse joints at least
IgG antibody             to type II collagen              (Fig. 3). In fact, we               1 wk before clinically             detectable        arthritis      is manifested.
were able to transfer              arthritis      from susceptible             mice to       Like antibody,           C3 can also be detected                       before overt
resistant       strains.     This suggested              that the basis of re-               inflammation           (unpublished            observation).
sistance in these specific strains was the failure to gener-                                     When we harvested               joints at the onset of arthritis                 and
ate sufficient        arthritogenic          antibody        and not phlogistic              eluted the bound              antibody        from them, we found that
factors such as complement                    deficiency        or reduced effec-            specific antibody            was concentrated               relative      to its con-
tiveness       of inflammatory               cells (e.g., macrophages                   or   centration       serum        (29). The relative              level of antibody
neutrophils).         The passively           transferred         arthritis     had all      was at least         15-fold higher than nonspecific                         immuno-
of the characteristics             of arthritis        induced        by active im-          globulin.     Finally, we found that antibody                        to type II col-
munization,           except that it was less severe. Recipients                             lagen will localize             to normal         joints.      Injection        of 1251
had synovial           proliferation,         infiltration        with inflamma-             labeled     antibody         was followed by concentration                        of the
tory      cells,     and     destruction           of cartilage            and bone          label in the limbs within 30 mm. It is also clear that the
manifested           by marginal            erosions.         However,          disease      deposition        of complement                 is essential          for passively
after    active     immunization              usually      lasts    several      weeks       transferred       arthritis,      because        administration            of transfer
and is often succeeded          by permanent                        ankylosis       and      antibody       to B10.D2/oSn                mice is not productive                       of
deformity.    Passively  transferred   arthritis                   usually      healed       arthritis     whereas          transfer       to B10.D2/nSn                results       in
without    consequences.                                                                     arthritis    (30). The only difference                  between         these strains
                                                                                             is that B10.D2/oSn               mice are complement                    deficient.
PATHOGENETIC                       MECHANISMS                                                    Based on the existing evidence,                     we postulate           that im-
                                                                                             munization         of susceptible          animals with type II collagen
An important       question      is whether    cellular    or antibody-                      results in the production                of both arthritogenic                and non-
mediated     effector mechanisms            are more important           in                  arthritogenic         antibodies.         The latter is exemplified                    by
the development          of active disease.        Neither     cells nor                     antibodies      specific for the species of immunizing                         collagen
antibodies    are able to completely             mimic arthritis        in-                  and not reactive with autologous                      collagen. Arthritogenic
duced by immunization,              and it is likely that both are                           antibodies       are autoreactive              and gradually             accumulate
involved.  However,        it is important     that the specific con-                        in normal joints. At some point a threshold                                is reached


                          -   _I

Figure     3. Deposition of antibody on the surface of articular cartilage after immunization   with type II collagen. Joints from a normal (a)
and type II collagen immunized       (b) rat were decalcified in neutral EDTA and stained for immunoglobulin          with an immunoperoxidase
technique.     The dark band extending uniformly over the surface of the cartilage      in the immunized    rat indicates  the presence  of IgG.

