CXCR5 is critically involved in progression of lupus through regulation of B cell and double-negative T cell trafficking.

The recruitment of immune cells to sites of tissue inflammation is orchestrated by chemokine/chemokine receptor networks. Among these, the CXCL13/CXCR5 axis is thought to be involved critically in systemic lupus erythematosus (SLE) and lupus nephritis pathogenesis. Beyond B cell abnormalities, another hallmark of SLE disease is the occurrence of aberrant T cell responses. In particular, double-negative (DN) T cells are expanded in the peripheral blood of patients with SLE and in lupus-prone mice. DN T cells induce immunoglobulin production, secrete proinflammatory cytokines and infiltrate inflamed tissue, including kidneys. We aimed to investigate how CXCR5 deficiency changes immune cell trafficking in murine lupus. We therefore crossed CXCR5(-/-) mice with B6/lpr mice, a well-established murine lupus model. B cell numbers and B cellular immune responses were diminished in CXCR5-deficient B6/lpr mice. In addition, we observed reduced accumulation of DN T cells in spleen and lymph nodes, paralleled by reduced splenomegaly and lymphadenopathy. In-vivo migration assays revealed reduced migration of CXCR5-deficient DN T cells into lymph nodes, and ex-vivo-activated CXCR5-deficient DN T cells failed to infiltrate kidneys of recipients. Moreover, DN T cells and B cells of CXCR5-deficient B6/lpr mice failed to migrate towards CXCL13 in vitro. We propose that CXCR5 is involved critically in B cell trafficking and germinal cell (GC) formation in murine lupus and in guiding pathogenic DN T cells into lymphoid organs and kidneys, and we therefore describe new pathomechanisms for the CXCL13/CXCR5 axis in SLE.

Toso regulates differentiation and activation of inflammatory dendritic cells during persistence-prone virus infection.

During virus infection and autoimmune disease, inflammatory dendritic cells (iDCs) differentiate from blood monocytes and infiltrate infected tissue. Following acute infection with hepatotropic viruses, iDCs are essential for re-stimulating virus-specific CD8(+) T cells and therefore contribute to virus control. Here we used the lymphocytic choriomeningitis virus (LCMV) model system to identify novel signals, which influence the recruitment and activation of iDCs in the liver. We observed that intrinsic expression of Toso (Faim3, FcµR) influenced the differentiation and activation of iDCs in vivo and DCs in vitro. Lack of iDCs in Toso-deficient (Toso(-/-)) mice reduced CD8(+) T-cell function in the liver and resulted in virus persistence. Furthermore, Toso(-/-) DCs failed to induce autoimmune diabetes in the rat insulin promoter-glycoprotein (RIP-GP) autoimmune diabetes model. In conclusion, we found that Toso has an essential role in the differentiation and maturation of iDCs, a process that is required for the control of persistence-prone virus infection.

Reactive oxygen species delay control of lymphocytic choriomeningitis virus.

Cluster of differentiation (CD)8(+) T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8(+) T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient (Ncf1(-/-)) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.

Cell-mediated immunity in bronchial asthma evaluated by purified protein derivative- and Candida albicans-skin reaction.

Cell-mediated immunity was examined in 45 patients with bronchial asthma by observing the delayed cutaneous reaction to purified protein derivative (PPD) and Candida albicans (C. albicans). The delayed skin reaction to PPD showed a decrease with age starting between 50 and 59 years old. The delayed reaction to PPD decreased more prominently with aging, being significantly depressed in the patients aged over 70 years than in those aged between 30 and 49 years (induration, p < 0.02; flare, p < 0.01). The C. albicans-induced skin reaction was significantly lower in the patients aged over 70 years than in those between 60 and 69 years old (induration, p < 0.01; flare, p < 0.05). The delayed skin reaction to PPD and C. albicans was significantly depressed in the patients with a serum IgE level over 1001 IU/ml. Delayed skin reaction to PPD and C. albicans was more depressed with aging and an elevated serum IgE, and the age (50-59 years) at the initiation of depression in the PPD-induced delayed skin reaction was younger than that (over 70 years) in the C. albicans-induced reaction.

