Some possibilities to explain these differences include differences in research protocol used, early versus advanced RA disease in study patients [ 14 , 15 , 35 ], and different criteria used to define the disease [ 13 — 15 ]. In our study, enhanced phagocytic capacity was repeatedly observed in both neutrophils and monocytes from RA patients.
Similarly, this enhance capacity was observed in the analysis of phagocytosis via both PRR and opsonin receptors. The concordance of all of these results renders our data more reliable. In addition, the clinical criteria used to define RA were strictly followed in this study. There are multiple possible mechanisms that may be suggested to explain the increase in phagocytosis via PRRs observed in RA patients.
Our data showed that the increase in phagocytic capacity of monocytes and neutrophils was caused by an increase in the number of phagocytosed particles per phagocyte and by a higher engagement of phagocytes in phagocytosis. Enhanced expression of PRRs involved in uptake of the yeast in neutrophils and monocytes may explain the increased number of particles phagocytosed in RA disease.
In fact, it has been shown that the scavenger receptor CD36 is up-regulated in THP-1 macrophages that are exposed to plasma from RA patients [ 36 ]. CD36 is a PRR that is expressed in phagocytes and mediates yeast uptake [ 25 , 30 , 31 ].
The fact that positivity for anti-CCP and RF only increased neutrophil phagocytosis via PRRs suggests that this increase was caused through an indirect mechanism, possibly through stimulation of cytokine production that enhanced PRR expression at the membrane surface of phagocytes. To be able to phagocytose, macrophages need to move towards the particle. Monocytes and neutrophils from RA patients also showed increased phagocytic capacity via opsonins. Immunofluorescence staining showed that both immunoglobulin and complement are present on the surface of sensitized yeast [ 25 ].
In fact, increased expression of CR3 in neutrophils recovered from the synovial fluid of patients with RA has been shown [ 38 ]. We suggest that the lack of difference between phagocytosis via opsonin receptors observed for anti-CCP-positive and -negative RA patients may have occurred because the antibody against CCP is of the IgG class and thus binds to an IgG receptor.
In our system, the IgG receptor may be occupied by anti-CCP antibodies, leaving a lower number of receptors available for occupation by sensitized S. In addition, the binding of anti-CCP to its IgG receptor should stimulate the phagocyte, enhancing phagocytosis and superoxide anion production, both of which we observed in this study. This situation would cause a decrease in the number of S. Furthermore, activation of complement via both classical and alternative pathways by immune complexes containing anti-CCP [ 42 ] and RF may indirectly activate phagocytes. It is unclear the different influence of antibodies anti-CCP and RF in phagocytosis by neutrophils and monocytes we observed.
We suggest that this difference may have occurred because the subsets of monocytes that was evaluated in peripheral blood in this work.
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Parallel to the observed increase in phagocytosis, RA patients also showed significantly increased superoxide anion production. Our data were similar to others that showed increased oxygen radical production in RA [ 45 — 47 ]. Conversely, Okuda et al. It is possible that this discrepancy was due to differences in the protocol used, the severity of disease, and the duration of the disease for patients in the two studies.
Although it was not our primary objective, we attempted to evaluate whether other variables, such as disease activity DAS28 , functional incapacity HAQ , use of synthetic or biologic DMARDs medication, dosage , lifestyle physical activity, current or prior smoking , education, comorbidities, or the presence of radiographic erosions, correlated with phagocyte functions in RA patients. Within this context, no association was observed between phagocytosis and ROS production and any of the stated variables.
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Although positivity to anti-CCP and RF predicts more erosive disease [ 48 , 49 ], several cohorts have reported that patients with early RA have a low frequency of joint damage during the first year of the disease [ 49 , 50 ]. Because our cohort was composed of RA patients who were followed for only a short duration of the disease, it may have been too early in the course of the disease to assess significant differences in correlation between radiographic erosions and phagocytic functions.
