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*
Section of Rheumatology and
Department of Pathology, Yale University School of Medicine, and
Department of Biology, Yale University, New Haven, CT 06510
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ß
T cells in conjunction with unaltered hypergammaglobulinemia,
autoantibody production, and immune complex renal disease. These
results indicate that cytolytic lymphoid regulation plays critical
roles in the immune homeostasis of lupus-prone animals, and identify
perforin-mediated cytotoxicity as a specific mechanism in the
regulation of systemic autoimmunity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several studies have established that MRL lupus is driven by pathogenic
CD4+ ß T cells that provide help to autoreactive B
cells (19, 20, 21). A more complex dysregulation of the immune system,
however, in which both pathogenic and down-regulatory T cells compete
for control of autoimmunity, is most likely associated with disease
pathogenesis (22). Proposed regulatory mechanisms include
cytokine-mediated modulation of immune responses, such as the skewing
of Th1- vs Th2-dominated environments (23), but most studies have
indicated pathogenic roles for several cytokines in murine lupus,
including IFN-
, IL-4, IL-6, IL-10, and IL-12 (24, 25, 26, 27, 28, 29, 30). On the other
hand, T cells may directly regulate pathogenic lymphocytes by
cytotoxicity, as suggested by the Fas-mediated regulation of some
activated T cells and B cells (31, 32, 33). Indeed, more recent work in MRL
lupus has suggested that 
T cells regulate pathogenic ß T
cells (34), while T cells and subsets of regulatory ß T
cells regulate B cells (22, 34, 35), via both Fas-dependent and
Fas-independent mechanisms (34, 35, 36).
Other than Fas, potential regulatory mechanisms in lupus include TNF and perforin (pfp);3 together, these three mediate the majority of cytotoxic lymphocyte responses (37). A role for TNF in the down-regulation of lupus has been strongly suggested by the exacerbation of disease in TNF receptor-deficient lpr animals (12); however, the regulatory role of pfp in systemic autoimmunity is unknown, despite its critical role in lymphocyte-mediated cytotoxicity (38, 39, 40, 41). Instead, investigations in murine lupus have focused upon the potential pathogenic role of pfp: one in MRL/lpr mice described the constitutive, functional expression of pfp by the expanded CD4-CD8- T cells (42), and two studies in New Zealand mice demonstrated the steroid-sensitive expression of pfp in T cells from disease lesions (43, 44).
The circumstantial evidence implicating a regulatory role for pfp in murine lupus (34, 35, 36) suggested that pfp deficiency may exacerbate, rather than ameliorate, murine lupus. To explore this possibility, pfp-deficient lupus-prone animals were generated by crossing pfp-/- mice (41) with MRL/lpr breeders. Pfp-deficient Fas+ animals developed accelerated autoimmune disease compared with pfp-intact Fas+ counterparts, characterized by increased hypergammaglobulinemia, autoantibody production, and end-organ disease. In comparison, in lpr animals pfp deficiency caused early mortality associated wtih T cell lymphoaccumulation reminiscent of lpr-related lymphoproliferative disease. These results demonstrate that pfp plays essential roles in the regulation of both humoral autoimmunity and lymphoid regulation, and emphasize the critical role of cytotoxicity in the modulation of systemic autoimmunity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pfp-/- (C57BL/6 x 129/Sv) mice (41) (Taconic, Germantown, NY) were crossed against MRL/lpr breeders (The Jackson Laboratory, Bar Harbor, ME) to generate pfp+/- Fas+/lpr double-heterozygotic offspring, which were intercrossed to generate pfp-intact (pfp+) and pfp-deficient (pfp-) Fas-intact (Fas+) or lpr/lpr (lpr) F2 animals. Genotypes were screened via PCR of tail DNA, using primers PFP451F (5'-GCCTACCTGTGGCAATCACCCACTG), PFP670R (5'-TCAGCTGCAAAATTGGCTACCTTGG), and NEOMS1 (45) (5'-CCTTGCGCAGCTGTGCTCGACGTTG). The PFP451F-PFP670R combination yielded a 219-bp fragment corresponding to the wild-type allele, while the PFP451F-NEOMS1 combination yielded an approximately 720-bp fragment corresponding to the mutant allele (not shown). Fas genotype was also determined by PCR, as described elsewhere (3). All animals were maintained under specific pathogen-free conditions at Yale University School of Medicine (New Haven, CT).
