Page 185 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 10 Chemokines and Chemokine Receptors 167

lesions and reduced accumulation of macrophages in the vessel
Malaria wall. Adoptive transfer studies with bone marrow from Cxcr2
−/−
Plasmodium vivax also uses a chemokine receptor for target cell mice have also revealed a role for CXCR2 in promoting athero-
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entry. The parasite ligand, named the Plasmodium vivax Duffy sclerosis in mouse models, apparently by promoting monocyte
Binding Protein (PvDBP), is expressed in micronemes of mero- adhesion to early atherosclerotic endothelium through interaction
zoites and binds to the N-terminal domain of ACKR1 (originally with its mouse ligand KC and activation of the VLA-4/VCAM-1
known as Duffy and later as DARC [Duffy Antigen Receptor for adhesion system.
Chemokines]) on erythrocytes via a cysteine-rich domain. This The CX3CR1 genetic variant CX3CR1-M280, which lacks
interaction is required for junction formation during invasion, normal CX3CL1-dependent adhesive function under conditions
but not for initial binding or parasite orientation. P. vivax-malaria of physiological flow, has been associated with reduced risk of
is rare in sub-Saharan Africa because of genetic deficiency in atherosclerotic vascular disease in humans. Mechanistic studies
ACKR1/Duffy caused by a single nucleotide substitution in the suggest that CX3CL1 on coronary artery smooth muscle cells
gene promoter (–46 C) affecting an erythroid-specific GATA-1 anchors macrophages via CX3CR1.
site. Fixation of the mutation in Africa presumably occurred
because of positive selective pressure from malaria. ACKR1/Duffy ON THE HOrIZON
deficiency in humans and in Ackr1 knockout mice is not associated
with any known health problems. ACKR1/Duffy is an obvious The Viral Chemokine System
drug target, but to date, no candidates have been reported. Studies of the viral chemokine system can yield insight into the role of
chemokines in immunoregulation. Viral chemokine elements may also
WHIM Syndrome have applications as therapeutic agents.
Truncating mutations in the C-tail of CXCR4 that increase
receptor signaling are the cause of most cases of WHIM syndrome, Structural Classification
a rare disease characterized by warts, hypogammaglobulinemia, • Chemokines (e.g., HHV8 vMIP-I, II, and III)
infection, and myelokathexis (neutropenia without maturation • 7TM chemokine receptors (e.g., HCMV US28, HHV8 vGPCR)
32
arrest). Myelokathexis and infection can be explained by exag- • Chemokine-binding proteins (e.g., γHV68 vCKBP-III)
• Chemokine mimics (e.g., HIV gp120)
geration of the normal bone marrow retention function of CXCR4
for myeloid cells, inhibiting their egress to blood. The exact Functional Classification
mechanism underlying the selective predisposition to human • Cell entry factors (e.g., HIV gp120)
papillomavirus infection is unknown. Dialing down the pathologi- • Leukocyte chemoattractants (e.g., HHV8 vMIP-II)
cally increased CXCR4 activity with a specific CXCR4 antagonist • Immune evasion
is a direct and rational strategy for treatment of patients with • Chemokine scavengers (e.g., γHV68 vCKBP-III)
WHIM syndrome. In this regard, clinical trials are in progress • Chemokine receptor antagonists (e.g., MCV MC148-R)
to repurpose plerixafor (Mozobil, AMD3100), a CXCR4 antagonist • Angiogenic factors (e.g., HHV8 vGPCR)
• Growth factors (e.g., HHV8 vGPCR)
approved by the FDA for use with granulocyte colony-stimulating • In mice, overexpression of this viral chemokine receptor induces
factor (G-CSF) to mobilize HSCs for autologous transplantation Kaposi’s sarcoma (KS)-like lesions.
in patients with multiple myeloma or lymphoma undergoing
cytoreductive therapy. 33,34
Remarkably, a patient who was spontaneously cured of WHIM Kaposi’s Sarcoma
syndrome by chromothripsis (chromosome shattering) on HHV8 is an example of a virus laden with genes encoding pirated
chromosome 2, which harbors the CXCR4 gene, has been identi- chemokines and chemokine receptors. It encodes three CC
35
fied. Chromothripsis is a newly described and uncommon chemokines, vMIP-I, -II, and -III, as well as a constitutively active
example of genomic instability first described in cancer. The CC/CXC chemokine receptor named vGPCR, encoded by ORF74.
chromothriptic event in the patient apparently occurred in a All of these factors are angiogenic and may contribute to the
single HSC that not only survived and lost the WHIM allele pathogenesis of Kaposi’s sarcoma (KS), a highly vascular mul-
(but not the normal allele of CXCR4) but also acquired a selective ticentric nonclonal tumor caused by HHV8, typically in the
advantage that allowed it to repopulate bone marrow, resulting setting of immunosuppression, such as in HIV/AIDS. Consistent
in correction of panleukopenia and clinical cure. This fortuitous with this, vGPCR induces KS-like tumors when expressed in
experiment of nature has been recapitulated in experimental transgenic mice. The mechanism may involve activation of NF-κB
mice, indicating directly that CXCR4 haploinsufficiency promotes and induction of angiogenic factors and proinflammatory
HSC engraftment and therefore may have been an important cytokines. This virus appears to have converted a hijacked receptor,
or even the sole mechanism of cure in the patient. Together, probably CXCR2, into a regulator of gene expression. 37
these findings point to a potential genetic cure strategy for WHIM
syndrome that might also be applied more broadly as an adjuvant Autoimmunity
to aid engraftment of gene-corrected cells in other genetic diseases Two human diseases in which chemokines act as autoantigens
of blood. for autoantibodies have been identified. The first, heparin-induced
thrombocytopenia (HIT), is the only human autoimmune disease
Atherosclerosis directly linked mechanistically to chemokines. An established
38
Macrophages are the dominant leukocytes present in athero- risk factor for thromboembolic complications of heparin therapy,
sclerotic lesions and are associated with the presence of HIT occurs in 1–5% of patients treated with heparin and is the
macrophage-targeted chemokines, such as CCL2, CCL5, and result of autoantibodies that bind specifically to CXCL4-heparin
−/−
−/−
−/−
−/−
36
CX3CL1. Ccl2 , Ccr2 , Cx3cl1 , and Cx3cr1 mice on the complexes in plasma. The second, autoimmune myositis, is
−/−
atherogenic ApoE genetic background demonstrate smaller associated with autoantibodies to histidyl transfer RNA (tRNA)