Page 308 - Hematology_ Basic Principles and Practice ( PDFDrive )

256 Part III Immunologic Basis of Hematology

158
182
and induced specific Tregs. Human DC deficiencies are associated been found. Additionally, the transfer of mature, collagen-pulsed
with a loss of Tregs, and it seems that DCs and Tregs reciprocally DCs is sufficient to induce arthritis in a mouse model through
control each other’s expansion, where DCs control Treg expansion induction of local inflammation and priming of autoreactive T
183
and Tregs control DC numbers through an Flt3-dependent feedback cells. DCs are currently being used to “tolerize” patients with
loop. RA in vivo. DCs suppressed with a NFκB inhibitor and exposed
The tolerogenic function of DCs can also be regulated intrinsi- to four citrullinated peptide antigens were recently shown to reduce
cally by signaling molecules such as NFκB, a key regulator of DC effector T cells, increase the ratio of regulatory to effector T cells,
function; A20, a ubiquitin-editing enzyme that is implicated in the and reduce serum cytokines and chemokines and a T-cell response
degradation of molecules that activate NFκB, negative regulators of to citrullinated vimentin. 184
NFκB (CD31), and mammalian target of rapamycin (mTOR); and An anomalous or persistent activation of DCs in the intestine
β-catenin, which promotes the tolerogenic activity of DCs. 159–164 in response to infectious agents with release of proinflammatory
Although DCs promote tolerance via a variety of mechanisms, cytokines can activate innate and adaptive immune cells, thus
they are also known to play a role in autoimmunity through activa- contributing to the establishment of a noxious environment in the
tion and differentiation of self-reactive T cells, a process that can be gut. 185,186 The dysregulation of DC function (related to pathogen
triggered either by inappropriate activation of DCs or by the collapse recognition and antigen presentation) was shown to be critical in
of negative regulation. Constitutive depletion of DCs in mice results driving pathologic inflammation in IBD. 185
in a syndrome resembling autoimmunity that was accompanied by DCs residing at the perivascular space of the blood–brain barrier
+
increased CD4 T-cell infiltration in peripheral tissues, higher Th1 act as a gatekeepers, presenting antigens to migrating T cells and
165
and Th17 cell numbers, autoantibody formation, and neutrophilia. thus contributing to inflammation in the central nervous system
In the steady state, DCs participate in maintaining tolerance, but (CNS). 187,188 However, experimental autoimmune encephalomyelitis
this balance can be altered by changes in DC number, phenotype, (EAE) can be induced in the absence of DCs, and the conditional
166
and function. In proinflammatory settings, or when there is an depletion of DCs does not affect pathogenic Th priming in this
absence of regulatory molecules to control DCs, they can potentially model. 189,190 Thus DCs contribute to the onset of EAE, but they are
present self-antigens to naive T cells, thus promoting self-reactive not strictly necessary for it, and other APCs might promote harmful
167
T-cell activation and contributing to autoimmunity. DCs are also T-cell differentiation.
191
believed to be important for the induction of the chronic phase of DCs play a tolerogenic role in preventing type 1 diabetes, but
autoimmune diseases. Some of these conditions are discussed in more they can promote it if, in an activated state, they cross-present β-cell
192
detail later. antigens to T cells, initiating pathogenic T-cell differentiation. A
+
DCs from patients with SLE exhibit altered CD40, CD86, and distinct subset of AIRE DCs was described to express antigen insulin
168
Fcγ receptor expression and have altered PD-L1 expression, which derived from β-cells, suggesting a role for tDCs in controlling activa-
169
can modulate T-cell suppression. Activated cDCs (possibly through tion of insulin-reactive T cells. 193
immune complexes or cell-derived microparticles) may promote lupus Overall, DCs play an important role in the development of auto-
pathogenesis by presenting RNA-associated proteins and chromatin immune disease, either via direct activation of self-reactive T cells
170
to self-reactive T cells. In mouse models of SLE, activated DCs or indirectly because of the proinflammatory environment that they
also enhance B-cell proliferation, IL-6 and IFN-γ secretion, and can create with secretion of cytokines and reduction of Tregs. When
antinuclear antibody production. 171,172 IFN-α produced by pDCs considering treatment approaches for these autoimmune diseases,
is thought to contribute to the autoimmune response in SLE. 173–176 there is a need to identify and define the balance between regulatory
pDCs can be activated through TLR7 and TLR9 by immune com- and pathogenic DC roles.
