Abnormal Production of and Response to B-Cell Growth Factor and B-Cell Differentiation Factor in Patients with Systemic Lupus Erythematosus

We examined the production of and the response to B-cell growth factor (BCGF) and B-cell differentiation factor (BCDF) in 21 patients with systemic lupus erythematosus (SLE) and 23 normal subjects. T cells, 2.5 × 10⁶/ml, were cultured for 24 or 72 h with 1% phytohaemagglutinin (PHA). After absorption of PHA by chicken erythrocytes (CRBC), they were used for BCGF and BCDF. In inactive SLE, BCGF activity was significantly lower than that in normal subjects. Active SLE contained two separate groups, one showing normal BCGF activity and the other showing lower activity than normal. In contrast. BCDF activity from initial culture in active SLE was elevated. The B-cell response both to BCGF and BCDF was elevated in active SLE without Staphylococcus aureus Cowan I antigen (SAC) preactivation. However, the B-cell response to SAC was markedly disturbed. Thus SLE B cells were shifted to the mature state in vivo. We also demonstrated pivotal abnormalities of monocytes in SLE B-cell growth and differentiation. These results may contribute to the understanding of the abormalities of T-B interactions and the overproduction of antibody in SLE.     

Th1 (IL-2, interferon-gamma (IFN-γ)) and Th2 (IL-10, IL-4) cytokine production by peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE)

We investigated the production of IL-2, IFN-γ, IL-10 and IL-4 by PBMC from 24 patients with SLE and 10 healthy individuals. Basal and mitogen-stimulated (lipopolysaccharide and phytohaemagglutinin (LPS + PHA)) cytokine production was determined in a whole blood assay (WBA). Supernatants were collected and assayed with specific ELISAs. Although the IL-2 and IFN-γ contents did not differ significantly between patients and controls under both conditions, statistically significant correlations were found between each cytokine and disease activity (SLAM index) after stimulation (respectively, r= 0.501, P = 0.01 and r = 0.631, P = 0.001). PBMC IL-10 production was significantly higher for patients than controls (P = 0.05), but no correlation between IL-10 levels and the SLAM index was obtained. IL-4 production was not statistically different between SLE patients and controls. For stimulated WBAs, the IL-10/IL-2 and IL-10/IFN-γ ratios were significantly correlated with disease severity (P = 0.02; P = 0.001, respectively). Overall, our data suggest that SLE is characterized by an elevated production of IL-10, reflecting the basal state of activation of the immune system. During exacerbation of SLE, IL-2 and IFN-γ are synthesized in larger amounts and may cause the tissue damage observed.     

Associations of B cell‐activating factor (BAFF) and anti‐BAFF autoantibodies with disease activity in multi‐ethnic Asian systemic lupus erythematosus patients in Singapore

To measure the levels of B cell‐activating factor (BAFF) and endogenous anti‐BAFF autoantibodies in a cohort of multi‐ethnic Asian systemic lupus erythematosus (SLE) patients in Singapore, to determine their correlation with disease activity. Serum samples from 121 SLE patients and 24 age‐ and sex‐matched healthy controls were assayed for BAFF and anti‐BAFF immunoglobulin (Ig)G antibody levels by enzyme‐linked immunosorbent assay (ELISA). The lowest reliable detection limit for anti‐BAFF‐IgG antibody levels was defined as 2 standard deviations (s.d.) from blank. Correlation of serum BAFF and anti‐BAFF IgG levels with disease activity [scored by SLE Activity Measure revised (SLAM‐R)], and disease manifestations were determined in these 121 patients. SLE patients had elevated BAFF levels compared to controls; mean 820 ± 40 pg/ml and 152 pg ± 45/ml, respectively [mean ± standard error of the mean (s.e.m.), P < 0·01], which were correlated positively with anti‐dsDNA antibody levels (r = 0·253, P < 0·03), and SLAM‐R scores (r = 0·627, P < 0·01). In addition, SLE patients had significantly higher levels of anti‐BAFF IgG, which were correlated negatively with disease activity (r = –0·436, P < 0·01), levels of anti‐dsDNA antibody (r = –0·347, P < 0·02) and BAFF (r = –0·459, P < 0·01). The majority of patients in this multi‐ethnic Asian SLE cohort had elevated levels of BAFF and anti‐BAFF antibodies. Anti‐BAFF autoantibody levels correlated negatively with clinical disease activity, anti‐dsDNA and BAFF levels, suggesting that they may be disease‐modifying. Our results provide further information about the complexity of BAFF pathophysiology in different SLE disease populations and phenotypes, and suggest that studies of the influence of anti‐cytokine antibodies in different SLE populations will be required when selecting patients for trials using targeted anti‐cytokine therapies.     

