A role for interleukin‐5 in promoting increased immunoglobulin M at the site of disease in leprosy

Abstract

SummaryLeprosy is an infectious disease in which the clinical manifestations correlate with the type of immune response mounted to the pathogen, Mycobacterium leprae. To investigate which biological pathways or gene sets are over-represented in lepromatous (L-Lep) versus tuberculoid (T-Lep) patients that might be relevant in disease pathogenesis, we compared the gene expression profiles of L-lep versus T-lep skin lesions using knowledgeguided bioinformatic analysis, incorporating data on likely biological functions, including gene ontology information and regulatory data. Analysis of probe sets comparatively increased in expression in L-lep versus T-lep revealed multiple pathways and functional groups involving B-cell genes (P values all < 0Á005) relevant to the dataset. Further pathways analysis of B-cell genes comparatively increased in expression in L-lep versus T-lep lesions revealed a potential network linking the expression of immunoglobulin M (IgM) and interleukin-5 (IL-5). Analysis of the leprosy lesions by immunohistology indicated that there was approximately 8% more IgMpositive cells in L-lep lesions than in T-lep lesions. Furthermore, IL-5 synergized in vitro with M. leprae to enhance total IgM secretion from peripheral blood mononuclear cells. This pathways analysis of leprosy in combination with our in vitro studies implicates a role for IL-5 in the increased IgM at the site of disease in leprosy.

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

“…A lipid-binding pathway was present in L-lep lesions, which is consistent with the observation that host-derived lipids accumulate in macrophages in L-lep lesions (63). Genes involved in humoral immunity, including IGAH1, IGHM, and IGJ genes, which encode the protein components forming IgA and IgM multimers, were prominent in L-lep lesions, consistent with the previous identification of B cell genes in L-lep lesions (24,64). These Ig genes were connected to B cells and plasma cells, which are present at a greater frequency in L-lep lesions versus T-lep lesions (24,65).…”

“…Genes involved in humoral immunity, including IGAH1, IGHM, and IGJ genes, which encode the protein components forming IgA and IgM multimers, were prominent in L-lep lesions, consistent with the previous identification of B cell genes in L-lep lesions (24,64). These Ig genes were connected to B cells and plasma cells, which are present at a greater frequency in L-lep lesions versus T-lep lesions (24,65). We previously found that IgA and IgM mRNA and protein were more strongly expressed in L-lep lesions versus T-lep lesions, with IgM colocalizing with CD138 + plasma cells (24).…”

“…These Ig genes were connected to B cells and plasma cells, which are present at a greater frequency in L-lep lesions versus T-lep lesions (24,65). We previously found that IgA and IgM mRNA and protein were more strongly expressed in L-lep lesions versus T-lep lesions, with IgM colocalizing with CD138 + plasma cells (24). These data support the dogma that humoral immune responses found in the L-lep disease do not contribute to effective host defense against M. leprae infection but could contribute to disease pathology.…”

Inflammation rapidly reorganizes mouse bone marrow B cells and their environment in conjunction with early IgM responses

“…All of these molecules have been implicated in influencing B-cell differentiation and antibody production. 2,[31][32][33][34] Eotaxin and CCL3/MIP-1a (macrophage inflammatory protein 1a) were also increased. We also noted marked expansion of the bone marrow DX5…”

Dual RNAseq of human leprosy lesions identifies bacterial determinants linked to host immune response

“…In the lesions of the self-limiting tuberculoid form (T-lep), bacilli are rare, and the immune response is characterized by a CD4 + T cell infiltrate (Modlin et al, 1982) and a IFN- transcriptional signature resulting in an effective antimicrobial responses in macrophages (Fabri et al, 2011;Montoya et al, 2009;Yamamura et al, 1991). By contrast, the lesions of the disseminated lepromatous form (L-lep) are characterized by abundant bacilli, B cells or plasma cells (Iyer et al, 2007;Ochoa et al, 2010), and expression of a type I interferon (IFN) gene program that suppresses macrophage antimicrobial activity (Teles et al, 2013). Some patients undergo a reversal reaction (RR) which manifests clinically as an upgrade from the L-lep to the T-lep form of the disease, associated with a change from a type I to type II IFN response.…”