Publications

Fibronectin is a multifunctional protein that is synthesized in several different forms that result from alternative splicing of mRNA. Although expression of splicing variants appears to be both developmentally regulated and tissue-specific, the functional significance of these isoforms is largely unknown. We found that cultured airway epithelial cells vectorially secrete two distinct species of fibronectin, one which contains the alternatively spliced EIIIA region (EIIIA+) and one in which the EIIIA segment is spliced out (EIIIA-). Fibronectin containing the EIIIA region is preferentially secreted apically. Although both apical and basal stimulation with transforming growth factor beta 1 increased fibronectin synthesis, the secretory response differed depending on which surface was being stimulated. Apical secretion of fibronectin and expression of EIIIA+ fibronectin mRNA increased only after apical stimulation. These data demonstrate a novel mechanism for the polarized regulation of targeted secretion and alternative splicing of fibronectin and suggest that the EIIIA segment may act as a targeting signal for the vectorial secretion of fibronectin.

OBJECTIVE

To propose a new classification for the primary immunodeficiency disorders and to review potential therapeutic applications of biologic response modifiers in these disorders.

DATA SOURCE

Relevant articles were identified through a search of MEDLINE using the following indexing terms: primary immunodeficiencies (and subclassifications), and human immunomodulators (and subclassifications).

STUDY SELECTION

Articles were critically reviewed and included if relevant.

DATA SYNTHESIS

The primary immunodeficiency disorders are classified according to functional abnormalities, specifically, abnormalities in early cellular maturation, differentiation, regulatory cell function, enzymatic function, and cytokine responses. Such a classification clarifies the potential role of biologic response modifiers in primary immunodeficiency disorders. Intravenous gammaglobulin and histamine-2 (H2)-receptor blockers modify regulatory cell function; retinoids modify abnormal cellular differentiation, gene transfer and enzyme replacement can be applied in disorders characterized by specific functional gene abnormalities; and interferons modify abnormal cytokine responses. Interleukin-2, thymic hormones, transfer factor, and levamisole appear to affect multiple functional defects.

CONCLUSIONS

Biologic response modifiers are currently important ancillary tools in the treatment of immunodeficiency disorders, and their therapeutic role will become even more important in the future. Multi-center cooperative trials of new and existing agents are needed to fully define their roles and efficacy in the treatment of these disorders.

The expression of interleukin (IL) 2, IL-4, IL-10, and interferon gamma (IFN-gamma) by lymphocyte subsets was examined during infection of resistant C57BL/6 and susceptible BALB/c mice with the protozoan parasite Leishmania major. CD4+ and CD8+ T lymphocytes and B lymphocytes were isolated from the lymph nodes draining infectious lesions, and their RNA was examined for lymphokine transcripts. Distinct patterns of CD4+ cell cytokine expression were apparent: C57BL/6 CD4+ cells contained IFN-gamma and IL-2 mRNA, whereas BALB/c CD4+ cells expressed IL-4 and IL-10 message. CD8+ cells contributed little lymphokine expression during disease, but B cells were a major source of IL-2 mRNA in both strains of mice. BALB/c mice made resistant by treatment with anti-CD4 antibody at the time of infection repopulated lymph nodes with CD4+ cells that expressed IL-2 and IFN-gamma. Protective treatment with anti-IL-4 antibody in vivo also resulted in the appearance of CD4+ cells with increased IFN-gamma and diminished IL-4 and IL-10 expression. These data establish CD4+ cells as the primary source of IFN-gamma in healing mice and of IL-4 and IL-10 during progressive infection and confirm that the spectral extremes of this disease are characterized by the presence of CD4+ cells expressing Th1 or Th2 phenotypes in vivo.

STUDY OBJECTIVE

To estimate the incidence of and risk factors for morbidity due to inhalation of respiratory irritants.

DESIGN

Six-month case series of inhalational exposures reported to a poison control center with follow-up, structured interviews of subjects.

SETTING

A regional poison control center providing 24-hour telephone consultation to health professionals and the public.

PATIENTS

Consecutive sample of 683 inhalation cases, with interviews of 323 subjects.

MEASUREMENTS AND MAIN RESULTS

Moderate to severe irritants accounted for 160 (50%) of the inhalational exposures in interviewed subjects. Persistent symptoms lasting 14 days or longer were reported by only 20 (6%) of the subjects. Irritant exposure was a statistically significant risk factor for acute respiratory symptoms (relative risk [RR] = 1.7; 95% confidence interval [Cl], 1.4 to 2.1) but was unrelated to persistent symptoms. Preexisting lung conditions (RR = 2.4; 95% Cl, 1.4 to 4.2) and cigarette smoking (RR = 1.7; 95% Cl, 1.3 to 2.2) were both statistically significant risk factors for persistent symptoms.

CONCLUSIONS

Symptomatic inhalational exposures due to irritants are frequent in reports from poison control centers. Residual morbidity was uncommon and did not appear to be statistically related to the degree of irritant exposure. Host-related factors may be better predictors of ongoing morbidity after inhalational exposure.