Collagen antibody-induced arthritis

Collagen antibody-induced arthritis (CAIA) is a simple mouse model of rheumatoid arthritis that can be used to address questions of pathogenic mechanisms and to screen candidate therapeutic agents. Arthritis is stimulated by the administration of a cocktail of monoclonal antibodies that are directed to conserved auto-antigenic epitopes in collagen type II, followed by endotoxin. The antibody-induced arthritis model offers several key advantages over the classic collagen-induced arthritis (CIA) model. These include rapid disease onset, high uptake rate, synchronicity, and the capacity to use genetically modified mice, such as transgenics and knockouts. This protocol takes 1-2 weeks to be completed.     

Collagen from human joint cartilage in deforming arthritis

Type II collagen of human cartilage has been comparatively studied in norm and at deforming arthrosis. Collagen preparations are characterized by aminoacid composition and electrophoretic mobility in polyacrylamide gel. It is supposed that at deforming arthrosis the degenerative-dystrophic processes in the articular cartilage of man are caused by appearance of procollagen.     

Ageing, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity – catalysts of autoimmunity and chronic inflammation

Rheumatoid arthritis (RA), like many other autoimmune syndromes, is a disease of adults, with the highest incidence rates reported in the elderly. The immune system undergoes profound changes with advancing age that are beginning to be understood and that need to be incorporated into the pathogenetic models of RA. The age-related decline in thymic function causes extensive remodeling of the T-cell system. Age-dependent changes in T-cell homeostasis are accelerated in patients with RA. The repertoire of naive and memory T cells is less diverse, possibly as a result of thymic insufficiency, and it is biased towards autoreactive cells. Presenescent T cells emerge that are resistant to apoptosis and that often expand to large clonal populations. These cells are under the regulatory control of nonconventional costimulatory molecules, display potent effector functions, and appear to be critical in the synovial and extra-articular manifestations of RA.     

Aging,autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity - catalysts of autoimmunity and chronic inflammation

Rheumatoid arthritis (RA), like many other autoimmune syndromes, is a disease of adults, with the highest incidence rates reported in the elderly. The immune system undergoes profound changes with advancing age that are beginning to be understood and that need to be incorporated into the pathogenetic models of RA. The age-related decline in thymic function causes extensive remodeling of the T-cell system. Age-dependent changes in T-cell homeostasis are accelerated in patients with RA. The repertoire of naive and memory T cells is less diverse, possibly as a result of thymic insufficiency, and it is biased towards autoreactive cells. Presenescent T cells emerge that are resistant to apoptosis and that often expand to large clonal populations. These cells are under the regulatory control of nonconventional costimulatory molecules, display potent effector functions, and appear to be critical in the synovial and extra-articular manifestations of RA.     

Anti-citrullinated collagen type I antibody is a target of autoimmunity in rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, but its autoimmune mechanisms are not clearly understood. Recently, anti-citrullinated peptide antibodies have been specifically observed in sera of RA patients. Furthermore, we identified RA-susceptible variant in a gene encoding citrullinating enzyme, peptidylarginine deiminase type 4 (PADI4). Therefore, we hypothesized that proteins which are modified in RA synovium by PADI4 act as autoantigens. Subsequently, we obtained human collagen type I (huCI) as one of the autoantigens using a RA synoviocyte cDNA library by immunoscreening. We also investigated that the levels of anti-citrullinated huCI were significantly higher in RA patient sera than in normal control sera with high specificity (99%) and positively correlated with the levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies. We concluded that huCI is a novel substrate protein of PADIs and that citrullinated huCI is a candidate autoantigen of RA.     

Immunoregulation and autoimmunity

Peripheral tolerance to extrinsic antigens or autoantigens involves regulatory T cells, numerous but probably distinct types of which seem to exist. The investigation of their phenotype, of the cytokines on which they depend and the circumstances for their appearance allow classifying them into two categories: 1. Cells for which the appearance is observed independently of the deliberate administration of an antigen (CD25+ T cells, NKT cells, gamma/delta cells). 2. Cells which seem to intervene exclusively in response to the antigens introduced into the organism (Th2 cells, Tr1 cells). These various cells, whether related to innate or adaptive immunity, can be used to advantage as new therapeutic targets.     

