Introduction to the Immune System (The Immune System in Health and Disease) (Rheumatology) Part 3

Dendritic Cells

Human dendritic cells (DCs) are heterogenous and contain two subsets, myeloid DCs and plasmacytoid DCs.

TABLE 1-7

CC, CXC1, CX3, C1, AND XC FAMILIES OF CHEMOKINES AND CHEMOKINE RECEPTORSa

CHEMOKINE

RECEPTOR

CHEMOKINE LIGANDS

CELL TYPES

DISEASE CONNECTION

CCR1

CCL3 (MIP-1a), CCL5 (RANTES), CCL7 (MCP-3), CCL14 (HCC1)

T cells, monocytes, eosinophils, basophils

Rheumatoid arthritis, multiple sclerosis

CCR2

CCL2 (MCP-1), CCL8 (MCP-2), CCL7 (MCP-3), CCL13 (MCP-4),

CCL16 (HCC4)

Monocytes, dendritic cells (immature), memory T cells

Atherosclerosis, rheumatoid arthritis, multiple sclerosis, resistance to intracellular pathogens, Type 2 diabetes mellitus

CCR3

CCL11 (eotaxin), CCL13 (eotaxin-2), CCL7 (MCP-3), CCL5 (RANTES), CCL8 (MCP-2), CCL13 (MCP-4)

Eosinophils, basophils, mast cells, TH2, platelets

Allergic asthma and rhinitis

CCR4


CCL17 (TARC), CCL22 (MDC)

T cells (TH2) dendritic cells (mature), basophils, macrophages, platelets

Parasitic infection, graft rejection, T-cell homing to skin

CCR5

CCL3 (MIP-1a), CCL4 (MIP-1 β), CCL5 (RANTES), CCL11 (eotaxin), CCL14 (HCC1), CCL16 (HCC4)

T cells, monocytes

HIV-1 coreceptor (T-tropic strains), transplant rejection

CCR6

CCL20 (MIP-3ß, LARC)

T cells (T regulatory and memory), B cells, dendritic cells

Mucosal humoral immunity, allergic asthma, intestinal T-cell homing

CCR7

CCL19 (ELC), CCL21 (SLC)

T cells, dendritic cells (mature)

Transport of T cells and dendritic cells to lymph nodes, antigen presentation, and cellular immunity

CCR8

CCL1 (1309)

T cells (TH2), monocytes, dendritic cells

Dendritic-cell migration to lymph node, type 2 cellular immunity, granuloma formation

CCR9

CCL25 (TECK)

T cells, IgA+ plasma cells

Homing of T cells and IgA+ plasma cells to the intestine, inflammatory bowel disease

CCR10

CCL27 (CTACK, CCL28 (MEC)

T cells

T-cell homing to intestine and skin

CXCR1

CXCL8 (interleukin-8), CXCL6 (GCP2)

Neutrophils, monocytes

Inflammatory lung disease, COPD

CXCR2

CXCL8, CXCL1 (GROa), CXCL2 (GROß), CXCL3 (GRO^, CXCL5 (ENA-78), CXCL6

Neutrophils, monocytes, microvascular endothelial cells

Inflammatory lung disease, COPD, angiogenic for tumor growth

CXCR3-A

CXCL9 (MIG), CXCL10 (IP-10), CXCL11 (I-TAC)

Type 1 helper cells, mast cells, mesangial cells

Inflammatory skin disease, multiple sclerosis, transplant rejection

CXCR3-B

CXCL4 (PF4), CXCL9 (MIG), CXCL10 (IP-10), CXCL11 (I-TAC)

Microvascular endothelial cells, neoplastic cells

Angiostatic for tumor growth

CXCR4

CXCL12 (SDF-1)

Widely expressed

HIV-1 coreceptor (T-cell-tropic), tumor metastases, hematopoiesis

CXCR5

CXCL13 (BCA-1)

B cells, follicular helper T cells

Formation of B cell follicles

CXCR6

CXCL16 (SR-PSOX)