Cytotoxicity assays
To assay cytotoxic activities in vitro, NK cell-enriched splenocytes were used as effectors against 51Cr-labeled YAC-1 targets (46). Briefly, twice-washed, erythrocyte-cleared splenocytes were passed through a prewarmed, prewetted nylon wool column, incubated at 37°C for 45 min. NK effectors were prepared from nonadherent cells, which were expanded for 48 h at 2 x 106 cells/ml in DMEM (Life Technologies, Gaithersburg, MD) containing 10% FCS and 500 U/ml of mouse rIL-2 (Sigma Chemical Co., St. Louis, MO). YAC-1 targets (TIB-160; American Type Culture Collection, Rockville, MD) were labeled for 2 h with 100 µCi of Na51CrO4 (Amersham Life Science Corp., Arlington Heights, IL), washed thrice, and resuspended in DMEM containing 10% FCS. A quantity amounting to 5 x 103 labeled target cells in 100 µl was mixed with an equal volume of effector cells at varying ratios in a round-bottom 96-well plate (Falcon 3077; Becton Dickinson, Lincoln Park, NJ). Cells were centrifuged at 100 x g to ensure contact, incubated for 4 h at 37°C, 5% CO2/air atmosphere, and then centrifuged again at 100 x g. One hundred microliters of supernatant were assayed for 51Cr release by standard gamma counter.
Ab analyses
Serum Ig and autoantibody studies were performed as previously
described (35). Briefly, antinuclear Abs were assayed by indirect
immunofluorescence (FANA) on sera diluted at 1/50 using HEp-2 substrate
cells (Quidel, San Diego, CA). Fluorescence was visualized with a Zeiss
Axioskop microscope at x1000 magnification, with intensity rated 0 to
4+, as determined by the light meter’s estimated
required exposure time for 10 to 12 cells per high power field on ASA
400 film (>120 s, 0; <120 s, 1+; <60 s, 2+;
<30 s, 3+; <15 s, 4+). Specific autoantibody
titers (IgG anti-dsDNA, IgG anti-small nuclear
ribonucleoprotein (snRNP), and 
rheumatoid factor) were determined
by ELISA using specific substrates on sera at 1/100 dilution. Serum Ig
titers were determined by ELISA (Pierce, Rockland, IL, or PharMingen,
San Diego, CA). Statistical significance was evaluated by paired
Student’s t test on mean Ig titers or autoantibody OD
values. FANA comparisons utilized t test on proportions.
Cell analyses
Spleens and six peripheral nonmesenteric lymph nodes were
weighed, homogenized, and cleared of erythrocytes by osmotic lysis.
Live cell count was determined by trypan blue exclusion. For phenotypic
analyses, cells were analyzed by FACSort flow cytometry and CellQuest
1.1 software (Becton Dickinson, Bedford, MA): Abs included H129.19 FITC
or PE (anti-CD4), GL3 PE (anti-TCR-), RA3-6B2 biotin
(anti-CD45R/B220), H57-597 FITC, or PE (anti-TCR-ß; all from
PharMingen), and/or 53-6.7 Quantum Red (anti-CD8; Sigma Chemical
Co.), followed by streptavidin-Texas Red (Life Technologies).
