Biomedical subjects

William Stohl

Publications and source records attributed to William Stohl.

At least 19 recordsLinked to original sources

PubMed2006

Patients with inflammatory arthritic diseases harbor elevated serum and synovial fluid levels of free and immune-complexed glucose-6-phosphate isomerase (G6PI).

In K/BxN mice, anti-glucose-6-phosphate isomerase (G6PI) IgG antibodies (Abs) cause joint-specific inflammation and destruction. Anti-G6PI Abs are also present in humans with inflammatory arthritis, especially among patients with rheumatoid arthritis (RA). A contributing factor to the induction of such autoantibodies may be upregulated expression of the corresponding antigen G6PI in affected tissues and/or increased levels of G6PI in the circulation. To determine G6PI levels and the presence of free G6PI and/or G6PI-containing immune complexes in sera and synovial fluids (SF) of patients with different arthritides, serum and SF obtained concomitantly from 91 clinically well-defined arthritis patients were assessed in a blinded manner for G6PI enzymatic assay and for G6PI protein concentration by ELISA. Sera and SF from patients with immune-based inflammatory arthritis contained significantly higher levels of G6PI enzymatic activity compared to sera or SF from patients with non-immune-based inflammatory arthritis or healthy controls. In addition, significantly higher levels of total G6PI protein concentration (including both enzymatically active and inactive forms) were present in sera of RA patients vs. those with other immune-based or non-immune-based inflammatory arthritis.G6PI in sera and SF were present both as G6PI-containing immune complexes and as free G6PI, with the majority of free G6PI existing as tetramers with lesser amounts of dimers and monomers. Levels of G6PI enzymatic activity in the sera of most immune-based inflammatory arthritis patients are elevated and may reflect ongoing inflammation and cell destruction. The high serum levels of enzymatically inactive forms of G6PI in RA relative to those in other arthritic diseases are partially due to G6PI-containing immune complexes, a portion of which also contains C1q. Overall, our study supports the notion that elevated G6PI levels present in patients with immune-based inflammatory arthritis may contribute to elevated levels of anti-G6PI Abs and G6PI/anti-G6PI immune complexes. This, in turn, may trigger production of proinflammatory cytokines and perpetuate the inflammatory process.

Arthritis↗

PubMed2006

Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand mixed 2328 mice deficient in BAFF.

Constitutive overexpression of B cell-activating factor belonging to the TNF family (BAFF) promotes development of systemic lupus erythematosus (SLE), and treatment of SLE mice with BAFF antagonists ameliorates disease. To determine whether SLE can develop de novo in BAFF-deficient hosts, BAFF-deficient New Zealand Mixed (NZM) 2328 (NZM.Baff(-/-)) mice were generated. In NZM.Baff(-/-) mice, spleen B cells (including CD5(+) B1a and CD5(-) B1b B cells), germinal centers, Ig-secreting cells, and T cells were reduced in comparison to NZM.Baff(+/+) mice. Serum total Ig and autoantibody levels were reduced at 4-6 mo but approached wild-type levels with increasing age, indicating that autoreactive B cells can survive and secrete autoantibodies despite the complete absence of BAFF. At least some of these autoantibodies are nephrophilic in that glomerular deposition of total IgG and IgG1 (but not of IgG2a, IgG2b, or C3) was substantial in NZM.Baff(-/-) mice by 12-13 mo of age. Despite proliferative glomerulonephritis, highlighted by widespread glomerular hyaline thrombi, being common among NZM.Baff(-/-) mice by 6-7 mo of age, severe proteinuria and mortality were greatly attenuated. These results demonstrate that the lifelong absence of BAFF does not protect NZM 2328 mice from serological autoimmunity and renal pathology. Nevertheless, the character of the renal pathology is altered, and the mice are largely spared from clinically overt disease (severe proteinuria and premature death). These observations may have profound ramifications for the use of BAFF antagonists in human SLE and related diseases.

Animals↗

PubMed2006

B cell depletion therapy in systemic rheumatic diseases: different strokes for different folks?