CD8+ T cells, natural killer cells, and memory CD4+ T cells

Inflammatory liver disease, atherosclerosis (CXCL16)

CX3CR1

CX3CL1 (fractalkine)

Macrophages, endothelial cells, smooth-muscle cells

Atherosclerosis

XCR1

XCL1 (lymphotactin), XCL2

T cells, natural killer cells

Rheumatoid arthritis, IgA nephropathy, tumor response

aMIP denotes macrophage inflammatory protein, MCP monocyte chemoattractant protein, HCC hemofiltrate chemokine, TH2 type 2 helper T cells, TARC thymus and activation-regulated chemokine, MDC macrophage-derived chemokine, LARC liver and activation-regulated chemokine, ELC Epstein-Barr I1-ligand chemokine, SLC secondary lymphoid-tissue chemokine, TECK thymus-expressed chemokine, CTACK cutaneous T-cell-attracting chemokine, and MEC mammary-enriched chemokine. GCP denotes granulocyte chemotactic protein, COPD chronic obstructive pulmonary disease, GRO growth-regulated oncogene, ENA epithelial-cell-derived neutrophil-activating peptide, MIG monokine induced by interferon-γ, IP-10 interferon inducible 10, I-TAC interferon-inducible T-cell alpha chemoattractant, PF platelet factor, SDF stromal-cell-derived factor, HIV human immunodeficiency virus, BCA-1 B cell chemoattractant 1, and SR-PSOX scavenger receptor for phosphatidylserinecontaining oxidized lipids

TABLE 1-8

MAJOR STRUCTURAL FAMILIES OF CYTOKINES

Four α-helix-bundle family interleukins

Interleukin-2 (IL-2) subfamily: Interleukins: IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-12, IL-13, IL-15,

IL-21,IL-23

Not called interleukins: Colony-stimulating factor-1 (CSF1), granulocyte-macrophage colony-stimulating factor (CSF2), Flt-3 ligand, erythropoietin (EPO), thrombopoietin (THPO), leukocyte inhibitory factor (LIF)

Not interleukins: Growth hormone (GH1), prolactin (PRL), leptin (LEP), cardiotrophin (CTF1), ciliary neurotrophic factor (CNTF), cytokine receptor-like factor 1 (CLC or CLF)

Interferon (IFN) subfamily: IFN-β, IFN-α

IL-10 subfamily: IL-10, IL-19, IL-20, IL-22,

IL-24 and IL-26

IL-1 family

^-1α, (IL1A), IL-1 β, (IL1B), IL-18 (IL18) and paralogues, IL-17A, IL-17B, IL-17C,

IL-17D, IL-17E, IL-17F

Chemokines

IL-8, MCP-1, MCP-2, MCP-3, MCP-4, eotaxin, TARC, LARC/MIP-3α, MDC,

MIP-^, MIP-1 β, RANTES, MIP-3ß,

I-309, SLC, PARC, TECK, GROα, GROß,

NAP-2, IP-19, MIG, SDF-1, PF4

Note: GRO, growth-related peptide; IL interleukin; IP, INFg-inducible protein; LARC, liver and activation-regulated chemokine; MCP, monocyte chemotactic protein; MDC, macrophage-derived chemokine; MIG monoteine-induced by IFNg; MIP, macrophage inflammatory protein; NAP, neutrophil-activating protein; PARC, pulmonary and activation-regulated chemokine; PF4, platelet factor; RANTES, regulated on activation normally T cell expressed and secreted; SDF, stromalcell derived factor; SLC, secondary lymphoid tissue.

Myeloid DCs can differentiate into either macrophages/ monocytes or tissue-specific DCs such as Langerhans cells in skin. Plasmacytoid DCs are inefficient antigen-presenting cells but are potent producers of type I interferon (IFN) (e.g., IFN-α) in response to viral infections. The maturation of DCs is regulated through cell-to-cell contact and soluble factors, and DCs attract immune effectors through secretion of chemokines.

