Altered Antibody Isotype in Cystic Fibrosis. Possible Role in Opsonic Deficiency

Abstract

ABSTRACT'. Patients with cystic fibrosis (CF) whose respiratory tracts are colonized with Pseudomonas aeruginosa (PA) may develop a specific opsonic deficiency for alveolar macrophage phagocytosis of PA. We examined the possible role of altered antibody (Ab) isotype in this phenomenom by measuring serum levels and distribution of IgG and IgG subclass Ab (IgGl, IgG2, IgG3, and IgG4) to the major opsonic immunodeterminant, serotype-specific lipopolysaccharide (LPS), by means of enzyme-linked immunosorbent assays employing monoclonal secondary antibodies, and comparing these results to the serum opsonic capacity in an in vitro murine alveolar macrophage phagocytic assay. Twenty-one patients with CF who were colonized with PA had approximately a 30-fold elevation of PA LPS IgG Ab levels and higher IgG subclass 1-4 Ab compared to 10 uncolonized patients with CF and 11 healthy controls (p < 0.05-0.0005 depending on the isotype). Colonized patients with CF had a shift in PA LPS Ab distribution toward IgG3 compared to uncolonized patients with CF (p < 0.02). A surprising finding was that uncolonized patients with CF had lower levels (p < 0.05) and proportion (p < 0.002) of PA LPS IgG2 Ab than controls, with an apparent shift to higher levels and proportion of PA LPS IgG4 (p < 0.01). Serum from colonized patients with CF showed diminished opsonic capacity for phagocytosis of PA compared to uncolonized patients and controls (p < 0.005), with 42% showing inhibitory activity.

Affinity Constants of Naturally Acquired and Vaccine-Induced Anti-Pseudomonas aeruginosa Antibodies in Healthy Adults and Cystic Fibrosis Patients

“…Fick et al [29] have proposed that opsonization is compromised by a weak interaction between antibody and Fe receptors expressed by phagocytic cells. Moss and coworkers [30,31] have noted an altered antibody isotype distribution in CF patients. Certain isotypes of antibody, specifically IgG2, were found to be far more efficient at opsonizing both mucoid and nonmucoid P. aeruginosa [8].…”

Altered Antibody Isotype in Cystic Fibrosis: Impaired Natural Antibody Response to Polysaccharide Antigens

“…As with IgG antibodies, PRP-specific IgG2 levels were generally lower in C F patients. These findings, particularly in light of our previous observations regarding P. ueruginosa LPS antibodies (8), suggest IgG2 responses to polysaccharide antigens, of potential functional importance, might be impaired in C F patients.…”

“…However, neither of these explanations account for the antigenic restriction of the opsonic defect to PA. In contrast, a change in the pattern (isotype distribution) of the antibody response subsequent to initial colonization might result in production of blocking antibody, an alteration capable of causing an antigen-specific immune deficiency (8)(9)(10).…”

“…In studying this phenomenon, we were struck by the unexpected finding that patients with CF who were not infected with PA appeared to have an impaired humoral immune response to PA LPS, as manifested by subnormal levels of PA LPS-specific IgG2 antibodies and an apparent redistribution of the response to nonopsonizing IgG4 (8).…”

Quantitative analysis of immunoglobulin G subclass responses to Pseudomonas aeruginosa antigens in cystic fibrosis

“…aeruginosa lipopolysaccharides (LPS), exoenzymes and polysaccharide antigens. [12][13][14][15][16][17][18] A1 though the results are not entirely consistent, it has generally been found that IgG2, IgG3 and IgG4 antibodies to these antigens are elevated in the sera of CF patients with chronic P . aeruginosa infections.…”