Pathophysiology and Pathogenesis of Immune-Mediated Inflammatory Diseases: Commonalities and Differences

Proposed paradigm linking HLA-B27 misfolding to innate immune activation. HLA-B27 misfolding is hypothesized to result in activation of an intracellular stress response pathway known as the unfolded protein response (UPR), which leads to production of IL-23. Enhanced upregulation of interleukin 23 (IL-23) promotes IL-17 production from CD4 T cells of the Th17 lineage. Th17 cells can produce tumor necrosis factor-α (TNF-α) and IL-6, and IL-17 is also a potent proinflammatory cytokine that acts on many tissue cell types and further induces TNF-α, IL-6, and IL-1, as well as chemokines and metalloproteinases. From Colbert, et al, Prion 2009;3:15-26²¹; with permission from Landes Bioscience.

Model for T helper (Th) or T regulatory (Treg) differentiation from naive CD4+ T cells. T cell signaling requires formation of a contact [interface between an antigen-presenting cell (APC) and a T cell]. The key event in T cell stimulation is the activation of the T cell receptor (TCR) by antigenic peptides presented by MHC molecules on the APC. Other factors required for T cell differentiation and signaling include: activation of costimulatory molecules and costimulation by various cytokines via cytokine receptors. Th1 cells differentiate in the presence of IL-12, interferon-α/-ß/-γ, IL-18, and IL-27. Th2 cells depend on the presence of IL-4, IL-6, and IL-11. Th17 cells require a combination of transforming growth factor-ß1 and proinflammatory cytokines (such as IL-6). Upregulation of the IL-23 receptor makes these cells responsive to IL-23. Human Th17 cells produce IL-23, IL-21, and IL-17. From Zhernakova, et al, Nat Rev Genet 2009;10:43–55⁴; with permission from Macmillan Publishers Ltd.

Contribution of known genetic risk factors for RA. HLA: human leukocyte antigen; PTPN2: protein tyrosine phosphatase, non-receptor type 2; STAT 3: signal transducer and activator of transcription 3; TRAF1/C5: tumor necrosis factor receptor-associated factor 1/complement component 5. From Bowes and Barton, Rheumatology 2008;47:399–402³¹; with permission of Oxford University Press.

Overview of normal NOD2-signaling pathway. Upon recognition of MDP, NOD2 recruits through homophilic interactions the adaptor RIP2. Once recruited, RIP2 activates NF-κB, p38, and ERK, which elicit immune response. NOD2-signaling has been shown to be essential for healthy conditions by modulating cytokines, chemokines, and defensin production. NOD2: nucleotide-binding oligomerization domain protein 2; Rip2: serine-threonine kinase (also known as RICK or CARDIAK); ERK: extracellular signal regulated kinases; MDP: muramyl dipeptide; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; Tak-1: transforming growth factor-ß-activated kinase 1. From Vignal, et al, Microbes Infect 2007;9:658–63⁴³; with permission from Elsevier.

Overview of interleukin 12 (IL-12) and IL-23 ligand and receptor complexes. IL-23R: interleukin 23 receptor; IL-12Rß: interleukin 12 receptor beta; STAT: signal transducer and activator of transcription. From Boniface, et al, Immunol Rev 2008;226:132–46⁶²; with permission from John Wiley and Sons Inc.

Development of anti-citrulline positive RA. From Klareskog, et al, Curr Opin Immunol 2006;18:650–5⁸⁵; with permission from Elsevier.

A potential model comparing the normal ileum and the ileum in Crohn’s disease (CD). The presence of proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), as well as exposure to adherent invasive Escherichia coli, results in increased expression of CEACAM6 in the ileal epithelium of patients with CD. Increased CEACAM6 expression then mediates the adhesion of adherent invasive E. coli to the ileal epithelium. From Abraham and Cho, N Engl J Med 2007;357:708–10⁹². With permission from Massachusetts Medical Society. All rights reserved.