Activated peripheral blood mononuclear cells detected by murine monoclonal antibodies to proliferating cell nuclear antigen in active lupus patients

Hybridoma producing monoclonal antibody to proliferating cell nuclear antigen (PCNA/cyclin) (TOB7, IgG1 ) was newly established. Using TOB7, PCNA was detected in the peripheral blood mononuclear cells (PBMC) in patients with systemic lupus erythematosus (SLE). Forty-four of 58 patients with SLE had PBMC expressing PCNA. The percentage of PCNA-positive PBMC in patients with SLE was 0–20% (mean: 2.63%) which was significantly higher (P<0.01) compared with normal controls (mean: 0.18%), patients with rheumatoid arthritis (mean: 0.83%), and patients with mixed connective tissue disease (mean: 0.38%). Patients with high numbers of PCNA positive PBMC tended to complicate pulmonary disorders (P<0.005), especially pulmonary fibrosis (P<0.005). In addition, the percentage of PCNA-positive cells in SLE patients correlated with the disease activity (r=0.45,P<0.01). The lymphocyte subsets of PCNA-positive PBMC were examined, and most of those cells belonged to CD4- or CD8-positive T-cell populations in three lupus patients. Our findings indicate that PCNA-positive activated PBMC are present in SLE patients and the percentage of PCNA-positive PBMC may be used as an indicator of disease activity.     

Relationship of in vitro phagocytosis of serotype 14 Streptococcus pneumoniae to specific class and IgG subclass antibody levels in healthy adults

The role of specific IgG2 antibody in the protection against serious infection with Streptococcus pneumoniae is unclear. We therefore decided to investigate the relationship between serum antibody levels and opsonization and phagocytosis of this microorganism. We have measured serum IgM, IgA and IgG subclass antibody specific for pneumococcal capsular polysaccharide and in vitro phagocytosis of serotype 14 pneumococcus by polymorphs, in healthy adults before and after immunization with Pneumovax II. IgM and IgG2 were the predominant anti-pneumococcal antibodies seen, IgA and IgGl being present at low titre. No significant relationship of phagocytosis with specific IgM and IgA antibodies was found. However, both specific IgG 1 and IgG2 antibodies in post-immunization sera correlated significantly with phagocytosis of the pneumococcus in the presence of complement (r= 0.57, P= 0.029 and r= 0.59, P= 0.022 respectively). After heat-inactivation, the remaining opsonic activity of sera correlated only with levels of specific IgG2 antibody (r= 0.61, P = 0.0006). Whereas phagocytosis supported by specific IgG 1 and IgG2 antibody to serotype 14 pneumococcus after immunization is mediated by complement activation, IgG2-specific antibody in high titre may also be able to function by complement-independent interaction with Fcγ receptors on polymorphs.     

