Target Antigen, Age, and Duration of Antigen Exposure Independently Regulate Immunoglobulin G Subclass Switching in Malaria

Abstract

The isotype/subclass of immunoglobulin determines antibody function, but rather little is known about factors that direct class switching in vivo. To evaluate factors that might influence the maturation of the antibody response during infection, we conducted a seroepidemiological study of the immunoglobulin G (IgG) subclass response to four merozoite-associated antigens of Plasmodium falciparum in a mountainous region of northeastern Tanzania, where malaria endemicity declines with increasing altitudes. We found that IgG1/IgG3 class switching is independently affected by the nature of the antigen, cumulative exposure to the antigen, and the maturity of the immune system (i.e., the age of the individual). These observations provide insights into the effects of immune system maturity, the duration and intensity of antigen exposure, and inherent characteristics of individual antigens on the process of class switching in human B cells. Our data also throw light on the consequences of class switch decisions on the gradual acquisition of antimalarial immunity.The isotype/subclass of immunoglobulin determines antibody function (e.g., complement fixation or the activation of phagocytes), and in humans, immunoglobulin G1 (IgG1) and IgG3 are important mediators of pathogen clearance. Specific combinations of cytokines and B-cell activators have been shown to induce class switching to certain isotypes or subclasses in model systems (13), but less is known about factors that direct class switching in vivo during infection. While it has long been suspected that characteristics of antigens themselves influence class switching in B cells (41,43), and while some antigens induce characteristic patterns of Ig class switching, most notably (in humans) encapsulated bacteria (IgG2) (27, 28) and allergens and helminths (IgG4 and IgE) (20), the characteristics of antigens that induce switching to human IgG1 and IgG3 are not well described.Numerous studies have reported that IgG subclass profiles differ among antibodies targeted to different malarial antigens, with the best example being the tendency of merozoite surface protein 2 (MSP-2) to induce very strong IgG3 responses (39,46), in contrast to the tendency of the C terminus of MSP-1, MSP-1 19 , to induce IgG1 or a mixed IgG1/IgG3 response (7,18). Here we demonstrate that characteristics of antigens per se can regulate the IgG1/IgG3 class switch, in that different antigens of Plasmodium falciparum, the causative agent of the virulent form of human malaria, elicit entirely different antibody subclasses even though they are presented to the immune system at the same time and as part of the same single-celled organism (i.e., the malaria merozoite). To evaluate the effects of antigens per se, immune system maturity (age), and cumulative exposure to antigens (which varies according to the intensity of malaria transmission) on the maturation of the IgG response, we conducted a seroepidemiological study in a mountainous region of northeastern Tanzania, where malaria endemicity declines wi...

IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression

“…In early stages, it IgG subclass in membranous glomerulonephritis is possible that there is an IgG1-dominant anti-PLA2R response, which, with disease progression, will turn into an IgG4-dominant antibody response. Such IgG subclass switch has been reported in a variety of diseases, such as in malaria, 20 leprosy and tuberculosis, 21 and paracoccidioidomycosis. 22 A Recent study by Segawa et al 23 from Japan, describes the IgG subclass distribution in 16 pediatric patients with 'idiopathic' membranous glomerulonephritis.…”

Determination of the processes driving the acquisition of immunity to malaria using a mathematical transmission model

“…However, if natural recovery from infection (e.g., from asymptomatic to subpatent) is solely determined by age (via physiological processes, provided there is exposure on which infection is conditional), we obtain patterns closer to those observed ( Figure 3). This suggests that parasite immunity in non-naïve individuals may be controlled by physiological development rather than by the amount of natural exposure (provided there is exposure) [7][8][9]14,15,30].…”

Immunoglobulin G Subclass-Specific Responses against Plasmodium falciparum Merozoite Antigens Are Associated with Control of Parasitemia and Protection from Symptomatic Illness

“…It has been suggested that IgG3 is more efficient at mediating these processes (7). For reasons that are not well understood, different merozoite antigens induce different relative levels of IgG1 and IgG3 (14,29,31,37,40,46,48). It is unclear whether individuals have a bias toward producing a specific subclass regardless of the antigen or if instead the IgG subclass response is generated independently for each antigen and how this relates to protective immunity.…”

“…It is unclear whether individuals have a bias toward producing a specific subclass regardless of the antigen or if instead the IgG subclass response is generated independently for each antigen and how this relates to protective immunity. While factors determining subclass responses to antigens are not clearly defined, antigen properties, host age, cumulative exposure, and genetic determinants have been linked with the nature of subclass responses (2,4,17,33,34,41,42,47,48). Some studies have suggested that increasing age (and therefore malaria exposure) leads to an increasing polarization of IgG subclass responses to merozoite antigens (41,48).…”

“…Knowledge of subclass responses associated with protection against malaria is important for understanding immunity and guiding vaccine development. IgG1 and IgG3 are the predominant subclasses produced in response to merozoite antigens (31,37,40,43,46,48). IgG1 and IgG3 are cytophilic and T cell dependent, have high affinity for Fc receptors, and mediate phagocyte activation and complement fixation (7).…”