Expansion of CD8+ T cells that express low levels of the B cell-specific molecule CD20 in patients with multiple myeloma

An expanded cytotoxic/memory T-cell subpopulation expressing low levels of the B-cell-specific CD20 molecule was found in peripheral blood and bone marrow of patients with multiple myeloma at the time of diagnosis, but returned to normal levels following treatment. CD3+CD20dim cells were also increased in monoclonal gammopathy of unknown significance albeit at lower levels. Lower CD3+CD20dim cell numbers at baseline may be associated with lack of response to treatment and a poor outcome. Because expansion of these T cells may be related to disease status, further studies should investigate their potentially unique function in plasma cell dyscrasias.     

Combination of intravenous pulses of cyclophosphamide and methylprednizolone in patients with systemic sclerosis and interstitial lung disease

The purpose of the study was to examine prospectively the efficacy and safety of the combination of intravenous pulses of cyclophosphamide and methylprednizolone, in the treatment of scleroderma lung disease. Thirteen patients were treated with the above combination for up to 24 months. Prior to this treatment, they underwent a pulmonary function evaluation and high resolution computed tomography (HRCT). Carbon monoxide diffusion lung capacity and forced vital capacity were repeated at 6, 12, 24 and 48 months. HRCT was repeated at the end of the treatment period, but in between and afterwards in some patients, as well. A significant percentage of patients (66.6%) showed stabilization or improvement of their pulmonary function. Patients with already seriously compromised function, before treatment, were the least likely to exhibit this evolution pattern. There was a tendency in some individuals to deteriorate on later evaluations, off treatment, although they had stabilized at the end of the treatment. There was rather a poor correlation between functional evolution and HRCT appearance. Finally, the regimen was well tolerated. Our results suggest that the employed combination is safe and effective, mainly in stabilizing the respiratory function of the patients. This goal is more realistic when treatment is given before significant functional compromise has ensued. The need for long-term immunosuppression to maintain the initial favorable response is suggested.     

Evidence that Dkk‐1 is dysfunctional in ankylosing spondylitis

Objective

Dkk‐1 is an inhibitory molecule that regulates the Wnt pathway, which controls osteoblastogenesis. This study was undertaken to explore the potential role of Dkk‐1 in ankylosing spondylitis (AS), a prototypical bone‐forming disease.

Methods

Serum Dkk‐1 levels were measured in 45 patients with AS, 45 patients with rheumatoid arthritis (RA), 15 patients with psoriatic arthritis (PsA), and 50 healthy subjects by sandwich enzyme‐linked immunosorbent assay (ELISA). A functional ELISA was used to assess the binding of Dkk‐1 to its receptor (low‐density lipoprotein receptor–related protein 6). Furthermore, we studied the effect of sera from patients with AS and healthy subjects on the activity of the Wnt pathway in the Jurkat T cell model, with and without a neutralizing anti–Dkk‐1 monoclonal antibody, by Western immunoblotting.

Results

Serum Dkk‐1 levels were significantly increased in patients with AS (mean ± SEM 2,730 ± 135.1 pg/ml) as compared with normal subjects (P = 0.040), patients with RA (P = 0.020), and patients with PsA (P = 0.049). Patients with AS receiving anti–tumor necrosis factor α (anti‐TNFα) treatment had significantly higher serum Dkk‐1 levels than patients with AS not receiving such treatment (P = 0.007). Patients with AS studied serially prior to and following anti‐TNFα administration exhibited a significant increase in serum Dkk‐1 levels (P = 0.020), in contrast to patients with RA, who exhibited a dramatic decrease (P < 0.001). Jurkat cells treated with serum from AS patients exhibited increased Wnt signaling compared with cells treated with control serum. In that system, Dkk‐1 blockade significantly enhanced Wnt signaling in control serum–treated, but not AS serum–treated, Jurkat T cells.

Conclusion

Our findings indicate that in patients with AS, circulating bone formation–promoting factors functionally prevail. This can be at least partially attributed to decreased Dkk‐1–mediated inhibition.

     

B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events.

To understand the molecular mechanisms that are responsible for the B cell overactivity that is observed in patients with SLE, we have conducted experiments in which the surface immunoglobulin (sIg)-mediated early cell signaling events were studied. The anti-sIgM-mediated free intracytoplasmic calcium ([Ca2+]i) responses were significantly higher in SLE B cells compared with responses of normal individuals and to those of patients with other systemic autoimmune rheumatic diseases. The anti-IgD mAb induced [Ca2+]i responses were also higher in lupus B cells than in controls. The magnitude of anti-sIgM-mediated Ca2+ release from intracellular stores was also increased in B cells from SLE patients compared with normal controls. The amount of inositol phosphate metabolites produced upon crosslinking of sIgM was slightly higher in patients with lupus than in normal controls, although the difference was not statistically significant. In contrast, the degree of anti-sIgM-induced protein tyrosine phosphorylation was obviously increased in lupus patients. Our study demonstrates clearly for the first time that SLE B cells exhibit aberrant early signal transduction events, including augmented calcium responses after crosslinking of the B cell receptor and increased antigen-receptor-mediated phosphorylation of protein tyrosine residues. Because the above abnormalities did not correlate with disease activity or treatment status, we propose that they may have pathogenic significance.     

B lymphocyte selection and survival in systemic lupus

B lymphocytes are an essential element in the body's immune system. Engagement of the B cell receptor is responsible for initiating the signaling events that can activate, inactivate or physically eliminate B cells, depending on the magnitude and duration of the signal. Control of B cell signaling occurs through both positive and negative regulation, as well as through the actions of molecular scaffolds that contribute to the formation of signaling complexes. Inactivation of genes encoding signaling molecules was shown to result in clinical manifestations reminiscent of systemic autoimmunity in experimental animals. Aberrant expression of some signaling molecules was also observed in patients with systemic autoimmune diseases. Understanding the mechanisms that subvert B cell receptor transduction pathways is likely to aid in the development of therapeutic agents to treat autoimmune diseases.     

Intestinal Involvement in Systemic Sclerosis: A Clinical Review

Systemic sclerosis (SSc) is a chronic systemic disease characterized by microvasculopathy, autoantibodies, and extensive fibrosis. Intestinal involvement is frequent in SSc and represents a significant cause of morbidity. The pathogenesis of intestinal involvement includes vascular damage, nerve dysfunction, smooth muscle atrophy, and fibrosis, causing hypomotility, which leads to small intestinal bacterial overgrowth (SIBO), malabsorption, malnutrition, diarrhea, pseudo-obstruction, constipation, pneumatosis intestinalis, and fecal incontinence. Manifestations are often troublesome and reduce quality of life and life expectancy. Assessment of intestinal involvement includes screening for small intestine hypomotility, malnutrition, SIBO, and anorectal dysfunction. Current management of intestinal manifestations is largely inadequate. Patients with diarrhea are managed with low-fat diet, medium-chain triglycerides, avoidance of lactulose and fructose, and control of bacterial overgrowth with antibiotics for SIBO. In diarrhea/malabsorption, bile acid sequestrant and pancreatic enzyme supplementation may help, and nutritional support is needed. General measures are applied for constipation, and intestine rest plus antibiotics for pseudo-obstruction. Fecal incontinence is managed with measures for associated SIBO, or constipation, and with behavioral therapies. Pneumatosis intestinalis is usually an incidental finding that does not require any specific treatment. Immunomoduation should be considered early in intestinal involvement. Multidisciplinary approach of intestinal manifestations in SSc by gastroenterologists and rheumatologists is required for optimum management.