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Diane Mathis

Publications and source records attributed to Diane Mathis.

52 records · Page 3Linked to original sources
PubMed2004

Progression to islet destruction in a cyclophosphamide-induced transgenic model: a microarray overview.

Type 1 diabetes appears to progress not as an uncontrolled autoimmune attack on the pancreatic islet beta-cells, but rather in a highly regulated manner. Leukocytic infiltration of the pancreatic islets by autoimmune cells, or insulitis, can persist for long periods of time before the terminal destruction of beta-cells. To gain insight on the final stage of diabetogenesis, we have studied progression to diabetes in a CD4(+) T-cell receptor transgenic variant of the NOD mouse model, in which diabetes can be synchronously induced within days by a single injection of cyclophosphamide. A time-course analysis of the gene expression profiles of purified islets was performed using microarrays. Contrary to expectations, changes in transcripts subsequent to drug treatment did not reflect a perturbation of gene expression in CD4(+) T-cells or a reduction in the expression of genes characteristic of regulatory T-cell populations. Instead, there was a marked decrease in transcripts of genes specific to B-cells, followed by an increase in transcripts of chemokine genes (cxcl1, cxcl5, and ccl7) and of other genes typical of the myelo-monocytic lineages. Interferon-gamma dominated the changes in gene expression to a striking degree, because close to one-half of the induced transcripts issued from interferon-gamma-regulated genes.

Animals↗
PubMed2003

Paradoxical dampening of anti-islet self-reactivity but promotion of diabetes by OX40 ligand.

Costimulatory signals received by diabetogenic T cells during priming by or upon secondary encounter with autoantigen are decisive in determining the outcome of autoimmune attack. The OX40-OX40 ligand (OX40L) costimulatory pathway is known to influence T cell responses, prompting us to examine its role in autoimmune diabetes. A null allele at OX40L completely prevented diabetes development in nonobese diabetic mice and strongly reduced its incidence in a TCR transgenic model (BDC2.5). However, somewhat paradoxically, the initial activation of T cells responsive to islet beta cell Ag was slightly faster and more efficient in the absence of OX40L, with an increased degree of cell proliferation and survival in the deficient hosts. Activated T cell migration into and retention within the islets was also slightly accelerated. When challenged in vitro, splenocytes from BDC2.5.OX40L(o/o) mice showed no altered reactivity to exogenously added peptide, no bias to the Th1 or Th2 phenotype, and no alteration in T cell survival. Thus, the OX40/OX40L axis has the paradoxical effect of dampening the early activation and migration of autoimmune T cells, but sustains the long-term progression to autoimmune destruction.

Adoptive Transfer↗
PubMed2003

Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model.

The prelude to type-1 diabetes is leukocyte infiltration into the pancreatic islets, or insulitis. This process begins in pancreatic lymph nodes when T lymphocytes reactive to islet beta cells encounter antigen-presenting cells (APCs) displaying peptides derived from beta cell proteins. We show here that a ripple of physiological beta cell death, which occurs at 2 wk of age in all mouse strains, precipitates the arrival of such APCs, and that the relevant APC is a dendritic cell of CD11c+CD11b+CD8alpha- phenotype. These findings have significant implications concerning the nature of the diabetes-provoking deficits in NOD mice, the identity of the primordial diabetogenic antigens, and our understanding of the balance between immunity and tolerance in a pathological context.

Animals↗
PubMed2003

Low prevalence of antibodies to glucose-6-phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders.

OBJECTIVE: Arthritis in the K/BxN mouse model results from pathogenic immunoglobulins that recognize glucose-6-phosphate isomerase (GPI), a glycolytic enzyme residing in the cytoplasm of all cells. Antibodies directed against GPI can, alone, transfer arthritis to healthy recipients. Previous experiments have revealed significant titers of anti-GPI antibodies in the serum of many patients with rheumatoid arthritis (RA). We evaluated the generality of these observations in cohorts of patients with 12 different arthritic and chronic autoimmune diseases and in population-matched healthy control subjects. METHODS: Anti-GPI antibodies were assayed in 811 individual serum samples by enzyme-linked immunosorbent assay with 2 forms of GPI, recombinant and native. Results were confirmed by immunoblotting. RESULTS: Several patients had significantly elevated anti-GPI antibody titers, but without the prevalence or the specificity reported previously. Only 15% of RA patients had anti-GPI antibodies (range 12-29% in different cohorts), with a higher prevalence in patients with active disease. Psoriatic arthritis, undifferentiated arthritis, and spondylarthropathy patients also displayed anti-GPI antibodies at similar frequencies (12-25%). Similar titers were detected in a proportion (5-10%) of control subjects or patients with Crohn's disease or sarcoidosis. Very high titers were found in rare cases of RA and systemic lupus erythematosus. CONCLUSION: No disease-specific pattern of antibody positivity to GPI was apparent. While the antibody-mediated mechanism at play in the mouse model may exemplify a generic mechanism for some forms of arthritis in humans, GPI itself does not appear to be a target common to the majority of RA patients.