COLLAGEN AUTOIMMUNITY                  AND ARTHRITIS                                                                                                                             2953
and overt inflammation                   develops.       What       triggers      the               fluid and be taken up by synovial                  tissue. No evidence
sudden       onset of overt inflammation                    is unclear        but it                has been found to support              this concept.       We have been
seems      likely that complement                 activation        may      be in-                 unable to inject immune             cells and trace them to joints
volved.       Susceptible        strains     all make         relatively       large                in unimmunized            mice; however,         there are many diffi-
quantities        of IgG2a          and IgG2b           antibody         isotypes.                  culties in the execution         of such experiments.           An alter-
These       isotypes      efficiently      activate       complement,            and                native possibility       would be that cells are attracted          by an
their presence         may be required              to generate         sufficient                  antigen-specific       lymphokine         such as that described        by
complement           products.         A schematic         representation           of              Helfgott     and co-workers        (24).
these          events         is depicted  in Figure     4.                                             CIA would in any case appear                 to bear several inter-
      The relative               contribution   of cells to the development                         esting    pathophysiological          similarities       to human     RA.
of     the initial              lesion  in CIA is less clear.         Of some                       The reaction         in synovial        fluid is to a large extent
relevance               may       be the ability    of specific  antibody   to                      humorally        mediated,     whereas       the reaction     in synovial
localize   to normal       cartilage.     Because       cartilage      is avas-                     tissue resembles         more closely the one associated             with
cular, it may        be an immunologically                privileged        site.                   delayed     hypersensitivity      reactions.
Since    cells   do not normally             traverse      cartilage,      they
would presumably            have to contact          this antigen        in the
synovium.        Once     inflammation           has begun,           collagen                      RELEVANCE                  TO     HUMAN              RHEUMATIC
fragments      may be generated            and diffuse into synovial                                DISEASE
fluid and ultimately           be taken up by macrophages                       in
the synovial      tissue. In the normal            state, however,         type                     The presence of collagen autoimmunity                              in some patients
II collagen     is not synthesized         in the synovium            and has                       with rheumatic            disease is now well established.                    Both anti-
not been demonstrated             to be present there. It is possible                               bodies and cellular               reactivity      have been detected,                   and
that, as a result of normal           wear or even of physiological                                 these findings have been confirmed                         by workers in several
replacement,       type  II collagen       may traverse         the synovial                        independent          laboratories        who used divergent                 techniques
                                                                                                    (2, 3, 31). It is also clear that under some circumstances
        PATHOGENESIS                    OF COLLAGEN-INDUCED                  ARTHRITIS
                                                                                                    antibodies       to collagen from patients with RA may be ar-
                         HYPOTHETICAL                CONSTRUCT                                      thritogenic.        Isolated antibodies            from a patient with high
                                                                                                    titers   of antibody         to type II collagen were capable of in-
                                                                                                    ducing      arthritis       when injected           into mice (32). It is in-
                        Immunization        with     type   II collagen                             teresting      that analysis          of these arthritogenic                 antibodies
                                                                                                    showed       them to be predominantly                           IgG3,       an isotype

     T Cell reactivity
                        /          __

                                                               B Cell reactivity
                                                                                                    known as a potent activator
                                                                                                    respect they resembled
                                                                                                                                                  of complement
                                                                                                                                          the antibodies            generated
                                                                                                                                                                             (33). In that
                                                                                                                                                                                      by mice
                                                                                                    susceptible        to CIA. Thus antibodies                     to type II collagen
                                                                                                    are regularly          associated       with RA and are capable                      of in-
 Localization to                                            Antibody      production                ducing      arthritis       when passively             administered             to mice.
  synovial tissue                                                                                   Many       patients        with RA also have cell-mediated                              im-
                                                     V                                              munity
                                                                                                                 to collagen
                                                                                                              been        identified
                                                                                                                                      and, in fact, collagen-reactive
                                                                                                                                            that      express          class      II major
                                           Arthrltogenic                Non arthritogenic
                                                                                                    histocompatibility              antigens       in synovial           tissue (27).
Lymphokine     production                                                                                What     problems           remain       before        these autoreactions
     (IL 1, etc.)
                                                                                                    are accepted             as a major             causative          factor       in RA?
                                                     1. BInds normal cartilage
                                                     2. Activates complement                        Although        the incidence            of collagen            autoantibodies             in
                                                                                                    RA populations              varies substantially,             it appears that im-
                                                                                                    munity      to native type II collagen                    is characteristic           only
Activation of loint cells                             Chemotaxis   of Inflammatory          cells   of a subset of patients.               However,         it is also possible that
     chondrocytes                                         neutrophils                               this subset is larger than that identified                              by observing
     synovlal cells                                       macrophages
                                                                                                    only serum antibodies,                inasmuch          as a much higher per-

