Page 184 - Clinical Immunology_ Principles and Practice ( PDFDrive )

166 ParT ONE Principles of Immune Response

CLINICaL rELEVaNCE
Tissue-Specific Lymphocyte Homing
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Cutaneous lymphocyte-associated antigen (CLA ) T lymphocytes, Examples of Chemokine and Chemokine
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which home to skin, preferentially express CCR4 and CCR10. Receptor Determinants of Human Disease
The CCR4 ligand CCL22 is made by resident dermal macrophages • WHIM syndrome: Mendelian combined immunodeficiency disorder
and DCs, whereas the CCR10 ligand CCL27 is made by kerati- caused by gain-of-function mutations in CXCR4
nocytes. Blocking both these pathways, but not either one alone, • Plasmodium vivax malaria: Protection conferred by a nonfunctional
has been reported to inhibit lymphocyte recruitment to skin in promoter variant in ACKR1/Duffy that abrogates expression of the
a delayed-type hypersensitivity model. This implies that these receptor on red blood cells preventing use of the receptor by the
two molecules act redundantly as well as independently of parasite for cell entry
inflammatory chemokines. • HIV infection: Protection from cell entry by the virus conferred by
homozygous mutation CCR5Δ32
Homing to the small intestine is determined, in part, by • AIDS disease progression rate: Slowed by heterozygous CCR5Δ32
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T-lymphocyte expression of the integrin α 4 β 7 and CCR9. The • West Nile virus disease: Increased risk with homozygous CCR5Δ32
α 4 β 7 ligand MAdCAM-1 and the CCR9 ligand CCL25 colocalize • Kaposi’s sarcoma: Human herpesvirus 8 vGPCR
on normal as well as on inflamed endothelium of the small • Age-related macular degeneration: Increased risk with CX3CR1 M280
intestine. Most T cells in the intraepithelial and lamina propria allele
zones of the small intestine express CCR9. These cells, which • Cardiovascular disease: Decreased risk with CX3CR1 M280 allele
• Autoimmune heparin-induced thrombocytopenia: Caused by CXCL4
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are mainly TCRγδ or TCRαβ CD8αβ , are reduced in the small autoantibodies
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intestine from CCR9 mice. • Chronic renal allograft rejection: Reduced risk with homozygous
As B cells differentiate into plasma cells, they downregulate CCR5Δ32
CXCR5 and CCR7 and exit the lymph node. B immunoblasts • Rheumatoid arthritis: Reduced risk with CCR5Δ32
expressing immunoglobulin G (IgG) coordinately upregulate • Eosinophilic esophagitis: Associated with CCL26 variant
CXCR4, which promotes homing to bone marrow, whereas B
immunoblasts expressing IgA specifically migrate to mucosal sites.
Like gut-homing T cells, B immunoblasts that home to the small heterozygotes have slower disease progression. Homozygotes
intestine express α 4 β 7 integrin and CCR9 and respond to CCL25. appear healthy, as do unstressed CCR5 knockout mice. This has
Our understanding of the chemokine-dependent mechanisms led to the development and the US Food and Drug Administration
for leukocyte subset trafficking in most tissues remains rudi- (FDA) approval of the specific CCR5 antagonist maraviroc for
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mentary. There are hundreds of subsets that need to be evaluated treatment of patients with HIV/AIDS. The clinical importance
in both healthy tissues and disease states. At stake is the potential of CCR5 in HIV disease is also illustrated by the outcome of an
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identification of important new targets for therapeutic develop- HIV patient from Germany who had leukemia and fortuitously
ment of specific, safe, and effective mechanism-based drugs in received bone marrow transplantation from a CCR5Δ32 homo-
human disease. zygote after cytoreductive therapy for leukemia. Remarkably,
this patient has remained well, with undetectable viral load
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CHEMOKINES AND DISEASE without antiretroviral therapy, suggesting a functional “cure.”
This has spurred on efforts to develop zinc finger nuclease,
There is a vast amount of literature addressing the presence and CRISPR (clustered regularly interspersed short palindromic
potential clinical relevance of chemokines in human disease. repeats), and other genetic methods to inactivate the CCR5 gene
This section provides only a sampling of this work. Diseases for as a cure strategy in infected patients. Positive preliminary results
which evidence is strongest for a clear role of chemokines in have been reported for a CCR5 zinc finger nuclease.
pathogenesis in humans are highlighted. In some cases, under-
standing the role of chemokines has led to specific therapeutic CLINICaL rELEVaNCE
interventions.
FDA-Approved Drugs Targeting the
Opposite Effects of CCR5 in HIV and West Nile Chemokine System
Virus Infection • Maraviroc: CCR5 antagonist for human immunodeficiency virus/acquired
HIV envelope glycoprotein gp120 mediates fusion of viral envelope immunodeficiency syndrome (HIV/AIDS) that works by blocking HIV
with the target cell membrane by binding to CD4 and a specific target cell entry
chemokine receptor, which is referred to in this context as an • Plerixafor: CXCR4 antagonist indicated together with granulocyte–
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HIV coreceptor. CCR5 and CXCR4, the most important HIV colony-stimulating factor (G-CSF) for hematopoietic stem cell (HSC)
coreceptors, have been shown to be physically associated with mobilization in autologous stem cell transplantation of patients with
CD4 and gp120. HIV viruses are classified into three main multiple myeloma and non-Hodgkin lymphoma receiving cytoreductive
therapy
subtypes by preferred chemokine receptor usage: X4 strains,
which use CXCR4 for entry; R5 strains, which use CCR5; and
R5X4 strains, which can use either coreceptor. Coreceptor prefer- CCR5 is also important in the pathogenesis of West Nile
ence is the main determinant of distinct cytotropisms between virus (WNV) infection, but in this case, it plays a protective
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primary macrophages and cultured T-cell lines that have been role. The mechanism appears to be increased antiviral defense
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observed for these strains. by increasing recruitment of CCR5 leukocytes to the brain.
The importance of CCR5 in clinical HIV/AIDS is revealed Theoretically, therefore CCR5 blocking agents could increase
most clearly by CCR5Δ32, a nonfunctional allele that occurs in the risk of WNV disease in infected individuals, particularly in
~20% of North American Caucasians. Homozygotes are highly the setting of HIV/AIDS, where the immune system is already
resistant to R5 HIV, the main transmitting strain, and HIV-infected compromised.