Objective. To assess the presence of fibroblast collagenase (MMP-l), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13) in osteoarthritic (OA) cartilage, with particular emphasis on areas of macroscopic cartilage erosion.Methods. Messenger RNA (mRNA) levels were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, and Northern blot analysis.Results. MMP-1 and MMP-13 were expressed at higher levels by OA chondrocytes than by normal chondrocytes. In addition, mRNA for MMP-8 was present in OA cartilage but not normal cartilage by PCR and Northern blot analyses. Chondrocytes from areas surrounding the OA lesion expressed greater quantities of MMP-1 and MMP-13 compared with normal chondrocytes, suggesting local modulation by mechanical and inflammatory factors. Tumor necrosis factor a stimulated the expression of all 3 collagenases. Retinoic acid, an agent which induces autodigestion of cartilage in vitro, stimulated only the expression of MMP-13.Conclusion. These findings suggest a key role of MMP-13 and MMP-8, as well as MMP-1 in osteoarthritis.The matrix metalloproteinase (MMP) family of enzymes consists of at least 15 distinct entities, including

One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease 1,2 . This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS) 1-4 . There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/ tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5 -7 ). HAM/TSP patients develop antibodies to neurons 8 . We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5 ,9 ). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged 7 . Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS. To test for molecular mimicry between an environmental agent and the central nervous system (CNS), we isolated immunoglobulin G (IgG) from the serum of patients with human Tlymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and tested it for reactivity with human tissues (Fig. 1a). There was intense staining of neurons in brain and no staining of glia, dorsal root ganglion (peripheral nervous system) or systemic organs. A monoclonal antibody to HTLV-1-tax (tax mAb) mimicked IgG staining of neurons. To identify the protein, cortical neurons were isolated, proteins extracted and subjected to SDS-PAGE and western-blot analysis. The IgG recognized a band of approximately 33 kD (Fig. 1b), whereas IgG isolated from controls did not. Importantly, the tax mAb that stained CNS neurons reacted with the antigen. All patients with HAM/TSP (13/13) developed antibodies recognizing the neuronal antigen 8 . Nine of ten HTLV-1-seropositive patients without neurological symptoms and 12 HTLV-1-seronegative controls showed no reactivity (P < 0.0001 versus HAM/TSP) 8 . Clinically, the HAM/TSP patients presented with progressive neurological disease in which corticospinal tract damage (weakness, spasticity and pathological reflexes) predominated 6 . Many of our patients were originally diagnosed with MS. In fact, one of our patients was diagnosed with MS for 20 years before HTLV-1 testing 10 .To establish a direct link between the immune response to HTLV-1 and the neurological...

The glycosylated minor hemoglobin components Hb A1a+b and HbA1c are elevated in insulin-dependent juvenile diabetic patients, 3.2+/-0.7 (+/-1 SD) and 10.0+/-1.9% of total hemoglobin respectively, versus 2.1+/-0.4 and 4.9+/-0.7% in a normal non-diabetic control population. Total glycosylated hemoglobin components, Hb A1a+b+c, correlated with the degree of diabetic blood glucose regulation as measured by antecedent 24-h urinary glucose excretion determined in 220 diabetic patients immediately before, 1, 2, and 3 months prior to the HB A1a+b+c measurement. This assay for long-term blood glucose regulation was utilized to determine the effect of hyperglycemia on plasma cholesterol levels in 112 diabetic patients. Hb A1a+b+c levels correlated with plasma cholesterol levels, suggesting that long-term hyperglycemia is associated with hypercholesterolemia. It is suggested that glycosylated hemoglobin measurement is a good index of long-term blood glucose levels in diabetic patients.

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