Adult↗
PubMed2003

Susceptible MHC alleles, not background genes, select an autoimmune T cell reactivity.

To detect and characterize autoreactive T cells in diabetes-prone NOD mice, we have developed a multimeric MHC reagent with high affinity for the BDC-2.5 T cell receptor, which is reactive against a pancreatic autoantigen. A distinct population of T cells is detected in NOD mice that recognizes the same MHC/peptide target. These T cells are positively selected in the thymus at a surprisingly high frequency and exported to the periphery. They are activated specifically in the pancreatic LNs, demonstrating an autoimmune specificity that recapitulates that of the BDC-2.5 cell. These phenomena are also observed in mouse lines that share with NOD the H-2g7 MHC haplotype but carry diabetes-resistance background genes. Thus, a susceptible haplotype at the MHC seems to be the only element required for the selection and emergence of autoreactive T cells, without requiring other diabetogenic loci from the NOD genome.

Alleles↗
PubMed2003

T-cell compartments of prediabetic NOD mice.

Given the importance of the NOD mouse as a model of type 1 diabetes, there is a surprising lack of published information on the overall composition of the thymic and peripheral T-cell compartments. In this study, we revisited some earlier reports of T-cell abnormalities in this strain and examined a number of additional parameters to provide a global view of T-cells in prediabetic NOD mice. In some cases, we concur with past conclusions, but in other important areas, we find that NOD mice closely resemble nonautoimmune strains. Specifically, and contrary to published reports, the thymocyte subset distribution, the rate and composition of thymic export, and the composition of the peripheral T-cell pool, including the proportion of CD25(+)CD4(+) T-cells, are essentially normal in prediabetic NOD mice. These factors are therefore unlikely to be involved in the loss of tolerance that leads to autoimmunity within this strain.

Animals↗
PubMed2002

Projection of an immunological self shadow within the thymus by the aire protein.

Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.

Aging↗
PubMed2002

Mast cells: a cellular link between autoantibodies and inflammatory arthritis.

Previous studies have revealed that autoantibodies, complement components, and Fc receptors each participate in the pathogenesis of erosive arthritis in K/BxN mice. However, it is not known which cellular populations are responsive to these inflammatory signals. We find that two strains of mice deficient in mast cells, W/Wv and Sl/Sld, were resistant to development of joint inflammation and that susceptibility was restored in the W/Wv strain by mast cell engraftment. Thus, mast cells may function as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis.

Animals↗
PubMed2002

B-cell signaling: protein kinase Cdelta puts the brakes on.

The phenotype of mice lacking the delta isoform of protein kinase C reveals that this isoform curtails signaling events after engagement of the antigen-specific receptor on B cells. The result is a state of non-responsiveness, termed anergy, that represents one form of immunological self-tolerance.

Animals↗
PubMed2002

Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis.

In spontaneous inflammatory arthritis of K/BxN T cell receptor transgenic mice, the effector phase of the disease is provoked by binding of immunoglobulins (Igs) to joint surfaces. Inflammatory cytokines are known to be involved in human inflammatory arthritis, in particular rheumatoid arthritis, although, overall, the pathogenetic mechanisms of the human affliction remain unclear. To explore the analogy between the K/BxN model and human patients, we assessed the role and relative importance of inflammatory cytokines in K/BxN joint inflammation by transferring arthritogenic serum into a panel of genetically deficient recipients. Interleukin (IL)-1 proved absolutely necessary. Tumor necrosis factor (TNF)-alpha was also required, although seemingly less critically than IL-1, because a proportion of TNF-alpha-deficient mice developed robust disease. There was no evidence for an important role for IL-6. Bone destruction and reconstruction were also examined. We found that all mice with strong inflammation exhibited the bone erosion and reconstruction phenomena typical of K/BxN arthritis, with no evidence of any particular requirement for TNFalpha for bone destruction. The variability in the requirement for TNF-alpha, reminiscent of that observed in treated rheumatoid arthritis patients, did not appear genetically programmed but related instead to subtle environmental changes.

Animals↗
PubMed2002

Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells.