Self-tolerance and autoimmunity

Studies of self-tolerance and autoimmunity have moved rapidly into new arenas. These include the definition of at least two mechanisms for tolerance induction in both T and B cells, the creation of new disease-susceptible strains such as the HLA-B27 transgenic rats, the creation of new disease-resistant strains such as I-E or I-Ak NOD transgenic mice, and the precise definition of both antigen and antigen receptor for pathogenic lymphocytes in some models. More effective therapies for autoimmune disease should result from the knowledge gained.     

Inflammasomes and autoimmunity

The NOD-like receptor (NLR) family members are cytosolic sensors of microbial components and danger signals. A subset of NLRs control inflammasome assembly that results in caspase-1 activation and, in turn, IL-1β and IL-18 production. Excessive inflammasome activation can cause autoinflammatory disorders, including the hereditary periodic fevers. Autoinflammatory and autoimmune diseases form a disease spectrum of aberrant, immune-mediated inflammation against self, through innate and adaptive immunity. However, the role of inflammasomes in autoimmune disease is less clear than in autoinflammation, despite the numerous effects IL-1β and IL-18 can have on shaping adaptive immunity. We summarize the role of inflammasomes in autoimmune disorders, highlight the need for a better understanding of inflammasomes in these conditions and offer suggestions for future research directions.     

Cytokines and autoimmunity

Cytokines have crucial functions in the development, differentiation and regulation of immune cells. As a result, dysregulation of cytokine production or action is thought to have a central role in the development of autoimmunity and autoimmune disease. Some cytokines, such as interleukin-2, tumour-necrosis factor and interferons--ostensibly, the 'bad guys' in terms of disease pathogenesis--are well known for the promotion of immune and inflammatory responses. However, these cytokines also have crucial immunosuppressive functions and so, paradoxically, can also be 'good guys'. The balance between the pro-inflammatory and immunosuppressive functions of these well-known cytokines and the implications for the pathogenesis of autoimmune disease is the focus of this review.     

Ageing, autoimmunity and arthritis: Senescence of the B cell compartment – implications for humoral immunity

Immunosenescence is associated with a decline in both T and B lymphocyte function. Although aged individuals have normal numbers of B cells in the periphery and are capable of mounting robust humoral responses, the antibodies produced are generally of lower affinity and are less protective than those produced by young animals. Here we review multiple studies that address the mechanisms that contribute to this decline. Taken together, these studies suggest that age-associated loss of the ability to generate protective humoral immunity results in part from reduced B lymphopoiesis. As the output of new, na?ve B cells declines, homeostatic pressures presumably force the filling of the peripheral B cell pool by long-lived antigen-experienced cells. Because the antibody repertoire of these cells is restricted by previous antigenic experience, they make poor quality responses to new immunologic insults.     

Ageing, autoimmunity and arthritis: senescence of the B cell compartment - implications for humoral immunity

Immunosenescence is associated with a decline in both T and B lymphocyte function. Although aged individuals have normal numbers of B cells in the periphery and are capable of mounting robust humoral responses, the antibodies produced are generally of lower affinity and are less protective than those produced by young animals. Here we review multiple studies that address the mechanisms that contribute to this decline. Taken together, these studies suggest that age-associated loss of the ability to generate protective humoral immunity results in part from reduced B lymphopoiesis. As the output of new, na?ve B cells declines, homeostatic pressures presumably force the filling of the peripheral B cell pool by long-lived antigen-experienced cells. Because the antibody repertoire of these cells is restricted by previous antigenic experience, they make poor quality responses to new immunologic insults.     

The devil in the details: the emerging role of anticitrulline autoimmunity in rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory autoimmune disease of unknown cause. The immune response against citrullinated Ags has recently become the prime suspect for disease pathogenesis. Immunity against citrullinated Ags is thought to play a pivotal role in the disease for several reasons: 1) citrullinated Ags are expressed in the target organ, the inflamed joint; 2) anti-citrullinated protein Abs are present before the disease becomes manifest; and 3) these Abs are highly specific for rheumatoid arthritis. In this review, data from clinical, genetic, biochemical, and animal studies is combined to create a profile of this remarkable autoantibody response. Moreover, a model is proposed of how the anti-citrullinated proteins response is generated and how it could eventually lead to chronic inflammation.