Fishing for mammalian paradigms in the teleost immune system

Abstract

Recent years have witnessed a renaissance in the study of fish immune systems. Such studies have greatly expanded the knowledge of the evolution and diversification of vertebrate immune systems. Several findings in those studies have overturned old paradigms about the immune system and led to the discovery of novel aspects of mammalian immunity. Here I focus on how findings pertaining to immunity in teleost (bony) fish have led to major new insights about mammalian B cell function in innate and adaptive immunity. Additionally, I illustrate how the discovery of the most ancient mucosal immunoglobulin described thus far will help resolve unsettled paradigms of mammalian mucosal immunity.

Figure 1

Hypothetical roles of phagocytic B-1 cells in antibody secretion and cytokine production after phagocytosis of microbes in a BCR-independent manner. (a) Commensal bacteria that have leaked from the gut lumen as a result of injury or inflammation are released into the peritoneal cavity, where phagocytic B-1 cells engulf them. (b) In a different scenario, the B-1 cells phagocytose pathogenic bacteria that have intruded into the peritoneal cavity or the liver. As a result, those B-1 cells may differentiate directly into antibody-secreting cells or they may activate, proliferate and turn into antibody-secreting cells (a,b). Those antibody-secreting cells will probably produce low-affinity polyreactive IgM that can recognize leaked commensals found in the peritoneal cavity (a) or pathogenic microbes (b). In addition, part of the secreted IgM will probably exit to the periphery, where it will add to the pool of natural antibodies (a,b). It may be possible that some of the secreted IgM recognizes self antigens and thus serves a role in autoimmunity (a,b). Alternatively, the phagocytic B-1 cells may migrate into the gut lamina propria (a) or to the spleen and peripheral lymph nodes (b). In those sites, the phagocytic B cells may directly differentiate into antibody-secreting cells and produce IgM (a,b), or IgA (a). IgA and IgM produced in the lamina propria may serve a role in immune exclusion (a). Phagocytic B-1 cells may also express pro- or anti-inflammatory cytokines depending on the tissue in which they are located (a,b). Ab, antibody; TNF, tumor-necrosis factor; IFN-γ, interferon-γ; TGF-β, transforming growth factor-β; M cell, microfold cell; CSR, class-switch recombination; sIgM and sIgA, secretory IgM and IgA.

Figure 2

Hypothetical roles of phagocytic B-1 cells in antibody secretion and cytokine production after phagocytosis of apoptotic bodies. Apoptotic bodies (AB) are engulfed by phagocytic B-1 cells from various lymphoid sites. As a result, those cells may differentiate directly into antibody-secreting cells or they may activate, proliferate and turn into antibody-secreting cells. Antibody-secreting cells will produce low-affinity polyreactive IgM that may recognize apoptotic bodies. It is also possible that some of the secreted IgM will recognize self antigens and thus have a role in autoimmunity. Moreover, part of the secreted IgM will probably exit to the periphery, where it will add to the pool of natural antibodies. After IgM binds to the apoptotic bodies, the IgM–apoptotic body complexes may bind C1q through the Fc portion of IgM to form C1q–IgM–apoptotic body complexes. Those complexes can activate the classical pathway of complement, which leads to the deposition of C3 activation fragments (such as iC3b) on the complexes. The resulting complexes can then be taken up by B-1 cells or other leukocytes (such as dendritic cells or macrophages). As presented here, they may be recognized by the C1q receptor (C1qR), the complement receptor CR3 and/or TIM-4. However, other receptors not shown here are also able to recognize apoptotic bodies, either directly or through other IgM, complement or lectin receptors.