Leveraging Antibody, B Cell and Fc Receptor Interactions to Understand Heterogeneous Immune Responses in Tuberculosis

Abstract

Despite over a century of research, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to kill 1.5 million people annually. Though less than 10% of infected individuals develop active disease, the specific host immune responses that lead to Mtb transmission and death, as well as those that are protective, are not yet fully defined. Recent immune correlative studies demonstrate that the spectrum of infection and disease is more heterogenous than has been classically defined. Moreover, emerging translational and animal model data attribute a diverse immune repertoire to TB outcomes. Thus, protective and detrimental immune responses to Mtb likely encompass a framework that is broader than T helper type 1 (Th1) immunity. Antibodies, Fc receptor interactions and B cells are underexplored host responses to Mtb. Poised at the interface of initial bacterial host interactions and in granulomatous lesions, antibodies and Fc receptors expressed on macrophages, neutrophils, dendritic cells, natural killer cells, T and B cells have the potential to influence local and systemic adaptive immune responses. Broadening the paradigm of protective immunity will offer new paths to improve diagnostics and vaccines to reduce the morbidity and mortality of TB.

Keywords: B cell; Fc effector function; Fc receptor; T cell; antibody; antigen presentation; iBALT; tuberculosis.

Figure 1

The spectrum of outcomes in human tuberculosis (TB) is heterogenous. Classical clinical states are defines by the presence of detectable bacteria and host response to Mycobacterium tuberculosis antigens by interferon γ release assay (IGRA), with uninfected having neither, latent TB infection having a positive IGRA but no detectable bacteria and active TB disease diagnosed by the capture of Mtb by growth in culture, nucleic acid amplification or cell wall stain. The transition between these states is fluid and poorly captured by these criteria: a. Individuals who have received antibiotic therapy for latent TB infection cannot be differentiated from those who are treatment naïve. b. Individuals who progress subclinically from latent infection to active disease (5-10%) and those who regress or remain asymptomatic (>90%) are indistinguishable. c. After successful treatment with antibiotics for active TB disease, individuals no longer have detectable bacteria as captured by standard assays but may have residual positive IGRA. Moreover, emerging epidemiological and immune correlates data suggest that beyond these classical states, there are groups who are highly exposed to Mtb who potentially represent an alternative state to latent TB infection not yet clearly defined.

Figure 2

Differential antibody engagement with Fc receptors mediate diverse innate and adaptive immune cell effector functions. Antibody diversity (A) in antigen specificity (theoretical n=10¹³), isotype (n=5), subclass (n=6) and post-translational glycosylation (theoretical n=36 possible different moieties) influence engagement of Fc receptors. Subsequent differential activation of high (red) and low (white) affinity Fc receptors (B) expressed on innate and adaptive immune cells (C) have the potential to mediate effector functions such as antibody dependent cellular phagocytosis and cytotoxicity (D) that in concert determine the heterogenous outcomes in human TB.

Figure 3

Direct and indirect B cell responses occur in Mtb infection. Direct responses include cytokine production and differentiation of B cells specific into plasma cells that secrete Mtb-specific antibodies (A). In response to Mtb infection in the lung, B cell effectors such as memory B cells, plasmablasts and plasma cells secrete pro-inflammatory cytokines (TNFα, IFNγ, IL2, IL6, GM-CSF and CCL3), while a subset of B cells can secrete inhibitory cytokines, such as IL10, which limits Th17 cell and neutrophil infiltration. In secondary and tertiary lymphoid organs such as lymph nodes and inducible bronchus-associated lymphoid tissue (iBALT), B cells facilitate antigen presentation to T cells (B, C). B cells receive T cell help from Tfh cells to initiate germinal center responses (B) and might also participate in priming T cells through the transfer of Mtb antigens (purple) to dendritic cells via exosomes and extracellular microvesicles (C). Finally, Fc-FcR interactions can enhance Mtb phagocytosis, macrophage and dendritic cell effecror functions, and antigen presentation to T cells in the lung granuloma (D).