When dendritic cells come in contact with bacterial products, viral proteins, or host proteins released as danger signals from distressed host cells (Figs. 1-2, 1-3), infectious agent molecules bind to various TLRs and activate dendritic cells to release cytokines and chemokines that drive cells of the innate immune system to become activated to respond to the invading organism, and recruit T and B cells of the adaptive immune system to respond. Plasmacytoid DCs produce IFN-α that is antiviral and activates NK cell killing of pathogen-infected cells; it also activates T cells to mature into antipathogen killer T cells.

TABLE 1-9

CYTOKINES FAMILIES GROUPED BY STRUCTURAL SIMILARITY

Hematopoietins

IL-2,IL-3,IL-4,IL-5,IL-6,IL-7,IL-9, IL-11, IL-12, IL-15, IL-16, IL-17, IL-21, IL-23, EPO, LIF, GM-CSF, G-CSF, OSM, CNTF, GH, and TPO

TNF-α, LT-α, LT-ß, CD40L, CD30L, CD27L, 4-1BBL, OX40, OPG, and FasL

IL-1

^-1α, IL-1 ß, IL-1ra, IL-18, bFGF, aFGF, and ECGF

PDGF

PDGF A, PDGF B, and M-CSF

TGF-ß

TGF-ß and BMPs (1,2,4 etc.)

C-X-C

chemokines

IL-8, Gro-α/β/γ, NAP-2, ENA78, GCP-2, PF4, CTAP-3, Mig, and IP-10

C-C chemokines

MCP-1, MCP-2, MCP-3, MIP-^, MIP-1 ß, RANTES

Note: aFGF, acidic fibroblast growth factor; 4-1 BBL, 401 BB ligand; bFGF, basic fibroblast growth factor; BMP, bone marrow morphogenetic proteins; C-C, cysteine-cysteine; CD, cluster of differentiation; CNTF, ciliary neurotrophic factor; CTAP, connective tissue activating peptide; C-X-C, cysteine-x-cysteine; ECGF, endothelial cell growth factor; EPO, erythropoietin; FasL, Fas ligand; GCP-2, granulocyte chemotactic protein-2; G-CSF, granulocyte colony-stimulating factor; GH, growth hormone; GM-CSF, granulocyte colony-stimulating factor; Gro, growth-related gene products; IFN, interferon; IL, interleukin; IP, interferon-y inducible protein; LIF, leukemia inhibitory factor; LT, lymphotoxin; MCP, monocyte chemoattractant; M-CSF, macrophage colony-stimulating factor; Mig, monokine induced by interferon-y; MIP, macrophage inflammatory protein; NAP-2, neutrophil activating protein-2; OPG, osteoprotegerin; OSM, oncostatin M; PDGF, platelet-derived growth factor; PF, platelet factor; R, receptor; RANTES, regulated on activation, normal T cell-expressed and -secreted; TGF, transforming growth factor; TNF, tumor necrosis factor; TPO, thyroperoxidase.

Following contact with pathogens, both plasmacytoid and myeloid DCs produce chemokines that attract T helper cells, B cells, polymorphonuclear cells, and naïve and memory T cells as well as regulatory T cells to ultimately dampen the immune response once the pathogen is controlled. TLR engagement on dendritic cells upregulates dendritic cell MHC class II, B7-1 (CD80), and B7-2 (CD86), which enhance specific antigen presentation and induce dendritic cell cytokine production (Table 1-1). Thus, dendritic cells are important bridges between early (innate) and later (adaptive) immunity. DCs modulate and determine the types of immune responses induced by pathogens via the TLRs expressed on DCs (TLR7-9 on plasmacytoid DCs, TLR4 on monocytoid DCs) and via the TLR adapter proteins that are induced to associate with TLRs (Fig. 1-1,Table 1-4). In addition, other PRRs, such as C-type lectins, NOTCH protein domain (NOD), and mannose receptors, upon ligation by pathogen products, activate cells of the adaptive immune system and, like TLR stimulation, by a variety of factors, determine the type and quality of the adaptive immune response that is triggered (Table 1-4).

