Tissues: the unexplored frontier of antibody mediated immunity

Abstract

Pathogen-specific immunity evolves in the context of the infected tissue. However, current immune correlates analyses and vaccine efficacy metrics are based on immune functions from peripheral cells. Less is known about tissue-resident mechanisms of immunity. While antibodies represent the primary correlate of immunity following most clinically approved vaccines, how antibodies interact with localized, compartment-specific immune functions to fight infections, remains unclear. Emerging data demonstrate a unique community of immune cells that reside within different tissues. These tissue-specific immunological communities enable antibodies to direct both expected and unexpected local attack strategies to control, disrupt, and eliminate infection in a tissue-specific manner. Defining the full breadth of antibody effector functions, how they selectively contribute to control at the site of infection may provide clues for the design of next-generation vaccines able to direct the control, elimination, and prevention of compartment specific diseases of both infectious and non-infectious etiologies.

Figure 1.

Antibody Structure, Diversity and Adaptor Functions. (top) Antibody molecules consist of a Fab region that recognizes the pathogen, an Fc region and a converved N-glycan site. Affinity maturation allows the Fab to explore a nearly infinite space of binding affinities and specificities. Class switching and glycans increase the depth of this variation by creating changes in Fc. The Fc portion bridges an antibody to a variety of effector functions (bottom). Antibodies bound directly to a pathogen (bottom left) can drive complement deposition, which can further connect to cellular responses through complement receptors. Fc receptors for each Fc class exist and are linked to different functions. For example, FcγR1 is activating while FcγR2b is inhibitory. Antibodies can also bind to infected cells (bottom right) and target those cells for destruction via phagocytosis or release of cytotoxic granules.

Figure 2.

Local and peripheral immune responses. Innate tissue-resident sentienels represent the first-line of defense against pathogens. These sentinels express different combinations and levels of antibody Fc receptors that are distinct from innate immune cells in the blood, allowing these cells to mediate tissue-specific immune functions.

Figure 3.

Antibodies orchestrate an effective immune response against S.aureus in the skin. Plasmacytoid DCs (left) bind opsonized S.aureus via FcRs on the cell surface. FcR binding leads to endocytosis and recognition by TLR7/9 within the endosome. TLR7/9 signaling promotes IFNα production and secretion by pDCs. IFNα activates NK cells to kill the pathogen. In parallel, neutrophils (right) sense opsonized S.aureus and are activated to clear the pathogen.

Figure 4.

Antibody mediated immunity in the gut. Commensal bacteria and the host are in constant dialogue, and antibodies contribute to this conversation. IgA binds to 45% of commensal bacteria in the gut lumen, helping to distinguish friends from foes. The microbiota is continuously sampled by IgA and carried to Peyer’s patches. Within Peyer’s patches microbiota-specific B cells are matured and migrate to the bone marrow, populating the systemic immune response with immunity against enteric bacteria. Conversely, colitogenic bacteria are more densely coated with IgA (bottom panel), activating gut neutrophils and driving their activation and contribution to chronic inflammation in Ulcerative Colitis patients.

Figure 5.

Antibody-mediated Functions in the Liver. (left) The liver play a critical role in filtering foreign antigens and immune-complexes (left) through direct recognition by pattern recognition receptors (PRR) or by binding to antibodies or complement found within immune-complexes. The liver is one of the most prominent sites of inhibitory FcγR2b expression, which induces immune-complex uptake in the absence of inflammation, while the complement receptor VSIG4 on Kupffer cells also drives tolerogenic activity following immune-complex uptake. The liver is also host to a large population of natural killer (NK cells), divided into tolerogenic liver-resident NK cells (LrNK) or inflammatory NK cells (cNK), that are poised to respond to infection within the tissue under the correct activating signals. (right) Parasitic infection of the liver can be prevented by the malaria vaccine, RTS,S, via the induction of antibodies able to: recruit NK cell killing of the parasite, phagocytic clearance of the parasite, or the immobilization of the parasite.

Figure 6.

Antibody-mediated Regeneration and Pathology in the Brain. (left) The cerebrospinal fluid (CSF) is separated from blood via a blood-brain barrier (BBB). Under normal conditions microglia remove cell debris from neurons and other cells. This debris leaks through the BBB into the blood, where it may be captured by low-affinity natural IgM, promoting immune tolerance. (middle) Viral encephalitis is an inflammation in the brain that is driven by viral replication. Debris from damaged cells, viral antigens, and inflammatory cytokines secreted by microglia leak through the BBB and induce inflammation. The resulting humoral response includes functional antibodies against both viral and self antigens, which promote BBB breakdown and perpetuates inflammation in the brain. (right) Self-targeting antibodies may be present in the humoral repertoire, where they can be activated later, in the absence of viral replication. These antibodies can mediate cell destruction and inflammation through microglia, resulting in BBB breakdown and igniting autoimmune encephalitis.