New arthritic pannus-specific protein promotes fibroblast motility and polarization

Rheumatoid arthritis (RA) is chronic inflammatory disease characterized by the development of hypercellular pannus tissue in the affected joints of patients. Pannus invasiveness and activation correlates with stronger tissue destruction and worse clinical prognosis. Using murine arthritis model, we recently discovered that synovial concentration of Collagen Triple Helix Repeat-containing 1 (CTHRC1) message and protein is directly correlated with arthritis severity. In carcinogenesis, overexpression of CTHRC1 is associated with enhanced metastatic potential of solid tumors and increased cell motility. Our goal is to investigate the mechanism of synovial cell motility and invasiveness and the role of non-canonical WNT signaling in pannus development

New serum biomarker for rheumatoid arthritis

Development of hypercellular invasive pannus tissue within synovial joints is a hallmark of Rheumatoid Arthritis (RA). Pannus produces proteases that damage bone and cartilage. Non-invasive monitoring of pannus activity is important for clinical assessment of patients as well as for control of the efficacy of therapeutic interventions. Available biomarkers are not satisfactory in terms of pannus specificity and sensitivity for monitoring local inflammation and bone erosion. Our goal is collecting clinical samples of synovial fluid and plasma from patients with RA and/or osteoarthritis (OA) to study the role of WNT signaling in pannus formation and developing set of serum biomarkers to monitor pannus activity

Molecular mimicry of brucella melitensis epitopes in mouse and human arthritis

Brucellosis is one of the most frequent zoonosis worldwide. Infection is transferable to humans, where brucellosis is associated with high incidence of osteoarticular disease including osteomyelitis, arthritis and spondyloarthritis. Peripheral arthritis and sacroiliitis often develop in patients with no or low count of live Brucella. Recently, we demonstrated that mice develop spontaneous arthritis several weeks after acute infection when bacteria are already eradicated. We aim to decipher immune mechanism of the brucellosis-associated delayed arthritis that has not been elucidated so far

Molecular mimicry of brucella melitensis epitopes in mouse and human arthritis

Brucellosis is one of the most frequent zoonosis worldwide. Infection is transferable to humans, where brucellosis is associated with high incidence of osteoarticular disease including osteomyelitis, arthritis and spondyloarthritis. Peripheral arthritis and sacroiliitis often develop in patients with no or low count of live Brucella. Recently, we demonstrated that mice develop spontaneous arthritis several weeks after acute infection when bacteria are already eradicated. We aim to decipher immune mechanism of the brucellosis-associated delayed arthritis that has not been elucidated so far

Protective effect of peptide vaccination in murine infection with influenza virus

Vaccination is a major tool to protect people from seasonal infections of different strains of influenza virus that presently infects millions of individuals worldwide. Virus genome is highly polymorphic, and universal vaccine that protects against permanently changing virus is still under development. Despite notable differences between humans and rodents in the disease course, immunobiology and clinical evaluations, murine infectious models remain one of the major tools to test approaches for influenza vaccine development

Protective effect of peptide vaccination in murine infection with influenza virus

Vaccination is a major tool to protect people from seasonal infections of different strains of influenza virus that presently infects millions of individuals worldwide. Virus genome is highly polymorphic, and universal vaccine that protects against permanently changing virus is still under development. Despite notable differences between humans and rodents in the disease course, immunobiology and clinical evaluations, murine infectious models remain one of the major tools to test approaches for influenza vaccine development

Genetic homongeneity and major histocompatibility complex haplotyping of white mice

Inbred murine strains are generated to insure genetic homogeneity and uniqueness and define immune characteristics, like major histocompatibility complex (MHC) haplotype, of the experimental model. Maintaining of the perfect inbred stock leads to increased level of homozygosity and sometimes encounters a problem of inbreeding depression and consequently deviation from strict inbreeding protocol. Our goals are (i) study genetic homogeneity of mice in the colony, and (ii) haplotyping of H-2 complex (MHC in mice) in this strain

Gene expression profiling in murine autoimmune arthritis during the initiation and progression of joint inflammation

We present here an extensive study of differential gene expression in the initiation, acute and chronic phases of murine autoimmune arthritis with the use of high-density oligonucleotide arrays interrogating the entire mouse genome. Arthritis was induced in severe combined immunodeficient mice by using adoptive transfer of lymphocytes from proteoglycan-immunized arthritic BALB/c mice. In this unique system only proteoglycan-specific lymphocytes are transferred from arthritic mice into syngeneic immunodeficient recipients that lack adaptive immunity but have intact innate immunity on an identical (BALB/c) genetic background. Differential gene expression in response to donor lymphocytes that migrated into the joint can therefore be monitored in a precisely timed manner, even before the onset of inflammation. The initiation phase of adoptively transferred disease (several days before the onset of joint swelling) was characterized by differential expression of 37 genes, mostly related to chemokines, interferon-γ and tumor necrosis factor-α signaling, and T cell functions. These were designated early arthritis 'signature' genes because they could distinguish between the naive and the pre-arthritic state. Acute joint inflammation was characterized by at least twofold overexpression of 256 genes and the downregulation of 21 genes, whereas in chronic arthritis a total of 418 genes with an equal proportion of upregulated and downregulated transcripts were expressed differentially. Hierarchical clustering and functional classification of inflammation-related and arthritis-related genes indicated that the most common biological activities were represented by genes encoding interleukins, chemokine receptors and ligands, and by those involved in antigen recognition and processing

Angiotensin I-Converting Enzyme Mutation (Trp1197Stop) Causes a Dramatic Increase in Blood ACE

BACKGROUND:Angiotensin-converting enzyme (ACE) metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases, including asthma. Previously, a molecular mechanism underlying a 5-fold familial increase of blood ACE was discovered: Pro1199Leu substitution enhanced the cleavage-secretion process. Carriers of this mutation were Caucasians from Europe (mostly Dutch) or had European roots. METHODOLOGY/PRINCIPAL FINDINGS:We have found a family of African-American descent whose affected members' blood ACE level was increased 13-fold over normal. In affected family members, codon TGG coding for Trp1197 was substituted in one allele by TGA (stop codon). As a result, half of ACE expressed in these individuals had a length of 1196 amino acids and lacked a transmembrane anchor. This ACE mutant is not trafficked to the cell membrane and is directly secreted out of cells; this mechanism apparently accounts for the high serum ACE level seen in affected individuals. A haplotype of the mutant ACE allele was determined based on 12 polymorphisms, which may help to identify other carriers of this mutation. Some but not all carriers of this mutation demonstrated airflow obstruction, and some but not all have hypertension. CONCLUSIONS/SIGNIFICANCE:We have identified a novel Trp1197Stop mutation that results in dramatic elevation of serum ACE. Since blood ACE elevation is often taken as a marker of disease activity (sarcoidosis and Gaucher diseases), it is important for clinicians and medical scientists to be aware of alternative genetic causes of elevated blood ACE that are not apparently linked to disease