Increased BCMA expression in lupus marks activated B cells,and BCMA receptor engagement enhances the response to TLR9 stimulation

B lymphocyte stimulator (BLyS) and APRoliferation inducing ligand (APRIL) are members of the TNF superfamily that regulate B-cell survival and autoreactivity. To further understand the significance of elevated BLyS and APRIL in systemic lupus erythematosus (SLE), we examined the expression profiles of their receptors (B-cell-activating factor (BAFF)-R, transmembrane activator and calcium modulator and cyclophilin ligand interactor, and B cell maturation antigen (BCMA)) on B-cell subsets in SLE and also investigated the differential expression and function of BCMA in TLR9-induced B-cell activation. While BAFF-R expression on SLE B cells was significantly lower compared to healthy control B cells (p = 0.003), BCMA expression was substantially higher on SLE B cells (p = 0.038), especially on memory cells and plasmablasts. BCMA⁺ cells had higher CD19 and CD86 expression, indicating a greater degree of activation in both healthy and lupus patients. CpG stimulation increased BCMA expression on B cells and induced the proliferation and maturation of BCMA⁺ B cells. A BCMA agonistic antibody also enhanced CpG-induced proliferation, activation, and IgG secretion by B cells in both healthy controls and lupus patients. Furthermore, the agonistic BCMA antibody co-stimulated auto-antibody production by CpG-stimulated lupus B cells in vitro. Signaling through BCMA enhances B cell activation following exposure to TLR9 agonists, and increased expression in SLE may contribute to the production of IgG autoantibodies.     

Correlation of disease activity and Clq-binding immune complexes with the neutrophil inclusions which form in the presence of SLE sera

Intracytoplasmic inclusions containing immunoglobulin (Ig) and complement (C3) are found in normal neutrophils (PMN) after incubation with sera from patients with SLE. These inclusions are believed to be immune complexes removed by phagocytosis from the SLE patients' sera in vitro. Similar inclusions were also noted in the circulating PMN from some patients with SLE. In the present study we have examined the relationship between the presence of intracytoplasmic inclusions and various clinical and laboratory features of SLE. Blood from forty-five patients with SLE was drawn and separated at 37°C. Fresh heparinized blood was also obtained from normal volunteers and allowed to stand for 90 min at 37°C. The buffy coat cells from both normal and SLE groups were removed, centrifuged, washed and examined (direct method) or incubated in the SLE sera for 90 min at 37°C (indirect method). Slides of washed cells were prepared in the cytocentrifuge, stained with fluorescein-conjugated goat anti-human IgG, IgM, IgA and C3 and examined under ultra-violet light.

By the direct method, 24% of patients had small intracytoplasmic inclusions in their neutrophils when stained for IgG suggesting that immune complexes were phagocytosed in vivo. None of twenty-one normal controls had similar inclusions. By the indirect method, 62% of SLE patients were positive for IgG, 15% for IgM, 8% for IgA and 31% for C3. None of the twelve normal controls were positive.

By the indirect method, PMN inclusions containing both IgG and IgM correlated with clinical activity (P<0·001), depressed serum complement (CH50, P=0·026; and C3, P<0·051), cryoglobulinaemia (P=0·014), anti-nDNA antibodies (P<0·001) and Clq-binding immune complexes (P=0·008). A suggestive correlation with granulocytopenia was also observed. The presence of inclusions containing IgG alone did not correlate with any of these parameters. C3 and IgM appeared to be mutually exclusive, i.e. neither was present simultaneously. These findings suggest (1) that normal PMN on exposure to SLE sera develop intracytoplasmic inclusions by phagocytosis of immune complexes, (2) the presence of such complexes correlates with a number of parameters of disease activity, particularly when IgG and IgM are both present and (3) such complexes may be phagocytosed in vivo as suggested by the presence of inclusions in vivo and contribute to a number of granulocyte disturbances seen in patients with SLE. These abnormalities in granulocyte function may be important, predisposing factors for infection in patients with active SLE.