Histopathology
Tissue specimens were fixed in 10% buffered Formalin, and
sections were stained with hematoxylin and eosin by standard procedures
at Department of Pathology, Yale University School of Medicine (15, 16, 35, 36). Disease was evaluated on a 0 to 4 scale in renal glomeruli,
tubules, and perivascular regions; salivary gland acini and
perivascular regions; and hepatic periportal regions. The degree and
histopathologic character of lymphoid infiltrates were evaluated in
kidney, liver, and salivary gland sections. Immunofluorescent studies
were performed onOCT-embedded frozen sections, as described (35, 36),
using FITC- and/or PE-conjugated 145-2C11 (anti-CD3)CD3),
H129.19 (anti-CD4), 53-6.7 (anti-CD8), RA3-6B2
(anti-B220), H57-597 (anti-TCR Cß), RR8-1 (anti-TCR
V11b,d), B20.6 (anti-TCR Vß2), RR4-7
(anti-Vß6), MR5-2 (anti-TCR Vß8.1/Vß8.2), 1B3.3
(anti-TCR Vß8.3), B21.5 (anti-TCR Vß10b), 14-2
(anti-TCR Vß14), and PE-conjugated KJ25 (anti-Vß3; all from
PharMingen). Immune deposit analyses utilized FITC-conjugated
polyclonal goat anti-mouse IgG (Sigma Chemical Co.). All
immunofluorescent photographs were taken on ASA 400 film at an exposure
time of 8 s.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pfp-/- (41) animals were crossed once against
MRL/lpr breeders, generating pfp+/-
Fas+/lpr offspring. These F1 animals
were intercrossed to generate pfp+/+ (pfp+) or
pfp-/- (pfp-), Fas+/+
(Fas+), or lpr/lpr
(lpr) F2 animals, generating four
genotypic groups of similar genetic backgrounds (approximately 50%
MRL). Since previous studies have demonstrated the dominance of MRL
autoimmunity-inducing genes in genetic crosses (34, 35, 47, 48), the
background of these animals conveys a lupus-like autoimmune phenotype.
Indeed, the disease of these mice can be considered representative of
typical MRL murine lupus, as indicated by their production of
hypergammaglobulinemia, specific autoantibodies, and end-organ disease
(34, 35, 48, and see below). PCR-assayed genotypes were confirmed by
flow cytometry for Fas staining, as well as by NK cytotoxicity assay:
consistently, NK cell-enriched splenocytes from pfp-
animals failed to lyse pfp-sensitive YAC-1 cells, whereas those from
pfp+ animals successfully achieved as high as 40% specific
target cell lysis, using E:T ratios varying from 40:1 to 1.25:1,
regardless of Fas genotype (Fig. 1
and
data not shown).
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Notably, the median survival of pfp-lpr animals (n = 8) was only 8 wk, whereas pfp+lpr animals (n = 12) had a median survival of 24 wk (p < 0.001), typical of most hybrid MRL lupus strains (30, 34, 36, 47, 48). In contrast, all nine pfp+Fas+ and nine pfp-Fas+ animals survived beyond 32 wk of age.
Abnormal lymphoaccumulation in pfp-lpr mice
The accelerated mortality of pfp-lpr
mice was most likely explained by uncontrolled lymphoaccumulation that
afflicted their kidneys, livers, and salivary glands, as well as
lymphoid organs (Table I and Figs. 2–4). In all organs
examined, pfp-lpr mice had substantial organ
destruction by a monomorphic, atypical lymphoid infiltrate,
characterized by enlarged, vesicular nuclei with indistinct nucleoli
and irregular nuclear contours (Fig. 2 and data not shown). Occasional
small mature lymphocytes were scattered throughout such lesions. In
salivary glands, only rare residual acini and salivary ducts remained
(Fig. 2H and data not shown), while in kidneys and livers,
similar infiltrates were restricted predominantly in a perivascular
location with a lesser degree of interstitial involvement (Fig. 2, G and J, respectively, and data not shown). These
infiltrates were highly reminiscent of lpr-induced
lymphoaccumulative disease.
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, E and
F, and data not shown) (12, 13, 14). Although mildly enlarged
lymphocytes were present, the cytologic atypia seen in
pfp-lpr animals was uniformly lacking. The
atypical cells in pfp-lpr animals were
ß+CD3+CD4-CD8-B220-
T cells, as determined directly by immunofluorescence on frozen tissue
sections and indirectly by flow cytometry on cell suspensions from
spleen and lymph nodes (p < 0.001; Figs. 3 and 4
and data not shown; note the expansion of a
TCR--ß+CD4-CD8-B220-
T cell subset in pfp-lpr compared with
pfp+lpr lymph nodes). In comparison, the
infiltrates of pfp+lpr mice consisted
predominantly of CD3-B220+ B cells, although
CD3+B220- and
CD3+B220+ T cells were occasionally seen. Thus,
pfp contributes to the regulation of cellular homeostasis in
lpr animals.
