Genetic Control of Inflammation and Connective Tissue Remodeling in Arthritis and Spondyloarthritis
Rheumatoid arthritis and ankylosing spondylitis are among the most common autoimmune diseases affecting about 1% of the human population worldwide. There are several million patients suffering from these autoimmune disorders only in the United States. Despite the therapeutic approaches become increasingly effective in managing inflammation and associated pain, modern drugs are unable to prevent autoimmune diseases or completely block the disease progression. There are several major areas of research in the lab.
Pro-invasive Markers of Activated Fibroblasts in Arthritic Pannus
Synovial hypertrophy accompanied by increased production of cartilage- and bone-degrading enzymes is a hallmark of inflammatory arthritides, including rheumatoid arthritis (RA). In RA, the synovial membrane develops into a hypercellular pannus that destroys bone and cartilage, and behaves like a locally invasive tumor. Activated fibroblast-like synoviocytes (a-FLS) in the pannus are capable of spreading the disease to as yet unaffected joints via vasculature-independent routes. The invasive properties of a-FLS from RA patients as well as from murine arthritis models directly correlate with the rate of joint destruction and deformities, and poor disease outcome.
We found that murine Pgia8 locus of chromosome 15 suppressed murine aggrecan-induced and collagen antibody-induced arthritis. Of the Pgia8 locus-specific genes, expression of the Collagen Triple Helix Repeat containing-1 (Cthrc1), a member of the non-canonical Wnt signaling pathway, exhibited the strongest correlation with arthritis severity. CTHRC1 is secreted by a-FLS located at the forefront of the invasive pannus attacking the bone and cartilage. We focus on mechanisms of invasion and FLS maturation promoted with CTHRC1 secretion into synovium.
Novel Spondyloarthritogenic T cell Epitope in Reactive Arthritis
Reactive arthritis (ReA) is a spondyloarthropathy (SpA) and the second most common cause of inflammatory arthritis in human population after rheumatoid arthritis (RA). Evidence of preceding genitourinary or gastrointestinal infections (e.g., Chlamydia, Salmonella, Shigella, Yersinia, Campylobacter) is found in the majority of ReA cases. ReA is a sterile synovitis; therefore, the disease can be positioned between septic arthritis and classical autoimmune RA.
We established a murine model for human brucellosis-induced SpA. Among known ReA-associated infections, Gram-negative intracellular bacteria Brucella melitensis produces the highest ratio of osteoarticular complications, such as spondylitis and sacroiliitis that affect as many as 47% of brucellosis patients. We found that BALB/c mice exhibited a SpA-like pathology of arthritis and spinal disease even when bacteria were already eradicated from the body weeks post-infection. This observation is consistent with human brucellosis data and with criteria for ReA. The immunodominant Brucella-derived CTL epitope that drives the host response to infection is derived from the bacterial methionine sulfoxide reductase B3 (MSRB3). The homologous mouse (host) MSRB3 protein carries a sequence that is 100% identical to the Brucella epitope. We showed that mice immunized with the corresponding peptide develop arthritis. Current studies are to further elucidate the spondyloarthritogenicity of the epitope in murine models of ReA, MHC class I restriction of the peptide binding, mechanisms of CD8+ T cell activation and the role of peptide as a marker of senescent/damaged chondrocytes.
Mechanisms of Inflammation and New Bone Formation (Osteophytosis) in Spondyloarthropathy
The balance between inflammation-driven cartilage and bone erosions and new bone formation is set at different levels in RA and ankylosing spondylitis (AS). Both human and murine SpA exhibits a complex genetic background. In BALB/c x DBA/2 murine cross, we identified two major loci that genetically linked to SpA. Pgis1 locus of chromosome 18 controlled terminal stages of spondylitis: osteophyte formation and spine ankylosis. Pgis2 locus controlled inflammatory cell accumulation around intervertebral disks in the spine; the locus harbors C5(Hc) complement component. These murine SpA loci cluster with human loci regulating AS.
BALB/c.DBA/2-Pgis2 congenic mice were partially susceptible to collagen antibody-induced arthritis despite they carry C5-complement deficiency. Biomarker analysis of differentially expressed genes showed the involvement of macrophages and effector T cells.
We developed a murine model of spondylitis induced with aggrecan immunizations. Antigen, human aggrecan G1 domain (rhAG1), was cloned using insect/baculovirus and bacterial systems. Antigen biochemical properties correlated with different arthritogenecity and the disease course. Osteophytosis was associated with low-grade spondylitis and showed disconnect from peripheral arthritis. We study the connection of biochemical and structural properties of the aggrecan antigen with activation of cytotoxic T cells and macrophages during induction of massive ventral chondroplasia and osteophytosis in aggrecan-immunized mice.