Autoantibodies have, until recently, been the overriding focus of investigators of autoantibody-associated diseases. Increasing attention is now being paid to B cells, which not only are the producers of autoantibodies but also contribute to autoimmune disease via autoantibody-independent mechanisms. Therapeutic measures that target B cells for depletion are gaining in popularity. In this review, we will focus on two distinct approaches of depleting B cells; one employing a direct-kill approach by engagement of B cell surface CD20 with an anti-CD20 monoclonal antibody (rituximab), and the other employing an indirect starvation approach by neutralization of B lymphocyte stimulator (BLyS), a potent B cell survival factor. Among the systemic immune-based rheumatic disorders, we will focus on rheumatoid arthritis and systemic lupus erythematosus, two disorders for which therapeutic B cell targeting is being intensely investigated.

Animals↗

PubMed2006

TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells.

Although positive CD28 costimulation is needed for the generation of natural CD4+CD25+ regulatory T cells, we report that negative CTLA-4 costimulation is necessary for generating phenotypically and functionally similar adaptive CD4+CD25+ suppressor cells. TGF-beta could not induce CD4+CD25- cells from CTLA-4(-/-) mice to express normal levels of FoxP3 or to develop suppressor activity. Moreover, blockade of CTLA-4 following activation of wild-type CD4+ cells abolished the ability of TGF-beta to induce FoxP3-expressing mouse suppressor cells. TGF-beta accelerated expression of CTLA-4, and time course studies suggested that CTLA-4 ligation of CD80 shortly after T cell activation enables TGF-beta to induce CD4+CD25- cells to express FoxP3 and develop suppressor activity. TGF-beta also enhanced CD4+ cell expression of CD80. Thus, CTLA-4 has an essential role in the generation of acquired CD4+CD25+ suppressor cells in addition to its other inhibitory effects. Although natural CD4+CD25+ cells develop normally in CTLA-4(-/-) mice, the lack of TGF-beta-induced, peripheral CD4+CD25+ suppressor cells in these mice may contribute to their rapid demise.

Animals↗

PubMed2006

Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B cell depletion, circulating antibodies, and clinical relapse.

OBJECTIVE: To assess the effects of B lymphocyte depletion on serum B lymphocyte stimulator (BLyS; trademark of Human Genome Sciences, Rockville, MD) levels in patients with rheumatoid arthritis (RA), and to assess the relationship of serum BLyS levels with peripheral blood B cell depletion, levels of autoantibodies and antimicrobial antibodies, the return of peripheral blood B cells, and clinical relapse. METHODS: Fifteen patients with active RA underwent rituximab-based B cell depletion therapy (BCDT). Disease activity was assessed clinically, peripheral blood CD19+ B cell counts were determined by flow cytometry, and serum levels of BLyS, IgM, IgA, and IgG rheumatoid factors (RFs), anti-cyclic citrullinated peptide, and antimicrobial antibodies were assessed using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood B cell depletion was achieved in all 15 patients, and an American College of Rheumatology 20% response was achieved in 13 patients. Following clinical relapse, 7 patients underwent at least 1 additional cycle of BCDT. In every case, serum BLyS levels markedly rose post-BCDT and remained elevated for at least 1-2 months. Serum levels of RF, but not those of anti-tetanus toxoid or anti-pneumococcal polysaccharide antibodies, fell significantly. A decline in serum BLyS levels was associated with the reemergence of B cells in peripheral blood, which, in turn, antedated clinical relapse by variable periods of time. The patterns of B cell depletion, serum BLyS and antibody levels, and clinical relapse for each BCDT cycle were remarkably similar in re-treated patients. CONCLUSION: Rituximab-based BCDT leads to marked increases in serum BLyS levels. This may contribute significantly to the survival and/or regeneration of B cell populations capable of triggering clinical relapse.

Adult↗

PubMed2006

B lymphocyte stimulator (BLyS) isoforms in systemic lupus erythematosus: disease activity correlates better with blood leukocyte BLyS mRNA levels than with plasma BLyS protein levels.