     

BACH2 regulates the function of human CD4+CD45RA−Foxp3l° cytokine-secreting T cells and promotes B-cell response in systemic lupus erythematosus

Although CD4⁺CD45RA⁻Foxp3^l° cytokine-secreting T cells (Fr.III cells) have been reported to be increased in systemic lupus erythematosus (SLE), their function and effects on response of B cells are still unclear. Here, we dissect how BACH2 regulates Fr.III cells function and promotes B-cell response in active SLE patients. We measured cytokines and BACH2 expression, and found that Fr.III cells from SLE patients produce much more inflammatory cytokines and were more able to promote B- cell proliferation, IgG, IgA, and TNF-α production than controls in a co-culture system. Fr.III cells expressed high levels of ICOS and CD154, but a low level of Tfr and BACH2, BACH2 expression was negatively correlated with SLE Disease Activity Index. Overexpressed of BACH2 in Fr.III cells, decreased cytokines expression and reduced B-cell response. Furthermore, we identified a reduction of H3K27ac level binding at the BACH2 locus in the SLE Fr.III cells and SLE serum stimulation decreased H3K27ac binding at the BACH2 locus, which could be restored using trichostatin A (TSA). In conclusion, BACH2 was associated with SLE disease activity, regulated the function of Fr.III cells, and promoted B-cells response. Targeting BACH2 may be a new immune intervention therapy of SLE.     

Skin tests, T cell responses and self-reported symptoms in children with allergic rhinitis and asthma due to house dust mite allergy

Background In allergic responses, a distinction is made between an early-phase response, several minutes after allergen exposure, and a late-phase response after several hours. During the late phase, eosinophils and T cells infiltrate the mucosa and play an important role in inflammation. Objective The aim of this study was to examine the relationship between allergen-induced late-phase skin responses and in vitro T cell reactivity. In addition, the relationship between allergen-induced skin or T cell responses and the severity of self-reported symptoms was studied in children with house dust mite allergy. Methods A total of 59 house dust mite-allergic children (6–18 years) were recruited in general practice. These children or their parents rated their nasal and asthma symptoms on diary cards during 1 month. Allergen skin tests were performed and read after 15 min (early phase) and 6 h (late phase). Allergen-specific T cell proliferation was determined, and Th2 cytokine (IL-5 and IL-13) secretion was analysed. Results The size of the late-phase skin response correlated with in vitro T cell proliferation (r_s=0.38, P=0.003) but not with Th2 cytokine secretion (r_s=0.16, P=0.2 for both IL-5 and IL-13). Moreover, the late-phase skin response and T cell proliferation correlated with asthma symptoms (r_s=0.30, P=0.02 for skin response and r_s=0.28, P=0.03 for T cell proliferation) but not with nasal symptoms (r_s=0.19, P=0.15 for skin response and r_s=0.09, P=0.52 for T cell proliferation). The early-phase skin response correlated with the nasal symptom score (r_s=0.34, P=0.01) but not with asthma symptom scores (r_s<0.005, P=0.97). Conclusion In this study, the late-phase skin test response correlated with in vitro T cell proliferation but not with Th2 cytokine secretion. We found weak or no correlations between late-phase skin responses and symptoms of asthma or rhinitis in children with house dust mite allergy. This suggests that late-phase skin responses reflect certain T cell properties but are of limited value for the evaluation of airway symptoms in atopic children.     

Peanut-specific B and T cell responses are correlated in peanut-allergic but not in non-allergic individuals