Clinical effects of complex spa therapy on patients with steroid-dependent intractable asthma (SDIA).

The clinical effects of spa therapy (swimming training in a hot spring pool+inhalation of iodine salt solution+fango therapy) were examined in 52 patients with steroid-dependent intractable asthma (SDIA). Clinical effects were found in 36 of the 52 (69.2%) patients with SDIA. The efficacy was higher in the patients between the ages of 41 and 50 (87.5%) and between 51 and 60 (84.2%) than in those in the other age groups. Regarding clinical asthma types, the efficacy of spa therapy was higher in patients with type Ia-2 (83.4%), type Ib (77.8%) and type II (80.0%) than in those with type Ia-1 (54.2%). Efficacy seemed to be related to airway inflammation: the proportion of neutrophils and eosinophils in bronchoalveolar lavage (BAL) fluid was higher in patients with marked and moderate improvement compared with those with slight and no improvement. Ventilatory function was improved by complex spa therapy. %MMF and %V25 values increased by more than 20% after therapy in patients with type Ia-2, Ib and II asthma. Bronchial hyperreactivity to methacholine was suppressed after therapy. Any decreased function of the adrenocortical glands expressed by low serum cortisol levels improved after therapy, accompanied by a reduction in the dose of glucocorticoids necessary to control asthma attacks.

A new modified classification of bronchial asthma based on clinical symptoms.

The clinical features of four asthma types, Ia-1 (bronchospasm with 0-49 ml/day of expectoration), Ia-2 (with 50-99 ml/day), Ib (over 100 ml/day), and II (bronchiolar obstruction), as classified by the clinical symptoms, were compared in 119 patients with bronchial asthma. The age of onset characteristic symptoms of each asthma type was in the 20's in types Ia-1 and Ia-2, in the 30's in type Ib, and in the 40's in type II patients. A significant increase in the number of neutrophils in bronchoalveolar lavage (BAL) fluid was found in type II patients. The proportion of BAL eosinophils was significantly higher in types Ia-2 and Ib asthma patients compared with that in type Ia-1 patients. The BAL eosinophil count was significantly higher in type Ib than in type Ia-2 patients. The FEV1.0% and %V25 values were significantly lower in patients with type II asthma than in the patients with the other asthma types. Steroid-dependent intractable asthma (SDIA) was more often observed in patients with type Ib or type II asthma.

Characteristics of airway responses in patients with bronchial asthma. Evaluation of asthma classification systems based on clinical symptoms and clinical findings.

Asthma was classified into three types according to clinical symptoms (clinical diagnosis, C.D.): Ia. simple bronchoconstriction type (further divided into two subtypes, type Ia-1 with 0-49 ml/day of expectoration and type 1a-2 with 50-99 ml/day); Ib. bronchoconstriction + hypersecretion type, and II. bronchiolar obstruction type. Asthma was also classified by a score related to clinical findings and examinations (score diagnosis, S.D.). The clinical features of each type of asthma according to the two classifications methods were compared. Type 1a-2 and 1b patients (C.D.) were characterized by mucus hypersecretion (more than 50 ml/day) and eosinophilia in the bronchoalveolar lavage (BAL) fluid. The characteristic findings for type II asthmatics (C.D.) were a lower %V25 value (less than 10%) and an increased proportion of neutrophils (more than 20%) in the BAL fluid. All of the patients classified as types 1a-1, Ib, and II by clinical diagnosis were evaluated as having the same types of asthma by score diagnosis. Patients with type Ia-2 evaluated by clinical diagnosis were classified as type Ib by score diagnosis, since these two types had similar pathophysiological features represented by the increased proportion of eosinophils in the BAL fluid.

Airway inflammation and bronchial hyperresponsiveness in patients with asthma. Comparison between atopic and nonatopic asthma.