Considerable evidence points to a role for B lymphocyte stimulator (BLyS) overproduction in murine and human systemic lupus erythematosus (SLE). Nevertheless, the correlation between circulating levels of BLyS protein and disease activity in human SLE is modest at best. This may be due to an inadequacy of the former to reflect endogenous BLyS overproduction faithfully, in that steady-state protein levels are affected not just by production rates but also by rates of peripheral utilization and excretion. Increased levels of BLyS mRNA may better reflect increased in vivo BLyS production, and therefore they may correlate better with biologic and clinical sequelae of BLyS overexpression than do circulating levels of BLyS protein. Accordingly, we assessed peripheral blood leukocyte levels of BLyS mRNA isoforms (full-length BLyS and DeltaBLyS) and plasma BLyS protein levels in patients with SLE, and correlated these levels with laboratory and clinical features. BLyS protein, full-length BLyS mRNA, and DeltaBLyS mRNA levels were greater in SLE patients (n = 60) than in rheumatoid arthritis patients (n = 60) or normal control individuals (n = 30). Although full-length BLyS and DeltaBLyS mRNA levels correlated significantly with BLyS protein levels in the SLE cohort, BLyS mRNA levels were more closely associated with serum immunoglobulin levels and SLE Disease Activity Index scores than were BLyS protein levels. Moreover, changes in SLE Disease Activity Index scores were more closely associated with changes in BLyS mRNA levels than with changes in BLyS protein levels among the 37 SLE patients from whom repeat blood samples were obtained. Thus, full-length BLyS and DeltaBLyS mRNA levels are elevated in SLE and are more closely associated with disease activity than are BLyS protein levels. BLyS mRNA levels may be a helpful biomarker in the clinical monitoring of SLE patients.

Arthritis, Rheumatoid↗

PubMed2006

Therapeutic targeting of B lymphocyte stimulator (BLyS) in the rheumatic diseases.

B lymphocyte stimulator (BLyS) is a vital B cell survival factor. Overexpression of BLyS in mice can lead to clinical and serological features of systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). Treatment with BLyS antagonists of mice with established SLE ameliorates disease progression and enhances survival. Moreover, similar treatment of mice with inflammatory arthritis ameliorates the ongoing inflammation and subsequent joint destruction. In humans, BLyS overexpression is common in patients with several rheumatic diseases, including SLE, rheumatoid arthritis (RA), Sjögren's syndrome, scleroderma, Wegener's granulomatosis, and ANCA-associated vasculitis. Results from phase-II clinical trials with a BLyS antagonist in human SLE and RA have shown the antagonist to have biological and clinical activity along with a favorable safety profile. These features collectively point to BLyS as an attractive therapeutic target in human rheumatic diseases.

Animals↗

PubMed2005

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus.

OBJECTIVE: To determine whether overexpression of BAFF can accelerate the development of systemic lupus erythematosus-associated end-organ disease in hosts with an underlying autoimmune diathesis. METHODS: We introduced a BAFF transgene (Tg) into autoimmune-prone B6.Sle1 and B6.Nba2 mice and evaluated these mice for serologic autoimmunity and renal pathology. RESULTS: B6.Sle1.BAFF and B6.Nba2.BAFF mice, but not non-Tg littermates, frequently developed severe glomerular pathology by 3 months of age. Age-matched B6.BAFF mice, despite renal Ig deposits and increases in B cells and Ig production similar to those in B6.Sle1.BAFF and B6.Nba2.BAFF mice, did not develop glomerular pathology. In B6.Sle1.BAFF and B6.Nba2.BAFF mice, severity of glomerular disease did not obligately correlate with circulating levels of IgG anti-chromatin and/or anti-double-stranded DNA antibodies or with amounts of these autoantibodies deposited in the kidneys. Even in mice with severe glomerular disease, renal tubulointerstitial infiltrates were very limited, and increased proteinuria was not detected. CONCLUSION: BAFF-driven effects on glomerular pathology may be mediated, at least in part, by autoantibodies with specificities other than chromatin and/or by autoantibody-independent means. There is an uncoupling of BAFF-driven precocious glomerular pathology from concomitant development of clinically apparent renal disease, strongly suggesting that BAFF overexpression works in concert with other factors to promote overt renal disease.

Animals↗

PubMed2005

Humoral autoimmunity in mice overexpressing B cell surface CD19: vital role for MHC class II.

