Local production of complement proteins in rheumatoid arthritis synovium

Neumann, Elena; Barnum, Scott R.; Tarner, Ingo H.; Echols, Josh; Fleck, Martin; Judex, Martin; Kullmann, Frank; Mountz, John D.; Schölmerich, Jürgen; Müller‐Ladner, Ulf

doi:10.1002/art.10183

Cited by 140 publications

(119 citation statements)

References 46 publications

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“…Uncontrolled activation of this system, however, can seriously damage host cells and tissues and contribute significantly to disease progression (178)(179)(180)(181). Activated components of the alternative pathway, for example, have been described in the pathology of glomerulonephritis, IgA nephropathy, asthma, lupus, rheumatoid arthritis, myositis, inflammatory central nervous system diseases like multiple sclerosis, cardiac valvular disease, cirrhosis, adult respiratory distress syndrome (ARDS), pemphigoid disease, and antiphospholipid syndrome (182)(183)(184)(185)(186)(187)(188). Thus, because of its spontaneous activating properties, continuous control of the alternative pathway is necessary to prevent damage to self tissues.…”

Section: The Complement System and Amdmentioning

confidence: 99%

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

et al. 2006

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Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden.Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage 'wet' form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common 'dry' AMD, except for the use of antioxidants that delay progression in 20%-25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene-which encodes the major inhibitor of the complement alternative pathway-is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel diagnostic and therapeutic approaches for this disease that will dramatically improve the quality of our prolonged lifespan.

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Section: The Complement System and Amdmentioning

confidence: 99%

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

et al. 2006

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“…Reduced levels of native complement components and increased levels of complement metabolites in the synovial fluid and synovial tissue of RA patients have implicated complement in the pathogenesis of RA (16). It has been suggested that key components in complement activation, such as C3 and B, are produced locally in RA synovium rather than being plasma derived (17). Aggarwal et al recently demonstrated alternative pathway activation with formation ofthe membrane attack complex in patients with juvenile rheumatoid arthritis (18).…”

Section: Complement and Autoantibodiesmentioning

confidence: 99%

Complement System and Rheumatoid Arthritis: Relationships with Autoantibodies, Serological, Clinical Features, and Anti-TNF Treatment

Muzio

Perricone

Ballanti

et al. 2011

Int J Immunopathol Pharmacol

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The first two authors contributed equally to this work Autoantibodies (rheumatoid factor, RF; anti-citrullinated-protein antibodies,ACPA) and complement system are involved in rheumatoid arthritis (RA). ACPA and anti-TNF agents are capable of in vitro modulating complement activity. We investigated the relationships between complement, autoantibodies, and anti-TNF treatment in vivo. One-hundred fourteen RA patients (89F/25M), diagnosed according to 1987 ACR criteria, and 30 healthy controls were enrolled. Serological analysis included ESR, CRP, complement C3, C4 and CH50, RF and ACPA (ELISA, cut-off>20U/ml). Split-products (SP) of C3 and B were studied by immunoelectrophoresis/counterimmunoelectrophoresis. Seventy-six patients started anti-TNF treatment and were studied at baseline and after 22 weeks. Disease activity was measured with DAS28 and response to therapy with EULAR criteria. At baseline, RA patients showed significantly higher levels of C3 and C4 than controls (C3 127.9±26.5 vs 1l0±25mgldl, P=O.0012; C4 29.7±10.2 vs 22.7±8.3mgldl, P=0.0003). No differences in C3, C4 and CH50 levels were observed between ACPA+ (n=76) and ACPA-(n=38) patients. After 22 weeks of anti-TNF, C3, C4 and RF were significantly reduced (P<0.003, <0.005 and <0.04, respectively) and RF changes showed negative correlation with CH50. SP of C3 and B were observed neither at baseline nor after 22 weeks. DAS28 significantly improved after 22 weeks. Patients showing higher baseline C3 or lower reduction of C3 levels after 22 weeks had a worse EULAR outcome (x2=22.793, P

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“…Deposited autoantibodies, immune complexes, apoptotic cells, and necrotic cells can activate this cascade, leading to the release of proinflammatory activators, recruitment of inflammatory cells (Figure 1), and formation of membrane attack complexes. The levels of complement activation components are elevated in the synovial fluid, synovium, and cartilage of patients with arthritis (19)(20)(21)(22)(23), and targeted deletion/inhibition reduces disease severity in murine arthritis models (7,24,25). These previous studies have led to the development of therapeutic approaches targeting complement components for the treatment of RA (for review, see ref.…”

Section: Complement Cascadementioning

confidence: 99%