IL-5 enhances secretion of IgA by B cells. The stage of B cell differentiation at which IL-5 enhances IgA secretion and the mechanism by which it exerts this effect are unknown. We examined these issues by separating Peyer's patch (PP) B cells into membrane IgA (mIgA)-positive and mIgA-negative cells with panning or cell sorting. When LPS was used to activate these cells, mIgA-positive PP B cells were induced by IL-5 (either as crude T cell supernatant or rIL-5 to secrete large amounts of IgA. In contrast mIgA-negative PP B cells showed no significant amount of IgA secretion with IL-5. In addition, rIL-5 did not cause expression of mIgA by mIgM-bearing B cells. The mechanism involved in enhancement of IgA secretion was evaluated by utilizing an ELISPOT assay to quantitate IgA secreting cells. Both unsorted PP B cells and mIgA-positive PP B cells, when incubated with IL-5, showed an increase in the number of IgA-secreting cells that was proportional to the increase in total secreted IgA. However, LPS-activated PP mIgA-positive B cells, when incubated with rIL-5, showed no increase in proliferation, as measured by [3H]thymidine incorporation indicating that the increase in IgA-secreting cells after incubation with IL-5 occurred not as a result of proliferation but rather through promotion of terminal differentiation. Thus, IL-5 acts as a differentiation factor on B cells which have already undergone isotype switch to IgA B cells, promoting differentiation into IgA-secreting cells with resultant increased IgA secretion.

Background: While smear positive patients with tuberculosis (TB) are considered more infectious than smear negative patients, the latter can also transmit TB. Methods: In a molecular epidemiology study of 791 patients in the Greater Vancouver regional district, the number of episodes of TB transmission from two groups of smear negative clustered patients by RFLP (assumed to be involved in recent transmission) was estimated after assessing for potential bias. Group 1 (n = 79) included patients with pulmonary TB or pulmonary + extrapulmonary disease (PTB or PTB+EPTB); group 2 (n = 129) included all patients in group 1 + extrapulmonary cases alone. Results: In the total sample the mean (SD) age was 51 (21) years, 54.3% were male, and 17.0% of patients were clustered. Compared with smear negative patients, smear positive patients were more likely to be in a cluster (OR = 2.0, 95% CI 1.1 to 3.6) and to have had a history of ethanol abuse (OR = 2.7, 95% CI 1.0 to 6.7), diabetes mellitus (OR = 2.8, 95% CI 1.1 to 7.0), injection drug use (OR = 3.1, 95% CI 1.1 to 8.3), and to have had a previous hospital admission (OR = 8.5, 95% CI 5.1 to 14.0). The proportion of episodes of transmission from smear negative clustered patients ranged from 17.3% to 22.2% in group 1 and from 25% to 41% in group 2. Conclusion: In Greater Vancouver, smear negative cases appear responsible for at least one sixth of culture positive episodes of TB transmission.

Tuberculosis as a primary cause of respiratory failure requiring mechanical ventilation (TBmv) is an uncommon occurrence. Over a 10 yr period in the province of Manitoba, Canada (population 1,091,942 in 1991), 13 patients with TBmv were identified. Non-drug-resistant M. tuberculosis was isolated from each case. The patients fell into two categories: miliary or disseminated tuberculosis (n = 7) and tuberculous pneumonia (n = 6); eight developed ARDS (adult respiratory distress syndrome) and another two probable ARDS. The hospital mortality for TBmv was compared with that for mechanically ventilated nontuberculous pneumonia and ARDS patients. Hospital mortality for patients with TBmv (69%, nine of 13) was significantly worse than hospital mortality for patients with nontuberculous pneumonia requiring mechanical ventilation (36%, 34 of 94; p < 0.025) and similar to the hospital mortality for patients with ARDS of any cause (56%, 15 of 27; p > 0.10). APACHE II scores for all groups of patients were similar. Compared with patients with tuberculous pneumonia, patients with miliary or disseminated tuberculosis were significantly more likely to develop TBmv (18.9 versus 0.8%, p < 0.0001). Despite the availability of effective antituberculous drugs, TBmv is often associated with ARDS and carries a similarly high mortality rate. Among patients with pulmonary tuberculosis, those with miliary or disseminated disease are especially prone to develop TBmv.

In these studies we determined the capacity of IL-6 to act as a differentiation cofactor for murine Peyer's patch B cells producing different Ig classes and subclasses. In preliminary studies we determined that sufficient endogenous IL-6 was produced in LPS-induced cell systems to obscure responses to exogenous IL-6. We therefore studied IL-6 effects on Peyer's patch B cells (T cell-depleted cell populations) in the absence of LPS, relying on responses of in vivo-activated cells. rIL-1 alpha or purified IL-6 only slightly enhanced synthesis of IgM over minimal baseline levels in Peyer's patch T cell-depleted cell cultures; however, when IL-6 was added to cultures also containing rIL-1, IgM synthesis was very substantially increased. In addition, rIL-5 alone gave rise to a modest increase in IgM synthesis and its effect was not enhanced by either rIL-1 or IL-6. IgG production (mainly IgG3) followed a similar pattern. In contrast, IgA production was only modestly increased above baseline by rIL-1, rIL-5, or IL-6 alone or by rIL-1 and IL-6 in combination, but was greatly increased by rIL-5 and IL-6 in combination. The effect of IL-6 on Ig synthesis in the above studies was not due to an effect on cell proliferation. In summary, these data indicate that B cells differ in respect to the cytokines supporting maximal terminal differentiation and thus the class of Ig produced may depend on the presence of a particular combination of cytokines and lymphokines.