Passage
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic synovial (joint) inflammation. RA immunopathogenesis involves LFA-1, a surface receptor found on leukocytes that is composed of an α-chain (CD11a) and a β-chain (CD18) . The binding of LFA-1 to ICAM-1, an adhesion protein on the surface of B cells and endothelial cells, stimulates the migration of leukocytes to specific areas of inflammation. After successful LFA-1/ICAM-1 binding, CD18 is released into the plasma and synovial fluid (SF) , where it exists in soluble form (sCD18) . The levels of sCD18 in SF can be used as a marker for inflammation in RA.CD18 release has been shown to increase in response to tumor necrosis factor (TNF) , a pro-inflammatory cytokine involved in the inflammatory response of RA. In patients with newly diagnosed and untreated RA (eRA) , leukocytes produce adequate quantities of LFA-1 and plasma sCD18 levels are unchanged. However, over time there is dysregulation of LFA-1 synthesis and an increase in competition for ICAM-1 by other ligands, leading to a reduction in CD18 shedding. As a result, sCD18 is decreased in patients with chronic RA (cRA) .Experiment 1An immunofluorescence assay was used to measure plasma sCD18 levels in patients with eRA and cRA, and in age- and gender-matched healthy controls (HC) .
Figure 1 Baseline sCD18 measurements (Note: 50% of data points are below the median value; median = line inside the box.) Experiment 2Clinical assessments were performed in eRA patients to establish a baseline disease status. eRA patients were assigned DAS28CRP scores measured by RA-specific laboratory values. This was followed by treatment with anti-inflammatory drugs. DAS28CRP scores were calculated at 3-month intervals for 12 months, with lower scores indicating decreased RA severity (Figure 2) .
Figure 2 DAS28CRP scores in eRA patientsExperiment 3Heterogeneous populations of mononuclear cells were cultured from the synovial fluid (SFMC) and peripheral blood (PBMC) of eRA patients during an acute exacerbation of their symptoms. sCD18 levels were measured in SFMCs and PBMCs that were untreated, treated with TNF, or treated with monoclonal antibodies targeting TNF (anti-TNF) .
Adapted from Kragstrup TW, Jalilian B, Keller KK, et al. Changes in Soluble CD18 in Murine Autoimmune Arthritis and Rheumatoid Arthritis Reflect Disease Establishment and Treatment Response. PLoS ONE. 2016;11(2) :e0148486.
-A self-directed antibody known as rheumatoid factor (RF) has been found to be involved in RA-mediated inflammation. RF is an antibody that targets a patient's own IgG antibodies, which results in the formation of immune complexes that induce an inflammatory response. High concentrations of self-antibodies such as RF are NOT typically found in the human body because:

Question

Passage
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic synovial (joint) inflammation. RA immunopathogenesis involves LFA-1, a surface receptor found on leukocytes that is composed of an α-chain (CD11a) and a β-chain (CD18) . The binding of LFA-1 to ICAM-1, an adhesion protein on the surface of B cells and endothelial cells, stimulates the migration of leukocytes to specific areas of inflammation. After successful LFA-1/ICAM-1 binding, CD18 is released into the plasma and synovial fluid (SF) , where it exists in soluble form (sCD18) . The levels of sCD18 in SF can be used as a marker for inflammation in RA.CD18 release has been shown to increase in response to tumor necrosis factor (TNF) , a pro-inflammatory cytokine involved in the inflammatory response of RA. In patients with newly diagnosed and untreated RA (eRA) , leukocytes produce adequate quantities of LFA-1 and plasma sCD18 levels are unchanged. However, over time there is dysregulation of LFA-1 synthesis and an increase in competition for ICAM-1 by other ligands, leading to a reduction in CD18 shedding. As a result, sCD18 is decreased in patients with chronic RA (cRA) .Experiment 1An immunofluorescence assay was used to measure plasma sCD18 levels in patients with eRA and cRA, and in age- and gender-matched healthy controls (HC) .

Figure 1 Baseline sCD18 measurements (Note: 50% of data points are below the median value; median = line inside the box.) Experiment 2Clinical assessments were performed in eRA patients to establish a baseline disease status. eRA patients were assigned DAS28CRP scores measured by RA-specific laboratory values. This was followed by treatment with anti-inflammatory drugs. DAS28CRP scores were calculated at 3-month intervals for 12 months, with lower scores indicating decreased RA severity (Figure 2) .

Figure 2 DAS28CRP scores in eRA patientsExperiment 3Heterogeneous populations of mononuclear cells were cultured from the synovial fluid (SFMC) and peripheral blood (PBMC) of eRA patients during an acute exacerbation of their symptoms. sCD18 levels were measured in SFMCs and PBMCs that were untreated, treated with TNF, or treated with monoclonal antibodies targeting TNF (anti-TNF) .
Adapted from Kragstrup TW, Jalilian B, Keller KK, et al. Changes in Soluble CD18 in Murine Autoimmune Arthritis and Rheumatoid Arthritis Reflect Disease Establishment and Treatment Response. PLoS ONE. 2016;11(2) :e0148486.
-A self-directed antibody known as rheumatoid factor (RF) has been found to be involved in RA-mediated inflammation. RF is an antibody that targets a patient's own IgG antibodies, which results in the formation of immune complexes that induce an inflammatory response. High concentrations of self-antibodies such as RF are NOT typically found in the human body because:

Quizplus · Accepted Answer

11ecba2d_0f8d_f949_a3bf_9fb2c8faed98_MD0008_00 Normally, the immune system is said to be self-tolerant because it does not attack itself but serves to protect the body from foreign substances (antigens). During the early stages of immune cell development, which occurs in the thymus (T cells) and bone marrow (B cells), cells undergo genetic recombination to rearrange their DNA. This rearrangement leads to the expression of novel antigen-binding receptors and antibodies on the surface of T cells and B cells, respectively. The production of billions of immune cells with varied receptor sets results in an immune system able to target many different antigens. However, the rearrangement also results in the expression of receptors that target endogenous molecules (self-antigens). To avoid rampant immune responses against self, these self-recognizing cells are normally destroyed. Negative selection is the process by which immature T cells and B cells possessing receptors that bind to self-antigens are destroyed. Elimination of these cells occurs either by programmed cell death (apoptosis) or by becoming unresponsive to antigens (anergic). According to the question, rheumatoid factor (RF) is an antibody that mediates an autoimmune response by targeting a patient's own IgG antibodies. RF is not usually made in high concentrations because B cells and T cells that mediate self-recognition and antibody production are typically destroyed during negative selection. (Choice A) Complement proteins are blood proteins that increase the effectiveness of antibodies by helping to recruit and activate phagocytes. The question describes RF as an antibody that targets self-IgG antibodies; it is not a complement protein. (Choices C and D) Rearrangement of DNA leads to the expression of surface antibodies/receptors that can identify self-antigens (B cells and T cells). Identification of self-antigens by B cells enables subsequent presentation of the self-antigens. However, these self-recognizing cells are normally destroyed during immune cell maturation. Educational objective: Autoimmunity disorders occur due to the immune system's failure to identify and destroy immune cells that recognize self-antigens. Self-reactive B cells and T cells are normally eliminated in the bone marrow and thymus, respectively.