Objective We aim to find what is the relationship between B cell antibody responses and specific T cell help in the specific cases of allergy and tolerance to peanuts. Background B cell antibody responses to foreign proteins usually depend upon antigen‐specific T cell help. However, specific antibody levels can sometimes be maintained lifelong after infections or vaccination. Methods We measured peanut‐specific proliferation and antibody levels in peanut‐allergic and non‐allergic children using tritiated thymidine incorporation and UniCAP, respectively. We also investigated the corresponding tetanus toxoid specific responses in both groups. Results We found that tetanus‐specific IgG did not correlate with lymphocyte proliferation (Spearman rank correlation coefficient r′=0.08, P=0.74) nor with tetanus‐specific cytokine production (IFN‐γ: r′=0.198, P=0.285; TNF‐α: r′=0.274, P=0.146; IL‐4: r′=?0.007, P=0.96; P=0.221; IL‐13: r′=0.363, P=0.056). Conversely, in peanut‐allergic donors, peanut‐specific IgE (average 21 kU/L, median 2.27 kU/L, range 0.34‐100 kU/L) but not peanut‐specific IgG was positively correlated with proliferation (r′=0.751, P=0.003). In these donors, specific IgE was positively correlated with peanut‐specific Th2 cytokines production: r′=0.635, P=0.02 for IL‐4 and r′=0.641, P=0.025 for IL‐13 and negatively correlated with Th1 cytokines (r′=?0.71, P=0.007 for IFN‐γ and r′=?0.746, P=0.005 for TNF‐α, respectively). However, peanut‐specific IgE was not correlated with T cell proliferation or cytokine production in non‐allergic individuals. In conclusion, in allergic individuals, B and T cell responses to peanut antigens are correlated whereas normal immune responses B and T cell responses are uncoupled. Conclusion Our results support the view that B cell responses to allergens but not those to non‐allergenic proteins are correlated with specific T cell responses and therefore specific immunotherapy targeting of such T cells would inhibit allergen‐specific B cells.     

The defect in peripheral blood B-cell activation in patients with multiple myeloma is not due to a deficiency in the production of B-cell growth and differentiation factors

The suppression of B lymphopoiesis is a major feature of multiple myeloma (MM). In this disease, there is a striking defect in the response of peripheral blood B cells to pokeweed mitogen (PWM). Normally, B-cell activation depends on B-cell growth factors (BCGFs) and B-cell differentiation factors (BCDFs), produced by peripheral blood mononuclear cells. We therefore evaluated whether the production of these cytokines was defective in patients with MM. We have studied the production of BCGFs (using the anti- assay) and, particularly, interleukin-2 and interferon-, two well-documented BCGFs. No defect in the production of BCGFs, interleukin-2, and interferon- was found in patients with active (N=14) or stable (N=10) MM, compared with healthy donors (N=13). The production of BCDFs (i.e., overall activity) was also evaluated and, more particularly, that of interleukin-6 (IL-6). This cytokine is a potent BCDF which is essential in the PWM-induced activation of B cells, acting at the terminal stages of B-cell differentiation. Again, no defect in the production of BCDFs and IL-6 was found in patients with MM. Therefore, the ability to secrete cytokines controlling the process of B-cell activation is not affected in such patients. This indicates that the profound failure of humoral immune response is not due to deficiency of peripheral blood mononuclear cells producing these factors.     

Relationship between natural and infection‐induced antibodies in systemic autoimmune diseases (SAD): SLE,SSc and RA

Infection or vaccine‐induced T cell‐dependent immune response and the subsequent high‐affinity neutralizing antibody production have been extensively studied, while the connection between natural autoantibodies (nAAbs) and disease‐specific antibodies has not been thoroughly investigated. Our goal was to find the relationship between immunoglobulin (Ig)M and IgG isotype nAAbs and infection or vaccine‐induced and disease‐related autoantibody levels in systemic autoimmune diseases (SAD). A previously described indirect enzyme‐linked immunosorbent assay (ELISA) test was used for detection of IgM/IgG nAAbs against citrate synthase (anti‐CS) and F4 fragment (anti‐F4) of DNA topoisomerase I in 374 SAD samples, with a special focus on systemic lupus erythematosus (SLE) (n = 92), rheumatoid arthritis (n = 73) and systemic sclerosis (n = 157) disease groups. Anti‐measles IgG and anti‐dsDNA IgG/IgM autoantibodies were measured using commercial and in‐house indirect ELISA tests. In all SAD groups the anti‐measles IgG‐seropositive cases showed significantly higher anti‐CS IgG titers (P = 0·011). In anti‐dsDNA IgG‐positive SLE patients, we detected significantly higher levels of anti‐CS and anti‐F4 IgG nAAbs (P = 0·001 and < 0·001, respectively). Additionally, we found increased levels of IgM isotypes of anti‐CS and anti‐F4 nAAbs in anti‐dsDNA IgM‐positive SLE patients (P = 0·002 and 0·016, respectively). The association between IgG isotypes of pathogen‐ or autoimmune disease‐related antibodies and the IgG nAAbs may underscore the immune response‐inducible nature of the diseases investigated. The relationship between protective anti‐dsDNA IgM and the IgM isotype of anti‐F4 and anti‐CS may provide immunoserological evidence for the beneficial roles of nAAbs in SLE patients.     

