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Immune Deposit Diseases Or Of Mink and Mice.

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CURRENT COMMENT
Immune Deposit Diseases
Or
Of Mink and Mice
Possible Analogies to the
Connective Tissue Disorders
B y RALPH C . WILLIAMS,
JR.
R
a persuasive analogy has become apparent between certain aspects of several naturally occurring or
experimental animal disease states and
features shared by some of the connective
tissue disorders-particularly disseminated
lupus erythematosus. These similarities relate to the presence of antinuclear antibodies as well as circulating nuclear antigens in the sera of mink with Aleutian
disease' as well as in NZB r n i ~ e in
~ -the
~
process of developing renal lesions. Most
recently the animal model invoked by
lymphocytic choriomeningitis has been
compared or studied by Dixon and cow o r k e r ~as~another
~~
possible animal model
for tissue lesions caused by deposition of
immune complexes. A burgeoning array of
new observations and evidence is now
available implicating, at least in part, antinuclear antibodies and complexed nuclear
antigens or other autologous immune complexes in the pathogenesis of immune deposit diseases*-ll and particularly glomerular lesions. In this setting the pathogenic
significance of so-called autoantibodies
must be carefully reappraised. Since disease
such as Aleutian disease of mink or the
ferret disease described by Buko and Kenyon12 appear to be directly related to very
small filterable agents,13 antibodies with
apparent antinuclear reactivity noted in
these conditions may conceivably be directed primarily a t the infecting agents.
Antinuclear antibodies in this setting may
not be auto-reactors at all unless infecting
virus or similar agents be generously classified as autologous materials. A review of
the background of this resurgence of interest in the animal models of NZB disease
of mice14J5 and Aleutian disease of mink
seems in order.
From the Department of Medicine, University
Hospitals, Minneapolis, Minnesota.
RALPH C. WILLIAMS,
JR., M.D.: Associate Professor of Medicine.
ECENTLY
ALEUTIANDISEASE
Aleutian disease of mink, first described
by Hartsoughl6 and later studied by many
independent groups of investigat~rs,l~-*~
afflicts many varieties of mink. It seems to
be unusually severe in animals homozygous
for the Aleutian gene; hence the origin of
the name. Quite early in the series of clinical and pathologic studies of this disease
the profound hypergammaglobulinemia
present in some infected animals was
noted.2l Further studies of the gamma
globulin abnormalities in these mink indicated interesting complexes detectable by
ultracentrifugation of some mink sera.22,23
Later this same group of workers described
emergence of myeloma-like monoclonal yG
immunoglobulin components in the sera of
10-15 per cent of diseased mink who sur-
ARTHRITIS
AND RHEUMATISM,
VOL. 11, No. 4 (AUGUST1968)
593
594
RALPH C. W I L L l A M S , JR.
vived and harbored the infection for peri- agent is present complexed to 7-globulins
ods longer than 12 months.24 The serum circulating in plasma.
protein abnormalities which also included
NZB DISEASE
OF MICE
the presence of anti-y-globulin factors2j
Considerable excitement was aroused by
were matched by the striking histologic
similarity of some of the lesions to those of the early reports2v3of serologic and pathoperiarteritis or disseminated lupus.26 These logic similarities between systemic lupus
tissue and histopathologic parallels were erythematosus and an affliction of a paremphasized quite early by Leader and ticular strain of mice. It is not the purpose
of this essay to trace the tremendous outof literature dealing with this interestput
The situation in Aleutian disease then
ing
disease, but rather to point out how
presented certain serum protein, serologic
recent
experimental work from several laband histologic similarities to human afflicoratories
brings out the analogy to Aleutian
tions like SLE or even the vasculitis of
rheumatoid arthritis. Central to the enigma disease of mustelids and the participation
of this interesting animal model was the of apparent immune complexes in the NZB
association of apparent high titers of the renal lesions. It was shown quite early in
infectious agent in the serum or circulating the work on NZB mice that serum antiplasma of infected animals with concomi- nuclear factors paralleled the clinical protant marked hypergammaglobulinemia. The gression of disease in these animals.14 Requestion was raised quite properly if the cently elution experiments by Lambert and
hypertrophy of y-globulin were truly anti- Dixon5 have indicated that the major porbody to the infecting agent or some type of tion of the yG globulin which can be eluted
auto or anti-tissue antibody stimulated by from NZB kidneys is antinuclear antibody.
cell breakdown and the chronic renal or Furthermore, the renal disease could be
hepatic lesions. Attempts to characterize markedly accentuated by “boosting” these
the exact segment of serum harboring the animals with DNA linked by methylation
infectious principle were undertaken,2* but to BSA and thereby made antigenic? When
it was not until the recent definitive experi- these recent findings are added to the prements of Porter and c o - w o r k e r ~that
~ ~ the liminary evidence cited by Mellors of viral
the
central core puzzle of co-existent infectious particles in lesions from NZB
case
for
the
possible
interrelationship
of
agent and marked hypergammaglobulinechronic
viral
infections
and
this
disease
bemia was solved.
comes even more intriguing. It is remarkIn this latter work it was shown that
able how closely the observations concernspecific antiserum to mink y-globulin when
ing elution of y-globulins from lesions in
reacted with an infectious mink serum pool,
human lupus glomeruli and NZB kidneys
markedly reduced infectivity of such sera have paralleled each ~ t h e r . ~ . ~One
J l finds
as the y-globulins were precipitated out. it difficult to escape from the conclusion
This fruitful approach, patterned after that the kidney lesions in both of these
similar experiments previously done with conditions may be what has been called
other chronic animal virus infections,30-32 immune deposit disease.s
has greatly added to our understanding of
Since the early observations on the posthis chronic infectious disease of mink. tulated contributions of antigen-antibody
From the experiments of Porter and Lar- complexes to tissue lesions of hypersensisenz9 it thus appears that the infectious tivity, as in experimental serum ~ i c k n e s s ~ ~ ~ ~
IMMUNE DFPOSlT DISEASES
595
or experimental glomerulonephritis in rabbit~~
the~ ;concept of immune complexes
being directly involved in tissue damage
has been tremendously amplified and ex~ a n d e d . ~ Now,
’ - ~ ~ as has been pointed out
above, in 2 animal models-Aleutian disease of mink and NZB disease of micethere is good experimental evidence for
circulating nuclear antigens and antinuclear antibodies. The same situation has
been carefully documented in a large series
of human patients with systemic lupus,4O
where in several instances serial observations have implicated disappearance of detectable nuclear antigens with a clinical
exacerbation and concomitant depression of
serum ~ o m p l e m e n t ~ oactivity.
.~~
Coupling
these interesting clinical observations with
the recent report by Pincus and co-workers,4* one may speculate that the quality of
antibody, particularly the non-precipitating
antibody molecules, may have a distinct
role in producing nephrotoxicity. The specific logistic requirements for production of
immune complex lesions in the animal models of Aleutian disease or NZB disease can
be more precisely approached when more
is known of the causative agents.
Precise knowledge of the intricate specificities and variability of various human
antinuclear antibodies as defined by the
work from many l a b o r a t o r i e ~may
~~-~
help
~
us to characterize or define the “nuclear”
antigens detectable among Aleutian disease
mink or NZB mice. The problem as to
whether the nuclear antigens-seemingly
so central to the main argument of immune
deposit disease of mink, mice or man-are
related to autologous nuclear breakdown
products or to specific viral antigens, remains to be solved.
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