Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Abstract

Dendritic cells (DCs) produce cytokines and are susceptible to cytokine-mediated activation. Thus, interaction of resting immature DCs with TLR ligands, for example nucleic acids, or with microbes leads to a cascade of pro-inflammatory cytokines and skewing of T cell responses. Conversely, several cytokines are able to trigger DC activation (maturation) via autocrine, for example TNF and plasmacytoid DCs, and paracrine, for example type I IFN and myeloid DCs, pathways. By controlling DC activation, cytokines regulate immune homeostasis and the balance between tolerance and immunity. The increased production and/or bioavailability of cytokines and associated alterations in DC homeostasis have been implicated in various human inflammatory and autoimmune diseases. Targeting these cytokines with biological agents as already is the case with TNF and IL-1 represents a success of immunology and the coming years will expand the range of cytokines as therapeutic targets in autoinflammatory and autoimmune pathology.

Fig. 1

Dendritic cells are composed of subsets. DC progenitors originate from bone marrow CD34⁺FLT3⁺ hematopoietic progenitor cells (HPCs). A myeloid pathway generates both Langerhans cells (LCs), found in stratified epithelia such as the skin, and interstitial (int)DCs, found in all other tissues. It also generates mDCs circulating in the blood. Upon inflammation monocytes can yield mDCs. Another pathway generates plasmacytoid DCs (pDCs), which secrete large amounts of IFN-α/β after viral infection. Activated (mature) mDCs and pDCs traffic to secondary lymphoid organs either via afferent lymphatics (mDCs) or blood (pDCs). Langerhans DCs home to cell zones while interstitial DCs home to follicles consistent with their functional specialization, i.e. generation of cellular (Langerhans DCs) and humoral (interstitial DCs) immunity, respectively. The origin of resident lymph node DCs remains to be determined.

Fig. 2

Cytokines and dendritic cell activation. DCs both produce cytokines and are susceptible to cytokine-mediated activation. Thus, exposure to DC activators, for example TLR ligands or microbes, triggers secretion of pro-inflammatory cytokines including type I interferons (IFN), acute phase cytokines such as TNF and IL-6, IL-1 as well as IL-12 family (left panel). Several cytokines are able to trigger DCs activation (maturation) either in autocrine or paracrine fashion including IL-1, TNF, type I IFNs and TSLP (right panel).

Fig. 3

Cross-regulation of TNF and IFN-α in autoimmune diseases. TNF and IFN-α represent opposite vectors (paths) of immune responses. The sum of the vectors yields an equilibrium point, which allows protective immunity when vectors are equal. When one of the vectors prevails beyond a certain threshold, the equilibrium point moves into a zone of autoimmunity: an excess of IFN-α/β is pathogenic in SLE, Sjogren's, dermatomyositis and early stages of psoriasis while excess of TNF is pathogenic in rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease and psoriasis.

Fig. 4

Nucleic acids regulate activation of DC subsets. Interaction of resting immature pDCs with nucleic acids leads to a cascade of cytokine secretion including high amounts of type I IFN as well as TNF. This leads to generation of activated (mature) DCs derived from pDCs, via autocrine TNF, and from immature mDCs, via paracrine type I IFN, both of which drive T and B cell responses. Nucleic acids, abundant in autoimmune diseases such as SLE, can be presented to pDCs via several pathways such as i) immune complexes containing double stranded DNA (green) or single stranded RNA (red) which are taken up via Fc receptors; ii) viruses (for example RNA viruses) taken up via surface receptors; and iii) complexes of nuclear protein HMGB1 bound to DNA-containing immune complexes which are taken up by pDCs via the interaction of HMGB1 with surface protein of the immunoglobulin superfamily RAGE. Ultimately, captured nucleic acids are targeted to endocytic compartments where they bind TLR7 (RNA) or TLR9 (DNA) resulting in activation of signalling pathways that trigger transcription of inflammatory cytokines.