                                                                                                    centage      of patients         have autoantibodies                  sequestered          in
                                                                                                    the cartilage         matrix (34). Most patients                      with RA have
                                                                                                    antibodies        that are of much                 broader          specificity        that
                                  Protelnases                                                       react with denatured                  collagen       of several           types. This
                                         proteoglycanase                                            latter specificity          may be induced                by breakdown              prod-
                                         gelatlnase                                                 ucts     in already            diseased        joints;        it also has been
                                                                                                    described       in other chronic             diseases.        For the most part,
                                                                                                    these have been rheumatic                    diseases,       although         nonrheu-
                                                                                                    matic disease associations                   have also been reported.                     In
                                                                                                    view of the diversity                  of the clinical             conditions,           the
            1.    Degrade         proteoglycans         from     cartilage    matrix
       2. Degrade collagen from cartilage and bone matrix                                           relevance        of the observed               collagen          autoimmunity               is
Figure   4. Proposed   schema  for the pathogenesis of collagen-                                    difficult to determine.              Among         the possibilities             are that
induced arthritis.                                                                                  immune        reactions        to collagen may be a common                         conse-

2954            Vol. 2         Nov. 1988                                                 The FASEB Journal                                                                   STUART ET AL.
quence         of tissue damage           that is unrelated           to disease;                  experimental              model     of   relapsing        polychondritis                   in-
the specificity          of the reaction,        hence its consequences,                          duced  with  type   II collagen. J. Exp. Med. 154:
may vary with different               diseases;    or the host milieu may                         534-540; 1981.
                                                                                            10. Stuart,J. M.; Dixon, F. J. Serum transfersof collagen-
influence           the expression         of collagen        autoimmunity.
                                                                                                  induced arthritisin mice. J. Exp. Med.   158: 378-
Finally, the means by which autoimmunity                             to collagen
                                                                                                  392; 1983.
is generated           in patients      remains      unknown.          Studies of           11. Yoo, T. J.; TOMODA,      K.; STUART, J. M.; CREMER,
mice suggest           that orally administered           collagen       is tolero-               M. A.; KANG,      A. H.; TowNEs,    A. S. Type    II
genic      (35). In other systems             it has been suggested             that               collagen-induced               autoimmune            sensorineural              hearing
cross-reactivity           of bacterial      products     with the host tis-                       loss    and     vestibular          dysfunction rats.            Ann.
sue may be responsible               for development          of autoimmune                      Rhinol. Laryngol. 92: 267-271; 1983.
                                                                                            12. Yoo, T. J.; TOMODA,    K.; HERNANDEZ,     A. D. Type II
arthritis        (36). No such reactivities           have been described
                                                                                                 collagen-induced autoimmune        inner ear lesions in
for collagen.                                                                                    guinea pigs. Ann.     Otol. Rhinol.    & Laryngol.      113
    It is also possible that autoimmune                     arthritis      may be                (Suppl.): 3-5; 1984.
generated           by any of several connective                tissue compo-               13. GRIFFITHS,  M. M.; EICHWALD,     E. J.; MARTIN,     J. H.;
nents,       inasmuch           as   immunization              with    proteoglycan              SMITH, C. B.; DEWITT,    C. W. Immunogenetic       control
has also been shown to be capable of inducing                       arthritis.                   of experimental       type   II collagen-induced         arthritis.   I.
Other types of collagen             are also exclusively          present      in                Susceptibility     and resistance      among       inbred strains     of
                                                                                                 rats.   Arthritis Rheum. 24: 781-789;            1981.
cartilage     (although       in much smaller            quantities),       and
                                                                                            14. WOOLEY,         P. H.; LUTHRA,        H. W.; STUART,                 M.;            J.
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2956     Vol. 22          Nov. 1988                                                  The FASEB Journal                                                           STUART ET AL.

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