B6 mice bearing a transgene (Tg) for human CD19 (hCD19) harbor increased numbers of splenic Ig-secreting cells (IgSC), increased serum levels of total Ig and autoantibodies, but decreased numbers of splenic B cells. To assess the influence of MHC class II (MHCII) to this phenotype, MHCII-deficient CD19-Tg mice were generated. Compared to MHCII-sufficient CD19-Tg mice, splenic IgSC numbers and serum Ig and autoantibody levels were markedly diminished, and the decrease in splenic B cell numbers was aggravated. Remarkably, genetic reconstitution of these MHCII-deficient mice with a human DQ8 Tg resulted in a hierarchical restorative pattern. Restoration of splenic B cell numbers was complete; restoration of numbers of splenic IgSC and of serum Ig levels was partial; and restoration of circulating autoantibody levels was virtually non-existent. Thus, MHCII expression has a profound effect on B cells which can be uncoupled from global Ig and autoantibody production in the hCD19-Tg model. This raises the possibility that MHCII affects B cells in a manner that, at least in part, is independent of helper T cell function.

Animals↗

PubMed2005

BlySfulness does not equal blissfulness in systemic lupus erythematosus: a therapeutic role for BLyS antagonists.

B lymphocyte stimulator (BLyS) is a vital B cell survival factor. Constitutive overexpression of BLyS in mice can lead to systemic lupus erythematosus (SLE)-like disease. Mice which naturally develop SLE harbor elevated circulating levels of BLyS, and treatment of these mice with BLyS antagonists ameliorates disease progression and enhances survival. In human SLE, BLyS overexpression is also common. Results from a phase-I clinical trial in human SLE with a neutralizing anti-BLyS monoclonal antibody have shown the antagonist to be biologically active and safe. These features collectively point to BLyS and/or its receptors as attractive therapeutic targets in human SLE.

Animals↗

PubMed2004

MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4).

One of the key downregulators of T cell activation is CD152 (CTLA-4). Mice genetically deficient in CD152 (cd152(-/-) mice) develop massive expansion of both CD4(+) and CD8(+) T cells as well as increased numbers of splenic Ig-secreting cells and serum Ig levels. To determine the dependence of the lymphoproliferation and B cell hyperactivity on MHC class II (MHCII), MHCII-deficient (mhcii(-/-)) cd152(-/-) mice were generated. Compared to that in their mhcii(+/+) counterparts, expansion of CD4(+) cells in mhcii(-/-)cd152(-/-) mice was markedly attenuated. Nonetheless, expansion of CD8(+) cells was identical in both sets of mice, demonstrating that the effects of CD152 deficiency on CD4(+) cells can quantitatively be dissociated from those on CD8(+) cells, and pointing to a critical downregulatory role for CD152 in MHCII-independent CD8(+) cell activation in vivo. B cell hyperactivity also developed in mhcii(-/-)cd152(-/-) mice, albeit in a manner less rapid and less intense than that in their mhcii(+/+) counterparts, demonstrating an underlying MHCII-independent diathesis to B cell dysregulation and pointing to a critical downregulatory role for CD152 in MHCII-independent B cell activation in vivo. When human DQ8 was introduced as a transgene into mhcii(-/-)cd152(-/-) mice, B cell hyperactivity was restored to levels observed in mhcii(+/+)cd152(-/-) mice, pointing to a critical downregulatory role for CD152 in MHCII-dependent B cell activation in vivo superimposed upon its downregulatory role on MHCII-independent B cell activation.

Animals↗

PubMed2004

Dichotomous effects of complete versus partial class II major histocompatibility complex deficiency on circulating autoantibody levels in autoimmune-prone mice.