A relationship of cellular composition in the airways and the release of chemical mediators from the cells to bronchial hyperresponsiveness was examined in two age-matched asthma groups: 15 atopic and 15 nonatopic patients. 1. A significant correlation between the proportion of eosinophils in bronchoalveolar lavage (BAL) fluid and bronchial reactivity (BR) was found in patients with atopic and nonatopic asthma. The proportion of the cells (combined eosinophils and neutrophils) in BAL fluid was closely correlated with BR in patients with atopic asthma, but not in those with nonatopic asthma. There was no correlation between the proportion of BAL neutrophils and BR in the two asthma groups. 2. There was a significant correlation between histamine release from BAL cells and BR in patients with atopic asthma. In contrast, LTC4 release from BAL cells was significantly corrected with BR in patients with nonatopic asthma. The results suggest that the humoral and cellular components in the airways, that participate in bronchial hyperresponsiveness, are different between patients with atopic and nonatopic asthma.

Asthma classification by pathophysiology and IgE-mediated allergic reaction: new concepts for classification of asthma.

Bronchial asthma was classified by the pathophysiology and by the mechanism of onset of the disease. Forty asthmatics who had serum IgE levels lower than 200 IU/ml were evaluated by two classification methods. 1. In asthma classified by a score based on clinical findings and examinations, the characteristics of the findings and examination results were compared among three asthma types, i.e., Ia. simple broncho-constriction type, Ib. bronchoconstriction+hypersecretion type, and II. bronchiolar obstruction type. Type Ib patients, in addition to manifesting hypersecretion, had a significantly higher proportion of eosinophils in the bronchoalveolar lavage (BAL) fluid compared to other asthma types. Significantly decreased values for ventilatory parameters and an increased proportion of BAL neutrophils were found in type II compared with other asthma types. 2. In a new classification by mechanism of onset, asthma was classified into three types according to the degree of participation of IgE-mediated reactions associated with specific IgE antibodies and serum levels of total IgE: asthma induced by definite IgE-mediated reaction (atopic asthma), possible IgE-mediated reactions (asthma), and asthma induced by non-IgE-mediated reaction (asthma syndrome).

Pathophysiological changes in the airways of asthma patients with aging.

Pathophysiological changes in the airways with aging were examined in 78 patients with bronchial asthma. The FEV1.0% values in patients over the age of 71, and the %MMF, %V50 and %V25 values in those over 51 were significantly lower than those of patients between the ages of 10 and 30. The frequency of lymphocytes in bronchoalveolar lavage (BAL) fluid was significantly higher in patients aged between 61 and 70 than in those aged between 41 and 50 (p < 0.05). The frequency of each clinical asthma type changed with aging; the number of patients with simple bronchoconstriction type (type Ia) decreased with increasing age in patients under the age of 60, and the number of those with bronchiolar obstruction type (type II) increased with aging. The frequency of patients with bronchoconstriction+hypersecretion type (type Ib) showed a peak between the ages of 51 and 60. Bronchial reactivity to methacholine showed a tendency to decrease with aging. The release of histamine from leucocytes induced by Ca ionophore A23187 was significantly higher in patients between the ages of 10 and 30 than in those between the ages of 51 and 60 (p < 0.05) and between 61 and 70 (p < 0.01).

Asthma classification by a score calculated from clinical findings and examinations in subjects sensitive to inhalant allergens.

Twenty-one patients with atopic asthma were classified into three types according to their symptoms (clinical diagnosis): Ia, simple bronchoconstriction; Ib, bronchoconstriction + hypersecretion; and II, bronchiolar obstruction, and this classification was compared with a classification made according to clinical findings and examinations (score diagnosis). Type Ib asthma was characterized by the increased incidence of eosinophils in bronchoalveolar lavage fluid (BALF), while type II was characterized by ventilatory dysfunction in small airways and the increased incidence of neutrophils in BALF. Four patients, whose expectoration was between 50 and 99ml/day, of the 12 with type Ia assessed by clinical diagnosis were evaluated as type Ib by score diagnosis. One patient with type II by clinical diagnosis was assessed as questionable type II by score diagnosis. In the other 16 patients, the clinical and score diagnoses were the same.