Both naive and memory T cells undergo antigen-independent proliferation after transfer into a T cell-depleted environment (acute homeostatic proliferation), whereas only memory T cells slowly divide in a full T cell compartment (basal proliferation). We show, first, that naive and memory CD8+ T cells have different cytokine requirements for acute homeostatic proliferation. Interleukin (IL)-7 receptor(R)alpha-mediated signals were obligatory for proliferation of naive T cells in lymphopenic hosts, whereas IL-15 did not influence their division. Memory T cells, on the other hand, could use either IL-7Ralpha- or IL-15-mediated signals for acute homeostatic proliferation: their proliferation was delayed when either IL-7Ralpha was blocked or IL-15 removed, but only when both signals were absent was proliferation ablated. Second, the cytokine requirements for basal and acute homeostatic proliferation of CD8+ memory T cells differ, as basal division of memory T cells was blocked completely in IL-15-deficient hosts. These data suggest a possible mechanism for the dearth of memory CD8+ T cells in IL-15- and IL-15Ralpha-deficient mice is their impaired basal proliferation. Our results show that naive and memory T lymphocytes differ in their cytokine dependence for acute homeostatic proliferation and that memory T lymphocytes have distinct requirements for proliferation in full versus empty compartments.

Animals↗
PubMed2002

Arthritogenic monoclonal antibodies from K/BxN mice.

Arthritis in the K/BxN mouse model is provoked by pathogenic antibodies (Abs) directed against a ubiquitously expressed protein, glucose-6-phosphate isomerase (GPI). To begin dissecting the repertoire of arthritogenic immunoglobulins (Igs) in the K/BxN model, and to provide a basis for comparison with RA patients we have generated anti-GPI monoclonal Abs (mAbs) from spontaneously activated B cells in the lymphoid organs of arthritic mice. B cell clones with anti-GPI specificities were present at extraordinarily high frequencies in the spleen, and less frequently in other lymphoid organs and in the synovial fluid. None of the anti-GPI mAbs induced arthritis when injected individually into healthy recipients, but most were effective when combined in pairs or larger pools. Arthritogenic combinations depended on mAbs of the IgG1 isotype, which bound to GPI with Kd in the 10(-9) M range, with no indication of cooperative binding between complementing pairs. Pathogenicity was not associated with recognition of a particular epitope, but the ability to form mAb/GPI multimers by simultaneous recognition of different epitopes was clearly required, consistent with the known role of complement and FcRs in this model. Sequence analysis revealed structural similarities amongst the mAbs, indicating that a particular subset of B cells may evade tolerance in K/BxN mice, and that affinity maturation by somatic mutation likely takes place. These results confirm that GPI itself, rather than a cross-reactive molecule, is the target of pathogenic Igs.

Animals↗
PubMed2002

How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease.

Arthritis in the K/BxN mouse model results from pathogenic immunoglobulins (Igs) that recognize the ubiquitous cytoplasmic enzyme glucose-6-phosphate isomerase (GPI). But how is a joint-specific disease of autoimmune and inflammatory nature induced by systemic self-reactivity? No unusual amounts or sequence, splice or modification variants of GPI expression were found in joints. Instead, immunohistological examination revealed the accumulation of extracellular GPI on the lining of the normal articular cavity, most visibly along the cartilage surface. In arthritic mice, these GPI deposits were amplified and localized with IgG and C3 complement. Similar deposits were found in human arthritic joints. We propose that GPI-anti-GPI complexes on articular surfaces initiate an inflammatory cascade via the alternative complement pathway, which is unbridled because the cartilage surface lacks the usual cellular inhibitors. This may constitute a generic scenario of arthritogenesis, in which extra-articular proteins coat the cartilage or joint extracellular matrix.

Animals↗
PubMed2002

Arthritis critically dependent on innate immune system players.

K/BxN T cell receptor transgenic mice are a model of inflammatory arthritis, similar to rheumatoid arthritis. Disease in these animals is focused specifically on the joints but stems from autoreactivity to a ubiquitously expressed antigen, glucose-6-phosphate isomerase (GPI). T and B cells are both required for disease initiation, but anti-GPI immunoglobulins (Igs), alone, can induce arthritis in lymphocyte-deficient recipients. Here, we show that the arthritogenic Igs act through both Fc receptors (in particular, FcgammaRIII) and the complement network (C5a). Surprisingly, the alternative pathway of complement activation is critical, while classical pathway components are entirely dispensable. We suggest that autoimmune disease, even one that is organ specific, can occur when mobilization of an adaptive immune response results in runaway activation of the innate response.

Animals↗
PubMedDate not supplied

Mast cells in autoimmune disease.

Mast cells are known to be the primary responders in allergic reactions, orchestrating strong responses to minute amounts of allergens. Several recent observations indicate that they may also have a key role in coordinating the early phases of autoimmune diseases, particularly those involving auto-antibodies.

Animals↗