Genetics of joint inflammation problems and possibilities

Medical Inflammation Research, BMC I11, Lund University, S-22184 Lund, Sweden The search for the heredity of rheumatic diseases is not a new issue for medical science or for millions of people that are affected or have relatives that are affected. The presence of rheumatic diseases is impossible to avoid they are easy to feel, to see and to diagnose. In addition, we nowadays have large resources of medical records and we know the genetic sequence of humans. So why have we not yet found the...

References

1 Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31 315-324 2 Arnett FC (1989) Revised criteria for the classification of rheumatoid arthritis. Bull Rheum Dis 38 1-6 3 Tak PP, Smeets TJ, Daha MR, Kluin PM, Meijers KA, Brand R, Meinders AE, Breedveld FC (1997) Analysis of the synovial cell infiltrate...

Epidemiology of rheumatoid arthritis

Rheumatoid arthritis (RA), the most common form of chronic inflammatory polyarthritis, represents a significant health burden in the developed world. The damage and deformity of the synovial joints characteristic of RA most commonly develops in the sixth decade but can occur at any age and will usually require treatments and interventions for the rest of an individual's life 1 . It is diagnosed and distinguished from other arthritic diseases on the basis of criteria defined in 1987 2 . The...

Index

Acute myeloid leukaemia 81 aggrecan 139 analysis, discovery driven 121 analysis, hypothesis driven 121 analysis, statistical 121 animal models, for arthritis regulating genes 165 ankylosing spondylitis (AS) 96, 136, 139 anti-citrullinated peptide antibody 50 association studies, rheumatoid arthritis 17 B27 transgenic rat model 92 bacterial infection 91 BALB c mouse 135 biobanked patient sample 107 bioinformatics, modelling 125 biomarker 30, 31, 108 biomarker pattern 108 Borrelia burgdorferi...

Contribution of environmental factors to the development of SKG arthritis

The ZAP-70W163C mutation alone is not sufficient, however, for triggering arthritis in SKG mice. In the presence of the genetic abnormality of ZAP-70, environmental factors are needed for triggering arthritis, as illustrated by the following findings. First, in contrast with a high incidence of severe arthritis in our conventional environment, SKG mice raised in a microbially clean environment fail to develop arthritis 26 . When the latter are transferred after weaning to a conventional...

SKG autoimmune arthritis as a model of human RA

As discussed above, clinical and immunopathological characteristics of SKG arthritis resemble those of RA in humans, making the strain a suitable model for studying human RA. A cardinal feature of this model is that a genetic defect of T-cells, but not the joint, leads to the development of autoimmune arthritis. Another is that in the presence of this genetic abnormality of the T-cell compartment, environmental stimuli are required for triggering arthritis. The ZAP-70 genetic defect affects the...

Heterogeneity in peripheral blood cells

Since RA is a systemic disease, several investigators study gene expression levels in peripheral blood cells to address the question, whether disease heterogeneity is detectable from gene expression levels in peripheral blood cells (Tab. 1, Fig. 1). Comparison of the gene expression profiles of peripheral blood mononuclear cells (PBMC) between 14 RA patients and seven healthy controls using DNA-microarrays containing 10K genes, revealed only nine genes that were differentially expressed 25 ....

The RUNX genes

RUNX1 is one of the three human genes belonging to the family of highly conserved runt-domain-encoding genes 16 . These are RUNX1 located on human chromosome 21q22.3, RUNX2 mapped to chromosome 6p21 and RUNX3 lying on chromosome 1p36 17-19 . All three regions have been linked to one or several autoimmune or rheumatic diseases 20 . RUNX proteins possess a striking feature to either repress or activate transcription of a large variety of genes depending on the co-factors present and architecture...

Humanized mice as models for rheumatoid arthritis

While rheumatoid arthritis (RA) remains an autoimmune disease of unknown etiology, susceptibility to RA is clearly associated with the expression of several human leukocyte antigens (HLA), including HLA-DR1 (DRB1*0101), HLA-DR4 Table 1 - Humanized mouse models of rheumatic diseases Table 1 - Humanized mouse models of rheumatic diseases DR6 (DRB1*1402) 1-3 . The relative risk and severity of RA varies among these susceptible HLA alleles, with Caucasian individuals expressing the *0401 allele...

Arthritogenic peptide hypothesis

Because the main function of HLA Class I molecules is to present peptide antigens to cytotoxic CD8+ T-cells it has been proposed that the antigen presenting properties of HLA-B27 could be crucial in the pathogenesis of spondy-loarthropathies, the so called 'arthritogenic peptide hypothesis' 24 . It suggests that some B27 subtypes, due to their unique amino acid residues, bind specific arthritogenic peptides, which are recognised by CD8+ T-cells. Furthermore, in response to these bacterial...

Immunopathology of arthritis in SKG mice

The SKG strain, which spontaneously develops chronic arthritis, is derived from our closed breeding colony of BALB c mice. It shows the following clinical and immunopathological features 12 . Clinically, hyperemia becomes macroscopically evident around 2 months of age, initially at a few interpharangeal joints of the fore paws, then progressing in a symmetrical fashion to swelling of other finger joints of the fore and hind paws, and larger joints (wrists and ankles). Although swelling of small...

Murine models for Lyme arthritis

Autoimmune arthritis associated with Lyme disease is yet another example where susceptibility to autoimmunity is strongly associated with expression of a specific HLA-DR allele. However, unlike almost all other autoimmune diseases, a causative agent for this autoimmune disease is known. Lyme disease is caused by an infection with Borrelia burgdorferi and the autoimmune arthritis develops as a sequela to this infection. Approximately 10 of infected individuals develop a chronic joint...

A point mutation of the ZAP70 gene as the primary cause of SKG arthritis

The primary cause of SKG arthritis is a genetic abnormality inherited in an autosomal recessive fashion with nearly 100 penetrance of the trait in homozygotes raised in our conventional environment. Linkage analysis between the development of macroscopically evident arthritis and the homozygosity of chromosome-specific microsatellite markers maps the skg locus to the centromeric portion of chromosome 1 with the lod score of the locus as infinite. Construction of a high-resolution genetic map of...