Novel effector molecules in type 2 inflammation: lessons drawn from helminth infection and allergy

Abstract

Type 2 cytokine-induced inflammatory responses are critical components of the mucosal immune response required for host defense against helminth infection and are also responsible for the pathogenesis of many debilitating diseases including asthma, allergy, and forms of inflammatory bowel disease. Given the global prevalence of helminth infections, with an estimated two billion individuals infected worldwide, and the pandemic levels of asthma and allergy, with 30% of the population affected in North America, it is essential to define the molecules and pathways that underlie the protective or pathologic consequences of type 2 inflammation. In this review, we will focus on four families of proteins that are highly induced in helminth infection and allergy: 1) the arginases; 2) the resistin-like molecules; 3) the chitinase-like mammalian proteins; and 4) the intelectins. Here, we summarize what is known about their regulation and potential function in protecting against infection and/or exacerbating inflammation.

FIGURE 1

The RELM family of secreted proteins. A, Aligned amino acid sequences from the Mus musculus (m) and Homo sapiens (h) RELM family. Gray shading indicates amino acid identity of two or more family members. Red shading indicates cysteine residue involved in oligomerization. B, Phylogenetic analysis of the RELM proteins. Percentage of confidence was calculated using the bootstrap method (results >70% shown).

FIGURE 2

Expression of RELM-α, RELM-β, and intelectin in the colonic tissue of T. muris-infected mice. BALB/c mice were infected with 150 T. muris eggs. Paraformaldehyde-fixed colonic tissue from naive (A, C, E) or day 18 infected (B, D, F) animals were wax-embedded, and 5-μm sections were prepared, as previously described (41). All sections were stained with nuclei-specific 4′,6′-diamidino-2-phenylindole (blue). Standard immunofluorescence staining was performed with monoclonal rabbit anti-RELM-α (red; A and B), monoclonal rabbit anti-RELM-β (green; C and D) (both obtained from PeproTech), and polyclonal chicken antiintelectin 1/2 (E and F) (a gift from H. Miller, University of Edinburgh, U.K.). Blocking peptides confirmed specificity of staining.

FIGURE 3

Novel type 2 cytokine-induced molecules in helminth infection and allergy. Schematic diagram of the mucosal sites (lung and intestine) and the cell types (epithelial cells, red; macrophage, blue) where these novel molecules are expressed.