OBJECTIVE: To assess the effects of altered class II major histocompatibility complex (MHCII) expression on circulating autoantibody levels in C57BL/6 (B6) mice congenic for the Sle1 (B6.Sle1 mice) or Nba2 (B6.Nba2 mice) regions. METHODS: H-2Ab(+/+) (MHCII-intact), H-2Ab(+/-) (MHCII-intermediate), and H-2Ab(-/-) (MHCII-deficient) littermate B6.Sle1 and B6.Nba2 mice were evaluated for spleen cell phenotype, numbers of splenic Ig-secreting cells, and serum levels of total IgM, total IgG, IgG antichromatin, IgG antihistone, and IgG anti-double-stranded DNA (anti-dsDNA). RESULTS: Compared with their MHCII-intact littermates, MHCII-deficient B6.Sle1 and B6.Nba2 mice developed markedly decreased circulating levels of IgG autoantibodies, along with decreased circulating levels of total IgG. In sharp contrast, MHCII-intermediate mice developed increased circulating levels of IgG autoantibodies. This was associated with increased numbers of splenic Ig-secreting cells and serum levels of total IgG in B6.Sle1 mice, but it occurred without concomitant increases in the numbers of splenic Ig-secreting cells or serum total IgG levels in B6.Nba2 mice. CONCLUSION: In 2 clinically healthy strains of mice with a genetic proclivity for developing autoantibodies, the effects of class II MHC expression on levels of circulating IgG autoantibodies were found to be complex. In the absence of MHCII expression, circulating IgG autoantibody levels were minimal. With full MHCII expression, circulating IgG autoantibody levels were considerable. With intermediate MHCII expression, circulating IgG autoantibody levels were even greater. These last findings may help explain why heterozygosity at the H-2 locus is associated with increased autoantibody titers and aggravated disease in certain lupus-prone mice.

Animals↗

PubMed2004

Increased CXCL8 (IL-8) expression in Multiple Sclerosis.

Multiple Sclerosis (MS) is a chronic inflammatory disease of the CNS which is characterized by large mononuclear cell infiltration and significant demyelination. CXCL8 is a chemo-attractant for both neutrophils and monocytes and triggers their firm adhesion to endothelium. In this study, we demonstrate that serum CXCL8 and CXCL8 secretion from PBMCs are significantly higher in untreated MS patients compared to controls and are significantly reduced in MS patients receiving interferon-beta1a therapy. We suggest that CXCL8 may serve as a marker of monocyte activity in MS and may play a role in monocyte recruitment to the CNS.

Adult↗

PubMed2004

Targeting B lymphocyte stimulator in systemic lupus erythematosus and other autoimmune rheumatic disorders.

B lymphocyte stimulator (BLyS) is a vital B cell survival factor. Overexpression of BLyS in mice can lead to systemic lupus erythematosus (SLE)-like disease and to Sjögren's syndrome (SS)-like disease. Treatment of mice with established SLE with BLyS antagonists ameliorates disease progression and enhances survival. Moreover, similar treatment of mice with inflammatory arthritis ameliorates the ongoing inflammation and subsequent joint destruction. In humans, BLyS overexpression is common in patients with SLE, rheumatoid arthritis or SS. Results from a Phase I clinical trial with a BLyS antagonist in human SLE have shown the antagonist to be biologically active and safe. These features collectively point to BLyS as an attractive therapeutic target in human disease.

Animals↗

PubMed2003

SLE--systemic lupus erythematosus: a BLySful, yet BAFFling, disorder.

BLyS/BAFF (B-lymphocyte stimulator/B-cell activating factor) is a vital B-cell survival factor. Overexpression of BLyS in mice may lead to systemic-lupus-erythematosus-like (SLE-like) disease, and BLyS overexpression is common in human SLE. Treatment of SLE-prone mice with a BLyS antagonist ameliorates disease progression and enhances survival, making BLyS an attractive therapeutic target in human disease. However, several unresolved issues remain, including what is the contributory role of APRIL (a tumor-necrosis-factor superfamily member related to BLyS) in the 'autoimmunogenic' effects of BLyS, identification of the 'optimal' BLyS antagonist, and identification of those SLE patients most likely to benefit from BLyS antagonist therapy.

Animals↗

PubMed2003

Local production of B lymphocyte stimulator protein and APRIL in arthritic joints of patients with inflammatory arthritis.