plexes containing RNA and DNA, respectively, from dead cells and
induced to secrete high amounts of IFN-α. This can further promote
the differentiation of monocytes into activated cDCs, thus enhancing SUBVERSION OF DENDRITIC CELL FUNCTION BY
presentation of self-antigens, increasing the cytotoxicity of CD8 and PATHOGENS AND TUMORS
NK cells, and promoting plasma cell differentiation and subsequent
generation of pathogenic autoantibodies. Several host factors can Several pathogens have evolved different mechanisms to inhibit DC
convert self-DNA into triggers of pDC activation. For example, the functions, allowing them to downregulate specific immune responses
antimicrobial peptide LL-37 forms large aggregates with self-DNA and hence persist in the host. Numerous viruses, such as measles,
released from dying cells, protecting it from extracellular nuclease vaccinia, herpes simplex, smallpox, and LCMV, can impair antigen
digestion, and is taken in pDCs for induction of type I IFN. LL-37 presentation by infected cells through different mechanisms. Thus
has been found to be overexpressed in psoriatic skin, and the gene human CMV induces downmodulation of MHC class I or class
encoding LL-37 is the most upregulated in the blood of patients II molecules and can inhibit activated T cells through secretion of
with lupus. 177 a virally encoded IL-10 homolog. Directly targeting DCs allows
A role of cDCs during disease onset is also strongly suggested in viruses to impair the generation and quality of the antiviral immune
arthritis, multiple sclerosis, diabetes, and atherosclerosis. 178–180 The responses. In mice, CMV has been shown to trigger paralysis of
similarity between outcomes of microbial infection and autoimmu- infected DCs, preventing them from secreting IL-12 or IL-2 upon
nity suggests that TLRs or PRRs triggered by microbial molecules TLR4 triggering, impairing their capacity to mature, and eventually
194
on DCs induce their maturation and secretion of cytokines and rendering them unable to prime an effective T-cell response. Some
chemokines. This may cause DCs to upregulate presentation of self- viral products interfere with IFN-α secretion pathways, such as the
antigens in instances such as apoptosis or necrosis induced directly E6 oncoprotein of human papillomavirus, inhibiting transactivation
by pathogens or antimicrobial immune response. Endogenous ligands of IRF3 or IRF7, or NS3/4A inhibiting RIG-I- and MDA5-mediated
such as extracellular matrix breakdown products (heparan sulfate and activation of IRF3.
hyaluronate), molecules released from necrotic cells (high-mobility It is now well documented that in HIV-infected patients not
group box 1 protein [HMGB1], uric acid, or even endogenous nucleic only are the number of pDCs and cDCs in blood reduced, but
acids), fibronectin, and HSPs, which can activate TLRs on cDCs, cDCs are also less efficient at stimulating primary T-cell responses
may also contribute to the generation of autoimmune responses. 181 and may generate IL-10–secreting T cells with a potential regula-
In rheumatoid arthritis (RA), DCs migrate into the synovium, tory role. DCs, such as Langerhans cells, may be the first cells to
where they produce proinflammatory molecules that concentrate encounter HIV in mucosal tissues and may mediate the spread of
+
in the vicinity of T cells, thereby possibly contributing to overall virus to CD4 T cells in lymphoid organs. Formation of virions and
inflammation. DCs are hypothesized to regulate the production of release from the cell surface are counteracted by tetherin, an IFN-
autoantibodies in RA, and a correlation between DC numbers and regulated restriction factor that retains virions at the cell surface. The
concentration of anticitrullinated peptide antibodies in RA sera has Vpu accessory protein antagonizes tetherin activity to allow virion