Immunoglobulins in the hyperimmunoglobulin E and recurrent infection (Job's) syndrome. Deficiency of anti-Staphylococcus aureus immunoglobulin A.

Abstract

Patients with the hyperimmunoglobulin E and recurrent infection syndrome (HIE) characteristically have frequent skin and respiratory infections caused by Staphylococcus aureus. We have developed a set of enzyme-linked immunosorbent assays that use whole S. aureus (Wood's strain) immobilized on 0.22-um filters and highly specific, affinity-purified enzyme conjugates of goat anti-human IgE, anti-human IgD, anti-human IgG, anti-human IgA, and anti-human IgM. These reagents were used to determine S. aureus-specific immunoglobulin (Ig) levels. As previously published, 10 patients with HIE had markedly higher levels of anti-S. aureus IgE than did 5 patients with eczema and recurrent superficial S. aureus infections (P < 0.001). The HIE patients were also found to have a deficit of anti-S. aureus serum IgA as compared with 12 normal subjects, 12 patients with chronic granulomatous disease, 5 patients with chronic eczema and recurrent superficial S. aureus infections, and 3 patients with the Chediak-Higashi syndrome (P < 0.01 for each comparison). In addition, the HIE patients had an excess of anti-S. aureus IgM as compared with normal subjects (P < 0.01). An expected excess of anti-S. aureus IgG was absent. These abnormalities cannot be explained by variations of total serum Ig levels or by a general inability to produce antigen-specific IgA because levels of naturally occurring IgA antibody against Escherichia coli lipopolysaccharide and the antigens of the pneumococcal vaccine are normal. Parotid saliva from patients with HIE contained less salivary IgA per milligram of protein (P < 0.01) and less salivary anti-S. aureus IgA per milligram of protein (P < 0.05) than did normal controls. The incidence of infection at mucosal surfaces and adjacent lymph nodes correlated inversely with serum anti-S. aureus IgA (r = -0.647, P = 0.034), serum anti-S. aureus IgE (r = -0.731, P = 0.016), total serum IgE (r = -0.714, P = 0.020), and total serum IgD (r = -0.597, P = 0.049). These findings are evidence of a previously undescribed immunoregulatory defect in patients with HIE, which may contribute to the increased susceptibility to infection in this syndrome.

Immunoglobulin E in primary immunodeficiency diseases

“…HIES patients have normal levels of anti-S. aureus IgG and modestly elevated levels of anti-S. aureus IgM. Unexpectedly, antistaphylococcal IgA levels are low in HIES patients (74) and total salivary IgA is also reduced. Quinti et al (86), reported high-molecular-weight immune complexes (>900 000 Da) composed of IgG anti-IgE.…”

“…Many studies have focused on the immune aspects of the disease, such as detection of eosinophilia in blood, sputum, and abscesses (51,69), defective granulocyte chemotaxis (34,35,40,70), abnormal T lymphocyte subsets (51,71), defective antibody production (72)(73)(74)(75), and decreased production of, or responsiveness to, cytokines such as IL-4 and interferon-gamma (IFN-c) (76)(77)(78)(79). Complement levels were normal when studied.…”

Insights into the Role of STAT3 in Human Lymphocyte Differentiation as Revealed by the Hyper-IgE Syndrome

“…Skeletal manifestations include joint hyperextensibility, short stature, coarse facial features, hypertelorism, osteopenia with fracture susceptibility, craniosynostosis, degenerative joint disease, and failure to shed primary teeth (44)(45)(46)48). Laboratory investigation reveal near-normal levels of IgG, IgA, and IgM, but IgE frequently exceeds 2000 IU/ml (47,(49)(50)(51). Specific IgE to common allergens is often positive, suggesting that at least a component of IgE is Ag driven.…”

“…Functional Ab deficiency. Poor specific humoral immune responses have been documented in HIES (45,(49)(50)(51). This resembles B cell STAT3-deficient mice, which do not mount Ag-specific T cell-dependent IgG responses (35).…”

“…Although most assessments of humoral responses in AD-HIES patients focused on Ag-specific IgG (47,50,51), these patients also exhibit reduced levels of specific IgA in their serum and saliva (49). Because mice lacking IL-6 have impaired mucosal IgA immune responses (74), and IL-10 and IL-21 can induce IgA secretion by activated human B cells (70 -72), it is likely that the generation of IgA-PC is also STAT3 dependent.…”