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In contrast, Fas-intact animals required pfp primarily to regulate
humoral and end-organ autoimmune disease.
Pfp-Fas+ animals had more
hypergammaglobulinemia, higher levels of autoantibodies, and more
severe end-organ disease than their pfp+Fas+
counterparts (Tables I-III, Figs. 5–7, and
data not shown). At 3 mo of age, pfp-Fas+ mice
had higher titers of IgM, IgG1, IgG2a, and IgG2b than
pfp+Fas+ counterparts
(p < 0.001), and 8-mo-old animals maintained
higher levels of IgM, IgG1, and IgG2b (p <
0.005; Table III and Fig. 5). Similarly,
pfp-Fas+ animals also developed higher levels
of autoantibodies: at both 3 and 8 mo of age, they contained higher
levels of rheumatoid factor and anti-snRNP Abs
(p < 0.01), and at 8 mo of age, they contained
higher levels of anti-dsDNA Abs (p < 0.01;
Fig. 6). In addition, all nine of nine
8-mo-old pfp-Fas+ animals tested positive for
antinuclear Abs, in comparison with only five of nine
pfp+Fas+ animals (p <
0.001). In contrast, no clear differences in serum Ig and autoantibody
titers were observed between pfp-lpr and
pfp+lpr animals, which developed higher levels
of hypergammaglobulinemia, particularly of the IgG2a and IgG3 isotypes
(p < 0.001), and autoantibodies, particularly
antinuclear Abs and rheumatoid factor (p <
0.001), compared with Fas+ animals.
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and Fig. 2 and
data not shown). Although all Fas+ animals at 3 mo of age
had only mild or absent end-organ disease,
pfp+Fas+ animals at 8 mo of age developed mild
glomerular disease and occasionally mild perivascular infiltrates in
salivary glands. Age-matched pfp-Fas+ animals,
however, consistently contained more glomerular, interstitial, and
perivascular renal lesions and/or infiltrates, as well as greater
acinar damage and perivascular infiltrates in salivary glands. Hepatic
infiltrates also appeared more common and perhaps more intense among
pfp-Fas+ animals as compared with
pfp+Fas+ counterparts, even though disease
remained generally mild among all Fas+ animals. Notably,
pfp+lpr animals developed renal, salivary gland,
and hepatic lesions typical of MRL/lpr autoimmune disease,
including glomerulonephritis, interstitial infiltrates, and
perivasculitis in kidneys; acinar atrophy with periductal and
perivascular infiltrates in salivary glands; and mild-moderate
periportal infiltrates in livers.
The accelerated end-organ disease of pfp-Fas+
animals most likely resulted from increased immune complex-related
formation secondary to accelerated humoral autoimmunity, since their
renal lesions consistently contained greater immune deposits, as
assayed by immunofluorescent studies (Table II and Fig. 7). Pfp-Fas+
animals generally had diffuse capillary wall and mesangial immune
deposits affecting all glomeruli, significantly more prominent than
their pfp+Fas+ counterparts. The former also
had more significant tubular basement membrane as well as occasional
intranuclear staining, which were not apparent in
pfp+Fas+ specimens. By comparison, both
pfp+lpr and pfp-lpr
animals developed severe diffuse mesangial and capillary wall deposits
as well as glomerular collapse, consistent with their proliferative
glomerulonephritis, and also developed tubular and intranuclear
deposits as well.
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). Comparable spleen and lymph node weights and cell
counts were found between pfp+Fas+ vs
pfp-Fas+ animals, as well as between
pfp+lpr vs pfp-lpr
animals. Furthermore, pfp+ animals also contained
numbers of ß T cells, T cells, and B cells
(B220+ß-- cells)
similar to pfp- animals, comparing
pfp+Fas+ with pfp-Fas+
animals, as well as pfp+lpr with
pfp-lpr animals.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The findings in Fas-intact animals indicate a significant role for pfp
in the regulation of systemic humoral autoimmunity and the consequent
development of end-organ disease. Pfp may play a direct role in the
regulation of autoreactive B cells by T cells or NK cells, such that
pfp deficiency results in increased generalized autoreactive B cell
hyperactivity, which previously has been suggested as pathogenic in
murine lupus models (49, 50, 51). Pfp appears subordinate to that of Fas in
the regulation of autoreactive B cells, however, since pfp deficiency
did not result in humoral and end-organ disease similar to
lpr disease; indeed, the grossly unchanged lymphocyte
populations in pfp-Fas+ animals (Fig. 4) argue
against an overt regulatory defect in the T cell or B cell lineages.