OBJECTIVE: To determine whether synovial fluid (SF) levels and cell-surface expression of B lymphocyte stimulator (BLyS) protein and SF levels of APRIL are elevated in patients with inflammatory arthritis (IA). METHODS: Same-day blood and SF samples from 89 patients with 103 knee effusions (81 knees with IA and 22 with noninflammatory arthritis [NIA]) were evaluated for BLyS protein and APRIL levels by enzyme-linked immunosorbent assay. Blood and SF mononuclear cells were double-stained for surface BLyS protein and surface CD14 (monocyte marker) and were analyzed by flow cytometry. Complete blood cell counts and SF nucleated cell counts were performed by the clinical hematology laboratory. RESULTS: BLyS protein levels were higher in SF than in corresponding serum samples from both IA and NIA patients. SF BLyS protein levels, but not surface expression of BLyS protein, were disproportionately elevated in IA patients. APRIL levels were higher in SF than in corresponding serum samples from most IA patients but not NIA patients. SF BLyS protein and APRIL levels correlated with each other, and each correlated with SF monocyte, lymphocyte, neutrophil, and total nucleated cell counts. Although SF and serum BLyS protein levels correlated with each other, SF and serum APRIL levels did not, suggesting that SF BLyS protein levels are more dependent upon systemic factors than are SF APRIL levels. Moreover, in 8 patients who underwent sequential arthrocenteses, changes in SF BLyS protein levels did not immutably parallel changes in SF APRIL levels, indicating their differential regulation. CONCLUSION: BLyS protein and APRIL are locally produced in inflamed joints. Their respective SF levels are differentially regulated, suggesting that they serve different functions. Together, their local production may foster survival and/or expansion of B cells that produce pathogenic autoantibodies and/or promote local T cell activation and consequent joint destruction.

Adult↗

PubMed2003

B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations.

OBJECTIVE: To assess the overexpression of B lymphocyte stimulator (BLyS) over time in patients with systemic lupus erythematosus (SLE). METHODS: Sixty-eight SLE patients were followed up longitudinally for a median 369 days. At each physician encounter, disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index, and blood was collected for determination of the serum BLyS level, blood BLyS messenger RNA (mRNA) level, and cell surface BLyS expression. Twenty normal control subjects underwent similar laboratory evaluations. RESULTS: In contrast to the uniformly normal serum BLyS and blood BLyS mRNA phenotypes in control subjects, SLE patients displayed marked heterogeneity, with 50% and 61% of patients manifesting persistently or intermittently elevated serum BLyS and blood BLyS mRNA phenotypes, respectively. Surface BLyS expression by SLE peripheral blood mononuclear cells was also often increased. Treatment of patients who had elevated serum BLyS levels with intensive courses of high-dose corticosteroids resulted in marked reductions in serum BLyS levels, and tapering of the corticosteroid dosage often resulted in increases in serum BLyS levels. Serum BLyS levels generally correlated with anti-double-stranded DNA (anti-dsDNA) titers (in those with detectable anti-dsDNA titers), but changes in serum BLyS levels did not correlate with changes in disease activity in individual patients. Serum BLyS phenotype did not associate with specific organ system involvement. CONCLUSION: Dysregulation of BLyS over extended periods of time is common in patients with SLE. Neutralization of BLyS activity with an appropriate BLyS antagonist may be therapeutically beneficial.

Adrenal Cortex Hormones↗

PubMed2003

In vitro and in vivo T cell oligoclonality following chronic stimulation with staphylococcal superantigens.

Microbial superantigens (SAg), including SEB and TSST-1, polyclonally activate T cells belonging to specific TCR BV families. A pathogenic role for SAg in various human diseases has been suggested, but enthusiasm for this view has been tempered by the T cell oligoclonality in these disorders. To assess whether T cell oligoclonality can emerge following protracted SAg stimulation, human PBMC were stimulated with SEB, TSST-1, or anti-CD3 mAb and maintained in culture with exogenous IL-2. Oligoclonality was appreciated by day 14 among CD4(+) and CD8(+) T cells. In addition, mice transgenic for human DR2 and DQ8 were injected weekly with SEB, and splenic CD4(+) and CD8(+) T cells were analyzed for oligoclonality. In mice that received one or three such injections, little-to-no oligoclonality was detected. In contrast, considerable oligoclonality was detected in mice that received eight weekly SEB injections. Many of these T cell oligoclones were identical to "spontaneously" arising oligoclones detected in SEB-naive mice. Thus, T cell oligoclonality can emerge following chronic SAg stimulation. In hosts who have lost tolerance to self Ag, chronic exposure to SAg may preferentially promote expansion of autoreactive T cells and facilitate development of clinical disease.

Animals↗