Exhaled breath condensate levels of eotaxin and macrophage-derived chemokine in stable adult asthma patients

Background Asthma is associated with esoinophilic airway inflammation and overproduction of T‐helper type 2 (Th2) lymphocyte‐related cytokines. Objective This study assessed the eosinophil chemoattractant eotaxin and Th2‐specific macrophage‐derived chemokine (MDC) in the adult asthmatic airway. Eotaxin and MDC levels were determined in exhaled breath condensate (EBC) obtained from adult patients with asthma. Methods Fifty‐four asthmatics (20 male, mean (SD) age 40 (12) years and percentage predicted forced expiratory volume in 1 s (FEV₁) 81.7 (20.8)) and 20 age‐ and sex‐matched controls were studied. EBC was collected using EcoScreen by 10 min of tidal breathing with a nose clip. Concentrations of eotaxin and MDC were measured by ELISA. Results Asthma patients on inhaled corticosteroid (ICS) had a higher median interquartile range (IQR) level of eotaxin than the steroid‐naïve asthmatics (18.5 (17.7–20.1) vs. 17.9 (17.0–18.6) pg/mL, P=0.02) and controls (18.5 (17.7–20.1) pg/mL vs 17.4 (16.3–18.0) pg/mL, P=0.001). Eotaxin level in EBC had a significant negative correlation with the FEV₁/forced vital capacity ratio (r=?0.43, P=0.03) in steroid‐naïve asthmatics. EBC MDC level was higher in subjects on ICS than the steroid naïve asthmatics (120 (118–125) vs. 117 (116–119) pg/mL, P=0.01) and the controls (120 (118–125) vs. 117 (116–120) pg/mL, P=0.02). Conclusions Eotaxin and MDC could be measured in EBC of adults with asthma. EBC eotaxin and MDC levels were higher in asthmatics on ICS than the steroid‐naïve asthmatics or controls. Exhaled chemokines may be potential non‐invasive markers for assessing airway inflammation in asthmatics.     

A study of immunoglobulin G subclasses in patients with allergic bronchopulmonary aspergillosis

Total IgG, IgG subclass and total IgE levels were measured in thirty-one patients with allergic bronchopulmonary aspergillosis (APBA), and age-matched groups of extrinsic asthmatics and normal controls. Compared to controls, total IgG was significantly greater in ABPA (P < 0.01) and asthmatics (P0.01); IgG1 levels were also greater in ABPA (P < 0.01) and asthma (P < 0.01). In ABPA alone the levels of IgG2 (P < 0.05), IgG3 (P < 0.01) and IgG4 (P < 0.05) were greater than in controls, while the asthmatics did not differ significantly from either of these groups. There was no correlation between total IgE and any of the subclases in the three groups.     