Rather, Fas-dependent regulation of B cells by T cells (31, 32, 33) or by
NK cells (52, 53) most likely helps to prevent otherwise severe
autoimmunity in pfp-Fas+ animals. As an
alternative, pfp may provide a mechanism by which regulatory T cells,
either ß and/or (22, 34, 35, 36), eliminate activated,
pathogenic ß T cells (22, 34).
The acceleration of end-organ disease in spite of relatively preserved humoral autoimmune parameters in pfp-lpr animals reinforces a role for pfp in cellular regulation, and suggests that pfp primarily regulates autoreactive T cells, rather than B cells, at least in the setting of Fas deficiency. Accordingly, autoreactive B cell activation appeared unchanged in pfp-lpr animals, as assayed by B cell counts, hypergammaglobulinemia, autoantibodies, and renal immune deposits, in comparison with the acceleration of autoimmunity by pfp deficiency in Fas+ animals. Indeed, Fas may be the primary mechanism by which B cells are regulated (31, 32, 33, 52, 53), and thus, pfp deficiency may not significantly affect lpr B cells. On the other hand, lpr T cells appear to rely heavily upon pfp for self-surveillance in the absence of Fas-Fas ligand interactions, resulting in T cell lymphoaccumulation in double-deficient states, even though other, tertiary pathways for cytotoxicity most likely remain (54). Alternatively, if pfp acts via other immune cell populations, such as NK cells, cellular effects may similarly predominate over humoral effects due to the roles of these cell types in primarily cellular immune effects, such as Ab-dependent or complement-mediated cytotoxicity.
Such considerations raise interest in the origin of the T cells that comprise the lymphoaccumulation syndromes of both pfp+lpr and pfp-lpr animals. Pfp deficiency may simply exacerbate lpr disease, such that the defective activation-induced cell death characteristic of lpr T cells is simply further propagated in double-deficient animals, resulting in the lymphoaccumulation of multiple autoreactive T cell clones previously stimulated by autoantigen(s) (3, 4, 5, 6). Pfp may also, however, play a role in the regulation of T cells undergoing different types of immune responses, such as during infection or tumor progression, such that combined pfp and Fas deficiency result in global dysregulation of ongoing immune responses. For example, the T cell infiltration in pfp-lpr animals may actually reflect an additional reactive lymphoproliferation to a distinct underlying malignancy, such as the hyperproliferation of atypical, clonal T cells in response to underlying EBV-induced B cell lymphoma in lymphomatoid granulomatosis (55, 56, 57), as suggested by the presence of a T cell-regulated B cell lymphoma in lpr animals (36). These considerations may be relevant to tumor progression in settings of immunodeficiency, such as AIDS, in which defective lymphocyte-mediated suppression may permit the development of malignant lymphoma (58, 59).
These demonstrations of the importance of cytotoxic mechanisms in systemic autoimmunity also provide new directions of study for therapeutic interventions. Traditional approaches have involved global down-regulation of the immune system, such as by anti-inflammatory drugs, corticosteroids, or antimetabolic agents (60, 61). The acceleration of autoimmunity in both TNF-deficient (12) and pfp-deficient lupus-prone animals (this study) strongly suggests that particular lymphocyte subsets provide significant regulatory functions that may be enhanced by specific therapeutic techniques. The identification and utilization of such cells will be of substantial interest to future investigations.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Joe Craft, P.O. Box 208031, LCI 609, 333 Cedar Street, New Haven, CT 06520-8031. E-mail address:
3 Abbreviations used in this paper: pfp, perforin; FANA, fluorescent antinuclear Ab; PE, phycoerythrin; snRNP, small nuclear ribonucleoprotein.
Received for publication February 19, 1997. Accepted for publication September 30, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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