Chronic mucocutaneous candidiasis. II. Class and subclass of specific antibody responses in vivo and in vitro

Abstract

SUMMARYPatients with chronic mucocutaneous candidiasis (CMC) succumb to persistent infections with the opportunistic yeast Candida. Impaired cell-mediated responses to Candida have been repeatedly reported while antibody responses were mostly found to be normal. The underlying defect remains poorly understood. It has recently been shown that CMC patients are also susceptible to infections with encapsulated bacteria, and may have associated IgG2 and IgG4 deficiency. Our previous studies demonstrated altered cytokine production in CMC patients. As cytokines can influence production and isotype of specific antibody, in 10 patients with CMC we measured the levels and isotype distributions of serum antibodies to Candida antigens (CAg), pneumococcal polysaccharide (PPS) and tetanus toxoid (TT) antigens. Peripheral blood lymphocytes were also stimulated in culture and the antibodies made in vitro were measured. Our data demonstrated that in vivo, CMC patients had very high levels of IgG and IgA CAg-specific antibodies. CAg-specific and PPS-specific IgG1 was markedly higher than in controls. Children but not adults with CMC had significantly lower levels of IgG2-specific antibody to CAg and PPS compared with age-matched controls. Patients had significantly higher levels of IgG3-specific antibody to all three antigens tested. These findings were in accordance with increased total IgG and IgG3 levels seen in CMC patients. In vitro, CMC patients, particularly children, did not respond as frequently to antigen stimulation as did their healthy controls. The level of specific antibody produced was also lower to all antigens tested, as was the amount of total immunoglobulins following antigenic and particularly mitogenic stimulation. Addition of interferon-alpha (IFN-®) or IFN-°to cultures had variable, sometimes marked, effects. Our results demonstrate that CMC patients manifest subtle alterations in specific antibody responses to CAg, PPS and TT, which are most pronounced in children. This may relate to altered cytokine production also seen in these patients.

Chronic mucocutaneous candidiasis. I. Altered antigen-stimulated IL-2, IL-4, IL-6 and interferon-gamma (IFN-γ) production

“…The consequences of this Th2 type bias in response to CAgs would be preferential development of vigorous humoral responses, i.e. very high levels of anti-Candida antibodies (which we indeed demonstrate in the accompanying study [12]) together with low or absent cell-mediated responses (which has consistently been demonstrated both in vivo and in vitro in CMC patients [1,3,4]). As antibodies do not confer protection against fungi, the result would be an inability to clear Candida infection, as is indeed the case in CMC patients.…”

“…In this and an accompanying study [12] we present results of our investigations addressing the question of cytokine production and antibody responses to antigens found on microorganisms poorly handled by CMC patients (Candida and PS antigens) and those handled well (protein antigens). We also assess various factors known to be involved in regulating levels of cytokine production: effects of in vitro addition of IFN-and IFN-on cytokine production, as both agents have been shown to exert profound effects on the types of cytokines produced, shifting the balance in favour of Th1 type cytokines [10,13]; soluble IL-6 (sIL-6R) receptors were measured, as they have been shown to upregulate IL-6 production by associating with secreted IL-6, thus promoting binding to cell membrane receptors and stimulating further IL-6 secretion [14].…”

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

“…20,69,70 Respiratory tract infections may be favored by low IgA, IgG2, and/or IgG4 levels as well as a poor Ab response, as documented in some patients. 71,72 The occurrence of mycobacterial and viral infections is paradoxical, as biallelic LOF STAT1 mutations underlie such infections by impairing IFN-g and IFN-a/b responses, respectively, while GOF STAT1 mono-allelic mutations enhance signaling downstream of these cytokines. 20,23,37,45,73 Viral disease might be because of exhaustion of virus-specific T cells, as described for patients with AD HIES, 74 and mycobacterial disease to refractory responses to IFN-g. 37 Patients with GOF STAT1 mutations also displayed autoimmunity, aneurysms, and malignancies.…”

Measurement of T-Cell-Derived Antigen Binding Molecules and Immunoglobulin G Specific toCandida albicansMannan in Sera of Patients with Recurrent Vulvovaginal Candidiasis

“…Anti-Candida antibody levels may be normal or even elevated in chronic mucocutaneous candidiasis (28), even though recurrent mucosal infections occur in this disorder. In patients with vaginitis, serum anti-Candida antibody levels are normal or elevated (4,33).…”