Patients with condyloma acuminatum exhibit decreased interleukin-2 and interferon gamma production and depressed natural killer activity

Peripheral blood mononuclear cells were obtained from 20 untreated condyloma acuminatum patients and from an equal number of sex- and age-matched controls and assayed for cell surface antigen expression, natural killer activity, and lymphokine production. Patient peripheral blood mononuclear cells had significantly lower helper-to-suppressor T-cell ratios (Leu3/Leu2) (p<0.05) and significantly higher percentages of Leu 2+ Tac+ cells (activated suppressor/cytotoxic cells) (P<0.05) and Leu 2+ OKM1+ cells (suppressor cells) (P<0.01). Natural killer activity of condyloma acuminatum patients was significantly lower (P<0.05) than that of controls. Production of interleukin-2 and interferon gamma, but not interferon alpha, was significantly (P<0.01) decreased in condyloma acuminatum patients. There was an inverse correlation between thein vitro production of interleukin-2 and interferon gamma and the percentage of Leu 2+ OKM1+ cells (suppressor) (P<0.01). Thus, patients with condyloma acuminatum differ from controls by demonstrating (1) decreased natural killer-cell activity, (2) decreased production of lymphokines which enhance natural killer-cell activity (i.e., interferon gamma and interleukin-2), and (3) an increased proportion of T cells with a suppressor phenotype.     

B-Cell Activation in Duodenal Mucosa after Oral Cholera Vaccination in IgA Deficient Subjects with or without IgG Subclass Deficiency

Alterations in duodenal Ig-producing cells induced by two oral cholera vaccinations were studied by two-colour immunofluorescence in mucosal tissue sections from adults with selective IgA deficiency (IgAD), cither with (n= 7) or without (n= 9) frequent infections, infection-prone patients with combined IgAD and IgG subclass deficiency (IgGSD) (n= 7), and normal control subjects (n= 11). The proportion of IgG-producing cells prior to immunization tended to be lower in the symptomatic IgAD subjects than in the clinically healthy ones. In the first subgroup the absolute number of IgG cells per intestinal length unit was significantly increased after immunization (P < 0.04), and this tendency was also observed in the healthy IgAD subjects (6/9) and in those with combined deficiency (5/7). Very few IgAD subjects responded with an increase of IgM-producing cells. The normal controls responded variably in all major immunocyte classes, in the order IgA > IgG > IgM. Compared with these controls, the patients with combined IgAD and IgGSD showed significantly increased IgG1 (P < 0.01) and reduced IgG2(P < 0.006) proportions, which was in accordance with their serum subclass levels. Our study showed that oral cholera vaccination preferentially activates intestinal IgG-producing cells in IgAD subjects. This result agreed with data recently obtained by ELISPOT in the same patients with regard to antibody-forming cells specific for cholera toxin. Both methods suggested that IgG rather than IgM antibodies are elicited as compensation for a lacking IgA response. However, our overall results showed that intestinal B-cell activation is quite variable after oral cholera vaccination. Although such vaccination might be of importance for enhancing mucosal immunity also in IgAD patients, a concurrent gut disease could possibly be aggravated by IgG-mediated mucosal immunopathology in the absence of anti-inflammatory IgA antibodies.     

Expressions of IL-22 in circulating CD4+/CD8+ T cells and their correlation with disease activity in SLE patients

Recently, Th17 cell-associated responses have received growing attention; however, the role of IL-22 (a cytokines also produced by Th17 cells) in the pathogenesis of systemic lupus erythematosus (SLE) has not been widely explored. In this study, we analyze the frequencies of IL-22-positive CD4+/CD8+ T cells in peripheral blood mononuclear cells (PBMCs) from patients with SLE and their correlations with disease activity and clinical data. Five-color flow cytometry (FCM) was used to assess IL-22 production of CD4+/CD8+ T cells in PBMCs from 31 patients with SLE and 22 healthy control subjects, following stimulation ex vivo with phorbol 12-myristate 13-acetate and ionomycin for 4 h. Results showed that the percentages of IL-22-positive CD4+ T cells were increased in the PBMCs of patients with SLE compared with healthy control subjects, whereas there were no significant differences in the percentages of IL-22-positive CD8+ T cells. There was a strong positive correlation between the proportion of CD4+ T cells expressing IL-22 and SLEDAI score (r _s = 0.65, P < 0.001). Furthermore, the frequencies of IL-22-positive CD4+ T cells were significantly higher in patients with SLE with nephritis than those without nephritis (Z = −2.72, P < 0.01). In conclusion, increased frequencies of IL-22-positive CD4+ T cells in patients with SLE and positive correlation with SLEDAI score and lupus nephritis suggest that this cytokine may be implicated in the pathogenesis of the disease.     