CD4+ helper T1 (TH1) cells and TH2 T cells secrete distinct but overlapping sets of cytokines. TH1 CD4+ cells are frequently activated in immune and inflammatory reactions against intracellular bacteria or viruses, while TH2 CD4+ cells are frequently activated for certain types of antibody production against parasites and extracellular encapsulated bacteria; they are also activated in allergic diseases. GM-CSF,granulocyte-macrophage colony stimulating factor; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.

FIGURE 1-3

CD4+ helper T1 (TH1) cells and TH2 T cells secrete distinct but overlapping sets of cytokines. TH1 CD4+ cells are frequently activated in immune and inflammatory reactions against intracellular bacteria or viruses, while TH2 CD4+ cells are frequently activated for certain types of antibody production against parasites and extracellular encapsulated bacteria; they are also activated in allergic diseases. GM-CSF,granulocyte-macrophage colony stimulating factor; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.

Large Granular Lymphocytes/Natural Killer Cells

Large granular lymphocytes (LGLs) or NK cells account for ~5-10% of peripheral blood lymphocytes. NKs cells are nonadherent, nonphagocytic cells with large azurophilic cytoplasmic granules. NKs cells express surface receptors for the Fc portion of IgG (CD16) and for NCAM-I (CD56), and many NK cells express some T lineage markers, particularly CD8, and proliferate in response to IL-2. NK cells arise in both bone marrow and thymic microenvironments.

Functionally, NK cells share features with both monocytes-macrophages and neutrophils in that they mediate both antibody-dependent cellular cytotoxicity (ADCC) and NK cell activity. ADCC is the binding of an opsonized (antibody-coated) target cell to an Fc receptor-bearing effector cell via the Fc region of antibody, resulting in lysis of the target by the effector cell. NK cell activity is the nonimmune (i.e., effector cell never having had previous contact with the target), MHC-unrestricted, non-antibody-mediated killing of target cells, which are usually malignant cell types, transplanted foreign cells, or virus-infected cells. Thus, NK cell activity may play an important role in immune surveillance and destruction of malignant and virally infected host cells. NK cell hyporesponsiveness is also observed in patients with Chédiak-Higashi syndrome, an autosomal recessive disease associated with fusion of cytoplasmic granules and defective degranulation of neutrophil lysosomes.

The ability of NK cells to kill target cells is inversely related to target cell expression of MHC class I molecules. Thus, NK cells kill target cells with low or no levels of MHC class I expression and are prevented from killing target cells with high levels of class I expression. NK cells have surface-inhibiting killer immunoglobulin-like receptors (KIRs) that bind to classic MHC class I molecules in a polymorphic way and inhibit NK cell killing of human leukocyte antigen (HLA) positive cells. NK cell inactivation by KIRs is a central mechanism to prevent damage to normal host cells. However, to eliminate malignant and virally infected cells, NK cells also require activation through recognition of NK activation molecules on the surface of target cells (Fig. 1-4).Three molecules on NK cells—NKp46, NKp30, and NKp44—are collectively referred to as natural cytotoxicity receptors (NCRs) and mediate NK cell activation against target cells; the ligands to which they bind on target cells remain unknown. In addition, two coreceptors on NK cells, 2B4 and NTB-A, can serve as either activators or inhibitors of NK cells, depending on the ligand and signaling pathways that become activated. Thus, NK cell signaling is a highly coordinated series of inhibiting and activating signals that are coordinated to all NK cells such that they do not respond to uninfected, nonmalignant self-cells, but they are activated to attack malignant and virally infected cells. Recent evidence suggests that NK cells, though not possessing rearranging immune recognition genes, may be able to mediate recall responses for certain immune reactions such as contact hypersensitivity.

Some NK cells express CD3 and are termed NK/T cells. NK/T cells can also express oligoclonal forms of the TCR for antigen that can recognize lipid molecules of intracellular bacteria when presented in the context of CD1 molecules on APCs.This mode of recognition of intracellular bacteria such as Listeria monocytogenes and M. tuberculosis by NK/T cells leads to induction of activation of DCs and is thought to be an important defense mechanism against these organisms.

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