Influence of IgG Subclass on Human Antimannan Antibody-Mediated Resistance to Hematogenously Disseminated Candidiasis in Mice

Abstract

bCandida albicans is a yeast-like pathogen and can cause life-threatening systemic candidiasis. Its cell surface is enriched with mannan that is resistant to complement activation. Previously, we developed the recombinant human IgG1 antimannan antibody M1g1. M1g1 was found to promote complement activation and phagocytosis and protect mice from systemic candidiasis. Here, we evaluate the influence of IgG subclass on antimannan antibody-mediated protection. Three IgG subclass variants of M1g1 were constructed: M1g2, M1g3, and M1g4. The IgG subclass identity for each variant was confirmed with DNA sequence and subclass-specific antibodies. These variants contain identical M1 Fabs and exhibited similar binding affinities for C. albicans yeast and purified mannan. Yeast cells and hyphae recovered from the kidney of antibody-treated mice with systemic candidiasis showed uniform binding of each variant, indicating constitutive expression of the M1 epitope and antibody opsonization in the kidney. All variants promoted deposition of both murine and human C3 onto the yeast cell surface, with M1g4 showing delayed activation, as determined by flow cytometry and immunofluorescence microscopy. M1g4-mediated complement activation was found to be associated with its M1 Fab that activates the alternative pathway in an Fc-independent manner. Treatment with each subclass variant extended the survival of mice with systemic candidiasis (P < 0.001). However, treatment with M1g1, M1g3, or M1g4, but not with M1g2, also reduced the kidney fungal burden (P < 0.001). Thus, the role of human antimannan antibody in host resistance to systemic candidiasis is influenced by its IgG subclass.

Complement activation by human IgG antibodies to galactose‐α‐1,3‐galactose

“…In agreement with our results, recent findings by others have also suggested that IgG1 and IgG2 may not differ significantly in their propensity to activate complement. 43 In further support of important CP activation by IgG2 antibodies, individuals with CP deficiencies are particularly prone to infections with encapsulated bacteria, mainly S. pneumoniae, 44 and human antibodies to such pathogens are mainly IgG2. 45,46 Second, the present results reveal that C3 fragments deposited on cells can conceal the detection of upstream components, such as C4b, and the initiating antibodies.…”

The Role of B-Cells and Antibodies against Candida Vaccine Antigens in Invasive Candidiasis

“…A separate study found that this human anti-mannan antibody had a distinct Fc-independent effector function in the regulation of C3 deposition to C. albicans through the alternative pathway [ 126 ]. Nishiya et al demonstrated that the role of human anti-mannan antibody (M1g1) in host resistance to systemic candidiasis is influenced by its IgG subclass [ 127 ]. On conjugating mannan with tetanus toxoid or BSA, high titers of mannan antibodies were found in rabbits but low titers of antibodies were observed in mice after immunization with both glyco-conjugate vaccines [ 128 ].…”

Monoclonal Antibodies as Tools to Combat Fungal Infections

“…Using a mannan-specific humanized IgG 1 antibody, Zhang et al observed enhanced phagocytosis of C. albicans by murine macrophages, increased deposition of complement component C3, and protection of mice from an otherwise lethal dose of C. albicans yeast cells [37]. Moreover, generation of recombinant switch variants of this antibody revealed that an IgG 2 variant was less protective than the corresponding IgG 1 , IgG 3 , or IgG 4 immunoglobulins [38].…”