Decreased paraoxonase activity in critically ill patients with sepsis

Paraoxonase 1 is believed to play a role in preventing lipid oxidation and, thus, limiting production of proinflammatory mediators. Systemic inflammatory response in sepsis increases oxidative stress and decreases high-density lipoprotein (HDL) concentrations. The objective of this study was to investigate serum paraoxonase 1 activities in critically ill patients with sepsis and after recovery. Serum paraoxonase 1 arylesterase/paraoxonase activities, concentration of total cholesterol, HDL cholesterol (HDL-C) and serum C-reactive protein (CRP) in septic patients of a medical intensive care unit (n = 30) and age/sex-matched outpatient controls without sepsis (n = 30) were analyzed. Paired convalescent samples were also taken 1 week after recovery (n = 11). In septic patients, both arylesterase (88.3 ± 36.5 vs. 162.1 ± 44.8 kU/l, P < 0.001) and paraoxonase (75.2 ± 50.0 vs. 125.2 ± 69.4 U/l, P < 0.01) paraoxonase 1 activities decreased as compared to controls. Both activities normalized after recovery. Negative correlation was found between CRP and both arylesterase (r = −0.676, P < 0.001) and paraoxonase (r = −0.401, P < 0.01) as well as positive correlation between HDL-C and both arylesterase (r = 0.585, P < 0.001) and paraoxonase (r = 0.405, P < 0.01) paraoxonase 1 activities. The decreased activity of paraoxonase 1 in negative correlation with CRP offers a potentially useful marker of sepsis progress and recovery in critically ill patients.     

The role of FFM accumulation and skeletal muscle architecture in powerlifting performance

The purpose of this study was to determine the distribution and architectural characteristics of skeletal muscle in elite powerlifters, and to investigate their relationship to fat-free mat (FFM) accumulation and powerlifting performance. Twenty elite male powerlifters (including four world and three US national champions) volunteered for this study. FFM, skeletal muscle distribution (muscle thickness at 13 anatomical sites), and isolated muscle thickness and fascicle pennation angle (PAN) of the triceps long-head (TL), vastus lateralis, and gastrocnemius medialis (MG) muscles were measured with B-mode ultrasound. Fascicle length (FAL) was calculated. Best lifting performance in the bench press (BP), squat lift (SQT), and dead lift (DL) was recorded from competition performance. Significant correlations (P≤0.01) were observed between muscle distribution (individual muscle thickness from 13 sites) and performance of the SQT (r=0.79 to r=0.91), BP (r=0.63 to r=0.85) and DL (r=0.70 to r=0.90). Subscapular muscle thickness was the single best predictor of powerlifting performance in each lift. Performance of the SQT, BP, and DL was strongly correlated with FFM and FFM relative to standing height (r=0.86 to 0.95, P≤0.001). FAL of the triceps long head and vastus lateralis were significantly correlated with FFM (r=0.59, P≤0.01; 0.63, P≤0.01, respectively) and performance of the SQT (r=0.45; r=0.50, respectively; P≤0.05), BP (r=0.52; r=0.56, respectively; P≤0.05), and DL (r=0.56; r=0.54, respectively; P≤0.01). A significant positive correlation was observed between isolated muscle thickness and PAN for triceps long-head (r=0.64, P≤0.01) and gastrocnemius medialis (r=0.48, P≤0.05) muscles, but not for vastus lateralis (r=0.35). PAN was negatively correlated with powerlifting performance. Our results indicate that powerlifting performance is a function of FFM and, therefore, may be limited by the ability to accumulate FFM. Additionally, muscle architecture appears to play an important role in powerlifting performance in that greater fascicle lengths are associated with greater FFM accumulation and powerlifting performance. Electronic Publication