| ITGAM, ITGAX |
Granulocyte pathway, Monocyte pathway, Cell adhesion molecules (CAMs), Hematopoietic cell lineage, Leishmania infection, Leukocyte transendothelial migration, Regulation of actin cytoskeleton |
ITGAM and ITGAX encode integrins αM and αX that mark intestinal dendritic cells that maintain the balance between inflammation and tolerance. ITGAM and ITGAX also combine with integrin β2 chain to form leukocyte-specific complement receptors 3 and 4 (CR3 and CR4, respectively). ITGAM is involved in the regulation of intestinal IgA-producing plasma cells in mice36. Integrin-αM-positive IgA plasma cells reside in Peyer’s patches, require microbial stimulation for development, and exhibit more proliferation and more IgA production compared to integrin-αM-negative cells36. In mice, intestinal dendritic cells that express high level of both αM and αX integrins are CD103+, express TLR5, produce retinoic acid, and induce T-cell-independent IgA class-switch recombination52, 53. Schistosome infection specifically impairs the ability of ITGAM-positive (CD11b+) dendritic cells to stimulate CD4+ T-cells49.
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| CARD9 |
NOD-like receptor signaling pathway, Innate immune system, Tuberculosis, Fungal infection |
CARD9 encodes a molecular scaffold for the assembly of a BCL10 signaling complex that activates NF-κB, which is responsible for both innate and adaptive immune responses54. The rs4077515 risk allele is associated with increased expression of CARD9, and has known association with increased risk of ulcerative colitis and Crohn’s disease11, 12, 34, 55, 56. Conversely, a rare protein-truncating splice variant in CARD9 confers additive protection from inflammatory bowel disease56, 57. Familial CARD9 deficiency predisposes to invasive fungal infections58. CARD9 mediates intestinal repair, T-helper 17 responses, and control of bacterial infection after intestinal epithelial injury in mice41.
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| VAV3 |
Chemokine signaling pathway, Focal adhesion, Natural killer cell mediated cytotoxicity, T cell receptor signaling pathway, B cell receptor signaling pathway, Fc epsilon RI signaling pathway, Fc gamma R-mediated phagocytosis, Leukocyte transendothelial migration, Regulation of actin cytoskeleton |
VAV proteins (Vav1, 2, and 3) are guanine nucleotide exchange factors essential for adaptive immune function13, 14 and NF-κB activation in B-cells, a process that stimulates IgA production43. VAV proteins are also required for proper differentiation of colonic enterocytes and preventing spontaneous ulcerations of intestinal mucosa42. VAV3 is a positional candidate for QTL for mouse intestinal inflammation in a parasite-induced (Trichuris muris) model-of infection59.
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| DEFA1, DEFA3, DEFA4, DEFA5, DEFA6 |
Innate immune system |
α-defensins are antimicrobial peptides involved in mucosal defense. DEFA5 and DEFA6 genes expressed by the intestinal Paneth cells. Deficiencies in α-defensins-5 and -6 have been associated with Crohn’s disease39, 40. While α-defensin-5 is broadly antimicrobial, α-defensin-6 promotes mucosal innate immunity through self-assembled peptide nanonets60.
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| TNFSF13 |
Cytokine-cytokine receptor interaction, Intestinal immune network for IgA production |
TNFSF13 encodes APRIL, a powerful B-cell stimulating cytokine that promotes CD40-independent IgA class switching35. The IgAN risk allele is associated with increased IgA levels4. TNFSF13 is induced by intestinal bacteria resulting in IgA class switching. APRIL levels are elevated in some patients with IgAN61. Mutations in the TNFSF13 receptor (TACI) produce IgA deficiency or combined variable immunodeficiency, with increased propensity to mucosal infections62.
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| LIF, OSM, HORMAD2, MTMR3 |
Cytokine-cytokine receptor interaction, Jak-STAT signaling pathway |
The IgAN risk allele at this locus is protective against Crohn’s disease11, 12, 63 and associated with increased serum IgA levels3. LIF and OSM are IL-6 related cytokines that use gp130 for signal transduction, and have been previously implicated in mucosal immunity64, 65. Genetic disruption of gp130 signaling leads to gastrointestinal ulceration and inflammatory joint disease in mice66. LIF is secreted by pericrypt fibroblasts67 and may be critical for proliferation and renewal of enterocytes68.
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| PSMB8, PSMB9, TAP1, TAP2 |
Phagosome pathway, Antigen processing and presentation, Primary immunodeficiency, Proteosome, Activation of NFkB in B-cells |
PSMB8 and PSMB9 are interferon-induced subunits of the immunoproteosome that mediate intestinal NF-κB activation in IBD69. PSMB8 is up-regulated in human intestinal tissue with active IBD lesions70. Treatment with bortezomib (PSMB8 inhibitor) or psmb8 deletion in mice attenuates experimental colitis71.
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| HLA-DQA1, HLA-DQB1, HLA-DRB1 |
Antigen processing and presentation, Adaptive immune system, Intestinal immune network for IgA production, Allograft rejection, Graft versus host disease, Asthma, Autoimmune thyroid disease, Leishmania infection |
The IgAN risk allele is associated with increased risk of Celiac disease72, 73 and increased risk of IgA deficiency24. The IgAN risk allele has an opposed (protective) effect on the risk of ulcerative colitis27, 74.
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