10  B cell and antibody responses to Cryptococcus
Antibodies are generated in response to cryptococcal challenge, with IgM, IgG and IgA each isolated from human patients in descending order of prevalence (Houpt et al., 1994). Antibodies against cryptococci have been found in adults and children (Abadi and Pirofski, 1999; Chen et al., 1999), indicating cryptococcal infection at a young age, and that cryptococcal infection is a common occurrence. Defects in antibody responses are seen in immunocompromised individuals, with B cell repertoire observed in both mouse and human in response to glucuronoxylomannan, a major constituent of cryptococcal capsule, being depleted in HIV infection (Pirofski, 2001). Specific IgM and IgG, but not IgA, against cryptococcal melanin has been observed after mouse infection (Nosanchuk et al., 1998) and immune sera were found to only have high affinity to bind to melanised cryptococci. This is interesting as melanin is considered to be found in the cryptococcal cell wall and suggest that antibodies may have access to the cell wall during infection. Passive immunisation with two different monoclonal IgM antibodies to melanin reduced fungal burden during mouse infection and was able to directly reduce cryptococcal growth in vitro (Rosas et al., 2001).
As described above, complement and antibody are required for efficient phagocytosis of C. neoformans in vitro, with potential compensation when one opsonin is missing or impaired. In agreement with this the reduced complement mediated phagocytosis caused by increased cryptococcal capsular size is compensated with increase in antibody mediated phagocytosis, demonstrated with C5 deficient mice which have an increased antibody response (Dromer et al., 1989; Zaragoza et al., 2003).
Antibodies have been shown to have a protective effect in lethally infected mice (Fleuridor et al., 1998; Mukherjee et al., 1992), showing that antibodies are effective as opsonins for C. neoformans. A mouse model deficient in secreted IgM showed increased death and fungal burden in the blood and brain. Mice with secreted IgM adopted a Th1 profile early during infection and had higher levels of phagocytosis (Marks and Pirofski, 2010). Furthermore, a B1 B cell deficient murine model showed increased fungal burden and decreased alveolar macrophage uptake (through decreased IgM) (Szymczak et al., 2013). This provides an association between B cell responses, and the effector function of phagocytes using antibody for phagocytosis, and suggests that there is requirement for antibody in the normal clearance of cryptococci. Therapy targeting B cell and antibody responses is a potentially fruitful area but further work is needed to understand the mechanisms involved and what defects are present in human disease.