In another cohort of patients, Ling at al. This finding is in accordance with our results. A longer follow-up study would be necessary to thoroughly evaluate the differences in the other clinical parameters by positivity to anti-CCP and RF. Specifically with regard to therapeutic regimens, a possible limitation for this study is that even though all patients were recruited from the same service, the drugs used in each case were not strictly the same. Nevertheless, all regimens followed the same standardized protocol [ 21 , 22 ].
No association between phagocytic functions and type of therapy used synthetic vs. It is important to consider that the sample size for this study was limited and that the number of patients under biologic therapy was therefore restricted. Assessment of larger groups would yield important data to be addressed in future studies.
As another limitation, our small sample size prevented many of our comparisons from reaching statistical significance, and this study did not control for many clinical and demographic variables among the patient subgroups. Another possible limitation of our study is the fact that phagocyte functions were evaluated in phagocytes derived from peripheral blood and not from synovial fluid cells, in order to evaluate directly the activation of phagocytes in the rheumatoid synovia.
However, the problem is that there are several experimental concerns in study synovial cells from rheumatoid arthritis individuals in order to evaluate the activation of phagocytes without bias, because of the influence of cytokines and substances produced in consequence of the inflammatory process that is present in the rheumatoid synovia in these patients on phagocyte functions.
Our study inevitably underscores the complexity of the pathophysiological interactions between phagocytes and autoantibodies. While RA pathogenesis is complex and not completely understood, in at least some patients it is thought to depend on induction of autoimmunity in predisposed individuals who begin to produce antibodies to citrullinated antigens in the synovium. This B cell response that is specific for citrullinated antigens can become pathogenic once citrullinated antigens are generated in the joint and anti-CCP is able to enter the joint [ 52 ]. Our data suggest that these antibodies indirectly act on neutrophils by increasing the phagocytic capacity and superoxide anion production, possibly by enhancing the production of cytokines that up-regulate functions of the phagocytes.
In addition, RF and anti-CCP may activate the classical and alternative complement system cascades, increasing the inflammatory process as a positive feedback loop [ 42 , 53 ]. By means of phagocytosis and cytotoxic oxygen radical production, these activated phagocytes can initiate and perpetuate synovial damage. As memory B lymphocytes are generated, these antibodies are always being produced, therefore sustaining the lesion.
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This finding may explain why individuals with positive autoantibodies have more severe disease and confirms the importance of targeting phagocytes in RA therapy. The adaptive and innate immune pathways then integrate in positive feedback loops that ultimately result in a clinical picture of joint destruction and extra-articular manifestations [ 1 — 3 ]. To our knowledge, the present study is the first to associate the increased neutrophil phagocytosis in RA with positivity for anti-CCP.
Our findings support the idea that phagocytes are precociously activated in RA, broaden understanding of the possible mechanisms by which anti-CCP and RF interact with neutrophils to cause more severe disease, and finally, suggest the importance of neutrophils and monocytes as the central effectors of tissue damage in RA. In conclusion, our data showed that overall phagocytosis and oxygen radical production by neutrophils and monocytes are enhanced in RA patients and that anti-CCP and RF positivity further enhances phagocytosis by neutrophils.
Our conclusions show that measures that prevent the production of these antibodies may be a promising strategy in the management of RA. The pathogenesis of rheumatoid arthritis. N Engl J Med. Recent advances in the management of rheumatoid arthritis. Rheumatoid arthritis. Doan T, Massarotti E. Rheumatoid arthritis: an overview of new and emerging therapies. J Clin Pharmacol. Anti-CCP antibody, a marker for the early detection of rheumatoid arthritis. Ann NY Acad Sci.
Innate immunity and rheumatoid arthritis. Rheum Dis Clin North Am. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis.
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Ann Rheum Dis. Mewar D, Wilson AG. Autoantibodies in rheumatoid arthritis: a review. Biomed Pharmacother. Puszczewicz M, Iwaszkiewicz C. Role of anti-citrullinated protein antibodies in diagnosis and prognosis of rheumatoid arthritis. Arch Med Sci. Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis.